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Annals 

of Oncology 

www.annonc.oxfordjournals.org 

www.esmo.org 

www.jsmo.umin.jp 

1 

ISSN 0923-7534 (print) 

ISSN 1569-8041 (online) 

Volume 23 Supplement 9 2012 

Abstract Book 

of the 37th ESMO 

Congress 

Vienna, Austria 

28 September – 2 October 2012 

Guest Editors: 

ESMO Educational Committee 

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Annals of Oncology 

Official Journal of the European Society for Medical Oncology and 

the Japanese Society of Medical Oncology 

editor-in-chief: 

J. B. Vermorken, Edegem, Belgium 

associate editors 

Supportive and palliative care 

M. S. Aapro, Genolier, Switzerland 

D. Schrijvers, Antwerp, Belgium 

Hematologic malignancies 

J. O. Armitage, Omaha, Nebraska, USA 

M. Pfreundschuh, Hamburg/Saar, 

Germany 

Geriatric oncology 

L. Balducci, Tampa, Florida, USA 

H. Wildiers, Leuven, Belgium 

Radiation oncology 

J. Bernier, Geneva, Switzerland 

editorial board 

editors emeriti 

F. Cavalli, Bellinzona, Switzerland 

D. J. Kerr, Oxford, UK 

Epidemiology 

C. La Vecchia, Milan, Italy 

Urogenital tumors 

K. Fizazi, Villejuif, France 

D. Raghavan, Cleveland, Ohio, USA 

Gastrointestinal tumors 

C. J. A. Punt, Amsterdam, The Netherlands 

R. Labianca, Bergamo, Italy 

Lung tumors 

E. Felip, Barcelona, Spain 

N. Saijo, Osakasayama, Japan 

Head and neck tumors 

L. Licitra, Milan, Italy 

E. E. Vokes, Chicago, Illinois, USA 

Breast tumors 

M. Castiglione-Gertsch, Geneva, 

Switzerland 

D. A. Vorobiof, Johannesburg, 

South Africa 

Gynecologic malignancies 

J. Ledermann, London, UK 

H. Yoshikawa, Tsukuba, Japan 

Surgical oncology 

L. Påhlman, Uppsala, Sweden 

Translational research 

H. McLeod, Chapel Hill, 

North Carolina, USA 

G. Tortora, Verona, Italy 

F. Andre, Villejuif, France W. Hiddemann, Munich, Germany E. A. Perez, Jacksonville, Florida, USA 

K. K. Antman, New York, New York, USA C. Ishioka, Sendai, Japan B. C. Pestalozzi, Zurich, Switzerland 

B. Arun, Houston, Texas, USA P. Jacobs, Cape Town, South Africa G. J. Peters, Amsterdam, The Netherlands 

J. Baselga, Boston, Massachusetts, USA Y. Kakehi, Kagawa, Japan M. Posner, New York, USA 

C. Bokemeyer, Hamburg, Germany N. Katsumata, Tokyo, Japan A. Poveda, Valencia, Spain 

F. Cabanillas, Houston, Texas, USA B. Kaufman, Tel Hashomer, Israel A. Psyrri, New Haven, Connecticut, USA 

K. Chi, Vancouver, Canada S. B. Kaye, Sutton, UK D. Quinn, Los Angeles, California, USA 

F. Ciardiello, Naples, Italy U. Keilholz, Berlin, Germany V. Raina, New Delhi, India 

A. S. Coates, Sydney, Australia H. M. Khaled, Cairo, Egypt M. Ranson, Manchester, UK 

J. M. Connors, Vancouver, Canada C.-H. Köhne, Dresden, Germany R. Rosell, Badalona, Spain 

H. Cortés-Funes, Madrid, Spain P. A. Kosmidis, Athens, Greece A. Roth, Geneva, Switzerland 

D. Cunningham, Sutton, UK H. Kunitoh, Tokyo, Japan M. Saghatchian, Villejuif, France 

S. Daryanani, Caracas, Venezuela T. Le Chevalier, London, UK M. Sasako, Nishinomiya, Japan 

S. Delaloge, Villejuif, France J. S. Macdonald, New York, New York, USA W. Scheithauer, Vienna, Austria 

A. Di Leo, Prato, Italy F. Mandelli, Rome, Italy J. H. M. Schellens, Amsterdam, The Netherlands 

C. Dittrich, Vienna, Austria P. Mauch, Boston, Masachusetts, USA H.-J. Schmoll, Halle, Germany 

J.-Y. Douillard, Saint-Herblain, France R. J. Mayer, Boston, Masachusetts, USA H. C. Schouten, Maastricht, The Netherlands 

L. H. Einhorn, Indianapolis, Indiana, USA M. Middleton, Oxford, UK K. C. Soo, Singapore 

E. A. Eisenhauer, Kingston, Canada H. Minami, Kobe, Japan C. N. Sternberg, Rome, Italy 

A. Eniu, Cluj-Napoca, Romania V. M. Moiseyenko, St Petersburg, S. T. Tagawa, New York, New York, USA 

B. Escudier, Villejuif, France Russian Federation M. Tahara, Chiba, Japan 

R. I. Fisher, Rochester, New York, USA F. M. Muggia, New York, New York, USA V. Tjan-Heijnen, Maastricht, The Netherlands 

G. Giaccone, Bethesda, Maryland, USA J. M. Nabholtz, Clermont-Ferrand, France S. Tjulandin, Moscow, Russian Federation 

A. J. Gelderblom, Leiden, The Netherlands Y. Nagata, Kyoto, Japan Y. Tokuda, Isehara, Japan 

B. Glimelius, Uppsala, Sweden T. Naoe, Nagoya, Japan M. Tonato, Perugia, Italy 

B. C. Goh, Singapore, Singapore T. Ngoma, Dar es Salaam, Tanzania T. Tursz, Villejuif, France 

A. Goldhirsch, Milan, Italy K. Nishio, Osaka, Japan C. Vallejos Sologuren, Lima, Peru 

M. D. Green, Melbourne, Australia K. Öberg, Uppsala, Sweden C. Verschraegen, Albuquerque, 

K. J. Harrington, London, UK A. Ohtsu, Kashiwa, Japan New Mexico, USA 

K. Hatake, Tokyo, Japan M. Peeters, Edegem, Belgium A. D. Zelenetz, New York, New York, USA 

executive editor: Lewis Rowett 

editorial office: Paola Minotti Bernasconi, Giovannella Porcu, Annals of Oncology, Via Luigi Taddei 4, CH-6962 Viganello-Lugano, 

Switzerland 

Annals of Oncology is covered in C.A.B. International, Current Clinical Cancer, Current Contents/Clinical Medicine®, Current Contents/ 

Life Sciences, Elsevier BIOBASE/Current Awareness in Biological Sciences, EMBASE/Excerpta Medica, IBIDS, Index Medicus/MEDLINE, 

The International Monitor in Oncology, Medical Documentation Service, Science Citation Index® and Science Citation Index Expanded.

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drug disclaimer 

All reasonable precautions have been taken by the authors, editors and publisher 

to verify drug names and doses, the results of experimental work and the clinical 

findings published in this journal. The opinions expressed are those of the 

authors, and not necessarily those of the editors or publisher. The ultimate responsibility 

for the use and dosage of drugs mentioned in Annals of Oncology 

and in the interpretation of published material lies with the medical practitioner. 

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© The European Society for Medical Oncology 2012 

All rights reserved; no part of this publication may be reproduced, stored in a 

retrieval system, or transmitted in any form or by any means, electronic, mechanical, 

photocopying, recording, or otherwise without prior written permission 

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Typeset by Techset Composition Ltd, Salisbury, UK. 

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Notice: 

The content of the abstracts contained in this Abstract Book is subject to an 

embargo. Abstracts accepted for presentation at ESMO 2012 (Proffered Paper 

(oral presentation), Poster Discussion and Poster) and for publication in the 

Congress Abstract Book, will be published online on the ESMO website on 

Monday, 17 September 2012. Late-breaking abstracts will be made public at the 

beginning of the official Congress session during which they are presented. 

Abstracts selected for the official ESMO Press Program will be made public at 

the beginning of the official Press Conference or Congress session during which 

they are presented, whichever comes first. 

Disclaimer: 

No responsibility is assumed by the organizers for any injury and/or damage to 

persons or property as a matter of products liability, negligence or otherwise, or 

from any use or operation of any methods, products, instructions or ideas contained 

in the material herein. Because of the rapid advances in medical sciences, 

we recommend that independent verification of diagnoses and drug dosages 

should be made. Every effort has been made to faithfully reproduce the 

abstracts as submitted. However, no responsibility is assumed by the organizers 

for any omissions or misprints.

Annals of 

Oncology 

Official Journal of the European Society 

for Medical Oncology and the Japanese 

Society of Medical Oncology 

Volume 23, 2012 Supplement 9 

Abstract Book of the ESMO 2012 Congress 

Vienna, Austria, 28 September – 2 October 2012 

Guest Editors: Scientific Committee of the ESMO 2012 Congress


Official Journal of the European Society for 

Medical Oncology and the Japanese Society of Medical Oncology 

Volume 23, 2012 Supplement 9 

Abstract Book of the ESMO 2012 Congress, Vienna, Austria 

28 September – 2 October 2012 

About ESMO ix7 

ESMO Committees ix8 

ESMO 2012 Congress Officers ix10 

ESMO 2012 Congress Organization ix12 

ESMO Congress Travel Grants ix13 

Acknowledgements ix14 

Exhibitors ix15 

ESMO Fellowships ix17 

Invited abstracts 

Hamilton Fairley Award ix21 

Keynote sessions 

PI 3-kinase and cancer metabolism ix21 

HPV biology and implications in gynecological 

malignancies ix22 

The hallmarks of cancer revisited ix23 

The characterization of lung cancer in multiple different 

diseases ix24 

Special Symposia 

The impact of the cancer genome project and high-throughput 

analyses on personalised oncology: today and tomorrow ix25 

Optimizing treatment in luminal breast cancer ix27 

How to integrate new drugs in the current therapeutic 

landscape of metastatic triple negative breast cancer ix29 

Molecular neuro-oncology: new avenues in diagnosis and 

treatment ix31 

A paradigm shift in early drug development: 

individualizing to more patient benefit ix32 

How can medical oncologists deal with the new wave 

of genetic information about their patients? ix34 

Pursuing the NED condition in stage IV colorectal cancer ix35 

From biology to treatment in advanced pancreatic and 

gastroesophageal cancer ix37 

Re-inventing the medical treatment of advanced 

prostate cancer ix38 

Molecular answers and targets on the horizon for the 

treatment of genitourinary malignancies ix39 

Emerging diagnostic and therapeutic targets in 

gynecological cancers: from science to clinical practice ix40 

Biologically based treatment in head and neck squamous 

cell carcinoma (HNSCC) ix42 

Molecular targets in malignant lymphomas: from 

basic science to clinical practice ix44 

Volume 23 | Supplement 9 | September 2012 

Melanoma therapy: from frustration to enthusiasm ix46 

Integrating targeted treatments with tumor biology and 

molecular imaging in the current and future management of 

neuroendocrine gastrointestinal tumors ix47 

Hot topics in early stage NSCLC ix49 

Latest innovations in NSCLC management ix51 

Evidence based answers to critical questions on cancer 

screening and prevention ix53 

Subtyping soft tissue sarcomas for treatment approaches ix54 

Key topics in supportive care ix56 

Joint Symposia 

ESMO-ASCO - Genomics in breast cancer: Opening new 

doors ix57 

ESMO/CSCO - Building the clinical trials of the future ix58 

ESMO-EACR - Targeted therapies: Promises, successes 

and failures ix59 

ESMO-EANM-ESR - Imaging biomarkers in the era of 

targeted therapies ix60 

ESMO-ESP - Molecular diagnostics for personalized 

cancer treatment ix61 

ESMO-ESTRO - Innovative approaches to the treatment 

of brain metastases ix62 

ESMO-JSMO - Recent advances in the treatment of 

GI tract and liver cancer in the EU and Japan ix63 

ESMO-MASCC - Integration between medical oncology 

and supportive care: Two sides of the same coin ix64 

ESMO DCTF-AORTIC-SLACOM-UICC-WHO - Independent 

and publicly funded research: A new global model ix65 

Society Symposium 

ESO – Celebrating 30 years of ESO and 50 issues of 

Cancer World. Cancer 2020: The road to personalized 

cancer care ix66 

Submitted abstracts 

Basic science ix67 

Biomarkers ix73 

Breast cancer, early stage ix95 

Breast cancer, locally advanced and metastatic ix116 

CNS tumors ix144 

Developmental therapeutics ix152 

Familial cancer and genetic syndromes ix175 

Gastrointestinal tumors, colorectal ix178 

Gastrointestinal tumors, non-colorectal ix224 

Genitourinary tumors, non-prostate ix258 

Genitourinary tumors, prostate ix294

Gynecological cancers ix319 

Head and neck cancer ix334 

Hematological malignancies ix348 

Melanoma and other skin tumors ix361 

Neuroendocrine tumors and CUP ix376 

New diagnostics ix383 

Non-small cell lung cancer, early stage ix385 

Non-small cell lung cancer, locally advanced ix389 

Non-small cell lung cancer, metastatic ix400 

Oncology and public health ix447 

Palliative care ix462 

Prevention and screening ix469 

Psycho-oncology ix474 

Sarcoma ix478 

Small cell lung cancer and other thoracic malignancies ix492 

Supportive care ix499 

Translational research ix528 

Tumor biology and pathology ix541 

Author index ix546 

Subject index ix586 

Drug index ix601 

Translational research index ix604 

Note: Abstract suffixes 

“IN” indicates an invited abstract 

"O" indicates a submitted abstract accepted for oral presentation 

"PD" indicates a submitted abstract accepted for poster discussion 

"P" indicates a submitted abstract accepted for poster presentation 

abstracts with no suffix have not been accepted for presentation at the Congress but are published in the Abstract Book. 

“TiP” indicates a submitted abstract accepted for poster presentation, trial in progress 

__PR indicates a submitted abstract selected for press coverage 

Volume 23 | Supplement 9 | September 2012

The European Society for Medical Oncology (ESMO) 

The European Society for Medical Oncology (ESMO) is the leading European professional organization, committed to 

advancing the specialty of medical oncology and promoting a multidisciplinary approach to cancer treatment and care. 

Since its founding in 1975 as a non-profit organization, ESMO’s mission has been to advance cancer care and cure. We 

achieve this through fostering and disseminating good science that leads to better medicine and determines best practice. In 

this way ESMO fulfils its goal to support oncology professionals in providing people with cancer with the most effective 

treatments available and the high-quality care they deserve. 

The ESMO community is a powerful alliance of more than 7,000 committed oncology professionals from over 120 

countries. As a trusted organization with 35 years of experience and over 500 expert committee members, ESMO serves its 

members and the oncology community through: 

• Excellence in post-graduate oncology education and training 

• Leadership in transforming evidence-based research into standards of cancer care in Europe 

• Dedicated efforts to foster a more favorable environment for scientific research 

• Innovative international platforms to share expertise, best practices and disseminate the most up-to-date scientific 

research to as wide an audience as possible. 

ESMO has expanded its membership offering through OncologyPRO, an exclusive scientific and educational website: http:\ 

\oncologypro.esmo.org. ESMO’s scientific journal, Annals of Oncology, ranks among the top clinical oncology journals 

worldwide. ESMO events are the meeting place in Europe for medical oncologists to update their knowledge, network and 

exchange ideas. ESMO also unites key oncology stakeholders and forges strategic partnerships to address critical issues 

related to the profession and practice of medical oncology. Recognized as an authoritative voice in the fight against cancer, 

ESMO is pleased to offer consultative expertise to oncology organizations and European authorities on important issues 

related to cancer research, prevention, diagnosis, treatment and care. 

Join the ESMO community today! Please visit www.esmo.org to learn more. 

European Society for Medical Oncology (ESMO) 

Via Luigi Taddei, 4, 6962 Viganello – Lugano, Switzerland 

T +41 (0)91 973 19 00 

F +41 (0)91 973 19 02 

W www.esmo.org 

E esmo@esmo.org

European Society for Medical Oncology Committees 

Executive Board 

President Martine Piccart, Belgium 

President-Elect Rolf A. Stahel, Switzerland 

Treasurer Fortunato Ciardiello, Italy 

Educational Committee Chair Jean-Yves Douillard, France 

National Representatives & Membership Committee Chair Razvan Popescu, Switzerland 

Public Policy Committee Chair Paolo Casali, Italy 

Guidelines Working Group Chair Andres Cervantes, Spain 

Member Elisabeth de Vries, Netherlands 

Member Cristiana Sessa, Switzerland 

Member Eric Van Cutsem, Belgium 

Chief Executive Officer Alan J. Howard, Switzerland 

Educational Committee Chair: Jean-Yves Douillard, France 

Cancer Patient Working Group Chair: Lorenz Jost, Switzerland 

Community Oncology Working Group Chair: Robert Eckert, Germany 

E-Learning and CME Working Group Chair: Claus-Henning Koehne, Germany 

Examination Working Group Chair: Richard Herrmann, Switzerland 

Global Curriculum Task Force Chair: Nicholas Pavlidis, Greece 

Palliative Care Working Group Chair: Nathan Cherny, Israel 

Publishing Working Group Chair: Michele Ghielmini, Switzerland 

Translational Research Working Group Chair: Giampaolo Tortora, Italy 

*Guidelines Working Group 

*The Guidelines WG reports directly to the EXC Board, the chair is sitting in the 

Educational Committee for informative purposes only. 

Chair: Andrés Cervantes, Spain 

ESMO Faculty Coordinators 

Head and neck cancer Marco Merlano, Italy 

Chest tumors Enriqueta Felip, Spain 

Gastrointestinal tumors Alberto Sobrero, Italy 

Breast cancer Fabrice André, France 

Gynecologic cancer Jonathan Ledermann, UK 

Genitourinary cancer Bernard Escudier, France 

Sarcoma Jean-Yves Blay, France 

Hematologic malignancy Martin Dreyling, Germany 

Principles of clinical trials and systemic therapy Christian Dittrich, Austria 

Cancer research Marco A. Pierotti, Italy 

Cancer prevention Hans-Joerg Senn, Switzerland 

Elderly Gilbert B. Zulian, Switzerland 

Supportive and palliative care Jorn Herrstedt, Denmark 

Cancer genetics Pierre Laurent-Puig, France 

CNS tumors Michael Weller, Switzerland 

CUP, endocrine tumors and others George Pentheroudakis, Greece 

Melanoma Richard Dummer, Switzerland

Audit Committee Chair: Fortunato Ciardiello, Italy 

Young Oncologists Committee Chair: Michalis Karamouzis, Greece 

Fellowship and Award Committee Chair: Josep Tabernero, Spain 

Press and Media Affairs Chair: Fortunato Ciardiello, Italy 

Nominating Committee Chair: Jean-Pierre Armand, France 

Developing Countries Task Force Chair: Adamos Adamou, Cyprus 

Annals of Oncology Editorial Board Editor-in-Chief: Jan B. Vermorken, Belgium 

ESMO National Representatives 

Country Name Country Name 

Chair Razvan Popescu 

Albania Alketa Ymeri Latvia Alinta Hegmane 

Austria Gabriela Kornek Lithuania Rasa Janciauskiene 

Belarus Yauheni Baranau Luxembourg Stefan Rauh 

Belgium Ahmad Awada Macedonia Petar Stefanovski 

Bosnia Herzegovina Timur Ceric Moldova Vasile Musteata 

Bulgaria Zhasmina Mihaylova Montenegro Vladimir Todorovic 

Croatia Borislav Belev Netherlands A.N.M. Wymenga 

Cyprus George Marcoullis Norway Eva Hofsli 

Czech Republic Tomas Svoboda Poland Renata Zaucha 

Denmark Ulrik Lassen Portugal Paolo Cortes 

Estonia Peeter Padrik Romania Alexandru Eniu 

Finland Maarit Barlund Russian Federation Vladimir Moiseyenko 

France Michel Ducreux Serbia Zorica Tomasevic 

Georgia Tamari Rukhadze Slovakia Jozef Mardiak 

Germany Ulrich Keilholz Slovenia Erika Matos 

Greece Gerasimos Aravantinos Spain Ramon Colomer 

Hungary Istvan Lang Sweden Roger K. Henriksson 

Iceland Helgi Hafsteinn Helgason Switzerland Giannicola D’Addario 

Ireland Michael J. Martin Turkey Ahmet Demirkazik 

Israel Ron Epelbaum Ukraine Iryna Kryachok 

Italy Marina Garassino UK Robert Coleman 

ESMO Regional representatives 

Region Name Region Name 

Central America and the Caribbean Jean-René Clemenceau North Africa Gaafar Rabab 

China Jun Ma Oceania Gary Richardson 

Far East Sumitra Thongprasert Sub-Saharan Africa Verna Vanderpuye 

India, Pakistan, Bangladesh Maheboob Mahamud Basade South America Ignacio Muse 

Japan Kazuo Tamura USA, North America Everett E. Volkes 

Middle East Ashraf Awad Elkarim

ESMO 2012 Congress Officers 

ESMO 2012 Congress President 

Martine Piccart, Brussels, Belgium 

ESMO 2012 Scientific Committee Chair 

Josep Tabernero, Barcelona, Spain 

ESMO 2012 Educational Chair 

Rolf A. Stahel, Zurich, Switzerland 

ESMO 2012 Press Officer 

Fortunato Ciardiello, Naples, Italy 

ESMO 2012 Local Officer 

Christoph Zielinski, Vienna, Austria 

Scientific Sub-Committees 

Basic science and translational research 

Yosef Yarden, Rehovat, Israel, Chair 

Alan Ashworth, London, UK 

Carlos Caldas, Cambridge, UK 

Maria Grazia Daidone, Milan, Italy 

Caroline Dive, Manchester, UK 

Sabine Tejpar, Leuven, Belgium 

Giampaolo Tortora, Verona, Italy 

Breast cancer, early stage 

Ian Smith, London, UK, Chair 

Fatima Cardoso, Lisbon, Portugal 

Angelo di Leo, Prato, Italy 

Paul Ellis, London, UK 

Christos Sotiriou, Brussels, Belgium 

Christoph Zielinski, Vienna, Austria 

Breast cancer, metastatic 

Fabrice André, Villejuif, France, Chair 

Javier Cortes, Barcelona, Spain 

Giuseppe Curigliano, Milan, Italy 

Wolfgang Eiermann, Munich, Germany 

Luca Gianni, Milan, Italy 

Nick Turner, London, UK 

CNS tumors 

Michael Weller, Zurich, Switzerland, Chair 

Michael Brada, London, UK 

Christine Marosi, Vienna, Austria 

Roger Stupp, Lausanne, Switzerland 

Martin Van den Bent, Rotterdam, Netherlands 

Wolfgang Wick, Heidelberg, Germany 

Developmental therapeutics 

Ahmad Awada, Brussels, Belgium, Chair 

José Baselga, Boston, USA 

Fiona Blackhall, Manchester, UK 

Christian Dittrich, Vienna, Austria 

Elisabeth Eisenhauer, Kingston, ON, Canada 

Tetsuya Mitsudomi, Aichi, Japan 

Jan Schellens, Amsterdam, Netherlands 

Gynecological cancers 

Nicoletta Colombo, Milan, Italy, Chair 

Stan Kaye, Sutton, UK 

Jonathan Ledermann, London, UK 

Andres Poveda, Valencia, Spain 

Cristiana Sessa, Bellinzona, Switzerland 

Ate van der Zee, Groningen, Netherlands 

Head and neck cancer 

Luis Paz-Ares, Seville, Spain, Chair 

Sandrine Faivre, Clichy, France 

Antonio Jimeno, Denver, Colorado, USA 

Jean Louis Lefebvre, Lille, France 

Lisa Licitra, Milan, Italy 

Amanda Psyrri, Athens, Greece 

Hematological malignancies 

Martin Dreyling, Munich, Germany, Chair 

Meletios Dimopoulos, Athens, Greece 

Michele Ghielmini, Bellinzona, Switzerland 

Håkan Mellstedt, Stockholm, Sweden 

Vincent Ribrag, Villejuif, France 

Lena Specht, Copenhagen, Denmark 

Melanoma and other skin tumors 

Alexander M.M. Eggermont, Villejuif, France, Chair 

Lars Bastholt, Odense, Denmark 

Reinhard Dummer, Zurich, Switzerland 

Ulrich Keilholz, Berlin, Germany 

David Khayat, Paris, France 

NETs and endocrine tumors 

Kjell Öberg, Uppsala, Sweden, Chair 

Dik Kwekkeboom, Rotterdam, Netherlands 

Eric Raymond, Paris, France 

Guido Rindi, Rome, Italy 

Ramon Salazar, Barcelona, Spain 

James Yao, Houston, USA

Familial cancer 

Judith Balmaña, Barcelona, Spain, Chair 

Elena Castro, London, UK 

Raphael Catane, Tel-Hashomer, Israel 

Isabel Chirivella Valencia, Spain 

Andrew Tutt, London, UK 

Eduardo Vilar, Ann Arbor, Michigan, USA 

Gastrointestinal tumors, colorectal 

Alberto Sobrero, Genoa, Italy, Chair 

Dirk Arnold, Hamburg, Germany 

Jean-Yves Douillard, Nantes, France 

Claus-Henning Koehne, Oldenburg, Germany 

Matt Seymour, London, UK 

Eric Van Cutsem, Leuven, Belgium 

Gastrointestinal tumors, non-colorectal 

Roberto Labianca, Bergamo, Italy, Chair 

Stefano Cascinu, Ancona, Italy 

Andres Cervantes, Valencia, Spain 

Manfred Lutz, Saarbrücken, Germany 

Emmanuel Mitry, Paris, France 

Arnaud Roth, Geneva, Switzerland 

Genitourinary tumors, prostate 

Johann S. de Bono, Sutton, UK, Chair 

Joan Carles, Barcelona, Spain 

Karim Fizazi, Villejuif, France 

Vesa Kataja, Kuopio, Finland 

Ian Tannock, Toronto, Canada 

Bertrand Tombal, Brussels, Belgium 

Genitourinary tumors, non-prostate 

Maria de Santis, Vienna, Austria, Chair 

Joaquim Bellmunt, Barcelona, Spain 

Carsten Bokemeyer, Hamburg, Germany 

Tim Eisen, Sutton, UK 

Christian Kollmannsberger, Vancouver, Canada 

Cora Sternberg, Rome, Italy 

NSCLC, early stage, SCLC and other thoracic malignancies 

Rafal Dziadziuszko, Gdansk, Poland, Chair 

Paul Baas, Amsterdam, Netherlands 

Benjamin Besse, Paris, France 

Giuseppe Giaccone, Bethesda, USA 

Rafael Rosell, Barcelona, Spain 

Suresh Senan, Amsterdam, Netherlands 

Walter Weder, Zurich, Switzerland 

NSCLC, metastatic 

Enriqueta Felip, Barcelona, Spain, Chair 

Federico Cappuzzo, Livorno, Italy 

Cesare Gridelli, Avellino, Italy 

Pasi Jånne, Houston, USA 

Tony Mok, Hong Kong, China 

Martin Reck, Grosshansdorf, Germany 

Oncology and public health 

Xavier Bosch, Barcelona, Spain, Chair 

Jan Willem Coebergh, Rotterdam, Netherlands 

Jack Cuzick London, UK 

Heinz Ludwig, Vienna, Austria 

Hans H. Storm, Copenhagen, Denmark 

Sarcoma 

Jaap Verweij, Rotterdam, Netherlands, Chair 

Jean-Yves Blay, Lyon, France 

Paolo Casali, Milan, Italy 

Alessandro Gronchi, Milan, Italy 

Ian Judson, London, UK 

Winette van der Graaf, Nijmegen, Netherlands 

Supportive and palliative care 

Fausto Roila, Perugia, Italy, Chair 

Matti Aapro, Genolier, Switzerland 

Mario Dicato, Luxembourg, Luxembourg 

Jørn Herrstedt, Copenhagen, Denmark 

Dorothy Keefe, Adelaide, Australia 

Dirk Schrijvers, Antwerp, Belgium 

The European Society for Medical Oncology wishes to express its appreciation and gratitude to all of the above persons for 

their major effort to select the content of this Abstract Book.

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47 travel grants have been awarded by the ESMO 2012 Scientific Committee on a competitive basis from among the 

accepted abstracts. 

Travel grant recipients are: 

Ahmed, Soha, Egypt Marín-Aguilera, Mercedes, Spain 

Alfaar, Ahmad, Egypt Mohamed, Zameer, UK 

Bariani, Giovanni, Brazil Nappi, Lucia, Italy 

Berardi, Rossana, Italy Necchi, Andrea, Italy 

Bianchini, Diletta, UK Olmos, David, UK 

Bria, Emilio, Italy Omlin, Aurelius, UK 

Chatterjee, Koushik, India Ostwal, Vikas, India 

Chen, Xiaosong, China Pan, LI, China 

Criscitiello, Carmen, Italy Parlak, Cem, Turkey 

Custodio, Ana, Spain Pereira, Allan, Brazil 

Das, Priyabrata, India Rodriguez-Vida, Alejo, Spain 

De Graan, Anne-Joy, Netherlands Samoylenko, Igor, Russia 

De Mattos-Arruda, Leticia, Spain Seligmann, Jenny, UK 

Diaz-Padilla, Ivan, Canada Sharawat, Surender, India 

Elkhouly, Enas, Egypt Supernat, Anna, Poland 

George, Angela, UK Tao, Jessica, USA 

Iwamoto, Takayuki, Japan Vaccaro, Vanja, Italy 

Jang, Raymond, Canada van Gaal, J Carlijn, Netherlands 

Janjigian, Yelena, USA Waddell, Tom, UK 

Jo, Jae-Cheol, Korea Weiss, Glenn, USA 

Ju, Lixia, China Yakout, Tarek, Egypt 

Kelly, Zoe, UK Yousif, Nasser, USA 

Kumar, Aalok, Canada 

Manji, Arif, Canada 

Zakharova, Natalia, Russia 

Thanks 

ESMO expresses its gratitude to: 

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Advertising of a specific product does not mean acceptance by ESMO and it is the full responsibility of the corporation that 

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ESMO Congress 2012 on Pain Management 

has been provided by TEVA 

Thank you

Exhibitors 

The following companies are exhibiting at the ESMO 2012 Congress (data correct at time of going to print). 

Almac Janssen 

Altos Solutions, Inc. KPS Molecular Diagnostic Centre 

Amgen Labceutics 

ARIAD Pharmaceuticals, Inc. Lilly Oncology 

Aspen Pharma Trading Ltd. MEDIAN Technologies 

Astellas Pharma Europe Medscape Oncology 

BN ImmunoTherapeutics Merck Serono 

Baxter Deutschland GmbH MSD 

Bayer HealthCare Myriad Genetics GmbH 

Boehringer Ingelheim GmbH Nordic Pharma 

Bristol-Myers Squibb Novartis Oncology 

Caris Life Sciences Panagene Inc. 

Cato Software Solutions GmbH Pfizer Oncology 

Celgene PharmaMar 

Celltrion Healthcare Co., Ltd. Pharmadab d.o.o. 

CROMSOURCE Srl PharmaNet / i3 

Daiichi Sankyo Europe Pierre Fabre Medicament 

Delcath Systems, Inc. prIME Oncology 

Dendreon Corporation PRMA Consulting 

Effe Emme S.p.A. QIAGEN 

Eisai Europe Limited SANDOZ, a Novartis Company 

Elekta Ltd Sanofi Oncology 

Exelixis SSIF (Serono Symposia International Foundation) 

F. Hoffmann-La Roche Ltd Sigma-Tau S.p.A. 

Fresenius Kabi Sintesi Research 

GE Healthcare Sirtex Medical Europe GmbH 

Genomic Health Source BioScience 

GlaxoSmithKline Oncology SPECTROPATH, Inc. 

Helsinn Healthcare SA Taiho Pharmaceutical Co., Ltd. 

Hospira Takeda Pharmaceuticals Europe, Ltd. 

Imedex Teva Europe 

Ipsen Pharma Varian Medical Systems 

Ipsos Healthcare Veridex, Part of the Johnson & Johnson family of companies

Publishers/ Booksellers Societies 

AlphaMed Press AIOM - Associazione Italiana di Oncologia Medica 

Elsevier AOG - Association of Oncologist of Georgia 

Informa Healthcare ASCO - American Society of Clinical Oncology 

Oxford University Press BDA - Biotherapy Development Association 

Wisepress Medical Bookshop BIG - Breast International Group 

COS - Czech Oncology Society 

DGHO - Deutsche Gesellschaft für Hämatologie und Onkologie e. V. 

E-CANCER 

ECCO - European CanCer Organization 

EORTC - Eurepean Organisation for Research and Treatment of Cancer 

ESO - European School of Oncology 

ETOP - European Thoracic Oncology Platform 

JSMO - Japanese Society of Medical Oncology 

MAGYOT - Hungary 

MASCC - Multinational Association of Supportive Care in Cancer 

MOGA - Medical Oncology Group of Australia 

MOT - Hungary 

NDDO Education Foundation 

NGO - Brazilian Non-Governmental Organization (clinical oncology) 

RSRMO - Romanian Society for Radiotherapy and Medical Oncology 

RUSSCO - Russian Society 

SIOG - International Society of Geriatric Oncology 

St. Gallen Oncology Conferences (SONK) 

TOD - Turkish Medical Oncology Society 

UNICANCER 

Vienna School of Clinical Research 

WIN Consortium

ESMO Fellowships, 1989–2011 

The European Society for Medical Oncology is thankful to the following companies for their generous support: 

Fellow Year Sponsored by 

Stephan Bodis, Switzerland 1989–1991 Boehringer Ingelheim 

Jean Gérain, Belgium 1989–1991 Amgen 

Paul Kiefer, Germany 1989–1991 Glaxo 

C. Rafael Lopez, Spain 1989–1991 Hoffman–La Roche 

Emanuele Zucca, Italy 1989–1991 Sterling Winthrop 

Pierre–Yves Dietrich, Switzerland 1990–1992 Schering–Plough 

Manuel Domin Gomez, Spain 1990–1992 Medgenix 

Albert von Rohr, Switzerland 1990–1992 Ciba–Geigy 

Miguel Izquierdo Delso, Spain 1991–1993 EuroCetus 

Panayiotis Panayiotidis, Greece 1991–1993 Bristol–Myers Squibb 

Anna Russo, Italy 1991–1993 Farmitalia Carlo Erba 

Ekaterini Boleti, Greece 1993–1995 SmithKline Beecham 

Christos A. Papadimitriou, Greece 1993–1995 Pharmacia 

Luis Paz–Ares, Spain 1993–1995 Hoffman–La Roche 

Konstantinos N. Syrigos, Greece 1994–1996 Rhône–Poulenc Rorer / ESMO 

Francesco Caponigro, Italy 1995–1996 Ciba–Geigy 

Vito Spataro, Switzerland 1995–1997 Bristol–Myers Squibb / ESMO 

Ignacio Garcia–Ribas, Spain 1995–1997 Lilly Deutschland / ESMO 

Jan Dürig, Germany 1997–1998 Eli Lilly / Lilly Deutschland 

Astrid Mayer, Austria 1996–1997 ESMO 

Adam Pawinski, Poland 1996–1998 Rhône–Poulenc Rorer 

Patricia A. Ribeiro, Portugal 1997–1998 Ciba Geigy 

Federico Cappuzzo, Italy 1997–1999 Glaxo Wellcome 

José M. Trigo Perez, Spain 1997–1999 Hoechst Marion Roussel 

Christos Tolis, Greece 1997–1998 SmithKline Beecham 

Eleni Tsiompanou, Greece 1998–2000 ESMO 

Ira I. Skvortsova, Russia 1998–2000 ESMO 

Linda C. Pronk, Netherlands 1998–2000 ESMO 

Ramon Salazar, Spain 1999–2001 Searle 

Francisca Vasquez, Spain 1999–2001 SmithKline Beecham 

Francesco Zappa, Switzerland 1999–2001 Rhône–Poulenc Rorer 

Michael Görn, Germany 1999–2001 Pharmacia & Upjohn / ESMO 

Mauricio Riofrio, Ecuador 1999–2001 ESMO 

Annarita Conconi, Italy 1999–2001 ESMO 

Anna Llado, Spain 2000–2002 ESMO 

Frank Mayer, Germany 2000–2002 ESMO 

Mohamed Saad Ismail, Egypt 2000–2002 ESMO 

Eleni Andreopoulou, Greece 2001–2003 ESMO

Martin Bard, France 2001–2002 ESMO 

Niklas Zojer, Austria 2001–2002 ESMO 

Emma Kulimova, Russia 2001–2003 ESMO 

Sylvie Rottey, Belgium 2001–2002 ESMO 

Fabrina Bologna, Argentina 2001–2003 ESMO 

Zhasmina Mihaylova, Bulgaria 2001–2002 ESMO 

Eleni Galani, Greece 2002–2003 ESMO 

Barbara Viscioni, Italy 2002–2004 ESMO 

Luciano Nicola de Wanneson, Argentina 2002–2003 ESMO 

Veronika Ballova, Slovak Republic 2002–2003 ESMO 

Vasiliki Michalaki, Greece 2002–2003 ESMO 

Alexei Teterin, Russia 2002–2003 ESMO 

Karina Vera, Argentina 2002–2003 ESMO 

Robert Godal, Slovak Republic 2003–2004 ESMO 

Joerger Markus, Switzerland 2003–2004 ESMO 

Benjamin Besse, France 2003–2004 ESMO 

Marzia Palma, Italy 2003–2004 ESMO 

Erika Martinelli, Italy 2004–2005 Ortho Biotech 

Robert Godal, Slovakia 2004–2005 Amgen 

Mikhail Akimov, Russia 2004–2005 Merck 

Silvia Neciosup Delgado, Peru 2004–2005 AstraZeneca 

Rosa Conforti, Italy 2004–2005 ESMO 

Maja Bradic, Serbia Montenegro 2005–2006 Amgen 

Semra Aydin, Germany 2005–2006 AstraZeneca 

Marzia Palma, Italy 2005–2006 Ortho Biotech 

Ioannis Mountzios, Greece 2005–2006 ESMO 

Francesco Atzori, Italy 2006–2007 Amgen 

Daniel Koychev, Bulgaria 2006–2007 Amgen 

Hendrik Wermann, Germany 2006–2007 Novartis 

Orestis Lyros, Greece 2006–2007 AstraZeneca 

David Olmos Hidalgo, Spain 2006–2007 Bayer Oncology 

Rodrigo Ruiz Soto, Mexico 2006–2007 Wyeth Pharmaceuticals 

Aleksandar Celebic, Serbia 2007–2008 Amgen 

Isabelle Opitz, Germany 2007–2008 Bayer Oncology 

Nicola Cresti, Italy 2007–2008 Amgen 

Sherene Loi, Australia 2007–2008 Novartis 

Ben Markman, Australia 2007–2008 Wyeth Pharmaceuticals 

Mustapha Zoubir, Algeria 2007–2008 GE Healthcare 

Andrea Alimonti, Italy 2008–2009 Amgen 

Ekaterina Chigrinova, Russia 2008–2009 Roche 

Armelle Dufresne, France 2008–2009 Merk Serono 

Roberta Ferraldeschi, Italy 2008–2009 ESMO 

Vassilios Golfinopoulos, Greece 2008–2009 ESMO

Ondrej Gojis, Czech Republic 2008–2009 GSK 

Viviane Hess, Switzerland 2008–2009 Novartis 

Christophe Massard, France 2008–2009 Amgen 

Floriana Morgillo, Italy 2008–2009 Roche 

Mahasti Saghatchian, France 2008–2009 ESMO 

Balazs Dome, Hungary 2009–2010 Roche 

Laurent Quero, France 2009–2010 Pfizer Oncology 

Yoko Yanagisawa, Japan 2009–2010 Novartis 

Giorgi Dzagnidze, Georgia 2009–2010 MSD 

Eleni Karapanagiotou, Greece 2009–2010 Roche 

Giannis Mountzios, Greece 2009–2010 Roche 

Hatem Azim, Egypt 2010–2011 Roche 

Giulia Pasello, Italy 2010–2011 Roche 

Teresa Troiani, Italy 2010–2011 Amgen 

Michalis Karamouzis, Greece 2010–2011 Amgen 

Konstantinos Kamposioras, Greece 2010–2011 Roche 

Karin Tamas, Hungary 2010–2011 Roche 

Leticia De Mattos Arruda, Brazil 2010–2011 Amgen 

Michael Baumann, Switzerland 2010–2011 MSD 

Elena Castro Marcos, Spain 2010–2011 Novartis 

Daniela Kolarevic, Serbia 2011–2012 Roche 

Sophie Postel–Vinay, France 2011–2012 Roche 

Alejandra Armengol Alonso, Mexico 2011–2012 Novartis 

Claudette Falato, Italy 2012–2013 Roche 

Jennifer Gibbons Marsico, Uruguay 2012–2013 Roche 

Angela Lamarca, Spain 2012–2013 Amgen 

Elisabetta Pietri, Italy 2012–2013 Amgen 

Loredana Vecchione, Italy 2012–2013 Roche 

Jean–Sebastien Frenel, France 2012–2013 Debiopharm, Ipsen 

Silvia Mihaela Ilie, Romania 2012–2013 Novartis

hamilton fairley award 

1IN FROM EMPIRICAL TO RATIONAL TREATMENT OF HUMAN 

CANCERS CELLS AND THEIR STROMA 

J-Y Blay 

Department of Medicine, University Claude Bernard Lyon I, Centre Léon Bérard, 

Lyon, FRANCE 

In the last 5 years, there has been a major acceleration of the understanding of the 

molecular alterations responsible for cancer cells development. Large variety of 

genomic and epigenetic alterations, resulting in abnormal gene expression patterns, 

and cellular behavior can now be uncovered for each individual tumor. New 

nosological classifications, across and within histological subtypes, are emerging as a 

consequence of this knowledge resulting in a fragmentations of previous disease 

types mainly organ-based in a myriad of rare tumors. This complexity is 

multidimensional, and only starts to be understood, with the additional challenge 

that it evolves over time within subclones of tumor cells in each individual patients. 

Despite these challenges, the partial understanding of this complexity we have 

reached has led to tremendous progresses for the treatment of patients with cancer 

recently, e.g. in CML, HER2+ breast cancer, GIST BRAF mutated melanomas, Alk 

mutated tumors. In each example, the targeting of a “key node”, a driver alteration in 

the process of neoplastic transformation, or tumor progression was often sufficient to 

achieve a major improvement. The identification of these driver mutations has 

sometimes been stochastic, emerging from translational research programs aiming to 

find predictive factors, but is now more often coming from a rationale systematic 

approach to identify subgroups of cancers with similar genomic alterations. Novel 

nosological classifications must be built with these tools, and our treatment 

paradigms will be based on these. However, obvious obstacles are already visible: 

clonal heterogeneity of cancer, frequent emergence of resistance, integration of 

treatment targeting the immune stroma, but also compliance for long term 

treatment, and economical considerations. In this presentation, we will show some 

successful and non successful examples of development of targeted treatment to 

which we have contributed, and the lessons which should be drawn from these 

examples for the future development of anticancer therapies. 

Disclosure: The author has declared no conflicts of interest. 

PI 3-Kinase and cancer metabolism 

2IN PI 3-KINASE AND CANCER METABOLISM 

Annals of Oncology 23 (Supplement 9): ix21, 2012 

doi:10.1093/annonc/mds365/mds366 

L.C. Cantley 

Division of Signal Transduction, Beth Israel Deaconess Medical Center and 

Department of Systems Biology, Harvard Medical School, Boston, MA, 

UNITED STATES OF AMERICA 

Phosphoinositide 3-kinase (PI 3-Kinase) generates 

phosphatidylinositol-3,4,5-trisphosphate (PIP3) at the plasma membrane in response 

to stimulation of cells with growth factors and hormones. This lipid recruits certain 

signal transduction proteins to the membrane, initializing cellular signaling cascades 

that control glucose uptake, cell metabolism, protein synthesis and cell growth. A 

central mediator of PI 3-Kinase signaling is the protein-Ser/Thr kinase, AKT. Over 

the past six years signaling networks downstream of AKT have been elucidated that 

regulate protein synthesis and glucose metabolism, in part via activation of mTOR. 

Importantly, we have found that while growth factor receptors enhance glucose 

uptake and glucose metabolism, they decrease the activity of pyruvate kinase, the last 

step in the pathway. Our studies indicate that the inhibition of pyruvate kinase allows 

cells to divert intermediates in glycolysis into pathways for synthesis of DNA, RNA, 

proteins and lipids that are needed for cell growth. 

Disclosure: Dr. Cantley is a founder and member of the BOD of Agios 

Pharmaceuticals, a company that targets metabolic enzymes for treating cancer. 

Dr. Cantley consults for Novartis and GSK, companies developing drugs that target PI3K. 

© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. 

All rights reserved. For permissions, please email: journals.permissions@oup.com 

abstracts

abstracts 

hpv biology and implications in 

gynecological malignancies 

3IN FROM HYPOTHESIS TO PREVENTION IN 40 YEARS 

S.K. Kjaer 

Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, 

Copenhagen, DENMARK 

Indications of a relationship between cervical cancer and sexual activity have been 

available for over a century. Early studies described sexual variables mainly in terms of 

marital status, age at first marriage and reproductive life, whereas more recent 

epidemiological studies have assessed the role of sexual habits and specifically 

identified the number of sexual partners and age at first intercourse as the most 

important risk factors. The finding of an independent effect of the number of sexual 

partners, and the increased risk for women whose husbands reported multiple sexual 

partners strongly pointed to the importance of a sexually transmitted infectious agent, 

although other factors such as smoking, parity and oral contraceptive use were also 

suggested to be important. For more than two decades, attention focused on herpes 

simplex virus type 2 as an etiological agent. However, subsequently it was suggested by 

Professor zur Hausen that certain types of human papillomavirus (HPV) might play a 

key etiological role. Although there at that time was laboratory evidence supporting 

this hypothesis, it was initially difficult to test it epidemiologically. With the 

technological development and the collaboration between epidemiologists, virologists 

and clinicians it became increasingly clear that HPV is a necessary factor in the 

development of cervical cancer and also is causing a proportion of other anogenital 

cancers in both women and men such as cancer of the vagina, vulva, penis and anus. 

In addition, it is associated with certain types of head and neck cancer. Based on the 

research within this area, vaccines against certain types of HPV have now been 

developed and we have moved from hypothesis to prevention in some 40 years. 

Disclosure: S.K. Kjaer: Received lecture fees, advisory board fees, and research grants 

through her institution from Merck and Sanofi Pasteur MSD. 


doi:10.1093/annonc/mds367 

4IN IMMUNE BIOLOGY OF HUMAN PAPILLOMAVIRUSES: 

IMPLICATIONS FOR VACCINE DEVELOPMENT 

L. Gissmann 

Division of Genome Modifications and Carcinogenesis, Gerrman Cancer 

Research Center, Heidelberg, GERMANY 

The “high-risk” types of human papillomaviruses (HPV), in particular PV 16 and 18 

are responsible for the development of almost all cases of cervical cancer, for a 

substantial fraction of other malignant anogenital tumors (penis, vulva and 

perianum) and for a proportion of head and neck cancer. The natural history of 

HPV infections and immunization experiments in animals with their respective 

papillomaviruses (e.g. the canine oral papillomavirus) clearly revealed the 

involvement of the immune system in controlling the viral infections and the 

diseases associated therewith. Antibodies appear to be the key molecules in 

preventing of an infection whereas mostly T cells and cytokines are involved in 

controlling virus persistence and progression towards malignancy. 

During the natural course of infection human papillomaviruses are not particularly 

immunogenic since their biology makes them barely “visible” by the immune system 

(infection is confined to the epithelium) but also since it has acquired the ability to 

actively suppress certain immune functions. This is in remarkable contrast to the 

strong immune response induced by i.m. immunization with virus particles when 

they become exposed to and interact directly with circulating antigen presenting cells. 

There is mounting awareness about the mechanisms of these interactions. 

Disclosure: Lutz Gissmann is a consultant to GlaxoSmithKline and Sanofi Pasteur 

MSD and, due to existing intellectual property, receives royalties from sales of 

Gardasil® and Cervarix® 


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the hallmarks of cancer revisited 

5IN HALLMARKS OF CANCER: A 2012 PERSPECTIVE 

D. Hanahan 

The Swiss Institute for Experimental Cancer Research (ISREC) School of Life 

Sciences, The Swiss Federal Institute of Technology Lausanne (EPFL) Lausanne, 

SWITZERLAND 

The Hallmarks of Cancer perspective (Hanahan & Weinberg, 2000; 2011) 

presents an organizing principle with which to distill the daunting complexity of 

human cancers into a rational commonality of their aberrant basis as 

proliferative disease, despite the disparate manifestations reflected in that 

complexity. A series of (now eight) acquired hallmark capabilities, each with 

distinctive properties, are arguably necessary for malignant progression, 

capabilities whose acquisition underlay the multistep nature of carcinogenesis. 

The mechanisms governing these acquired capabilities involve not only genetic 

and epigenetic changes in the cancer cells that form the basis of chronic 

proliferation and persistence. Ostensibly normal cells recruited to compose the 

neoplastic stroma of the tumor microenvironment – notably endothelial cells 

and pericytes, infiltrating immune cells, and activated cancer associated 

fibroblasts –are also instrumental, functionally contributing to most of the 

hallmark capabilities (Hanahan & Coussens 2012). The hallmarks 

conceptualization, of discrete and quasi-independent capabilities necessary for 

progression, suggests new therapeutic approaches involving targeting multiple 

hallmark functions, which are beginning to be tested in pre-clinical and 

clinical trials. Hanahan D, & Weinberg RA. (2000). The hallmarks of cancer. 

Cell.100: 57-70. Hanahan D, & Weinberg RA. (2011). Hallmarks of cancer: the 

next generation. (2011). Cell.144: 646-674. Hanahan D, & Coussens LM. 

(2012). Accessories to the crime: functions of cells recruited to the tumor 

microenvironment. Cancer Cell. 21: 309-322. 

Disclosure: D. Hanahan: Member, Scientific Advisory Panel for Oncology, 

PfizerMember,SAB,&stockoptions,JennerexBiotherapeuticsunpaid 

consultant & stockholder, Onyx Pharma unpaid consultant & stockholder, 

Aveo Pharma. 

Annals Of Oncology 23 (Supplement 9): ix23, 2012 


6IN FROM LANDMARKS OF CANCER TO TARGETED THERAPIES: 

LESSONS LEARNT AND PERSPECTIVES 

A. Awada 

Department of Medical Oncology, Institute Jules Bordet, Brussels, BELGIUM 

TKIs and antibodies (trastuzumab, imatinib,..) emerged as “revolutionary” drugs. 

Nevertheless, testing different agents in studies turned to be negative or “marginally” 

positive. Negative trials highlighted important issues: 1) The genetic complexity of 

carcinogenesis 2) Defining the implication of a target to oncogenesis is essential. 

3) Due to the “plasticity” of signaling pathways, combination agents or multitargeted 

kinase may be needed but “cumulative” toxicities emerged. 4) A well performed early 

study is a prerequisite for the succes of a new agent. Marginally positive studies lead 

in limited circumstances to retrospective identification of subpopulations likely to 

benefit (e.g., WT KRAS and sensitivity to EGFR MoAbs in CRC). The 

sensibilisation towards tumor selection has demonstrated better results. NSCLC 

with ALK gene rearrangements are senstitive to ALK inhibitors. Melanoma with 

BRAF mutation responded to vemurafenib. A drawback would be the 

heterogeneity of the tumor. Moreover, modern techonologies allows the 

development of agents with a higher selectivity. Although advances have been 

achieved further, efforts are needed: Biomarkers of sensitivity have been evaluated 

but not optimaly validated. Mechanisms of resistance have been described, but a 

proper assessment is lacking. So it is fundamental to prioritize “powered” clinical 

trials. Prospective collection of biospecimens during disease evolution and 

therapies must become a standard approach. A comprehensive drug development 

plan (in advanced or neoadjuvant setting) has the potential to identify drugs to be 

tested in the adjuvant setting in subgroups where cure will be much higher. The 

lessons learnt so far should bring the concept of “personalized treatment” closer to 

the reality. A close collaboration of scientists, chemists, investigators and 

statisticians is needed to reach this goal. 



All rights reserved. For permissions, please email: journals.permissions@oup.com. 

abstracts

abstracts 

the characterization of lung cancer 

in multiple different diseases 

7IN THE CHARACTERIZATION OF LUNG CANCER 

J. Soria 

Medicine Department, Institut Gustave Roussy, Villejuif, FRANCE 

The characterization of lung cancer Lung cancer is the leading cause of 

cancer-related deaths worldwide. Non-small cell lung cancer is currently being 

revisited on the basis of modern molecular portraits that allow the identification of 

new molecular subtypes. Larges scale studies have identified frequent mutations 

mainly in TP53, RB1, CDKN2A, and STK11 tumor suppressor and in EGFR, 

KRAS and NRAS oncogenes. Many other molecular abnormalities have been 

reported in other genes such as PI3K, PTEN, AKT1, MDM2, APC, HER2, KDR, 

MET, CTNNB1, ATM, BRAF, AKT1 and more recently ALK, RET, ROS as well as 

FGFR1. Beyond the now classical oncogene-drivers represented by EGFR mutation 

and ALK translocation, many other molecular abnormalities could be used for 

selection of specific therapy such as amplification of HER2 and FGFR1, 

translocation of RET or ROS, or activating mutations of HER2, HER3, HER4, 

FGFR2 … Nevertheless the correlation between the presence of such abnormalities 

and clinical response are not definitively documented, although some interesting 

small series or case reports have been reported. The table below provides a 

summary of specific alterations, their frequencies and their potential corresponding 

molecular targeted interventions. DNA repair players are also potential predictors of 

standard anti-cancer therapies (ERCC1, MSH2, BRCA1, PARP). In summary, 

characterization of the genomic changes that drive an individual patient’s disease is 

now critical to inform rationally targeted therapies and treatment planning for 

patients with NSCLC. 


Table: 71N 

Molecular alteration 

Frequency in 

Adenocarcinoma 

8IN THE EVOLUTION OF CANCERS UPON TREATMENT WITH 

TARGETED THERAPIES 

No abstract submitted at time of going to press. 

Frequency in Squamous 

cell carcinoma Potential Drugs 



EGFR mutation 10-40% 2-5% Gefitinib Erlotinib Afatinib PF-00299804 

EML4-ALK translocation 5-7% Rare Crizotinib, ASP3026, AP26113, CH5424802 LDK-378 HSP90 inhibitors 

ROS translocation 2% Rare Crizotinib, ASP3026, AP26113, CH5424802 LDK-378 HSP90 inhibitors 

RET translocation 6% Rare Vandetanib 

HER2 mutation or amplification 2% 6% Rare 2% Trastuzumab PF-00299804 Afatinib 

PI3K mutation or amplification 5% < 10% 5% < 10% GDC-0941 GDC 0980 

XL-147 

XL-765 

BEZ-235 

BKM120 BYL 719 PF-05212384 

MET amplification < 10% < 10% XL184 ARQ917 MetMab 

RAS mutation RAF mutation 10-30% 3% 5% 2% Sorafenib AZD6244; GSK1120212; AS703026, RO4987655 MEK162 

FGFR1 amplification 5% 20% BJG398, AZD4547, TKI258 EOS 3810 



the impact of the cancer genome 

project and high-throughput analyses 

on personalised oncology: today and 

tomorrow 

9IN THE MOLECULAR HETEROGENEITY OF BREAST TUMORS 

A. Børresen-Dale 

Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo 

University Hospital, Oslo, and the K.G. Jebsen Center for BC Research, 

University of Oslo, Norway, Oslo, NORWAY 

Breast Cancer (BC) is a complex disease caused by accumulation of genetic 

alterations leading to a disturbed balance between proliferation and apoptosis, 

genetic instability and acquisition of an invasive and resistant phenotype. The 

inherent heterogeneity, including the microenvironment, contributes to each 

tumors phenotype and dictate tumors molecular portraits. We have generated 

high-throughput data of tumors from mRNA and miRNA expression, SNP-CGH 

and DNA-methylation, paired-end sequencing, protein expression by RPPA, and 

metabolic profiles from HR-MAS MR analyses. We have explored to which extent 

combining the various profiles derived from each level, can further subdivide the 

initially discovered expression subclasses and improve prognostic potential. 

Patterns of genomic aberrations that underlie specific expression subgroups may 

infer paths of tumor progression and shed light on mechanisms involved. We 

recently developed two platform-independent algorithms to explore genomic 

architectural distortion using aCGH data to measure whole-arm gains and losses 

(WAAI) and complex rearrangements (CAAI), and were able to separate the cases 

into eight subgroups. Within each subgroup data from expression analyses, 

sequencing and ploidy indicated that progression occurs along separate paths into 

more complex genotypes. The results emphasized the relation among structural 

genomic alterations, molecular subtype, and clinical behavior and showed that 

objective score of genomic complexity (CAAI) is an independent prognostic 

marker. By integrating data from the patient’s own genotype with multiple layers 

of data derived from the primary tumor, the different subclones within the tumor, 

as well as the metastases, we seek to reach a more fundamental understanding of 

the biological dynamics of breast cancer. This will facilitate identification of risk 

factors, search for novel cancer diagnostics, prediction of therapeutic effects and 

prognosis and identification of new targets for therapy, that may lead to a more 

personalized treatment of BC. Ref: Stephens P et al. Nature. 2009, Russnes HG 

et al. STM, 2010, Van LP et al. PNAS 2010, Kristensen VN et al, PNAS 2011, 

Russnes et al JCI, 2011, Curtis et al, Nature, 2012 


10IN INITIAL SEQUENCING OF BREAST CANCER GENOMES 

M. Stratton 

Cancer Genome Projects, The Wellcome Trust Sanger Institute, Hinxton, 

UNITED KINGDOM 

Over the last decade since the provision of the reference human genome DNA 

sequence, increasingly extensive sequence analyses of cancer genomes have led to the 

discovery of new mutated cancer genes and have explored the extant patterns of 

somatic mutation. The scope of these investigations has been constrained by 

sequence throughout and cost. However, the recent advent of novel sequencing 

technologies has ushered in a new era of cancer genome characterisation leading to 

partial or complete catalogues of somatic mutations in individual cancers. The 

combinations of mutated cancer genes and the mutational processes that are 

operative in the subclasses of breast cancer are becoming apparent. These studies are 

bringing new insights into the etiology, pathogenesis and classification of the 

genetically heterogeneous set of diseases that are collectively termed breast cancer. 


Annals Of Oncology 23 (Supplement 9): ix25, 2012 


11IN TOWARDS DECIPHERING THE GENETIC LANDSCAPE IN 

MELANOMA 

Y. Samuels 1 , T.D. Prickett 1 ,X.Wei 1 , J.C. Lin 2 , J.K. Teer 1 , S.A. Rosenberg 3 

1 National Institutes of Health, NHGRI, Bethesda, MD, UNITED STATES OF 

AMERICA, 2 Washington University School of Medicine, St Louis, MO, UNITED 

STATES OF AMERICA, 3 National Institutes of Health, NCI, Bethesda, MD, 


Melanoma is the deadliest form of human skin cancer, accounting for 70% of 

skin-cancer related deaths although it comprises only 4% of skin cancer cases. As 

opposed to the steady decrease in overall rate of other cancers, the incidence of 

melanoma continues to rise worldwide. The median patient survival is six months 

following diagnosis. There is a clear need to develop improved therapy for this 

disease. Melanoma develops through acquired mutations in cancer genes. Cancer 

genome sequencing can identify recurring genetic alterations that will generate 

new approaches to the treatment of melanoma, enabling a more personalized 

approach, based on gene mutation profiles of each patient’s tumor. To 

systematically survey mutations in melanoma, we performed whole-exome 

sequencing of 14 matched normal and metastatic tumor DNAs. This allowed us to 

discover GRIN2A, a member of the ionotropic glutamate receptor family (iGluR), 

to be a significantly mutated gene that had not previously been identified as 

playing a role in melanoma. The comprehensive nature of the acquired data in 

this study allowed the identification of the glutamate signaling pathway to be 

significantly mutated, which includes GRIN2A, GRM3 and ERBB4, found to be 

mutated at 25, 16 and 19 percent of melanomas, respectively GRIN2A and GRM3, 

a metabotropic glutamate receptor (mGluR) are regulated by glutamate. GRIN2A, 

which is a ligand-gated ion channel, allows cations such as calcium to pass 

through the plasma membrane of the cell after the binding of glutamate to the 

receptor. GRM3 activates pathways such as the MEK pathway upon glutamate 

binding. The functional interplay between GRIN2A, GRM3 and ERBB4 in 

melanoma will be discussed and preliminary data presented. Our findings have 

potential therapeutic implications, as glutamate pathway modification has 

previously been shown to limit tumor growth. Further investigation of the 

glutamate pathway in melanoma a development of glutamate pathway inhibitors is 

therefore warranted. 

Disclosure: All authors have declared no conflicts of interest. 

12IN MUTATIONAL AND CHROMOSOMAL SURVEYS 

OF PANCREATIC TUMORS 

A. Scarpa 

ARC-NET Research Centre and Department of Pathology and Diagnostic, 

University of Verona, Verona, ITALY 

Mirroring the cellular diversity within the pancreas, the spectrum of distinct 

pancreatic neoplasms shows histological and molecular features partially recalling 

the characteristics of the cell of origin. Pancreatic ductal adenocarcinoma (PDAC) 

is the most common neoplasm and bears the worst prognosis. Pancreatic 

neuroendocrine tumors (pNETs) are the second most common neoplasm with an 

incidence that is considerably increasing over the last 30-years. Our limited 

knowledge of the genetic basis of these diseases based on candidate gene 

approaches has now been expanded by the use of massive parallel sequencing 

(MPS). These have helped to uncover the genomic landscape of cancers showing 

that, beyond high frequency mutations (Table 1), a plethora of different molecular 

features are identified at low frequency and define potential cancer subgroups of 

clinical interest. This is particularly true for PDAC that represents the real “social 

problem” among pancreatic neoplasms. Recent works exploring the structural 

variations’ landscape of PDAC have also highlighted a high degree of genetic 

heterogeneity in metastatic deposits, which substantially reflects the presence of 

different subclones within the primitive disease. When ignored, molecular 

heterogeneity can lead to failure in therapeutic treatments, as drugs that may have 

efficacy in subgroups of patients with specific molecular phenotypes may show 

marginal response when tested in a large group of unselected patients. This calls 

for the revisitation of the classical pathological diagnosis of cancer where the 



abstracts

abstracts 

description of intra-tumor heterogeneity at both morphological and molecular 

level are taken into account for a diagnoistic report to be clinically useful to 

devise first, second and additional therapeutic choices. 

Table: 12IN Commonly mutated genes in different pancreatic neoplasms. 

Tumor Type a 

Genes b 

PDAC KRAS (100%), TP53 (85%), SMAD4 (38%), CDKN2A (25%) 

pNET MEN1 (44%), DAXX (25%), ATRX (17%), PTEN (7%), TSC2 (9%) 

IPMN KRAS (62%), GNAS (62%), RNF43 (75%) 

MCN KRAS (75%), RNF43 (37%) 

SPN CTNNB1 (100%) 

§ PDAC, pancreatic ductal adenocarcinoma; pNET, pancreatic neuroendocrine 

tumors; IPMN, intraductal papillary mucinous neoplasm; MCN, mucinous cystic 

neoplasm; SPN, solid pseudopapillary neoplasm. 

b Percentages within brackets refer to mutation frequencies assessed in specific 

clinical cohorts 


Annals Of Oncology

optimizing treatment in luminal breast 

cancer 

13IN INTRODUCTION: LUMINAL A AND B: HOW CURABLE ARE 

THEY? 

A. Di Leo 1 , N.H. Turner 1 , L. Malorni 1 , C. Guarducci 2 

1 Oncology- Istituto Toscano Tumori, Ospedale di Prato Sandro Pitigliani Med. 

Oncology Unit, Prato, ITALY, 2 Ospedale di Prato, Translational Research Unit, 

Prato, ITALY 

Hormone receptor positive (HR+) breast cancers can be separated by molecular 

subtyping into luminal A breast cancer (LUM A), which is more prevalent though 

less aggressive, and luminal B breast cancer (LUM B), which is associated with 

higher grade, increased proliferation rates, and an overall poorer prognosis. Other 

than genetic molecular subtyping, which can be expensive and not readily available, 

it may be possible to differentiate between these two subgroups using 

immunohistochemical assessment of the proliferative marker Ki67, as reported by 

Cheang et al, where a cut off of Ki67 14% was used. This method of assessment 

demonstrated utility in providing prognostic information, however the false positive 

and false negative rates were around 25%, suggesting there is significant room for 

improvement within such a method, and thus highlighting an area for ongoing 

research. Methodology aside, differentiation of HR+ breast cancers by molecular 

subgroups is critical, in order to identify appropriate treatment options for patients. 

Generally, endocrine therapy alone would be recommended for LUM A, which 

carries an excellent ten year breast cancer specific survival rate of approximately 90%. 

However, tumor dormancy and late recurrences beyond 10 years are characteristic of 

LUM A. There is a significant lack of knowledge of the mechanisms behind tumor 

dormancy, highlighting a crucial area for further research. Additionally, the optimal 

manner and duration of endocrine therapy in either pre- or postmenopausal women 

is, as yet, unknown; extension of endocrine treatment beyond 5 or even 10 years, as 

well as the most effective endocrine therapy agent, requires ongoing study to better 

define treatment algorithms for LUM A. LUM B, which is inherently more 

aggressive, requires more aggressive therapy and thus is generally treated with both 

endocrine therapy and chemotherapy, though this approach is not always effective. 

Potential alternate or additional treatment options may include targeting of other 

pathways of importance in this subgroup. This therefore requires firstly identification 

of pathways active in LUM B, and secondly, development and assessment of targeted 

agents against these pathways. The utility of inhibitors against mTOR, PI3K or 

IGFR-1 is of particular interest. 


14IN HOW TO OPTIMISE ENDOCRINE THERAPY 

S.R.D. Johnston 

Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UNITED 

KINGDOM 

For post-menopausal women with early stage ER+ breast cancer, aromatase 

inhibitors are recommended to be part of adjuvant endocrine therapy either as 

up-front therapy or as a switch strategy following initial tamoxifen therapy. Both 

approaches are equally effective, and both are superior to tamoxifen alone for 5 

years. The current duration for aromatase inhibitors given as adjuvant therapy is 5 

years based on current safety and efficacy data. However, the optimal duration of 

adjuvant endocrine therapy is currently unknown, and extended adjuvant therapy 

with aromatase inhibitors after tamoxifen is an increasingly utilised strategy for 

reducing ongoing risk of recurrence, especially for those deemed to be at greater 

risk such as those with node-positive disease or other indicators for late relapse. In 

pre-menopausal women with ER+ early breast cancer the added benefit of ovarian 

suppression over and above tamoxifen remains unknown. In women aged 10% the tumor is very unlikely to fall into the 

lowest relapse risk category at post neoadjuvant endocrine therapy surgery 

(preoperative endocrine prognostic index zero or PEPI-0 (defined as ER+ Stage 1 or 

2A, Ki67 < 2.7%) and therefore not suitable for continued neoadjuvant endocrine 

therapy (since one of the objectives of our studies is to avoid chemotherapy in AI 

sensitive tumors). We have recently completed a successful pilot of triaging 35 

patients with an early on treatment high Ki67 values to chemotherapy with the 

efficacy results to be reported at the San Antonio Breast Cancer Symposium. The 

ALTERNATE trial is based on these principles (ALTernate approaches for clinical 

stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment) and 

will screen over 2000 patients to identify up to 400 cases of ER+ HER2- AI resistant 

breast cancer who will be suitable candidates for investigational neoadjuvant 

approaches to improve outcomes in this understudied group of high risk patients. 

Patients with PEPI-0 disease will be managed without adjuvant chemotherapy with a 

prospective plan to demonstrate that the 5 year relapse rate is 5% or less. 


16IN NEW TARGETED AGENTS IN LUMINAL BC 

J. Baselga 

Massachusetts General Hospital Cancer Center and Harvard Medical School, 

Boston, MA, UNITED STATES OF AMERICA 

In recent years the description of well-defined molecular subtypes of breast cancer, 

together with the identification of driving genetic alterations and signaling 

pathways, has led to the clinical development of a number of successful molecular 

targeted agents. Among them, luminal B breast cancer is emerging as an important 

subset of ER+ tumors that are less responsive to hormonal therapy. Novel targets 

under exploration in this group of patients include inhibitors of the 

PI3K-AKT-mTOR. In this regard, a recently reported phase III study the mTOR 

inhibitor everolimus and exemestane to exemestane and placebo in 724 patients 

with HR+ breast cancer refractory to nonsteroidal aromatase inhibitors showed that 

the combination of everolimus and exemestane resulted in marked improvement in 

progression-free survival as determined by local investigator assessment (6.9 vs. 2.8 

months; hazard ratio [HR], 0.43; P = 1.4 × 10 −15 ) 1 .The clinical benefit observed in 

the combination arm also far exceeds the clinical benefit of single-agent everolimus 

in a similar population of patients. In addition novel PI3K inhibitors are being 

tested in patients with breast cancer including PI3K alpha specific agents that have 

shown activity in patients with breast cancer harboring PI3K mutations. Other 

approaches include inhibitors against the MEK pathways, as well as receptor 

tyrosine kinase inhibitors such as the Insulin-like growth factor receptor (IGF-1R) 

and the fibroblast growth factor receptor (FGFR). The clinical development of these 

agents will require a change from the current large randomized trials in unselected 

patient populations to smaller trials in molecular defined tumor types that 

incorporate tumor biomarker endpoints as well as functional imaging. New 

challenges include the appearance of resistance either by acquired secondary 

mutations, or via induction of adaptive activation of compensatory pathways that 



abstracts

prevent cell death. It is anticipated that combinatorial approaches, acting on the 

secondary mutations and/or compensatory pathways, may markedly improve on the 

effects of targeted agents used alone. 1. Baselga J, Campone M, Piccart M, et al. 

Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. 

N Engl J Med 2012;366:520-9. 

Disclosure: J. Baselga: Consulting activity with Novartis and Genentech 

17IN PHARMACOGENETICS /GENOMICS (PGX) TO OPTIMIZE 

ENDOCRINE THERAPY 

J. Ingle 

Oncology, Mayo Clinic, Rochester, MN, UNITED STATES OF AMERICA 

Endocrine therapy of breast cancer is associated with substantial variability between 

patients in terms of efficacy, adverse events and end organ effects indicating genetic 

variability. This discussion will consider the host (germline) genome and consider 

SERMs and 3 rd generation AIs. In of terms of single gene studies, most of the work 

has been done with CYP2D6 and tamoxifen efficacy (first reported by our group in 

2005) but the results have been mixed, related (in this author’s opinion) to a series of 

flawed retrospective studies. Additional studies focusing on tamoxifen have examined 

polymorphisms in phase II (conjugating) enzymes (UGTs, SULTs), ESR1 and ESR2, 


but results remain preliminary. Our group conducted the largest PGx GWAS to date 

in women receiving tamoxifen or raloxifene on NSABP P-1 and P-2 and identified 

SNPs associated with development of breast cancer and SNP-dependent mechanisms 

underlying SERM and estrogen-dependent regulation of BRCA1 expression. 

Considering AIs, substantial research has occurred relating to the aromatase gene 

CYP19. Our group has conducted GWAS in postmenopausal women with baseline 

hormone levels as the phenotype and identified SNPs related to estradiol levels, that 

achieved genome-wide significance, with one SNP creating an estrogen response 

element (ERE), and regulation by these SNPs of estrogen-dependent TSPYL5 

induction and CYP19 adipose promotors induction. We also identified a 

genome-wide significant non-synonymous SNP in SLCO1B1 associated with 

estrone-conjugate levels. We have completed a GWAS in women receiving AIs with 

musculoskeletal adverse events (MS-AE) as the phenotype and identified a SNP that 

created an ERE, was associated with estrogen-dependent TCL1A expression, which in 

turn altered interleukin (IL) 17 receptor (R) A expression, IL-17, IL-12, IL-RB2, and 

IL-1R2 expression, as well as NF-κB transcriptional activity. These finding provide a 

pharmacological explanation for MS-AE in women treated with AIs. To date, PGx 

studies have not produced changes in clinical practice of endocrine therapy for breast 

cancer. In several instances they have served as discovery tools that provided 

direction for research that has led to new knowledge of the biology underlying 

endocrine therapy. 


ix28 | Abstracts Volume 23 | Supplement 9 | September 2012

how to integrate new drugs in the 

current therapeutic landscape of 

metastatic triple negative breast 

cancer 

18IN INTRODUCTION: RECENT FAILURES IN DRUG DEVELOPMENT 

FOR TN MBC 

F. André 

Breast Cancer Unit, Department of Medical Oncology, Institut de Cancérologie 

Gustave Roussy, Villejuif Cedex, FRANCE 

Several compounds have been developed in the recent years in triple negative BC. 

Although associated with promising initial results, they all failed to be fully 

implemented. Iniparib failed because the compound was not fully characterized, and 

because phase II trials amplified the effect of the drug. Olaparib failed because it 

targeted a rare population, and partially because its position in the therapeutic 

sequence was unclear. Finally, bevacizumab, although registered, was not fully 

optimized in the practice. Overall, these failures are illustrative of current questions 

in drug development. The first relates to the amount of information needed before 

moving to registration trials: is the compound characterized in preclinical models? 

Do we have evidence for bioactivity in early trials? Are phase II randomized trials 

optimal for decision to phase III? The second relates to the difficulties to develop 

drug in small populations defined by a biomarker: how to develop a predictive test? 

How to organize clinical research when less than 1 out of 10 patients screened will 

enter the trial? What is the path to registration for a drug targeting a rare 

population? 

Disclosure: F. André: advisory board : SANOFI, Roche, Astrazeneca, novartis 

speaker bureau: Novartis 

19IN DOES MOLECULAR TRIAGE HELP TO IDENTIFY HIGHLY 

SENSITIVE DISEASE? 

L. Pusztai 

Medical Oncology, Yale University, New Haven, CT, UNITED STATES OF 

AMERICA 

It is helpful to consider predictive biomarkers within three distinct categories that 

also represent different degrees of difficulty in terms of the predictor discovery 

process. (1) There are broad treatment response markers that are based on detecting 

a fundamental biological process that is relevant for the action of a class of drugs. 

Such markers have a large transcriptional (or other molecular) footprint and hence 

represent relatively low hanging fruits in the discovery process. For example, high 

tumor proliferation is such a marker for general chemotherapy sensitivity or for 

worse baseline prognosis. It may be possible in the future to discover similar broad 

markers for metabolism-targeted agents or for immunotherapies. (2) There are drug 

class-specific predictors such as estrogen receptor (ER) expression or human 

epidermal growth factor 2-receptor (HER2) amplification or activating mutations in 

critical signaling genes (e.g EGFR, bRAF, c-KIT, etc..) that represent singular driver 

events in tumors. These alterations reflect partial dependence on a given molecular 

pathway and can predict sensitivity to a variety of agents that target the involved 

pathway. Similar driver events for distinct small subsets of cancers are likely to be 

discovered in the next decade and could yield predictors with clinically useful 

negative predictive value. (3) Single drug-specific response markers that could be 

used to select one agent over another have remained elusive despite extensive 

research efforts. This may be due to the case-to-case heterogeneity of molecular 

mechanisms that can converge to cause sensitivity or resistance to a particular 

molecule. Molecular markers under points (2) and (3) and their combinations exist 

and are useful to select adjuvant therapies in breast cancer (e.g. Ki67, OncotypeDX, 

MammaPrint, ER, HER2, PAM50) or triage patients to clinical trials who are 

unlikely to do well with existing treatment modalities. Prospectively designed 

molecular triaging studies that directly test the positive predictive value of candidate 

response markers also remain an important research strategy to rapidly assess the 

clinical utility of predictive markers. 


Annals of Oncology 23 (Supplement 9): ix29–ix30, 2012 


20IN DEVELOPMENT OF NEW TARGETED AGENTS FOR TNBC 

N. Turner 

Breakthrough Breast Cancer, Institute of Cancer Research, London, UNITED 

KINGDOM 

Triple negative breast cancers are a highly diverse and heterogenous group of 

tumours. A number of different approaches to tackling this heterogeneity are 

emerging for the targeted treatment of TNBC. Targeting common genetic events 

of TNBCs. TNBCs have a high frequency of TP53 mutations in ∼60% of TNBC, 

a rate substantially higher than other breast cancer subtypes. Targeting TP53 

inactivation has historically been challenging, although preclinical data suggests 

that combinations of DNA damaging chemotherapy with CHK1 or WEE1 

inhibitors has the potential to target TP53 deficiency. Other common targetable 

events include genetic activation of the PI3 kinase pathway in ∼15-20% cancers, 

through PTEN deletions/ inactivating mutations and PIK3CA activating mutations, 

and loss of HR based DNA repair, though mutation of BRCA1/2 and BRCA1 

promoter methylation, that could be targeted with PARP inhibitors. A further 

potentially targetable common event includes loss of the phosphatase PTPN12 and 

upregulation of specific receptor tyrosine kinases. Targeting TNBC subtype specific 

features. Gene expression studies have revealed multiple different gene expression 

subtypes in TNBC. The luminal AR subtype expresses the androgen receptor (AR) 

and now both preclinical and tentative clinical data to support AR as a 

therapeutic target. Mesenchymal-like basal TNBC express autocrine FGF2 ligand 

that is important for their biology. 

Targeting individual rare events. A diverse set of potentially targetable oncogenic 

mutations and amplifications occur in TNBC that are likely important 

therapeutic targets for individual cancers, but these present a substantial 

challenge to drug development due to their individual rarity. Through such 

strategies to sub-segment TNBC progress will be made in delivering targeted 

therapies for TNBC. 

Disclosure: N. Turner: Dr Nicholas Turner has received honoraria from Novartis, 

Astra Zeneca, Roche, Clovis, EOS 

21IN IS THERE A ROLE FOR NEW CYTOTOXIC AGENTS IN TNBC? 

J. Cortes 

Medical Oncology Department, Vall d’Hebron Institute of Oncology, Vall 

d’Hebron University Hospital, Barcelona, SPAIN 

Triple-negative breast cancer (TNBC), which accounts for 15% to 20% of all 

cases of breast cancer, is characterized by having estrogen-receptor 

(ER)-negative and progesterone-receptor (PR)-negative and has no 

overexpression of human epidermal growth factor receptor 2 (HER2). It is an 

aggressive subtype of breast cancer marked by higher rates of visceral and 

central nervous system metastases and poor disease-free survival compared with 

hormone receptor-positive sybtypes. In recent years, an increasing appreciation 

and identification of somatic mutations and other genetic aberrations that drive 

human malignancies have led us within reach of personalized cancer medicine. 

However, after a high expectation with iniparib, a non optimal PARP inhibitor, 

final data from a randomized phase III trial did not demonstrate this drug to 

improve outcomes in combination with chemotherapy in patients with advanced 

TNBC and bevacizumab is the only “targeted” agent which has shown to 

improve outcomes in combination with chemotherapy in patients with 

metastatic TNBC. Thus, chemotherapy continues to be the standard of care in 

these patients. Although taxanes and anthracyclines are still the most important 

compounds for patients with metastatic TNBC, the majority of them will 

progress and patients will need new chemotherapeutic drugs. Thus, new 

cytotoxic drugs are being studied in patients with TNBC in late-line. Among 

them, new antimicrotubule agents such as eribulin mesylate have shown to 

increase survival versus the treatment of physiciańs choiceandseemstobe 

active also in this tumor type. Other agents which seem to play a role are 

vinflunine and KNTR-102, a new polymeric conjugate of irinotecan, both in 

phase III trials. NKTR-102 has shown an impressive response rate in patients 

with very heavily pretreated TNBC, including taxanes, anthacyclines and 

capecitabine. 

Disclosure: J. Cortes: Consultant: Roche, Novartis, Celgene Honoraria: Roche, 

Celgene, Novartis, Cephalon/Teva 



abstracts

22IN TARGETING THE HOST IN TNBC 

G. Curigliano 

Medicine, Istituto Europeo di Oncologia, Milano, ITALY 

Cancer medicine is increasingly moving toward a new era of personalized 

therapeutics that embraces integrative approaches. Combinatorial strategies will target 

not only cancer cell-intrinsic pathways, but also cancer cell-extrinsic cells, pathways, 

and mediators of the tumor microenvironment. As the strategic goal of defining the 

roles of the tumor microenvironment in primary and metastatic tumor progression, 

new discoveries can be envisioned to produce innovative multitargeting strategies that 

will be able to more thoroughly extinguish primary and metastatic disease, 

overcoming adaptive resistance mechanisms to such therapies. The cancer 

microenvironment is constituted of non-transformed host stromal cells such as 

endothelial cells,fibroblasts, various immune cells, and a complex extracellular matrix 

secreted by both the normal and neoplastic cells embedded in it. The importance of 

the microenvironment and its potential in cancer therapy is just being established. 

Among modalities that target the microenvironment, harnessing immune responses 


has long been pursued. Efforts to turn on the immune system against cancers with 

inactivated tumor vaccines or intratumor injections of bacterial products to induce 

local inflammation and recruit an antitumor immune response have led to anecdotal 

successes. A major limitation of the various approaches to turning on an immune 

response to cancer is that the immune system exerts a major effort to avoid 

immune over-activation, which could harm healthy tissues. Cancer takes 

advantage of this ability to hide from the immune system by exploiting a series of 

immune escape mechanisms that were developed to avoid autoimmunity 

(mechanisms of tolerance). Among these mechanisms are the hijacking of 

immune-cell–intrinsic checkpoints that are induced on T-cell activation. Blockade 

of one of these checkpoints, cytotoxic T-lymphocyte–associated antigen 4 

(CTLA-4) or the programmed death 1 (PD-1) receptor, provided the first evidence 

of activity of an immune-modulation approach in the treatment of a solid tumor. 

The future frontier in the treatment of cancer requires identification of potential 

targets in order to personalize therapies. The immune system remembers what it 

targets, so once the system is correctly activated, it may mediate a durable tumor 

response. 



molecular neuro-oncology: new 

avenues in diagnosis and treatment 

23IN ANAPLASTIC GLIOMA: WILL MOLECULAR PROFILING 

OVERRIDE HISTOLOGY? 

M.J. van den Bent 

Neuro-Oncology, ErasmusMC - Daniel den Hoed Cancer Center, Rotterdam, 

NETHERLANDS 

The histopathological diagnosis of anaplastic glioma is complicated by a disturbing 

interobserver variation. Several molecular assays are now of demonstrated value in 

anaplastic glioma. Recent randomized trials have shown that 1p/19q co-deletion is 

not only prognostic, but also predictive for improved outcome to RT with adjuvant 

PCV. Also, testing for IDH mutations is helpful for the in diagnosis of grade II and 

grade III, and has significant prognostic implications. MGMT promoter methylation 

in anaplastic gliomas seems to be the result of alter cell metabolism induced by IDH 

mutations which leads to the CpG island hypermethylation. Therefore, in anaplastic 

glioma MGMT promoter methylation appears to reflect IDH status. 

Conclusion: over the past two years, the role of molecular testing has greatly 

increased in the management of anaplastic gliomas. 


24IN MANAGEMENT OF GLIOBLASTOMA: THE ROAD TOWARDS 

STRATIFIED CANCER CARE 

M. Weller 

Department of Neurology, University Hospital Zurich, Zurich, SWITZERLAND 

Glioblastomas are highly malignant primary brain tumors presumably originating 

from neuroglial progenitor cells. Median survival is less than one year. Cytoreductive 

surgery, focal radiotherapy, and alkylating agent chemotherapy are standard of care 

for favourable prognosis patients. These tumors can be classified by morphology, 

imaging parameters, clinical characteristics, single biomarkers or complex molecular 

signatures, Some of these characteristics, including age and Karnofsky performance 

score, provide important prognostic information. In contrast, neither histological 

subtyping of glioblastoma nor specific imaging features have assumed prognostic 

relevance. Among multiple candidate biomarkers, only one, that is, promoter 

methylation of the O 6 -methylguanine methyltransferase (MGMT) gene, helps for 

clinical decision making. Patients with glioblastomas with MGMT promoter 

methylation derive more benefit from alkylating agent chemotherapy. In the growing 

population of elderly patients with glioblastoma, combination radiochemotherapy has 

not been shown to be superior to monotherapy and may be mess well tolerated than 

either radiotherapy or chemotherapy alone. Here, MGMT promoter methylation may 

assume a major role as a predictive biomarker. Results from registration trials for two 

anti-angiogenic compounds, bevacizumab and cilengitide, are awaited. Biomarkers 

for benefit from anti-vascular endothelial growth factor therapies have not been 

introduced into the clinic. Positron emission tomography for the detection of avb3/5 

integrins might be used to select patients for treatment with anti-integrin 

anti-angiogenic approaches. Screening for a specific type of epidermal growth factor 

receptor mutation, EGFRvIII, is currently being explored as a biomarker for selecting 

patients for vaccination in two randomized clinical trials. Despite extensive efforts at 

defining biological markers as a basis for selecting therapies, most treatment 

decisions for glioblastoma patients are still based on age and performance status 

today. However, several ongoing clinical trials may enrich the repertoire of criteria 

for clinical decision making in the very near future. 

Disclosure: M. Weller: The author has received honoraria for advisory 

boards and lectures from Antisense Pharma, Magforce, MSD, Merck Serono 

and Roche, as well as research support from Merck Serono, Roche and 

Antisense Pharma. 



25IN THE MOLECULAR DISSECTION OF MEDULLOBLASTOMA 

S.M. Pfister 

Pediatric Neurooncology, German Cancer Research Center Heidelberg, 

Heidelberg, GERMANY 

Medulloblastoma is the most common malignant brain tumor in childhood, 

displaying tremendous biological and clinical heterogeneity. Four biological 

subgroups are consistently revealed in various studies based on gene expression 

profiling, but details of the genetic events driving each of these subgroups remain 

elusive. We have performed an integrative deep-sequencing analysis to identify 

genetic alterations in 200 tumor-normal pairs. Strikingly, tetraploidy was found to 

be a common early event in clinically challenging Group 3 & 4 tumours. For 

SHH tumors in contrast, we have identified a subgroup of tumors in older 

children that show striking patterns of chromothripsis, all of which have 

underlying TP53 mutations, either early somatic or germline. SHH tumors in 

adults, which are the predominant subgroup in this age group, in turn show a 

largely different mutation spectrum from their pediatric counterparts. Overall, 

beside known alterations (CTNNB1, PTCH1, MLL2, SMARCA4), several genes not 

previously implicated in medulloblastoma (DDX3X, CTDNEP1, KDM6A) were 

recurrently mutated, often in subgroup-specific patterns and many of them 

involved in chromatin-remodelling. These findings provide a detailed insight into 

medulloblastoma tumorigenesis, and disclose novel targets for therapeutic 

approaches, especially for Group 3 and 4 patients in children, and SHH tumors in 

adults. 


26IN BRAIN METASTASIS: CHALLENGES IN UNDERSTANDING 

PATHOGENESIS AND IN DESIGNING CLINICAL TRIALS 

M. Brada 

Clinical Oncology, UCLH & Leaders in Oncology Care, London, 


The presence of brain metastases (BM) remains a therapeutic challenge as most 

trials with the exception of local treatment with surgery and radiosurgery in 

patients with solitary BM have failed. The negative trials suggest that the disease 

in the brain is not the principal determinant of life expectancy in patients with 

disseminated disease. Large trials without enrichment of the study population by a 

predictive biomarker are also unlikely to be successful. The blanket use of whole 

brain radiotherapy for multiple BMs is also no longer tenable. The concept of 

blood brain barrier, unlikely to be of significance in patients with enhancing brain 

metastases, should not be a bar to the use of chemotherapy, where the principal 

determinant of efficacy is likely to be chemoresponsiveness of systemic disease. 

Successful use of prophylactic brain treatment is predicated on the assumption 

that brain dissemination is a late metastatic event. Metastases suppressors, with 

mode of action spanning the metastatic cascade, have prophylactic efficacy in vivo, 

although the studies are mostly based on non-spontaneous models, which are 

unlikely to reflect the true clinical situation. Nevertheless some agents are 

approaching the time of clinical application. The successful development of new 

therapies for BMs needs refinement of the current trial design. Phase I/II studies 

of new agents should not exclude patients with BM to provide “proof of 

principle” of therapeutic efficacy in the brain. Subsequent trials, with survival as 

the primary endpoint, should focus on patient population where BM are likely to 

be the determinants of outcome (i.e. with inactive systemic disease) and enriched 

for a predictive biomarker. Large trials, even in a single tumour type, testing a 

single agent or a combination, either alone or in addition to standard treatment 

without appropriate patient selection are likely to continue to fail. 




abstracts

abstracts 

a paradigm shift in early drug 

development: individualizing 

to more patient benefit 

27IN THE IMPORTANCE OF PATIENT SELECTION IN TREATMENT 

EFFICACY 

S. Aamdal 

Dept of Oncology, Oslo University Hospital, Oslo, NORWAY 

The importance of patient selection in treatment efficacy Cohorts of patients selected 

according to biomarkers are shifting the cancer treatment paradigm from population 

based to personalized medicine introducing a new area termed theragnostics in 

which the combination of diagnostics and therapeutics identifies patients most likely 

to benefit or not from a treatment regimen. Apart from safety and toxicity 

assessment phase I trials now also test hypothesis, determine target engagement, 

biologic response, identify the appropriate patient population, proof-of-concept, and 

identify potential predictive biomarkers in Phase II and Phase III trials. There are 

several strategies to select patients on molecular bases for early drug development. 1) 

The molecular alterations are sufficient frequent in a tumor type that without 

pre-selection retrospective analysis of the mutation can be carried out. A 

retrospective analysis on fixed tissue can confirm the drug activity in presence of the 

molecular alteration. Selection is then based on tumor type, not on molecular 

analysis. Such selection would put a number of patients at risk of exposure to a study 

drug despite not presenting the target of interest. 2) Prescreening patients by sending 

tumor tissue to a central laboratory for analysis just before inclusion in a trial. This 

ensures state-of the art central laboratory analyses. Amount of tumor tissue may 

become an issue if several labs are involved. Turnaround time between molecular 

analyses and trial initiation may become too lengthy for patients with advanced 

disease. 3) Local prescreening of patients while still on standard treatment. Less 

tumor material is needed and no delay from progression on standard therapy to 

recruitment in a clinical trial. Multiple patient consent forms are not necessary. 

However patients will be screened for participating, but never will enter trial due to 

early disease progression. Intra-tumor heterogeneity, presence of more than one 

clone in the tumor and inter-tumor heterogeneity, the presence of different genetic 

alterations in different metastases from a single patient is a major challenge to patient 

selection. Single cor biopsy may lead to underestimation of the mutations in the 

tumor and could influence the efficacy of molecular targeted therapies even in 

carefully selected patients. 


28IN THE ROLE OF TUMOR/MOLECULAR TARGET SELECTION 

IN THE SUCCESS OF A NEW AGENT 

C. Dittrich 

3rd Med. Dept.-Centre for Oncology and Haematology, Kaiser Franz 

Josef-spital, Vienna, Austria, LBI-ACR VIEnna & ACR-ITR Vienna, Vienna, 

AUSTRIA 

Rational drug discovery/development is targeted at structures and pathways, which 

cause, permit, or maintain malignancy. This let restrain from the histopathologically 

characterized organ entities and substitute them for merely molecularly characterized 

entities, such as EGFR, HER2, KRAS, BRAF driven entities. The presence of a target 

and its therapeutic consequence in one organ cannot be extrapolated to another. As 

an example, a BRAF mutation positive (m+) status in melanoma, which is highly 

predictive for response to the anti-BRAF directed TKI vemurafenib (Flathery 2010), 

cannot be extrapolated to the situation in BRAFm+ CRC (Kopetz 2010). A further 

difficulty in switching from tumor entity to target entity lies in the experience that 

clinical effectiveness does not only depend on whether a functional axis is hit by a 

drug or a class of drugs anyhow and anywhere, but moreover in a much more 

defined context; TKIs like erlotinib (Zhou 2011; Rosell 2012) yielded increased OS 

and PFS, respectively, in EGFRm+ tumors. But, the interference of the same axis at a 

different site and via the anti-EGFR MoAb cetuximab (in combination with standard 

therapy) led to an OS advantage independent of the EGFR mutational status of 

NSCLC (O’Byrne 2011). This touches upon the necessity to discover, identify, 

develop, and finally validate the most relevant biomarker(s) for the purpose of drug 

development, notably with high predictive accuracy early in the developmental 

process. In NSCLC, it took almost a decade of trial and error to better define the 

position/clinical usefulness of various biomarkers and methodologies, respectively, to 



characterize/measure the probability to benefit clinically in form of EGFR expression/ 

gene amplification/copy number and mutations on the one side, and ORR, PFS, and 

OS, respectively, on the other side. A shortcoming derived from the earlier 

developmental process is the lack of fixing the right time point to preselect/enrich the 

relevant patient population. This is of utmost importance, especially if patient 

segments are small. In addition, it has to be found out whether a new targeting 

substance is not only reaching /modulating the target, but has also enough impact on 

the relevant biology of the tumor to gain clinical effectiveness. 

Disclosure: C. Dittrich: Unrestricted research grants to the research institutes 

Honoraria for consulting services by several companies 

29IN WHAT IS THE FEATURE OF AN OPTIMAL NEW AGENT: 

SELECTIVE TARGET VERSUS MULTI-TARGETED VERSUS 

COMBINATION DRUGS 

J.H.M. Schellens, S. Marchetti 

Department of Clinical Pharmacology, The Netherlands Cancer Institute, 

Amsterdam, NETHERLANDS 

There are in principle two pharmacological ways to address the question whether 

selective targeted or multitargeted drugs are to be preferred as single agent and/or in 

combination. One approach is to focus on benefit and the other is to focus on safety. 

The modern era of development of targeted agents started with the launch of two 

key molecules: one monoclonal antibody (MoAb) rituxumab and one so-called small 

molecule imatinib. Rituximab was registered in the EU in 1998 and since then about 

seven other MoAbs have been registered. All MoAbs tend to have a selective 

mechanism of action and target on average one key protein, for example CD-20 

(rituximab), or Her2 (trastuzumab). The benefit of these drugs has been clearly 

demonstrated and the safety of these MoAbs is on average good. Possible exception is 

where they target the same proteins in normal tissues such as the skin (cetuximab, 

panitumumab), or the heart (trastuzumab) resulting in sometimes poorly predictable 

but on average manageable side-effects. The small molecule imatinib was registered 

in the EU in 2001 and since then more than 13 other targeted small molecules have 

been registered. Some of these drugs are rather selective, such as erlotinib (mainly 

EGFR) and vemurafenib (mainly BRAF V600) whereas others are less selective and 

certainly less selective than the MoAbs, for example sorafenib, pazopanib and 

sunitinib. This translates into sometimes significant normal tissue toxicity (sunitinib). 

From the safety perspective one would prefer selective drugs targeting unique tumor 

expressed proteins or deranged pathways, which would result in a wide therapeutic 

window. From a benefit perspective at first glance one might prefer multi targeted 

drugs as tumors show a multitude of mutations and amplifications and a double- or 

even multi-barreled shotgun approach might hit one or more of these targets at the 

same time. The disadvantage however is that the mutational profile may not fit to 

the activity spectrum of the “targeted” drug and that this approach will probably 

increase normal tissue toxicity. In view of increasing insight in the molecular 

derangements of tumors one would prefer to have many selective anticancer drugs 

that can safely be combined on the basis of a patient’s individual tumor genetic 

profile. This would fit into the concept of a “personalized treatment”. 

Disclosure: J.H.M. Schellens: Research grants have been received from: Roche, Eisai, 

GSK and Astrazeneca.S. Marchetti: No conflicts of interest to declare 

30IN BIOMARKERS OF RESISTANCE TO TARGETED AGENTS 

R. Bernards, S. Huang 

Molecular Carinogenesis, The Netherlands Cancer Institute, Amsterdam, 

NETHERLANDS 

Unresponsiveness to therapy remains a significant problem in the treatment of 

cancer, also with the new classes of cancer drugs. In my laboratory, we use functional 

genetic approaches to identify biomarkers that can predict responsiveness to targeted 

cancer therapeutics; drugs that specifically inhibit molecules or pathways that are 

often activated in cancer. Nevertheless, it remains poorly explained why a significant 

number of tumors do not respond to these therapies. We aim to elucidate the 

molecular pathways that contribute to unresponsiveness to targeted cancer 

therapeutics using a functional genetic approach. This will yield biomarkers that may 

be useful to predict how individual patients will respond to these drugs. 

Furthermore, this work may allow the development of drugs that act in synergy with 

the established drug to prevent or overcome drug resistance. To identify biomarkers 

that control tumor cell responsiveness to cancer therapeutics, we use multiple 

complementary approaches. First, we use genome wide loss-of-function genetic 

screens (with shRNA interference libraries) in cancer cells that are sensitive to the 

drug-of-interest to search for genes whose down-regulation confers resistance to the 




drug-of-interest (resistance screens). In addition, we use shRNA screens with a low 

dose of the drug to screen for genes whose inhibition enhances the toxicity of the 

cancer drug (sensitizer screens). As a third approach, we use gain of function genetic 

screens in which we search for genes whose over-expression modulates drug 

responsiveness. Once we have identified candidate drug response biomarkers in relevant 

cell line models, we ask if the expression of these genes is correlated with clinical 

response to the drug-of-interest. For this, we use tumor samples of cancer patients 

treated with the drug in question and whose response to therapy is documented. In a 

fourth and distinct approach we perform high throughput sequencing of the “kinome” 

(some 600 genes) of tumor samples to identify connections between cancer genotype 

and drug responses Examples of these approaches to identify biomarkers of response to 

different cancer drugs will be presented. 


31IN THE ROLE OF MOLECULAR IMAGING IN EARLY DRUG 

DEVELOPMENT 

K. Muylle 

Nuclear Medicine, Institut Jules Bordet, ULB, Brussels, BELGIUM 

Molecular cancer biology revealed an ever-increasing number of disease regulating 

intracellular and extracellular tumour targets. These new insights in the pathogenesis 

of tumor cells have lead to the development of a broad range of targeted therapeutic 

agents. In cancer, few targets have been identified that cover all types of cancer from 

a given site of origin. Hence, patient selection by molecular characterization of 

disease subtype in an individual patient becomes increasingly important in order to 

avoid unnecessary toxicity, improve patient outcome and reduce the costs for clinical 

trials. Biomarkers are objectively measured indicators of biological and pathogenic 

processes and can be used to predict patient outcome (regardless of therapy), to 

predict response to specific therapies and for response assessment (monitoring). The 

advantages of imaging biomarkers over those that require a biopsy sample include 

non-invasiveness, the ability to quantify cellular targets for the entire disease burden, 

and thereby to avoid the sampling error that can occur with heterogeneous receptor 

expression and the potential for serial studies of the in vivo effects of a drug on the 

target. In terms of drug development, predictive imaging biomarkers have a high 

potential for reducing costs of clinical trials, as they can be used for enriching patient 

selection by assessing drug targeting and/or early-on response prediction. The scope 

of this presentation is to highlight the potential of molecular imaging in drug 

development, illustrated by examples where molecular imaging has been 

implemented in clinical trials. 


32IN CONCLUSIONS AND PERSPECTIVES 

A. Awada 

Department of Medical Oncology, Institute Jules Bordet, Brussels, BELGIUM 

Early clinical drug development in cancer included mainly the phase I program 

(aims: DLTs and recommended doses) and early phase II studies (aim: antitumor 

activity). In the era of molecular biology and the development of targeted agents, the 

frontier between these phases became less visible. Individualizing the early drug 

development process (from study design to patient/tumor selection) has lead to more 

patient benefit as recently illustrated in several commom and orphan solid tumors. 

This paradigm shift will be intensified in the near future by better patient selection, 

molecular target discovery, anticancer drugs selectivity, deeper understanding of the 

biology of the tumors and mechanisms of sensitivity/resistance and the emerging role 

of molecular imaging to “map” the tumor and to document as early as possible the 

tumor progression to the costly new anticancer agents. All these issues will be 

developed by colleagues in this special symposium. My task will be to conclude and 

to present some perspectives. These will be based among others on the development 

of new technologies, the understanding of the behaviour of primiray tumors and 

metastases and the integration of biological and technological advances into early 

clinical research investigation of new targeted agents. 


Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds374 | ix33

abstracts 

how can medical oncologists deal with 

the new wave of genetic information 

about their patients? 

33IN CHALLENGES OF DEALING WITH NEXT GENERATION 

SEQUENCING FOR HEREDITARY CANCER IN CLINICAL 

PRACTICE 

K. Claes 

Center for Medical Genetics, Ghent University Hospital, Ghent, BELGIUM 

Next generation sequencing is one of the most significant technological advances in 

the biological sciences of the last 20-30 years. These recent advances have brought a 

paradigm shift in how medical researchers investigate both rare and common 

disorders. The ability to generate enormous amount of sequence data in a short time 

at an affordable cost makes this approach ideal for a wide range of applications from 

1) sequencing a panel of genes associated with a particular disease, 2) all coding 

regions (« exome sequencing ») to 3) the entire human genome. However, while the 

technology promises to reduce the cost of sequencing an entire human genome to 

less than US$1000, one must question the diagnostic utility of complete genome 

sequencing for routine clinical testing, given the many interpretive challenges posed 

by this approach. Knowing that in 5-6% of the breast cancer patients analysed for the 

coding regions of BRCA1/2 variants of unknown clinical significance (VUS) are 

identified, several thousands of VUS are being found by whole exome sequencing 

whereby the coding region of more than 20,000 genes are investigated. These, 

individually rare, VUS potentially have a negative impact on the individual 

concerned as they create greater uncertainty. Currently, large scale implementation of 

functional assays is not a realistic option in diagnostic settings. Therefore, at present, 

to our opinion, for familial cancer syndromes, it appears that next-generation DNA 

sequencing may provide the greatest benefit to routine clinical testing by enabling 

comprehensive multigene panel sequencing. This should provide an advantage over 

traditional Sanger-based sequencing strategies while limiting the total test output to 

sets of genes with known diagnostic value. The finding of a deleterious mutation in 

such genes guarantees the patient the possibility of adequate clinical management 

and follow up according to (international) established guidelines. 

During the presentation we will discuss the current and near future state of clinical 

testing approaches for the best known and most frequent familial cancer syndromes 

and explore what (bioinformatic, quality control metrics and other) challenges must 

be addressed in order to extract diagnostic value from whole-exome and 

whole-genome sequencing for hereditary cancers. 


34IN IS IT NECESSARY TO SCREEN EVERYBODY FOR INHERITED 

CANCER? WHEN, WHY AND HOW 

E. Levy-Lahad 

Shaare Zedek Medical Center, Hebrew University Medical School, Medical 

Genetics Institute, Jerusalem, ISRAEL 

Individuals who inherited mutations conferring high cancer risks should ideally be 

identified before they ever develop cancer. Such mutation carriers stand to reap the 

greatest benefit from surveillance and prevention measures. This begs the question of 

the optimal means of identifying such carriers. Currently, carriers are usually 

identified after they have already been diagnosed with cancer, representing a lost 

opportunity for prevention, or through a family history of cancer. Identification of 

carriers based on family history is limited by sufficient family size, sufficient 

information on family history of cancer, and familial communication about cancer 

diagnoses, and especially about results of genetic testing. We will present data on 

BRCA1/BRCA2 testing in the general Ashkenazi (European) Jewish population, 

which has common BRCA1/BRCA2 mutations, as a model for comprehensive 

genetic screening. In particular, we will discuss our findings that approximately half 

of BRCA1/BRCA2 families do not have significant family history, so that many 

carriers would not be identified without a general screening program. There are both 

technical and ethical challenges to such an approach, and these will be discussed. 


35IN HOW CAN CANCER RISK AND GENETIC PREDICTION 

MODELS HELP ONCOLOGISTS IN THE CLINICS? 

D.G.R. Evans 

Regional Genetic Service, St Mary’s Hospital, Manchester, UNITED KINGDOM 

There are two forms main outputs of risk prediction models. These are the likelihood 

of a patient harbouring a mutation in a cancer predisposition gene and the likelihood 

of developing specific cancers. Whilst there are a number of these models for 

different cancer types, the most well developed area is that of breast cancer. An 

oncologist treating a breast cancer patient may be influenced in discussing treatment 

options by future risks of contralateral breast cancer and ovarian cancer. Entry into 

treatment trials such as those of targeted treatments with PARP inhibitors may also 

be influenced by genetic testing for BRCA1 and BRCA2. Finding a mutation in 

BRCA1/2 may also influence treatment choices including risk reducing surgery. 

Outputs of genetic risk for BRCA1/2 will usually drive the offer of mutation 

screening if the likelihood exceeds 10% although this is currently 20% in the UK. 

Models include computer based: BRCAPRO, BOADICEA, Tyrer-Cuzick and paper 

scoring systems such as the Manchester system. There have been numerous 

validations of the models which show that they all perform reasonably well. The 

breast cancer risk element is most used for unaffected women and in the context of 

family history have only really been validated through one study where the 

Tyrer-Cuzick model was the best performer. Incorporation of genetic testing 

information from Single Nucleotide Polymorphisms (SNPs) and mammographic 

density is likely to improve the precision of these models in the near future. 


36IN NEW TREATMENT APPROACHES IN HEREDITARY CANCER: 

THE ROUTE TOWARDS PERSONALIZED CARE 

E. Vilar 

Department of Clinical Cancer Prevention, U.T. - M.D. Anderson Cancer Center, 

Houston, TX, UNITED STATES OF AMERICA 

Patients diagnosed with tumors arising on the basis of hereditary cancer syndromes 

represent a relatively small fraction from the total of cancer cases. However, the 

risks to develop different types of tumors among carriers highlight the need to 

develop surveillance strategies and preventive interventions to decrease the burden 

of cancer in this population. The specific molecular characteristics displayed by 

these tumors make them ideal candidates to identify new targets and implement 

not only personalized cancer treatments but also targeted chemoprevention 

strategies. In addition, hereditary tumors have served as a model to gain further 

knowledge in the molecular biology of cancer and to develop targeted drugs. 

The best example in this context is the case of PARP inhibitors and breast and 

ovarian tumors arising in families diagnosed with Hereditary Breast and Ovarian 

Cancer Syndrome (BRCA 1 and 2 mutations). In this presentation we will review 

the most recent research advances on target identification and drug development 

for hereditary cancer syndromes with a special emphasis in hereditary 

gastrointestinal cancers. 


37IN CONCLUSIONS AND PERSPECTIVES 



R. Catane 

Division of Oncology, Chaim Sheba Medical Center, Ramat Gan, ISRAEL 

The aim of this session was to familiarize practicing oncologists with the concept of 

modern genetics and its implication for the daily practice. As busy oncologists, we 

are inundated with information, and unfortunately the important new genetic facts 

related to oncology are frequently presented with code words and acronyms, that 

make the information unusable. It is hoped that such regular session, in which expert 

geneticist would give us the needed genetic knowledge, coupled with “user’s manual”, 

will make us better medical oncologists. Moreover, we will be able to pass on the 

required information to our patients, and be in a vantage position to present them 

the oncology guidelines. 




pursuing the ned condition in stage iv 

colorectal cancer 

38IN WHEN TO THINK OF SURGERY PLUS OR MINUS HIPEC 

FOR PERITONEAL CARCINOMATOSIS 

D. Elias 

Department of Surgical Oncology, Institut Gustave Roussy, Villejuif, FRANCE 

The occurrence of PC considerably worsens the prognosis of cancers. The classic 

treatment yields an overall survival of below 5% at 5years. However, in 20% of the 

cases, the disease is exclusively peritoneal, and a treatment combining complete 

cytoreductive surgery (CCRS) plus hyperthermic intraperitoneal chemotherapy 

(HIPEC) has made it possible to achieve a major increase in 5-year overall survival. 

HIPEC is only proposed for treating residual infra-millimetric,PC and therefore, is 

logical and useful exclusively after CCRS. The current appropriate indications are as 

follows: For peritoneal pseudomyxomas (5-year OSR is above 80%). For colorectal 

PC (5-year OSR exceed 40%, with 18% of patients definitively cured). For 

mesotheliomas (the 5-year OSR is close to 58%) Current doubtful indications are as 

follows: For gastric tumours (the 5-year OSR is close to 15%). For ovarian cancers 

(OSR are very low when CCRS + HIPEC is used as a salvage treatment). For few rare 

PC (not detailed). 

Conclusion: CCRS + HIPEC are the current gold standard therapy for peritoneal 

extension of pseudomyxoma, mesotheliomas and colorectal PC, for selected patients. 


39IN PRIORITIZING LIVER DIRECTED THERAPIES: SURGERY PLUS 

MINUS ABLATIVE TECHNIQUES 

T.J.M. Ruers 

Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, 

NETHERLANDS 

Background: In patients with unresectable CRC LM there is an increasing tendency 

to combine systemic chemotherapy (CT) with local tumour destruction by RFA. 

Many retrospective studies indicate a possible benefit of this approach but definite 

proof was only obtained recently. 

Methods: In a randomised phase II intergroup study conducted by the EORTC 

the benefits of adding RFA to systemic CT was evaluated in patients with ≤9 

unresectable CRC LM and no extrahepatic disease. Between 2002 and 2007, 

119 pts were randomised between CT alone (59) or RFA plus CT (60) In 

both arms, CT consisted of 6 months FOLFOX (oxaliplatin 85mg/m2 and 

LV5FU2) plus, since October 2005, bevacizumab. The primary objective was to 

exclude a 30-months overall survival (OS) rate ≤38% with RFA + CT 

(Fleming Design). Safety and progression free survival (PFS) were secondary 

endpoints. 

Results: Baseline characteristics were similar between arms: 60% had ≥ 4 LM. 51 

patients (85%) received CT in the RFA + CT arm and 59 (all) in the CT arm. The 

median number of CT cycles for patients who started CT was 10 in both arms. 

Toxicity profiles for CT were comparable between both arms. At a median follow up 

of 4.4 years, the 30-month OS rate was 61.7% (95% CI, 48.21-73.93) in the RFA +CT 

arm and 57.6% (44.07 – 70.39) in the CT arm. In eligible patients (RFA + CT; 57 pts, 

CT; 58 pts) these figures were 64.9% (95% CI, 51.13 – 77.09) and 56.9% (43.23 

-69.84), respectively. The median PFS was 16.8 months in the RFA + CT arm (95% 

CI, 11.7-22.1) and 9.9 months (9.3-13.7) in the CT arm (p = 0.025). The number of 

patients with first recurrence at the RFA site only was 5 (9%). 4 more patients (7%) 

had a first recurrence at a RFA site in combination with a recurrence elsewhere in 

the liver. In total 11 lesions (in 9 pt) out of 170 lesions treated by RFA recurred 

locally at first progression (6.5%). 

Conclusion: The EORTC CLOCC study is the first study that prospectively 

investigates the efficacy of RFA in combination with CT. The primary endpoint 

(30-months OS > 38%) was met, although also 30 months OS in the CT arm 

was much higher than 38%. RFA in combination with systemic therapy resulted 

in a significant prolongation of PFS of nearly 7 months. Local control of the 

lesions treated by RFA was high (93.5%). The study was not powered for OS. 



Longer follow-will have to be awaited to eventually assess the effect of RFA 

on OS. 


40IN INTEGRATING LIVER DIRECTED THERAPIES SUCH AS 

EMBOLIZATION AND IMRT INTO SYSTEMIC TREATMENT 

D. Arnold, A. Stein 

Medical Oncology, Hubertus Wald Tumor Center, University Cancer Center 

Hamburg (UCCH), Hamburg, GERMANY 

Metastatic colorectal cancer confined to the liver is a distinct entity characterized by 

different prognosis and a broad variety of available local treatment approaches. 

Beneath the classical, albeit continuously developed approaches like surgery, radio 

frequency ablation (RFA) and transarterial chemoembolization (TACE), local 

radiotherapy (delivered either by conventional, intensity modulated (IMRT) or 

stereotactic techniques (SBRT)) or selective intraarterial radiotherapy (SIRT) have 

been established in the last years. However, spread to the liver - even without 

extrahepatic manifestation - is the expression of systemic disease and thus urges for 

systemic control besides local ablation of existing metastases. For example, in liver 

metastases of mCRC, combination of systemic therapy and surgery or RFA has 

demonstrated beneficial impact. The sequence of systemic and local treatment is not 

well defined yet. Although individual patients tumour characteristics will strongly 

impact the choice of upfront treatment approach (e.g. single small metastases after a 

long disease free interval versus “upfront” large manifestations with high tumour 

burden), upfront systemic treatment followed by local treatment and postprocedural 

systemic treatment if feasible may generally bear several benefits: beside prompt 

control of systemic disease and potential extrahepatic spread, an interval with 

systemic chemotherapy will provide information about biology of metastatic cancer 

(e.g. rapid progression during chemotherapy) and will furthermore enable a more 

tailored approach for remaining lesions after treatment induced tumour shrinkage. 

Therefore, current treatment approaches for localized liver metastases are using 

sequential either neoadjuvant or periprocedural systemic and local treatment (e.g. 

RFA or surgery) or a concomitant approach with systemic treatment and local 

ablation in given intervals (e.g. TACE). Some local treatment approaches (e.g. SIRT 

or TACE) have demonstrated efficacy in malignant disease refractory to 

chemotherapy, but the possibly greater impact in earlier disease settings combined 

with or after systemic treatment have not been elucidated yet. Further research will 

need to determine the optimal combination and timing of local and systemic 

treatment approaches. 

Disclosure: D. Arnold: has received honoraria from Roche, sanofi-aventis, Merck 

Serono and Amgen, and research support from Roche and sanofi-aventis. A. Stein: 

received honoraria from Roche and Merck Serono 

41IN PURSUING THE NED CONDITION IN ADVANCED COLORECTAL 

CANCER: IMPLICATIONS FOR CLINICAL PRACTICE AND 

TRIAL DESIGN 

A. Sobrero 1 , A.A. Cogoni 2 

1 Oncologia Medica, IRCCS AOU San Martino - IST-Istituto Nazionale per la 

Ricerca sul Cancro, Genova, ITALY, 2 Medical Oncology, “SS. Annunziata” 

Hospital, Sassari, ITALY 

Cure is the most relevant endpoint in cancer treatment. Next comes OS followed 

by DFS. Cure actually transits through DFS of sufficiently long duration to assure 

no relapse. Hence the value of DFS and its link to cure. The appeal of getting a 

NED state is so strong just because of this link. However its clinical value is 

dependent upon two factors: the toxicity of the multimodal intervention and the 

duration of the NED state. If the absence of disease lasts 12 months, giving the 

patient the hope for cure during this period, anybody may consider this a 

meaningful result; but if RFS lasts only 4 months and the “toll” paid by the 

patient has been substantial, this is clearly an irrelevant benefit. The heart of the 

issue is that whenever a treatment has the potential of rendering the patient 

NED, we should consider it, but at the same time we should not be deceived by 

this perspective if the chances of benefit are too remote, as it is in the great 

majority of cases. Therefore our strategic choice towards aggressive programs 

should not be guided by eradicating all visible tumor deposits (technical 



abstracts

feasibility), but by how high the chances are of obtaining a DFS of at least 6-12 

months. There are a series of concepts and data guiding us between what is 

technically feasible and what is oncologically sound. First, curability of stage IV 

may be as high as 50% in very selected case series, but in unselected cases 

curability is extremely low, 1 to 4% in non-dedicated randomized trials. Second, 

whenever we “push” for very extensive surgery, the median RFS is < 12 and 

sometimes < 6 months. Third the disease might accelerate its course under the 

“shower” of wounds–related growth factors. Fourth, toxicity and costs of these 

approaches are very high. The contrast between the appeal (and sometimes 


strong benefit) of the NED state and the questionable clinical value of this 

condition, when short lived, has implications on both clinical practice and the 

design of clinical trials. Wrong deviations from the classical palliative systemic 

treatment, pursuing miraculous results, but actually promoting clinical 

deterioration, are the most common consequences of these approaches in 

practice. Very high originality and relevance, but low intrinsic and external 

validity of the results are the classical features and limits of the trials designed 

andconductedinthisfield. 



from biology to treatment in advanced 

pancreatic and gastroesophageal 

cancer 

42IN TUMOR MARKERS AND BIOLOGY IN PANCREATIC CANCER 

M.A. Tempero 

Hematology / Oncology, University of California, San Francisco, CA, UNITED 

STATES OF AMERICA 

As we move forward into precision medicine, biomarkers will be required to define 

critical targets or to distinguish the diverse components of all cancers. Using 

biomarkers in therapeutic strategies has been very successful for many malignancies, 

especially breast cancer, lung cancer, and hematologic malignancies. Many barriers 

exist for similar applications in pancreatic ductal adenocarcinoma. First, the unusual 

aggressiveness of this malignancy overall, suggests that the diversity in this disease is 

constrained within a more narrow spectrum. Second, until recently, drug therapy has 

been only minimally effective in this disease. Finally, because so few patients proceed 

to resection and diagnosis is often made on scant fine-needle aspirates, access to 

tissue has been limited. However, this landscape is changing. Studies show that there 

are distinct metastatic patterns which may be governed by early genetic aberrations. 

In addition, genetic subclasses exist which, when evaluated in available human cell 

lines, also track with varying sensitivity to available chemotherapy. New 

chemotherapy combinations, albeit with more traditional cytotoxic drugs, are 

producing striking improvements in survival, even in the setting of metastatic 

disease. New and more successful treatments, such as FOLFIRINOX and selected 

gemcitabine combinations, provide more options and enlarge the playing field for the 

introduction of targeted therapeutics. This also brings the importance of clinically 

actionable biomarkers to the foreground. As this story unfolds, attention must be 

given to the importance of building biorepositories from primary and secondary 

tumor sites, with associated germline DNA and providing clinical annotation for the 

specimens. As technology improves and the cost of genomic sequencing decreases, 

we can expect a dramatic escalation in our understanding of the critical biologic 

pathways amenable to therapeutic intervention 


43IN POTENTIAL CLINICAL APPLICATION AND TRIALS 

S. Cascinu 

Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università Politecnica 

delle Marche, Ancona, ITALY 

Ductal pancreatic adenocarcinoma remains a disease with dismal prognosis and 

several treatment approaches resulted in disappointing results. A better knowledge of 

molecular pathways involved in its development are mandatory in order to improve 

therapeutic results. Infact, though a model for the development of pancreatic 

adenocarcinoma has been proposed some years ago, this is not able to explain the 

role of stroma as well as which pathways could be effectively druggable. Furthermore, 

the results of clinical trials with biological agents (tipifarnib, cetuximab, 

bevacizumab, axitinib, sorafenib) are really disappointing. Therefore, biological 

characterization of ductal pancreatic adenocarcinoma may help to identify new 

pathways in order to select the best treatment for each patient. We should consider 



ductal adenocarcinoma as an heterogeneous disease probably due to the different 

pathogenesis: chronic inflammatory disease, mucinous tumors, hereditary tumors, 

resulting in different specific genetic alterations. The knowledge of these alterations 

may allow the identification of subgroups as well as the definition of specific 

treatment approaches. An assessment of potentially relevant pathways and how to 

inhibit them will be presented. 


44IN TUMOR MARKERS AND BIOLOGY IN GASTROESOPHAGEAL 

CANCER 

M. Ebert 

Medicine II, Universitätsklinikum Mannheim, Mannheim, GERMANY 

Most patients with gastric cancer present with advanced disease. In these cases either 

multimodal therapy or palliative treatment is required. In most cases patients with 

locally advanced gastric cancer undergo neoadjuvant therapy and resection. In cases 

with distant metastasis palliative chemotherapy is given. While many patients show 

treatment response, in most patients cancers progress and change of treatment lines 

is required. Therefore, predicting treatment response in neoadjuvant and palliative 

chemotherapy is of special interest. While different molecular markers of treatment 

response have been described in various cancer, so far for esophageal and gastric 

cancer molecular response predictors are not well established. In some cases HER2/ 

neu testing has shown additional value in combining chemotherapy with 

trastuzumab. However, molecular response predictors in Her2/neu positive cases are 

also lacking. Interestingly, recent data from breast cancers have shown that activation 

of src may mediate resistance to trastuzumab. Inasmuch as targeting of active src 

could be option to resensitize breast cancers to trastuzumab these studies need to be 

conducted in gastric cancers. Our own studies indicate that the inhibition of histone 

deacetylases may sensitize gastric cancers cells to epirubicine, which may also help to 

further individualize chemotherapy in gastric cancer. 


45IN CLINICAL TRIALS WITH BIOLOGICAL ENDPOINTS 

A.D. Roth 

Oncology, University Hospitals of Geneva, Geneva, SWITZERLAND 

Neoadjuvant chemotherapy or radiochemotherapy is a modality increasingly applied 

in the curative treatment of cancers of the esophagus and of the stomach. Complete 

pathological response (pCR) obtained after neoadjuvant therapy of esophageal cancer 

is an indicator of good prognosis (up to 70% at 5 years). However, a mean for earlier 

assessment of the efficacy of neoadjuvant therapy allowing to change regimen in case 

of no response or to go directly to surgery would be extremely welcome. Based on 

early reports of early extinction of PET-CT scan uptake in case of good response to 

chemotherapy in several tumor type, the MUNICON trial investigated this biological 

endpoint in esophageal cancer showing a fairly good correlation between PET-CT 

extinction and pathological response. Several trials aiming at the validation of these 

data have been started or are in preparation both in Europe and in the US. The 

strength and the weaknesses of this approach shall be discussed during this 

presentation. 




abstracts

abstracts 

re-inventing the medical treatment 

of advanced prostate cancer 

46IN IMMUNOTHERAPY FOR ADVANCED PROSTATE CANCER 

P.W. Kantoff 

Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, UNITED STATES 

OF AMERICA 

While the concept of immunotherapy for cancer has been proposed for many years, proof 

of principle did not exist. In the context of prostate cancer, the allogeneic cell based agent, 

GVAX has been tested. GVAX consists of a platform of irradiated hormone sensitive 

(LNCaP) and hormone resistant (PC-3) prostate cancer cell lines transduced with a 

replication-defective retrovirus bearing GM-CSF. Unfortunately, two phase III studies in 

men with metastatic castration resistant prostate cancer (CRPC) failed to demonstrate a 

survival advantage. More recently, the improved survival observed with sipuleucel-T, an 

autologous antigen presenting cell (APC)-based agent, for the treatment of patients with 

metastatic CRPC supports immunotherapy as a valid approach for this disease. 

Sipuleucel-T uses a fusion antigen of prostatic acid phosphatase and GM-CSF. Evidence 

exists to support activation of APCs and T cells in an antigen specific fashion and that the 

degree of activation correlates with overall survival. PROSTVAC-VF TRICOM, a poxvirus 

vector based PSA antigen targeted vaccine showed promising results in a randomized 

Phase II study and is now being tested in a international Phase III study. The CTLA-4 

inhibiting human monoclonal antibody, ipilimumab, has extended survival in advanced 

melanoma. Early phase I clinical trials of ipilimumab have yielded clinical and PSA 

responses in advanced CRPC. A Phase I/II trial was conducted using ipilimumab 10 mg/ 

kg every 3 weeks x 4 with or without prior priming by single fraction of radiation to a 

metastatic bony site. Results were promising enough to launch 2 phase III clinical trials in 

men with metastatic CRPC who were either chemo-naive or following prior 

chemotherapy. The outcomes of these 2 studies are pending. 

Disclosure: P.W. Kantoff: Amgen USA consultant (con), Bayer con, Bellicum con, 

BIND Biosciences SAB, BN Immunotherapeutics con, Celgene DSMB, Dendreon 

con, Genetech con, Progenics Pharmaceuticals con, Janssen con, Takeda/Millenium 

DSMB, Oncogenex DSMB, Tokai con 

47IN HOW SHOULD WE USE CYTOTOXIC CHEMOTHERAPY IN THE 

TREATMENT OF CASTRATION-RESISTANT PROSTATE 

CANCER? 

O. Sartor 

Department of Medicine: Section of Hematology & Medical Oncology and 

Department of Urology, Tulane Cancer Center, New Orleans, LA, UNITED 


The recent incremental advances in metastatic castrate-resistant prostate cancer 

(mCRPC) may one day translate into more meaningful change. Today mCRPC 

therapeutic choices are a sequential series of affairs with several either/or decisions. 

Optimal sequencing is unstudied and endless speculation abound as to which drug is 

best best for which patient. Combination therapies are in their infancy. In the past, 

the world of mCRPC was conveniently divided into the pre- and post-docetaxel 

space. That being said, the biologic basis for this was lacking and now we have new 

spaces such as the post-abiraterone/MDV3100 space that might in fact be more 

biologically meaningful. What do we do with patients progressing post-abiraterone or 

MDV3100? The data are sparse to date and so we gear up with new studies and read 

tea leaves in the interim. What is the role for cytotoxic chemotherapies today’s 

mCRPC therapeutic armamentarium? The new hormonal therapies are now 

marching forward with provovative data in the “pre-chemotherapy” space. Novel 

immunotherapies have seized imaginations. The new world of truly active 

bone-targeted radiopharmaceuticals has arrived. Several facts seem clear. 1) the 

newer hormonal therapies are not effective for very long in mCRPC and after they 

fail, the progression rate can be very rapid. Exotic new molecular mechanisms of 

resistance are discovered with regularity; the CRPC cells are truly devious little 

Darwinian machines. 2) Today, death from prostate cancer is a foregone conclusion 

for mCRPC patient. So does this help us answer how we use cytotoxic chemotherapy 

today? Perhaps it si reasonable to point out that both docetaxel and cabazitaxel are 

clearly active agents and that some but not all patients will tolerate them well. 

Currently many men die from prostate cancer without having had the opportunity to 

benefit from known active agents. The best responses to chemotherapy, as with any 

agent, occur in patients with the best performance status. The concept that therapies 

of lesser toxicity should be administered first is appropriate but the concept that 



active therapies should be on the shelf when treating an incurable disease is not. 

Striving for patients to receive as many active therapies as feasible seems reasonable 

in an era when predicting therapeutic response is more art than science. 

Disclosure: O. Sartor: Investigator and consultant for Algeta, Bayer, JNJ, Sanofi, and 

Dendreon. Consultant for Medivation and Astellas. 

48IN INTEGRATING NOVEL ENDOCRINE THERAPIES: SEQUENTIAL 

OR CONCOMITANT TREATMENT? 

J.S. de Bono 

Division of Cancer Therapeutics, Institute of Cancer Research Royal Marsden 

Hospital, Sutton, UNITED KINGDOM 

Prostate cancer progression is associated with continued androgen receptor (AR) 

activation despite treatment with castration and/or currently available anti-androgens. 

Abiraterone, a rationally- designed inhibitor of CYP17A1 has been recently approved 

for the treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is 

often effective, but requires co-administration with glucocorticoids to curtail side 

effects. Enzalutamide (MDV3100) is a novel AR antagonist that effectively blocks AR 

signaling when currently available AR antagonists are unable to do this and has shown 

impressive antitumor activity and a similar impact on overall survival as abiraterone. 

We now report that these two drugs in combination may be superior to either drug 

alone. We have hypothesized that progressive disease on abiraterone may occur 

secondary to glucocorticoid-induced activation of mutated AR. We also found that 

prednisolone plasma levels in CRPC patients were sufficiently high to activate mutant 

AR. Mineralocorticoid receptor antagonists, such as spironoloactone and eplerenone 

that are used to treat side-effects related to mineralocorticoid excess, also bound to and 

activated signaling through both wild-type and mutant AR. Activation of mutant AR 

was inhibited by MDV3100, bicalutamide or greater concentrations of abiraterone. 

Moreover, higher androgenic steroid concentrations resulted in decreased enzalutamide 

antitumour activity. Together, our findings provide a strong rationale for the clinical 

evaluation of combined CYP17A1 inhibition and AR antagonism by enzalutamide. 

Disclosure: J.S. de Bono: I am an employee of The Institute of Cancer Research that 

has a commercial interest in abiraterone. I have served as an advisor for J&J, 

Medivation, Astellas and Takeda. 

49IN HOW SHOULD WE UTILIZE BONE TREATMENTS: 

BISPHOSPHONATES, DENOSUMAB AND RADIUM-223 

C. Parker 

Academic Urology, Royal Marsden Hospital NHS Foundation Trust, Sutton, 


How should we utilize bone treatments: Bisphosphonates, denosumab and 

radium-223? Bone metastases are a prominent feature of CRPC, and can lead to 

significant skeletal-related events (SREs) such as spinal cord compression, 

pathological fracture, and the need for surgery or external-beam radiotherapy. 

Zoledronate, a bisphosphonate, reduces the risk of SREs (1) and has been widely, 

although not universally, regarded as a standard treatment for metastatic CRPC. 

More recently, denosumab, an antibody targeted at the RANK-ligand, has shown 

greater efficacy for SRE prevention with an acceptable toxicity profile (2), and has 

also been licensed for use. Radium-223, a bone-targetted alpha emitter, has been 

reported not only to reduce the risk of SREs, but also to improve overall survival. 

Although radium-223 is the first bone-targetted agent to improve overall survival in 

CRPC, it is not yet licensed for clinical use. I will review the clinical trial data 

concerning these bone-targetted agents in CRPC, and give my personal view as to 

how they should be used. 

References 1. A randomized, placebo-controlled trial of zoledronic acid in patients 

with hormone-refractory metastatic prostate carcinoma. Saad F, Gleason DM, Murray 

R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B; 

Zoledronic Acid Prostate Cancer Study Group. J Natl Cancer Inst. 2002 Oct 2;94 

(19):1458-68. 2. Denosumab versus zoledronic acid for treatment of bone metastases 

in men with castration-resistant prostate cancer: a randomised, double-blind study. 

Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, 

Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C. Lancet. 2011 Mar 5;377 

(9768):813-22. 3. Overall survival benefit of radium-223 chloride (Alpharadin) in 

the treatment of patients with symptomatic bone metastases in castration-resistant 

prostate cancer (CRPC): A phase III randomized trial (ALSYMPCA). C. Parker, 

D. Heinrich, J.M. O’Sullivan, S. Fosså, A. Chodacki, T. Demkow, A. Cross, B. Bolstad, 

J. Garcia-Vargas, and O. Sartor. Eur J Cancer 47:Supp 2, Sept 2011 p3 

Disclosure: C. Parker: Advisory board membership for Amgen, BMS, Bayer, 

Dendreon, Janssen and Takeda 



molecular answers and targets 

on the horizon for the treatment 

of genitourinary malignancies 

50IN GENES, CHROMOSOMES AND THE TREATMENT 

OF BLADDER CANCER 

J.E. Rosenberg 

Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, 

New York, NY, UNITED STATES OF AMERICA 

Molecular analysis of bladder cancer is transforming our understanding of this 

disease. The relative abundance of bladder tumor tissue from these patients due to 

frequent resections provides a major opportunity to understand the molecular 

pathogenesis. Non-muscle invasive bladder cancer tends to be characterized by 

oncogenic activation events (FGFR3 mutation, PIK3CA mutation), while muscle 

invasive bladder cancer is more associated with tumor suppressor gene inactivation 

(p53, Rb). DNA copy number analysis identifies multiple regions of recurrent 

chromosomal gains and losses, many of which delineate known oncogenes and 

tumor suppressor genes. High-throughput analysis of bladder cancer specimens is 

identifying multiple new targets that may be therapeutically tractable in subsets of 

patients, including Her2 overexpression and amplification, b-raf mutation, and TSC1 

mutation. The clinical implications of the molecular events in bladder cancer have 

yet to be identified. Large-scale genomic efforts linking clinical data to outcome 

should lead to an improved understand of the molecular landscape of bladder cancer. 

Next-generation sequencing technologies are allowing the rapid assessment of 

molecular alterations, which may lead to clinical trials enriched for patients whose 

tumors contain druggable alterations. To capitalize on the genomic knowledge 

gained in bladder cancer, reliable molecular tests that are accepted by regulatory 

authorities, along with targeted agents aimed at actionable alterations are, need to 

break out of the current therapeutic stalemate. Trials targeting some of these novel 

alterations are beginning to enroll patients. 

Disclosure: J.E. Rosenberg: 1. Imclone- research funding 2. Oncogenex- consulting 

3. Boehringer-Ingelheim- consulting 4. GSK- research funding 5. Novartis- research 

funding 

51IN GENOMICS IN RENAL CANCER: FROM SCIENCE 

TO CLINICAL PRACTICE 

B.T. Teh 

Director and Principal Investigator, Nccs-vari Translational Research Laboratory, 

National Cancer Centre Singapore, Singapore, SINGAPORE 

Approximately 290,000 new cases of renal cell carcinoma (RCC) are diagnosed each 

year worldwide and 102,000 deaths. It is a morphologically, and genetically 

heterogenous disease with distinct underlying molecular mechanisms in each 

subtype. In this lecture, the evidence of this molecular heterogeneity with more 

recent discoveries will be presented and discussed. For example, we have recently 

identified the frequent mutations of PBRM1, a member of the SWI-SNF complex, in 

clear cell RCC (the most common type of RCC) and a lesser degree of mutations in 

a group of histone modifiers. This has opened up a new field of investigations, from 

basic biology to clinical implications. In addition, we also demonstrated the 

involvement of LRRK2, a gene associated with early-onset Parkinson’s disease, in 

papillary type 1 RCC (second most common type of RCC) and its interaction with 

c-MET, a gene that has been previously implied in this subtype of tumors. We have 

also recently discovered a novel metabolic pathway that is integral to the 

tumorigenesis of papillary type II (an aggressive type of papillary tumor). All these 

present new opportunities for further investigations to establish their biological and 

therapeutic roles in RCC. 




52IN SIGNALING PATHWAYS, MECHANISMS OF RESISTANCE 

AND TREATMENT DECISIONS IN RENAL CELL CANCER 

G. Tortora 

Medical Oncology, University of Verona Policlinico Borgo Roma, Verona, ITALY 

Renal cell cancer (RCC) is a highly vascularised disease and angiogenesis plays a 

critical role in tumor growth and spreading. For this reason, the main angiogenic 

pathways, involving the Vascular endothelial growth factors (VEGFs), the VEGF 

receptors (VEGF-Rs), and the mammalian target of rapamycin (mTOR) are the 

targets of drugs that have dramatically improved the outcome of patients affected by 

this disease. An increasing number of active agents directed against the above targets 

and other angiogenesis-related proteins, including the Fibroblast growth factors 

(FGFs) and their receptors (FGF-Rs), is now available. However, a biologically-based 

therapeutic algorithm is still missing and the onset of drug resistance and the lack of 

validated biomarkers predictive of response to single agents and, more in general, to 

antiangiogenic drugs, do not allow to take full advantage of the therapeutic options 

available. Interlukin 8 (IL-8) and FGF seem to play a role in the induction of 

resistance to TKIs. IL-8 overexpression is associated to resistance to sunitinib and 

IL-8 gene polymorphisms correlate with survival in patients treated with pazopanib. 

Increases in the FGF/FGF-Rs signalling is observed as escape to inhibition of the 

VEGF-Rs by TKIs. On the other hand, activation of the PI3K/Akt pathway is 

responsible for the onset of resistance to mTOR inhibitors. Several studies are now 

extensively analyzing the predictive value of a variety of angiogenesis-related 

biomarkers, including soluble VEGF and VEGF-Rs, IL-8 expression and secretion, 

polymorphisms of VEGF and IL-8 genes, and VHL mutations. In addition imaging 

techniques are also under evaluation as promising dynamic biomarkers of 

antiangiogenic drugs activity or resistance in RCC. A better understanding of the 

mechanisms of resistance and the validation of reliable biomarkers predictive of drug 

activity or resistance will help to select patients who can benefit from current and 

future treatments. 


53IN MOLECULAR INSIGHTS AND TREATMENT OUTLOOK 

FOR GU MALIGNANCIES 

J. Bellmunt 

Medical Oncology, University Hospital del Mar-IMIM, Barcelona, SPAIN 

The use of targeted therapies has significantly improved outcomes for patients with 

mRCC. At present, in Europe and/or the USA, six/seven targeted agents are 

approved for first- and second-line treatment of clear cell mRCC: sunitinib, 

sorafenib, temsirolimus, everolimus, bevacizumab (in combination with interferon) 

pazopanib and axitinib (in the US). In addition, several new targeted agents, such as 

axitinib (in EU) and tivozanib, are also currently being filed for the treatment of 

mRCC after successful results of the phase III trials .New treatment options include 

targeting new pathways like c-MET or the use of novel more selective 

inmunotherapies such as the anti-PD1 agent. The novel chemotherapeutic agent 

Cabazitaxel with activity for CRPC in patients failing docetaxel is now available 

filling an unmet medical need for these patients.In addition immunotherapy with 

sipuleucel-T, the androgen biosynthesis inhibitor abiraterone acetate, the radioisotope 

alpharadin and the anti-androgen MDV3100 have all shown to improve overall 

survival in randomized phase III studies for patients with mCRPC. Agents such as 

the dual VEGFr/MET inhibitor cabozantinib, the clusterin inhibitor custirsen and the 

Src inhibitor dasatinib have shown encouraging results in phase II studies, and phase 

III results with theses agents are eagerly awaited.Novel immunotherapeutics such as 

prostate-specific membrane antigen-directed therapy and the anti-cytotoxic T 

lymphocyte-associated receptor 4 (CTLA4) antibody ipilimumab are also under 

investigation. Targeted therapy with novel drugs directed at specific molecular 

pathways opens promising new avenues in urothelial tumors to improve patient 

outcome. Several phase II/III trials, with focus on bevacizumab, aflibercept, sunitinib, 

sorafenib, gefitinib, lapatinib and trastuzumab have not clarified any specific role for 

these therapies. However, the presently accruing trial comparing CG +/bevazicumab 

is in its half way to shed light on the role of antiangiogenics in 

urothelial tumors. Other novel, promising targeted agents, including pazopanib, 

cetuximab and everolimus has shown limited benefit. Identifying pathways critical 

for tumorigenesis can provide potential strategies for therapeutic intervention in 

specific tumor types. 




abstracts

abstracts 

emerging diagnostic and therapeutic 

targets in gynecological cancers: from 

science to clinical practice 

54IN ANTIANGIOGENICS IN OVARIAN CANCER: WHERE ARE WE 

NOW? 

E.A. Eisenhauer 

Clinical Trials, Queen’s University NCIC Clinical Trials Group, Kingston, CANADA 

Vascular endothelial growth factor (VEGF) is often over expressed in ovarian cancer 

(OVCA), promoting ascites and effusions. Preclinical studies of inhibition of VEGF 

and its receptors (VEGFR) show activity in OVCA xenografts. Clinical interest in 

evaluating VEGF (R) inhibition was triggered when the Gynecologic Oncology 

Group demonstrated single agent activity of the VEGF targeted antibody, 

bevacizumab (BEV) in recurrent OVCA. Since that time, BEV and small molecular 

VEGFR inhibitors have been studied in numerous phase II and III trials in OVCA. 

Randomized BEV trials are the most mature with results reported in first line 

(GOG218, ICON7), platinum sensitive recurrent disease (OCEANS trial) and 

platinum resistant recurrent disease (AURELIA trial) settings. All trials gave 

concurrent chemotherapy + BEV with some providing maintenance BEV after 

chemotherapy. All have shown a biological effect of the addition of BEV with higher 

response rates and longer progression free survival (PFS) in BEV arms. To date, no 

trial has shown overall survival (OS) improvement, although mature analyses for OS 

are awaited. Quality of life data have not suggested a benefit with BEV and toxicity is 

greater. Results of phase III trials of VEGFR inhibitors cedarinib, pazopanib and 

nintedanib are awaited. The BEV results lead to several important questions: 1) in 

the absence of significant OS improvement to date, is there sufficient patient benefit 

from PFS increases to warrant incorporation of BEV into ovarian cancer treatment? 

And when over the course of the disease should the agent be given? 2) Is the use of 

BEV cost effective and affordable? 3) Which patient subset is benefiting most? 

Subgroup analysis of the ICON7 study, suggests that patients with greater bulk 

disease (Stage III> 1 cm residual and Stage IV) seem to derive more PFS benefit. 

Indeed in this subgroup, overall survival also was improved. However, in the 

GOG0218 trial, the hazard ratio for PFS was observed to be better in patients with < 

1 cm residual. Some have suggested VEGF A plasma levels may be predictive of BEV 

benefit, but no results from the BEV OVCA trials are yet published. In summary, 

clinical results to date show significant PFS improvements from BEV in 4 trials, but 

it is unclear if this will translate into improved OS and how best and in whom BEV 

should be used in OVCA management. 


55IN TARGETING DNA REPAIR DEFICIENCY IN OVARIAN AND 

ENDOMETRIAL CANCERS 

S.B. Kaye 

Royal Marsden Hospital and Institute of Cancer Research, Sutton, UNITED 

KINGDOM 

The key repair deficiency in cancer cells which has led to recent therapeutic 

innovation is homologous recombination deficiency (HRD), which is a defining 

feature of those cancers, particularly ovarian and breast, arising in patients with germ 

line BRCA mutations. Poly ADP ribose polymerase (PARP) inhibitors take advantage 

of HRD, through tumour specific synthetic lethality to provide clear clinical efficacy 

as single agents with an excellent toxicity profile in patients with these diseases. 

Response rates of 30%-60% have been documented according to prior platinum 

sensitivity. Their application has subsequently been broadened into patient with 

recurrent high grade serous ovarian cancer and platinum-sensitive disease, but who 

are not know to have germ line BRCA mutations. In these cases a clear benefit was 

seen with the PARP inhibitor olaparib in a randomised maintenance therapy trial in 

terms of progression-free survival (but not overall survival). A similar benefit in PFS 

was seen in a second maintenance trial in which olaparib was also combined with 

carboplatin - paclitaxel in the chemotherapy phase of treatment. Several PARP 

inhibitors are now in active development in ovarian cancer and the focus is 

increasingly moving to their application in germ line BRCA associated disease where 

the extent of benefit of these agents may after all be the greatest. As regards 

gynaecological cancers in general, the other disease of interest is endometrial cancer, 

in which in vitro data have also indicated substantial potential for PARP inhibitors. 

In endometrial cancer cell lines, HRD has also been noted and thought likely to 

relate to the characteristic PTEN loss seen in this disease (particularly Type I) rather 



than BRCA dysfunction. Clinical trials with PARP inhibitors are therefore awaited 

with interest. 

References Banerjee S & Kaye SB; PARP inhibitors in BRCA gene-mutated ovarian 

cancer and beyond. Current Oncology Reports - 13: 442-449, 2011. 


56IN PI3K/AKT PATHWAYS IN OVARIAN AND ENDOMETRIAL 

CANCERS 

C. Sessa 

Oncology, IOSI Istituto Oncologico Svizzera Italiana Ospedale Regionale 

Bellinzona e Valli, Bellinzona, SWITZERLAND 

The PI3K pathway is frequently activated in many human tumors, including ovarian 

(OC) and endometrial cancer (EC). Mutations of the gene PIK3CA, which codes for 

the p110α subunit, have been reported in 6% of OC, with a higher incidence in 

endometrioid and clear cell type; a 24% incidence of amplification has been reported, 

with no difference among subtypes, with an overall incidence of 30% PIK3CA 

alterations regardless histotypes, and of 45% in endometrioid and clear cell. In a 

retrospective study in patients with gynaecologic malignancies receiving 

combinations with PI3K/AKT/mTOR inhibitors in Phase I studies, the objective 

response in patients with PIK3CA mutations, including OC, was higher (30%) than 

in patients with wild type PIK3CA (10%). The presence of many confounding factors 

(retrospective analysis, treatment with mTOR inhibitors, combinations with 

cytotoxics) did not allow to determine whether a relationship existed between 

PIK3CA mutations and sensitivity to PI3K or mTOR inhibitors. Loss of PTEN has 

been reported in 35%-50% of patients with EC; PIK3CA mutations have been 

reported in 39% of patients with EC with both PIK3CA and PTEN mutations in 

44%. The most recent data in EC in 243 patients samples indicate >80% PI3K 

pathway alterations including mutations of PIK3R1 and PIK3R2, the genes encoding 

p85α and p85β. KRAS mutation has been reported in 20% of EC with divergent 

results on the mutual exclusiveness of PI3K and KRAS mutations. The significance 

of a crosstalk between the two pathways is unknown and the role of a combinatorial 

approach is under investigations. The PI3K oncogene is a promising target for the 

treatment of EC and clinical studies with pan PI3K, isoform specific PI3K or dual 

PI3K/mTOR inhibitors are ongoing in advanced EC. The general strategy in targeted 

therapy is to switch from an empirical approach to a more personalized treatment, 

based on genetic alterations and mechanistic studies. So far, the available data with 

PI3K inhibitors don’t justify the selection of patients according to PI3K mutations. 

Treatment of patients with both wild type or mutant tumors, together with the 

availability of representative tumor samples, could lead to the identification, through 

genetic analysis in responders, of the alteration(s) of the target genes indicative of 

sensitivity to the agents administered. 


57IN MOLECULAR IMAGING OF GYNECOLOGICAL CANCERS: 

OVARIAN CANCER AS ROLE MODEL 

E.G.E. De Vries 1 , G.M. van Dam 2 , A.W.J.M. Glaudemans 3 , A.K.L. Reyners 1 , 

A.G.J. van der Zee 4 , G.A.P. Hospers 1 , M.N. Lub-De Hooge 5 

1 Department of Medical Oncology, University Medical Center Groningen, 

Groningen, NETHERLANDS, 2 Department of Surgery, University Medical Center 

Groningen, Groningen, NETHERLANDS, 3 Department of Nuclear Medicine and 

Molecular Imaging, University Medical Center Groningen, Groningen, 

NETHERLANDS, 4 Department of Obstetrics and Gynaecology Department, 

University Medical Center Groningen, Groningen, NETHERLANDS, 5 Department 

of Hospital and Clinical Pharmacy and Nuclear Medicine and Molecular Imaging, 

University Medical Center Groningen, Groningen, NETHERLANDS 

Standard imaging work-up in ovarian cancer comprises chest imaging, ultrasound 

and abdominal/pelvic CT. To determine the extent of disease however, these 

modalities have poor sensitivity. In addition, they do not provide information about 

tumor characteristics such as tumor aggressiveness or presence of possible drug 

targets. Molecular imaging can provide serial non-invasive information about tumor 

characteristics and can be performed with various imaging techniques such as PET, 

SPECT and optical imaging. For this purpose, tumor-directed agents can be 

labeled with a radioactive nuclide, or a fluorescent dye. The PET-tracer 

18 F-fluorodeoxyglucose (FDG), visualizes glucose metabolism, which is often 

increased in tumors. Increasingly, it is possible to image specific drug-targets of 

tumors, such as hormone receptors, growth factors and growth factor receptors. 

Molecular imaging in metastatic breast cancer patients is feasible for the estrogen 

receptor with the 18 F-fluoroestradiol PET tracer and for HER2 with 111 In- and 




89 Zr-trastuzumab for SPECT and PET respectively. A trial with 18 F-fluoroestradiol 

in ovarian cancer is ongoing. Imaging of vascular endothelial growth factor 

(VEGF) with 89 Zr-bevacizumab has been performed by us in various tumor types. 

In addition, modulation of drug targets can be visualized by molecular imaging. 

Down-regulation of HER2 and VEGF tumor expression by HSP90 inhibition and 

of VEGF by mTOR inhibition was visualized in a human ovarian cancer bearing 

mice. Finally, optical imaging can provide real-time visualization of small lesions 

during surgery, allowing intra-operative staging and image-guided surgery. Folate 

receptors are often over-expressed in ovarian cancer and in a pilot-study we 

demonstrated, that ovarian cancer can be imaged intraoperatively by 

folate-fluorescein-isothiocyanate (folate-FITC). We are currently performing a 

feasibility fluorescence imaging study with the NIFR 800CW-bevacizumab tracer 

in primary breast cancer. Molecular imaging is still in its infancy and not part of 

current standards. However, the emerging possibilities of molecular imaging for 

staging, treatment decision-making, monitoring of treatment effects and 

image-guided surgery, justifies further validation of molecular imaging in ovarian 

cancer. 

Disclosure: E.G.E. De Vries: Research grant Roche and Novartis. All other authors 

have declared no conflicts of interest. 


abstracts 

biologically based treatment in head 

and neck squamous cell carcinoma 

(hnscc) 

58IN THE IMPORTANCE OF WINDOW OF OPPORTUNITY STUDIES 

J.P. Machiels 1 , S. Schmitz 2 

1 Medical Oncology, Cliniques Universitaires St. Luc, Brussels, BELGIUM, 2 Head 

and Neck Surgery, Cliniques Universitaires Saint-Luc, Brussels, BELGIUM 

One way to better understand the molecular activity of a particular treatment is to 

perform trials with collection of pre- and post-treatment tumor biopsies. Squamous 

cell carcinoma of the head and neck (SCCHN) represents an attractive disease for 

this approach because these tumors are generally easily accessible to iterative 

biopsies. We performed trials investigating figitumumab and sunitinib in recurrent 

and/or metastatic SCCHN after platinum failure. Pre-and post- treatment biopsies 

could be obtained in some patients. However, this trial design has some major 

limitations in regard of translational research. First, most patients have received 

radiation and/or chemotherapy and/or surgery, and so have developed multifactorial 

resistance and are less likely to respond to new agents and, second, feasibility of 

conducting translational research is hampered by ethical considerations in obtaining 

iterative tumor biopsies in palliative patients. One way to resolve some of these issues 

is to perform “window” studies where a targeted agent is given during the 

incompressible period of time between the diagnosis and surgery in patients selected 

for a primary surgical treatment. Evaluation of compounds in the pre-operative 

window setting could maximize the chance of observing tumor response. In addition, 

the collection of biopsies before treatment and after treatment may provide insights 

into the pharmacodynamic effects of novel agents as well as their mechanisms of 

action and also help to identify some hypotheses regarding treatment resistance. In 

SCCHN, the EGFR and its downstream molecular pathways are crucial and EGFR 

overexpression is linked with poor prognosis. Cetuximab combined with RT or CT 

improves survival. However, only a minority of patients benefits from anti-EGFR 

mAbs. We designed trials to investigate the safety, molecular and imaging response 

of anti-EGFR treatments in the window pre-operative study in SCCHN. Briefly, the 

anti-EGFR drug was given during two weeks before surgery. 18FDG-PET, CT-scan 

or MRI, tumor biopsies, and plasma collection were taken before and after treatment. 

We demonstrated the safety and feasibility of this approach. Biological samples are 

currently analyzed to better understand the molecular mechanisms involved. 

Disclosure: J.P. Machiels: Advisory role for Boerhinger Research grant from Sanofi 

All other authors have declared no conflicts of interest. 

59IN STRATEGIES TO OPTIMIZE EGFR THERAPIES 

B. Burtness 

Department of Medical Oncology Fox Chase Cancer Center, Philadelphia, PA, 


The epidermal growth factor receptor remains the best validated target for systemic 

therapy of squamous cell carcinoma of the head and neck (SCCHN), with the 

EGFR-directed monoclonal antibody cetuximab the only targeted therapy to impact 

overall survival in this disease. However, the augmentation of response when 

cetuximab is added to conventional chemotherapy for recurrent/metastatic disease is 

modest, as is the delay in time to progression; thus, de novo and acquired resistance 

to EGFR inhibition are significant problems. De novo resistance may result when 

downstream signaling intermediaries are altered, as with H-ras mutation or PTEN 

loss. To date, no signature of abnormality in the signaling stream has been shown to 

predict cetuximab resistance in SCCHN in a manner analogous to K-ras mutation as 

a predictor of cetuximab resistance in colorectal cancer. Combinations of cetuximab 

with PI3K, mTOR or Aurora kinase inhibitors are in clinical trial currently. Nuclear 

translocation of phosphorylated EGFR is documented in SCCHN and associated 

with worsened outcome. Once present in the nucleus, EGFR interacts with 

transcription factors and phosphorylates and stabilizes PCNA. Gefinitib and lapatinib 

appear to inhibit nuclear translocation. Nuclear translocation of EGFR and its 

intranuclear functions may represent targets more amenable to tyrosine kinase 

inhibitors than to cetuximab, and we are currently studying the combination of 

cetuximab and erlotinib together with standard chemotherapy for recurrent/ 

metastatic disease. Acquired resistance may result from the upregulation of alternate 

HER family member receptor tyrosine kinases, and dual EGFR/HER2 or pan-HER 

inhibitors such as lapatinib and afatinib are under study. Afatinib is the first kinase 

inhibitor to show activity comparable to that of cetuximab. As an oral agent, it is 



more suited to prolonged administration than is cetuximab, and an international 

phase III trial of afatinib vs. placebo for patients with poor risk locally advanced 

head and neck cancer who have completed chemoradiation. MET is another receptor 

tyrosine kinase overexpressed in head and neck cancer, and associated with 

cetuximab resistance. Novel agents targeting MET include monoclonal antibodies 

and tyrosine kinase inhibitors. 

Disclosure: Paid consultant to Bristol Myers Squibb in 2012. Unpaid Steering 

Committee member Boehringer Ingelheim, unpaid consultant Millenium 

Pharmaceuticals. 

60IN PREDICTORS OF SENSITIVITY AND RESISTANCE 

MECHANISMS 

A. Psyrri 

Internal Medicine, Attikon University Hospital, Athens, GREECE 

The epidermal growth factor receptor (EGFR) is a validated molecular target in 

squamous cell carcinoma of the head and neck (HNSCC). However, despite high 

expression levels of EGFR protein in these cancers, EGFR-targeted agents have only 

had modest single-agent activity. Therefore, major research aims are to better 

understand the underlying causes of intrinsic or acquired resistance, and to develop 

novel treatment strategies that potentiate the impact of EGFR inhibitors. At this 

point, the mechanisms of resistance to EGFR-targeted therapies in patients with head 

and neck cancer are largely unknown. Potential mechanisms of resistance include the 

following: (i) constitutive up-regulation of downstream targets of EGFR (i.e. the 

downstream target is no longer regulated by EGFR), (ii) compensatory up-regulation 

of redundant receptor tyrosine kinases (RTKs) that signal through common effectors 

(pAKT is one such effector), (iii) Ligand-independent signaling (i.e. EGFRvIII): 

EGFRvIII is a mutant receptor with an in-frame deletion of the extracellular domain 

that renders the receptor constitutively active despite its inability to bind EGF, (iv) 

Transcriptional regulatory mechanisms that control EGFR expression: 

single-nucleotide polymorphisms (SNPs) in EGFR promoter region [i.e. GC 

(EGFR*1)] or common CA dinucleotide repeat in intron 1 of EGFR affects EGFR 

mRNA levels; (v) Inhibition of the ubiquitin-mediated degradation of EGFR: the 

chromosome 11q13 region is frequently amplified in HNSCC (36%) and results in an 

increased expression of cortactin; (vi) Epithelial to mesechymal transition. Strategies 

to optimize EGFR-targeted therapy in head and neck cancer include not only the 

selection for patients most likely to derive benefit but also the use of combination 

strategies to override resistance. 


61IN PARP INHIBITORS AND OTHER STRATEGIES IN 

CHEMORADIATION 

K.J. Harrington 

Targeted Therapy Laboratory, Institute of Cancer Reserach, London, UNITED 

KINGDOM 

Chemoradiotherapy (CRT) is the treatment of choice for many locally-advanced 

tumour types. In particular, platin-based CRT is the gold-standard for stage III/IV 

squamous cell cancers of the head and neck (SCCHN). Most SCCHN have defects in 

the DNA damage response. For example, p53 pathway signalling is frequently 

defective, either through mutation or post-translational silencing by viral 

oncoproteins. Therefore, HNC are reliant on the G2/M cell cycle checkpoint – and 

this represents a potential point of attack for strategies combining RT and novel 

targeted radiosensitisers. In this presentation, approaches involving PARP, HSP90 

and Chk1 inhibition will be discussed. Poly (ADP-ribose) polymerase (PARP) 

inhibitors are potent radiosensitisers and should be the subject of careful clinical 

evaluation in combination regimens with RT or CRT. Data relating to their 

development will be reviewed. HSP90 maintains the stability and activity of a 

number of proteins key in cell cycle arrest, DNA damage repair and apoptosis linked 

to cellular response to radiation. NVP-AUY922 potently radiosensitized a selection 

of cell lines in in vitro clonogenic assays corresponding to depletion of 

radioresistance markers at equivalent concentrations. Radiosensitization was verified 

in vivo by delayed tumour growth and increased survival. Mechanistic analysis at 

clinically achievable concentrations show NVP-AUY922 in combination with RT 

exhibits multi-target interference in both cell cycle progression and DNA damage 

repair. In addition, we have explored the effect of Chk1 inhibition (SAR-020106) in 

combination with RT in vitro and in vivo. Colony and caspase activity assays in cell 

lines with non-functional p53 revealed significant radiosensitization by Chk1 

inhibition, in direct contrast to cell lines with functional p53. In vivo 

radiosensitization was confirmed by delayed tumour growth and increased survival 




utilizing a fractionated drug and radiation schedule. Abrogation of RT-induced G2 

phase arrest using the Chk1 inhibitor was compensated by an increase in G1 phase 

population for cell lines with functional p53 (normal and malignant), in contrast to 

tumour cell lines with non-functional p53 (p53 mutant or HPV + ). In addition, 

Chk1 inhibition combined with RT caused inhibition of homologous recombinationmediated 

DDR. 


62IN NOVEL AGENTS AND PARADIGMS IN DEVELOPMENT IN 

HNSCC 

A. Jimeno 

Medicine/Oncology, University of Colorado School of Medicine, Aurora, CO, 


HNSCC is a particularly challenging disease due to the rarity of activating oncogene 

mutations and prevalence of mutations in tumor suppressor genes such as P53 and 

NOTCH1 with 47% and 19% mutation rates, respectively. The epidermal growth 

factor receptor (EGFR) inhibitor cetuximab is the only targeted drug for HNSCC, 

but to date, and despite its relatively low clinical efficacy, there are no validated 

patient selection strategies. HPV types 16 and 18 through integration and replication 

of the E6/E7 proteins are the etiologic cause of an increasing percentage of HNSCC, 

which is becoming an epidemic among younger patients in Western countries. There 

is growing evidence that HPV+ and HPV- HNSCC have a different biology, and we 

can expect it will require different therapy. In addition to embellishments to 

anti-EGFR therapy new areas of research in HNSCC include PI3K inhibition (with 

the role of genetic selection still to be determined), novel anti-angiogenesis and 

anti-lymphangiogenesis such as ALK1 modulators, multikinase inhibitors, 

multi-targeted monoclonal antibodies aimed at more efficiently abrogating EGFR 

signaling and co-activated pathways, and agents aiming at inhibiting the HNSCC 

stem cell compartment such as Hedgehog pathway inhibitors. 

Disclosure: A. Jimeno: Research laboratory funding: - Infinity - Oncothyreon - 

Onconova Patent ownership: - Oncothyreon - Onconova 

63IN IMPLICATIONS FOR CLINICAL PRACTICE AND TRIAL DESIGN 

A. Psyrri 

Internal Medicine, Attikon University Hospital, Athens, GREECE 

Targeted strategies have been developed in head and neck squamous cancer 

(HNSCC) in order to increase effectiveness and decrease toxicity. Epidermal growth 

factor receptor (EGFR) inhibitors are firmly established in HNSCC but the critical 

issue has been patient selection. Other recently developed novel pathway inhibitors 

hold significant promise and are being tested in phase 1, 2 and 3 trials either alone 

or concomitantly with radiotherapy or chemoradiotherapy. One such class of 

agents, the poly(ADP-ribose) polymerase (PARP) inhibitors, has shown activity in 

conjunction with radiotherapy in head and neck cancer cell lines. Pre-clinical data 

suggest that PARP inhibitors may potentiate the effects of radiotherapy in head and 

neck cancer cell lines and xenograft models. Sonic hedgehog (Shh) pathway plays 

an important role in HNSCC progression and should be considered a potential 

therapeutic target. One clinical arena where targeted therapies may also find place 

is in the adjuvant or prevention setting where minimal disease or precancerous 

lesions can be affected by shutdown of a single or few targets. Future directions lie 

in understanding the molecular basis of the mechanism of action of the drugs 

currently undergoing clinical evaluation. Increased understanding of the cell 

signaling processes involved might aid patient selection. Advances in genomics are 

revolutionizing the discovery of biomarkers and should improve the tumor 

selectivity of novel agents. There is also a need for the development of methods 

that can be used in pharmacodynamic studies in humans. A better understanding 

of the signaling pathways will not only inform our knowledge of cancer 

development but also help to refine the classification as well as the treatment of the 

disease. 



abstracts 

molecular targets in malignant 

lymphomas: from basic science 

to clinical practice 

64IN NEW ANTIBODIES IN THE POST-RITUXIMAB-ERA: ANOTHER 

BREAKTHROUGH? 

P. Johnson 

Cancer Research UK Centre, University of Southampton, Southampton, 


Monoclonal antibodies (mAb) are one of the successes of modern cancer medicine, 

with rituximab the first to enter widespread clinical application following the 

demonstration of significant activity as a single agent, and superior results when 

combined with chemotherapy for a variety of CD20+ lymphoma types. In parallel to 

extensive clinical studies, we continue to uncover novel aspects of biology of the 

lymphoid cell surface. The molecules to which mAb have been targeted were 

identified several decades ago and few new ones have emerged recently, but there is 

now increasing interest in effector mechanisms, selective delivery of radionuclides or 

toxins, and bispecific molecules to target T- or NK- cells. Once thought of as a 

comparatively inert component of the cell membrane, CD20 is in fact a dynamic 

molecule. It can undergo rapid redistribution, and different mAb cause different 

effects: those like Rituximab (“type I”) elicit redistribution into lipid-rich rafts, 

mediate complement fixation and antibody-directed cell-mediated cytotoxicity 

(ADCC). In contrast, those like the first anti-B-cell mAb characterised, B1 (“type II”) 

do not cause redistribution into rafts but mediate homotypic cell adhesion and 

programmed cell death. These differences have important therapeutic results, and we 

have found that in lymphomas expressing the CD32 antigen (Fcgamma-R2b), type 

ImAb mediate rapid internalization of CD20 with lysosomal consumption, while 

type II do not. This has potential consequences for the therapeutic effect, as does the 

avidity with which mAb with different sugar groups bind to various Fc receptors. As 

well as radioconjugates, we are also returning to previously discarded approaches 

such as immunotxins, which have benefitted from advances in linker chemistry to 

improve their therapeutic ratio. Problems of toxin liberation and systemic toxicity 

have been largely overcome, and a new generation of conjugates is finding 

application in lymphoma therapy. Finally, the capacity to generate bispecific 

constructs that allow targeting of T-cells to the malignant cell surface holds the 

promise of harnessing cellular as well as humoral immunity. The initial promise of 

antibody therapy for lymphoma is already being fulfilled, and the next generation of 

compounds holds exciting challenges and great potential. 

Disclosure: P. Johnson: Advisory Boards for Pfizer, Millenium Takeda, Roche, 

Boehringer Ingelheim. Research funding from Janssen-Cilag. 

65IN MTOR INHIBITORS AND BEYOND: TARGETING A CRITICAL 

PATHWAY 

M.H. Dreyling 

Department of Medicine Iii, University of Munich, Munich, GERMANY 

Upregulation of the PI3K/AKT/mTOR signal pathway has been detected in 

numerous lymphoma subtypes including mantle cell lymphoma (MCL). Accordingly, 

the mTOR inhibitor Temsirolimus has been registered in EU based on a prospective 

randomized trial in 162 patients with relapsed MCL. In comparison to 

monochemotherapy, Temsirolimus achieved significantly higher response rates (22% 

vs 2%) and longer progression-free survival (4.8 vs. 1.9 months). Moreover, the 

efficacy of the mTOR inhibitor was confirmed not only in MCL, but also follicular 

and diffuse large B-cell lymphoma in numerous phase II studies. Based on in vitro 

studies current trials investigate the combination with chemotherapy. Thus, all 12 

initial patients with relapsed MCL responded to a 

Bendamustin-Rituximab-Temsirolimus combination (BeRT). Recent research has 

confirmed the critical role of the B-cell receptor pathway upstream of mTOR in the 

molecular pathogenesis of malignant lymphoma. This pathway represents the 

physiological survival signal for maturating lymphocytes in the germinal center. 

Accordingly, small molecules attacking this pathway displayed high efficacy in 

various lymphoma subtypes even in monotherapy. Thus, a SYK inhibitor has been 

shown to be effective in patients with relapsed diffuse large cell lymphoma. Especially 

both, an inhibitor of the PI3K delta isoform (GS-1101, formally Cal-101) only 

expressed in lymphoid cells and the BTK inhibitor ibrutinib showed high efficacy in 

relapsed mantle cell lymphoma (response rate about 70%) as well as CLL (response 



rate between 70–90% in relapsed or previously untreated disease). In contrast, 

response rates were lower in follicular lymphoma presumely indicating the different 

survival signal of the constitutive BCL-2 overexpression in this lymphoma subtype. 

These data also confirm the crucial role of the micromilieu in lymphoid diseases 

which are hampered by the inhibition of the B-cell receptor pathway. Finally, recent 

in vitro data suggest some synergism of different members of the B-cell receptor 

pathway in combination with mTOR inhibition. Such molecular targeted strategies 

have therefore the potential to become part of the new treatment strategies in a broad 

spectrum of lymphoid neoplasias. 

Disclosure: M.H. Dreyling: Pfizer (Temsirolimus): scientific advisory board, speaker\ 

\\’s honoraria Janssen (Ibrutinib): scientific advisory board, support of IITs, speaker\\ 

\’s honoraria 

66IN PROTEASOME INHIBITORS: REALLY A TARGETED THERAPY? 

D. Colomer 1 , P. Perez-Galan 2 , G. Roué 2 

1 Hematopathology Unit, Hospital Clínic, Institut d’ Investigacions Biomèdiques 

August Pi i Sunyer (IDIBAPS), Barcelona, SPAIN, 2 Hematology-oncology. Cek, 

Institut d’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 

SPAIN 

Bortezomib is the first-in-class proteasome inhibitor that targets the critical process 

of intracellular protein modification and degradation. In 2006, bortezomib was 

approved for the treatment of relapsed or refractory MCL. The mechanisms of 

proteasome inhibition are very complex as they affect many pathways. The Initial 

rationale for bortezomib use was inhibition of NF-kB activity. However, bortezomib 

does not block constitutive NF-kB activity in MCL and induces oxidative and 

endoplasmic reticulum (ER) stress. This cellular stress leads to the activation of a 

cytoprotective response called Unfolded Protein Response (UPR), that tries to aliviate 

ER stress and rescue the cell by different adaptive mechanisms. However under 

conditions of prolonged stress, apoptosis is activated. Apoptosis commitment starts 

with the transcriptional activation of the propapoptotic BH3-only protein Noxa, 

leading to mitochondrial apoptosis. However, half of MCL cases fail to respond, and 

resistance often appears after initial treatment. By gene expression analysis it has 

been reported that MCL bortezomib-resistant cell lines showed partial plasmacytic 

differentiation, including increased expression of IRF4 and its target genes, and of the 

cell-surface markers CD38 and CD138. Tumors from patients with inferior clinical 

responses to bortezomib also had high IRF4 and CD38 expression, identifying 

possible clinical markers of bortezomib resistance. Also, a correlation between loss of 

sensitivity to bortezomib and up-regulation of the prosurvival chaperone BiP/Grp78 

controlling ER homeostasis has been observed. BiP/Grp78 forms a large multiprotein 

complex with other ER molecular chaperones, including HSP90. Combination of 

bortezomib with IPI-504, a HSP90 inhibitor that displace the client proteins and 

target them for destruction by the proteasome system, prevented BiP/Grp78 

accumulation, thereby promoting apoptosis and inhibiting the growth of 

bortezomib-resistant tumor xenotransplants. In summary, targeting the 

ubiquitin-proteasome pathway with bortezomib represents a potent arsenal in the 

treatment of MCL, although we need to find new combinations and specific 

biomarkers that may help us to recognize which cases will be benefit from each 

specific treatment. 


67IN IMIDS: MULTIPLE PATHWAYS BUT DOES IT REALLY WORK? 

G. Morgan, C. Pawlyn, F. Davies 

Division of Molecular Pathology, The Institute of Cancer Research, London, 


The mechanism of action of IMiD® compounds has been the subject of much recent 

research which has highlighted the dual effects of these drugs, with both direct 

tumoricidal effects and immunomodulatory activity. Lenalidomide exerts its 

tumoricidal effects through a number of mechanisms, including decreased 

production of cytokine and growth factors causing disruption of stromal support, 

induction of tumor suppressor genes leading to cell cycle arrest and activation of 

caspases triggering tumor cell apoptosis. A recent study showed that IMiD® 

compounds increase p21 expression by a novel epigenetic mechanism. Lenalidomide 

also provides sustained disease control by improving immune function, resulting in 

continued tumour killing. Lenalidomide exerts immunomodulatory effects via 

enhanced antigen-specific CD8+ T-cell cytolysis and by increasing natural killer 

(NK)-cell expression of death effector molecules. Lenalidomide and pomalidomide 

have greater tumoricidal effects than thalidomide. Lenalidomide also has a more 

potent effect on the immune system. Both thalidomide and pomalidomide have 




potent anti-angiogenic properties. Evidence now indicates that clinical benefit can be 

gained in thalidomide-treated and refractory patients. In this respect cereblon has 

been identified as an intracellular imid binding moiety which is responsible for the 

teratogenic effects of these agents loss of which can mediate resistance to imids.It is 

possible to build combinations which improve the activity of Imid drugs. 

Co-administration of dexamethasone may synergistically improve the tumoricidal 

effects of lenalidomide but during maintenance the inhibition of the 

immune-enhancing effect of lenalidomide may impair its activity. There are a number 

of antibodies, including elotuzomab, which may be combined with lenalidomide. In 

view of the effects of lenalidomide on the epigenetic upregulation of tumour suppressor 

genes combination with other epigenetic agents such as HDAC inhibitors and 

demethylating agents may be useful. As research continues, additional insights into the 

mechanism of action of Imid drugs which may help to further maximize the use of 

lenalidomide and subsequently pomalidomide in the treatment of MM. 

Disclosures: All authors have declared no conflicts of interest. 

68IN TARGETED THERAPY IN MALIGNANT LYMPHOMA: CLINICAL 

IMPLICATIONS AND PERSPECTIVES 

M. Ghielmini 

Medical Oncology, IOSI Istituto Oncologico Svizzera Italiana Ospedale Regionale 

Bellinzona e Valli, Bellinzona, SWITZERLAND 

With a whole range of new drugs showing activity in different types of 

lymphoma, we question if any of these will make the new step forward as it has 

been the case with the introduction of doxorubicin, high-dose chemotherapy or 

rituximab. If we look at some most significant diseases, we can hope that for 

Hodgkin’s lymphoma (HL) the advent of active drugs as brentixumab vedotin 

and panobinostat could make chemotherapy more effective, reducing the number 

of cycles needed or allowing the avoidance of drugs with long-term side effects. 

In the treatment of diffuse large B-cell lymphoma (DLBCL) what is needed is a 

drug improving on the cure rate. The new available substances have not yet 

shown to be so promising but not all of them have yet been combined with 

classical chemotherapy. Follicular lymphoma (FL) is a well controllable disease 

but we want a drug which will render this disease curable; in the meanwhile we 

hope that patient-friendly treatments will allow long-term maintenance and 

disease control. The combination of lenalidomide with rituximab, but also the 

new CAL 101, BTK inhibitors or inotuzumab ozogamicin could increase the 

possibility of prolonging the time without symptoms of disease or treatment. The 

impact of these drugs on survival though will be long to ascertain in such an 

indolent disease. Mantle cell lymphoma (MCL) remains rapidly progressing and 

difficult to treat. It is considered not curable and it will therefore be important 

ascertain the impact of bortezomib, temsirolimus, BTK and PI3K inhibitors or 

blinotumumab combined with standard treatment on survival or cure. Finally, 

peripheral T-cell lymphoma (PTCL) is an orphan disease compared to the B-cell 

lymphomas as it could not take advantage of the introduction of rituximab. In 

anaplastic large cell lymphoma (ALCL) brentuximab vedotin has shown very 

important activity and might make the difference, while the addition of 

pralatrexate, romidepsin or vorinostat could change the prognosis of the other 

entities. Despite many of these drugs having shown promising data, the challenge 

is now to combine them with standard treatment in order to obtain regimens 

which are more active but not more toxic. Phase II trials are ongoing to develop 

the optimal combination schedules. 

Disclosure: M. Ghielmini: Member of advisory board for Roche, Lilly, BMS, Celgene, 

Pfizer, Jansen 


abstracts 

melanoma therapy: from frustration to 

enthusiasm 

69IN NEW MOLECULAR TARGETS IN MELANOMA 

R. Marais 

Chester Beatty Laboratories, The Institute of Cancer Research, London, 


Recent years have seen dramatic advances in the development of targeted and 

immunological therapeutics for melanoma. In the area of targeted therapy, the 

development of BRAF inhibitors has led to new paradigms of melanoma treatment, 

because BRAF drugs such as vemurafenib and dabrafinib can achieve objective 

responses in BRAF mutant melanoma patients. However, these responses are 

generally short-lived, and relapse may be inevitable. Notably, BRAF inhibitors drive 

an unexpected paradox: while they inhibit RAF signalling in cells expressing mutant 

BRAF, they activate RAF signalling in cells expressing oncogenic or activated RAS. 

This is because these inhibitors drive the formation of homo and hetero-dimers 

between BRAF and the closely related protein CRAF. The activation of this paradox 

appear, at least in some instances to underlie the mechanisms of resistance, and they 

also drive one of the curious side-effects of these drugs, the induction of 

non-melanoma neoplasms in the skin. Critically, it appears that upon activation of 

the paradox, the tumour cells can switch from being sensitive to the drug to being 

addicted to it. This creates an unexpected complication when managing these 

patients, but shows how improving our knowledge of the processes that drive 

tumourigenesis is critical to developing novel therapeutic strategies for cancer 

patients. 

Disclosure: I have received an honourarium from Roche. I have consulted (unpaid) 

for novartis; I have consulted (unpaid) for Genentec. 

70IN HOW TO OVERCOME RESISTANCE IN MUTATION DRIVEN 

THERAPIES COMBINATION TARGETED THERAPY REGIMENS 

K.T. Flaherty 

Developmental Therapeutics, Cancer Center, Massachusetts General Hospital, 


The identification of BRAF mutations in 2002 was the watershed event that turned 

the attention of the melanoma field to this concept. Seven years passed between the 

identification of BRAF mutations and the validation of this target in melanoma 

patients with a potent and specific BRAF inhibitor, PLX4032. As phase II and phase 

III single-agent trials have established BRAF inhibition as a new standard of care for 

the BRAF mutated subpopulation, attention now turns to understanding mechanisms 

of resistance and rational combination approaches. The available evidence regarding 

acquired resistance mechanisms does not point to an obvious approach for 

developing second line or salvage therapy for these patients. Current efforts are 

focused on combining other targeted therapies with BRAF inhibitors in the subgroup 

of patient who have BRAF mutations to overcome de novo resistance. The spectrum 

of potential combination therapy regimens is broad. It has been known for several 

years that BRAF mutations are accompanied by genetic alterations that activate the 

PI3K pathway and CDK4. Characterizing more than one genetic alteration before 

selecting such combinations is feasible and an appropriate way to stratify patients for 

next-generation combination therapy clinical trials. Recent evidence suggests that 

stromal secreted by the tumor microenvironment confers resistance to BRAF 

inhibitor therapy and HGF antibodies o small molecule c-met inhibitors represent 

available investigational agents to combined. Additionally, emerging evidence 

suggests that BRAF inhibitors induce a secondary immune response and 

combinations with various active immunotherapies is being pursued. However, the 

current inability to predict which patients are most likely to benefit from 

immunotherapy represents a persistent challenge in arriving at a personalized 

approach with such combinations. Similarly, combination therapy with BRAF 

inhibitors and anti-apoptotic drugs and agents that target developmental pathways in 

melanoma show promise but do not have an associated predictive biomarker. 

Disclosure: K.T. Flaherty: Consultant - Roche/Genentech, GlaxoSmithKline 

71IN ANTI CTLA4 AND PREDICTIVE BIOMARKERS 

J.S. Weber 

Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research 

Institute, Tampa, FL, UNITED STATES OF AMERICA 

The recent US FDA and EU EMA regulatory approval of ipilimumab, a CTLA-4 

antibody, has highlighted the need for pharmacodynamic and predictive markers of 

its clinical benefit. Ipilimumab’s RECIST response rate is in the realm of 10%, with 

another 10-20% of patients having clinical benefit with stable disease past 6 months. 

Response and overall survival are related pharmacokinetically to its Cminns levels, 

although the rate of immune related adverse events also rises with increased dose. 

Several studies in the metastatic and adjuvant settings have defined 

pharmacodynamics and predictive markers for ipilimumab and determine if they are 

associated with clinical benefit. HLA-DR, as well as the activation marker ICOS are 

increased on CD4 and CD8 T cells after ipilimumab treatment. An increase in the 

early total lymphocyte count may be associated with outcome. Microarray analyses 

suggest that expression of a large number of genes are altered in CD4 T cells by 

ipilimumab, but fewer genes are impacted in CD8 T cells. Central memory cells are 

increased, with a corresponding decrease in naïve T cells. Gata3, a Th2 polarizing 

molecule was increased, yet TH17 cell induction and IL-17 levels were increased. 

Examination of tumors in patients treated with ipilimumab revealed a significant 

influx of CD8 T cells, which may be primarily PD-1 positive. In an adjuvant trial, 

pre-treatment CD8/EOMES/Ki67 positive T cells were significantly associated with 

relapse-free survival, and CD4/EOMES/Ki67 T cells were associated with low levels 

of irAEs, the mechanism-based side effects of ipilimumab. Analysis of tumor gene 

expression by microarrays suggest that an immune signature may also be predictive 

of benefit. The newly developed checkpoint inhibitor antibodies against PD-1 have 

been associated with excellent responses of long duration in melanoma, renal cell 

cancer and non-small cell lung cancer. Increases in circulating T regulatory cells and 

CD4/CTLA-4 expressing T cells was associated with response in one study. In 

tumors, PD-1 expression assessed by immunohistochemical staining was associated 

with outcome, and no patient with absent PD-L1 expression responded. These data 

provide a rationale for further marker testing and novel trials of sequenced 

antibodies. 

Disclosure: J.S. Weber: I have received honraria of less than 10,000 USD from BMS, 

have sat on advisory boards for BMS, and my institution has received research 

money from BMS 

72IN THE COMBINATION OF CHEMO AND IMMUNOTHERAPY: HOW 

FOES BECOME FRIENDS 






integrating targeted treatments with 

tumor biology and molecular imaging in 

the current and future management of 

neuroendocrine gastrointestinal tumors 

73IN CLASSIFICATION AND TUMOR BIOLOGY OF NETS 

G. Rindi 

Università Cattolica - Policlinico A. Gemelli, Instituto di Anatomia Patologica, 

Rome, ITALY 

First recognized as “carcinoids” in the gastroenteropancreatic (GEP) tract, 

neuroendocrine tumors (NET) are a variety of neoplastic lesions distributed in most 

organs and apparata. The current World Health Organization (WHO 2010) define 

low and high grade neuroendocrine cancer types with the broad definition of 

neuroendocrine neoplasms and introduces grading (G1-G3) and Tumour Node 

Metastasis (TNM) staging for class definition. The proposed WHO 2010 grading 

system defines three classes (G1-G3) according to both mitotic count and Ki67 

index. Three classes are defined as WHO class 1, neuroendocrine tumor (NET), G1; 

WHO class 2, NET G2 and WHO class 3, neuroendocrine carcinoma (NEC), by 

definition G3. The definition of NET equalizes the previous definition of carcinoid 

(typical and atypical as variably utilized in the pathology literature) and of 

well-differentiated endocrine tumor/carcinoma as from the previous WHO 

classification. The WHO 2010 TNM substantially endorsed the classification 

originally proposed by the European Neuroendocrine Tumour Society (ENETS) with 

two exceptions in that i) it limits its application to NET G1-G2 (carcinoids) and ii) it 

shows significant differences for pancreas and appendix TNM definitions. In general 

a common staging system frame was defined with stage I tumors with limited 

growth, stage II larger or more invasive tumors, in absence of metastases, stage III 

tumors invading the surrounding structures or with loco-regional metastases and 

stage IV implying distant metastases. This classification system was first adopted by 

the International Union Against Cancer (UICC) and subsequently endorsed by both 

the American joint Cancer Committee (AJCC) and the WHO. Current oncology 

guidelines for Neuroendocrine neoplasms are largely based on proliferation fraction 

and stage to define specific therapeutic options. 

Disclosure: G. Rindi: In the last three years I acted as consultant for Ipsen pharma 

and received speaker’s fee/honoraria from Novartis pharma, Ipsen pharma and 

Pfizer. 

74IN MOLECULAR IMAGING OF NETS 

A. Kjaer 

Clinical Physiology, Nuclear Medicine & Pet, Rigshospitalet, 

University of Copenahgen, Copenhagen, DENMARK 

The change in paradigm towards individualized, tailored therapy has led to a 

need for diagnosing at the molecular level. Most of the molecular biology 

methods used today need tissue sampling for in vitro analysis. In contrast, 

molecular imaging allows for non-invasive studies at the molecular level in living, 

intact organisms. With PET it is possible to label bio-molecules with radioactive 

isotopes. This method can be used for non-invasive visualization of tumor 

specific receptors and tissue characteristics such as receptor expression, 

angiogenesis and ability to metastasize. Especially within cancer biology the 

technique is expected to lead to a break-through in diagnosing and treatment. 

Among the different techniques for molecular imaging, the nuclear medicine 

based technologies have the greatest potential for translational use since methods 

developed in animal models may directly be transferred and used in humans. 

Furthermore, PET has a high sensitivity and allows for quantification. The lecture 

will review the current state of molecular imaging of NET with focus on the use 

of PET. Areas of recent developments include several new somatostatin receptor 

PET ligands that has improved diagnostic accuracy compared with previous 

methods using SPECT. In addition, FDG has been shown as a valuable 

prognostic tool and recent data from our institution will be shown. Finally, 

several new PET tracers seem valuable for tailoring and monitoring effect of new 

targeted therapies. Examples of such tailoring and monitoring of therapy will be 

reviewed and it will be discussed what the future clinical role in NET of such 

PET tracers may be. 


75IN PEPTIDE RECEPTOR RADIONUCLIDE THERAPY OF 

NEUROENDOCRINE TUMOURS 

L. Bodei 1 , C.M. Grana 2 , M. Cremonesi 2 , G. Paganelli 2 

1 Nuclear Medicine Division, European Institute of Oncology, Milan, ITALY, 

2 Nuclear Medicine, European Institute of Oncology, Milano, ITALY 

In the past two decades a new approach to neuroendocrine tumors based on specific 

receptor targeting was introduced in the clinical practice. Peptide receptor 

radionuclide therapy (PRRT) consists in the systemic administration of a synthetic 

analogue, radiolabelled with a suitable beta-emitting radionuclide. These compounds 

are able to irradiate tumors and their metastases via the internalization through a 

specific receptor subtype, generally over-expressed on the cell membrane. Pre-clinical 

studies have indicated many potential receptor candidates for PRRT. To date, the 

mostly exploited system is the somatostatin-somatostatin receptor. PRRT can deliver 

high absorbed doses to tumors, adequate to achieve significant volume reduction. 

Treatment with radiolabeled somatostatin analogues, such as [ 90 Y-DOTA 0 , 

Tyr 3 ]-octreotide (or 90 Y-DOTATOC) and [ 177 Lu-DOTA 0 ,Tyr 3 ]-octreotate (or 

177 Lu-DOTATATE), is an efficient new tool in the management of patients with 

inoperable or metastasized gastro-entero-pancreatic (GEP) neuroendocrine tumors. 

Clinical trials performed in several countries, despite different phase I-II protocols, 

showed complete and partial responses in 10 to 30% of patients for 90 Y-DOTATOC. 

In the clinical trial with 177 Lu-DOTATATE, 47% overall response rate was observed, 

with a median time to progression of >36 months and a significant impact on 

survival. FDG PET evaluation is useful to predict progression free survival to PRRT 

in G1/G2 neuroendocrine tumors. Significant biochemical and symptomatic 

responses in functioning tumors were encountered for both radiopeptides. Toxicity, 

requiring renal-protective agents, is generally mild and may involve kidneys and 

bone marrow. These data indicate that PRRT is a convincing therapeutic tool in the 

treatment scenario of GEP tumors. Newer strategies to increase the therapeutic 

potential of PRRT, such as the combination with radiosensitizing chemotherapy, are 

presently under investigation. Incoming phase III protocols comparing PRRT with 

177 Lu-DOTATATE versus conventional therapies will help clarifying the position of 

PRRT in the therapeutic algorithm of neuroendocrine tumors. 


76IN TARGETED TREATMENT OF NETS 



J.C. Yao 

Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, 


Low to intermediate grade neuroendocrine tumor (NET) constitutes a group of 

malignancies that share the capacity for secreting hormones and causing distinctive 

clinical syndromes. Until recently, there were few evidence-based treatment options. 

Recent advances in targeted therapy and completion of pivotal phase III studies have 

brought the approval of both everolimus and sunitinib for pancreatic NET. These 

large randomized studies demonstrated improvement of progression-free survival 

validating the PI3K/Akt/mTOR pathway and angiogenesis as important targets for 

further advances. These studies also showed some of the challenges of NET including 

patient accrual and disease heterogeneity. Ongoing phase III studies comparing 

bevacizumab versus interferon and everolimus versus placebo among patients with 

other NET subtypes may bring much needed advances in areas of unmet need. 

Development of rational combinations is also ongoing. These ongoing studies as well 

as our improved understanding of the underlying molecular biology will bring 

needed advances. 

Disclosure: J.C. Yao: Consultant relationship with Ipsen, Lexicon, Novartis, Pfizer. 

1703IN IMPLICATIONS FOR CLINICAL PRACTICE AND TRIAL 

DESIGN 

K. Oeberg 

Endocrine Oncology, University Hospital Uppsala Akademiska Sjukhuset, 

Uppsala, SWEDEN 

Neuroendocrine GI tumors have demonstrated increase in incidence and prevalence 

during the last decades, reaching an incidence of 6/100,000 population recently. One 

of the reasons for the increasing incidence and prevalence is greater awareness 

among physicians about these conditions but also a better diagnosis and treatment. 

Development of specific biomarkers, such as chromogranin A both for 

histopathology and marker in the circulation, facilitate the establishment of correct 



abstracts

diagnosis and can also be used for follow-up of the patient. Molecular imaging is 

another important step forward including somatostatin receptor scintigraphy, 

Gallium-68 DOTATATE, PET/CT as well as more specific PET-tracers such as 

C11-5HTP and GLP1 binding tracers. Molecular images are not only for localisation 

of the disease, but also for staging and of course also give information about the 

metabolism and tumor biology. For several decades biotherapy has been applied in 

patients with slow-growing NETs including somatostatin analogs and alpha 

interferon. The tumor cells express specific receptors for somatostatin as well as 

interferon. In recent days targeted treatment has been instituted with tyrosine kinase 

and mTOR inhibitors. These treatments have been particular useful for pancreatic 

NETs where preclinical evaluation of a single transduction pathways, such as IGF1 

receptor signalling as well as the mTOR signalling pathway has been explored and 


demonstrated to be activated in many of these tumors. In recent years peptide 

receptor radiotherapy based on somatostatin analogs, such as 177 Lutetium 

DOTATATE and 90 Yttrium DOTATOC has been applied in NETs with significant 

antitumor effect and prolongation of survival. In the future the treatment will be 

based on tumor biology, molecular genetics and thereby aiming at personalized 

medicine. It will include combinations of new cytotoxic therapies (temozolomide, 

capecitabine) together with targeted agents such as sunitinib and everolimus, but also 

combined with PRRT. 

Disclosure: K. Oeberg: Advisory Board: Ipsen, Novartis. Speakers Buerau: Ipsen, 

Novartis, Pfizer 


hot topics in early stage nsclc 

77IN CUSTOMIZED ADJUVANT CHEMOTHERAPY: PROGNOSTIC 

AND PREDICTIVE FACTORS 

G. Bepler 1 , J. Moon 2 , R. Zinner 3 , R. Calhoun 4 , K. Kernstine 5 , C. Williams 6 , 

P. Mack 7 , V. Oliveira 4 , D. Gandara 8 

1 Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, 

Detroit, MI, UNITED STATES OF AMERICA, 2 Research, SWOG Statistical Center, 

Seattle, WA, UNITED STATES OF AMERICA, 3 Research, MD Anderson Cancer 

Center, Houston, TX, UNITED STATES OF AMERICA, 4 Cardiovascular, University 

of California Davis, Sacramento, CA, UNITED STATES OF AMERICA, 5 Thoracic 

Surgery, City of Hope, Duarte, CA, UNITED STATES OF AMERICA, 6 Research, 

Moffitt Cancer Center, Tampa, FL, UNITED STATES OF AMERICA, 7 Research, 

University of California Davis, Sacramento, CA, UNITED STATES OF AMERICA, 

8 Thoracic Oncolology Program, UC Davis Cancer Center, Sacramento, CA, 


Background: Adjuvant chemotherapy provides a small, but significant, survival 

advantage for patients (pts) with completely resected stage II and III non-small-cell 

lung cancer (NSCLC). Prior data suggest that benefit from platinum-based adjuvant 

therapy is limited to pts with low levels of ERCC1 (E1) expression. RRM1 (R1) is the 

molecular target and key efficacy determinant for gemcitabine. We conducted a 

prospective clinical trial (SWOG-0720, NCT00792701) to determine if treatment 

selection based on in situ tumoral levels of E1 and R1 is feasible in a mixed 

environment of academic and community practices. 

Methods: Eligibility was confined to pts with a complete resection of stage I disease 

and a tumor diameter of 2 cm or larger. Biomarker levels were determined at the 

protein level using automated quantitative analysis (AQUA, range of expression 1 - 

255), and classified as high or low based on a priori cut-off values (E1 >65.0; R1 

>40.0). Treatment consisted of four three-weekly cycles of cisplatin/gemcitabine (80 

mg/m 2 on day 1 and 1 g/m 2 on days 1 & 8) for those with low E1 and/or R1 levels. 

Pts with high levels of both markers were observed. Feasibility was defined as 

treatment assignment within 12 weeks from surgery in at least 75% of eligible pts. 

Results: 85 pts accrued between March 2009 and April 2011. Two pts were ineligible 

because of inadequate mediastinal lymph node sampling. E1 and R1 levels were 

successfully determined in all 83 eligible pts, and 72 pts (87%) were successfully 

assigned within the allotted time period. 64 pts (77%) were assigned to 

chemotherapy and 19 (23%) to observation. E1 levels ranged from 4.3 – 211.2 

(median 44.7), and R1 levels ranged from 2.5 – 234.4 (median 39.3). Pts 

demographics: median age 64 y, age range 41-84 y, ♂/♀ = 48/52%, adeno/squam/ 

other = 59/28/13, stage IA/IB = 38/62%, PS 0/1 = 52/48%. 

Conclusions: Adjuvant treatment assignment is feasible in pts with completely 

resected NSCLC in the cooperative group environment, and treatment assignment to 

chemotherapy vs observation was not significantly different from prior experience. 

Support: NCI grants U10-CA014028, U10-CA032102, U10-CA038926, 

U10-CA046368, U10-CA046441, U10-CA105409, P30-CA022453, R01-CA129343 


78IN IS THERE A ROLE FOR TARGETED AGENTS OR BIOLOGICALS 

IN STAGE I–III NSCLC? 

O. Gautschi 

Medizinische Onkologie, Luzerner Kantonsspital, Luzern, SWITZERLAND 

More than half of the patients with non-small cell lung cancer (NSCLC), including 

different tumor stages and histology subtypes, have actionable driver mutations. In 

patients with advanced NSCLC and activating EGFR mutations, randomized phase 

III trials with EGFR inhibitors (gefitinib, erlotinib and afatinib) demonstrated 

superior response rates and progression free survival compared with chemotherapy. 

Phase II trials showed high response rates for crizotinib in advanced NSCLC with 

ALK-translocation and the results of two randomized phase III trials are awaited. 

Preliminary data from phase I-II trials and retrospective series suggest further targets 

for tumor-specific therapies, including MET, ROS1, HER2, BRAF, KRAS, PI3K and 

others. Moreover, bevacizumab and cetuximab have shown clinical activity in phase 

III trials in combination with chemotherapy in patients with advanced NSCLC 

selected by histology and EGFR expression, respectively. Rapid molecular testing is 

now available at many institutions, and the translation of these novel therapies from 

stage IV to earlier stages has begun. Caution is warranted, because cure – not tumor 

response – is the ultimate goal of therapy, and the use of new drugs outside of a 



clinical trial in patients with stage I-III NSCLC may be risky. Of note, S0023 and 

BR.19 showed no benefit with the addition of gefitinib to a radical treatment in 

patients with localized NSCLC, irrespective of EGFR mutation status. Furthermore, 

phase III trials suggested a possible antagonism when EGFR-TKIs were combined 

with chemotherapy in patients with stage IV NSCLC. More recent studies indicate 

that such negative interaction may be avoided by pharmacodynamic separation (or 

"intercalation"), and that EGFR-TKIs as single agents could be used safely and 

effectively as induction therapy before surgery in carefully selected patients with stage 

I-III NSCLC. At the meeting, these data will be reviewed, and ongoing trials in this 

field will be discussed, including RADIANT (erlotinib), ADJUVANT (gefitinib), and 

ECOG 1505 (bevacizumab). Clinical cases will be presented to highlight problems 

and pitfalls of treating patients outside of controlled trials, and new avenues for 

clinical and translational research will be elucidated. 


79IN WHO SHOULD BE CONSIDERED FOR SURGERY FOR STAGE III 

DISEASE AND WHY? 

G. Stamatis 

Thoracic Surgery and Endoscopy, Ruhrlandklinik/University Essen, Essen, 

GERMANY 

For the treatment of patients with locally advanced NSCLC is important to recognize 

the variety of manifestations of the disease and the heterogeneity in the subgroups, 

so that surgery, multidisciplinary care or non-surgical approach can be tailored to 

the individual patient. For stage T3N1 and T1-3 N2A1/2 disease primary complete 

resection and systematic lymphadenectomy is beneficial for patients with functional 

and medical operability. Adjuvant chemotherapy is recommended. After incomplete 

resection reoperation is indicated, otherwise radiation is necessary. Patients with 

functional and/or medical inoperability are best treated by simultaneous or sequential 

chemo-/ radiotherapy or radiotherapy alone. For stageT1-3 N2A3 disease by 

technically resectabel patients, induction treatment (CTx or CTx/RTx) followed by 

resection results the best long term results. For patients with surgery and R0 

resection after induction CTx alone, postoperative RTx is recommended. For patients 

with single LNstation involved, primary surgery followed by CTx/RTx is possible. For 

patients with StageT1-3 N2A4 bulky disease and acceptable performance status, 

combination of chemotherapy and radiation is the choice of treatment. For selected 

cases after induction chemotherapy and good response the integration of surgery 

could be followed (if possible inside of studies). For stage T4N0-1 disease primary 

surgery or integration of surgery in a multimodality treatment is recommended for 

patients with functional and medical operability and involvement of carina, trachea, 

atrium, vena cava, pulmonary artery, vertebral body or metastasis in other lobe 

ipsilateral. Treatment strategies for IIIB disease are reduction of tumor associated 

symptoms and increasing of survival. For stageT4 N2, T1-3N3 disease combination 

of chemotherapy and radiation is the choice of treatment. For selected cases after 

induction CTx/RTx and good response the integration of surgery could be followed 

(if possible inside of studies). For sulcus superior tumors stage II-IIIB induction 

CTx/RTx followed by surgery is recommended. Technical or functional inoperable 

patients should receive a definitive CTx/RTx. The multidisciplinary approach 

maximizes the chance of long term survival and minimizes the treatment related 

morbidity and mortality. 


80IN WHAT IS THE OPTIMAL RADIOTHERAPY COMBINED 

WITH CHEMOTHERAPY FOR STAGE III DISEASE? 

D. De Ruysscher 

Department of Radiation Oncology (Maastro), Grow, Maastricht University 

Medical Centre, Maastricht, NETHERLANDS 

For most stage III (T4, N2/3) NSCLC concurrent chemo-radiotherapy is the first 

choice treatment. Many series used a “standard” radiotherapy schedule of 60-66 Gy 

in 2 Gy QD fractions, combined with cisplatin and etoposide or vinorelbin or 

carboplatin-paclitaxel (CP). However, local recurrences (LR) occur in 30-50 % of the 

patients. The observation that an improvement of local control (LC) leads to higher 

overall survival (OS) rates even at 5 years, has fuelled research aiming at increasing 

LC. Based on a phase II trial suggesting OS with 74 Gy/ 35 QD fractions over 60 Gy/ 

30 QD fractions given concurrently with CP followed by two cycles adjuvant CP, and 

the possible beneficial effect of cetuximab as well, the RTOG embarked with the 

randomised phase III trial RTOG 0617. Patients were treated with weekly CP and 

either 60 Gy or 74 Gy in 2 Gy QD fractions, either with or without cetuximab, 

followed by two cycles of consolidation CP ± cetuximab. At a planned interim 



abstracts

analysis at 11 months median follow-up and including 213 patients in the 60 Gy arm 

and 204 having received 74 Gy, the high-dose arm had a worse OS (20.7 months vs. 

21.7 months, p = 0.02) and was closed. However, dose escalation can also be achieved 

by increasing biological intensification, rather than by adding fractions and thus 

increasing the overall treatment time. Most ongoing clinical trials on radiation dose 

intensification thus use individualised, accelerated iso-toxic radiotherapy (INDAR), 

based on organ at risk (OAR) constraints as their backbone. Obviously, much more 

knowledge needs to be obtained on the complex interactions between systemic 

treatments and radiotherapy and their effects on malignant tissues and OARs. RTOG 

0617 nevertheless illustrates that with current standard radiotherapy doses and 


fractionation, when delivered in well selected patients and when the whole treatment 

chain is of high quality, much better long-term survival can be achieved than in 

historical series. In view of the preliminary data of RTOG 0617 and ongoing dose 

intensification trials, radiation dose intensification is certainly not obsolete. For 

standard practice, current protocols and guidelines should not be changed but 

emphasis on quality assessment and if needed adjustment of the entire diagnostic, 

treatment and supportive care process should be the main goal. 



latest innovations in nsclc management 

81IN PERSONALIZED THERAPY AND BIO-MOLECULAR DRIVEN 

TREATMENT IN LUNG CANCER 

T. Mitsudomi 

Department of Thoracic Surgery, Kinki University Faculty of Medicine, 

Osaka-Sayama, JAPAN 

Discovery of activating mutation of the EGFR gene in 2004 opened the era of 

personalized therapy in thoracic oncology. These tumors are highly dependent on 

the EGFR pathway and inhibition of this pathway results in dramatic induction of 

apoptosis in vitro, even though cancer cells may have various genetic alterations 

(oncogene addiction). These observations were soon translated into clinical trials. 

Recent 4 phase III clinical trials for patients with EGFR mutation (NEJ 002, 

WJTOG3405, OPTIMAL, EURTAC) reproducibly showed significantly longer 

progression free survival for those treated with EGFR-tyrosine kinase inhibitors 

(TKI) than those treated with platinum doublet chemotherapy. Although there was 

no difference in overall survival probably due to high crossover rate, it was 

noteworthy that 40% of patients in EGFR-TKI arm were able to go without 

platinum doublet and yet had similar survival outcome in WJTOG3405 In 2007, it 

was found that ∼5% of adenocarcinoma of the lung harbors EML4-ALK 

translocation and that these tumors are also addicted to the ALK pathway. Clinical 

development of the first ALK-TKI, crizotinib, focusing on tumors with ALK 

translocation was quick in spite of its rarity. Just 4 years after discovery of 

EML4-ALK, crizotinib was approved by FDA for lung cancer with ALK 

translocation in 2011 We have learned how effective the targeted therapy is, when 

“addicted oncogene” was pharmacologically inhibited. List of addicted oncogenes is 

expanding continuously and now it includes HER2, ROS1 or RET in 

adenocarcinoma of the lung. Efforts are also being made to identify addicted 

oncogenes in squamous cell carcinoma. Variant III of the EGFR gene, mutations of 

the DDR2 gene, amplification of the FGFR1 gene seem to be attractive targets of 

therapy. However, even in patients with dramatic initial response in these addicted 

tumors, resistance almost inevitably develops typically after less than 1 year. 

Mechanisms of the resistance include secondary mutation of the targeted gene and 

activation of alternative pathways. The future clinical trials should be based on 

individual mechanism found in re-biopsy specimens. It is also a challenge how 

efficaciously these oncogene alterations are identified in each clinical specimen. 

Disclosure: T. Mitsudomi: I received honorarium from AstraZeneca, Chugai, 

Elo-Lilly, Pfizer, Daiichi-Sankyo and Taiho. I also served as an advisory board for 

Boehringer-Ingelheim, Pfizer, AstraZeneca, Chugai, Eli-Lilly, Merck-Serono. 

82IN MOLECULAR MECHANISMS OF ACQUIRED RESISTANCE 

TO KINASE INHIBITORS 

L.V. Sequist 

Cancer Center, Massachusetts General Hospital, Boston, MA, UNITED STATES 

OF AMERICA 

The discovery of mutations in the epidermal growth factor receptor (EGFR) gene was 

been a turning point in clinical lung cancer care. We now know from multiple phase 3 

randomized clinical trials that patients with advanced lung cancer should be screened 

for EGFR mutations at the time of diagnosis and that first-line genotype-specific 

therapy with EGFR tyrosine kinase inhibitors (TKIs) can improve progression-free 

survival and quality of life compared to standard chemotherapy. In the last few years 

we have seen other examples of successful genotype-directed therapy for lung cancers 

with ALK and ROS translocations. However, one significant obstacle that we face in 

the clinic today is the development of acquired resistance to therapy. In this lecture, we 

will review what is known about acquired resistance to TKI therapies and discuss 

possible strategies for treating and/or preventing acquired resistance. 

Disclosure: L.V. Sequist: I have done paid consulting for Clovis Oncology and GSK. 

I have done pro-bono consulting for Merrimack Pharmaceuticals, 

Boehringer-Ingelheim and Daiichi-Sankyo 



83IN NEW STRATEGIES ON THE HORIZON 

T.S.K. Mok 

Department of Clinical Oncology, Chinese University of Hong Kong Prince of 

Wales Hospital, Shatin, Hong Kong, CHINA 

Since the discovery of activating epidermal growth factor receptor (EGFR) mutation 

in 2004, personalized therapy for patient with advanced non-small lung cancer 

(NSCLC) has become a reality. EGFR TKI and ALK inhibitor are standard treatment 

for pt with the target. Mutational status of signalling genes is key to management of 

lung cancer. Base on this principles, there are a number of new treatment strategy on 

horizon. Clinical application of genome profiling is a strategy that may improve the 

outcome of personalized therapy. Population genome profiling has provided 

important information on patients with adenocarcinoma. A number of population 

based genome profile from patients with adenocarcinoma in USA, France, China and 

Japan have been reported. EGFR mutation is more common in Asian population 

while KRAS mutation is much less common. Other mutations on ALK, BRAF, 

HER-2, PI3K, or MET are less frequent and similar across population. Future 

strategy will be personal genome profiling. With the improvement in efficiency and 

reduction in cost of second-generation sequencer, it will be feasible and practical to 

formulate treatment strategy according to genome profile. However, genome profile 

may vary over time and between tumors. Genomic heterogeneity must be addressed 

if attempt is comprehensive control of all tumor sites by a single targeted therapy. 

Gerlinger et al (NEJM 366:883, 2012) performed extensive exome sequencing from 

multiple site of renal cells tumor and its metastasis, and found 63 to 69% of somatic 

mutations are not consistently present in all tumor regions. Intra-tumor 

heterogeneity included the mTOR gene which is the primary target for approved 

therapy such as everolimus. Thus authors concluded that single site needle biopsy 

may not be representative of the genomic status of the tumor. Other examples 

including pancreatic cancer and breast cancer also review similar heterogeneity. 

There is no reason to believe lung cancer to be different. New strategy must be form 

to address tumor heterogeneity. In summary, new treatment strategies included 

individualized genome profiling and study of tumor heterogeneity. More specifically 

there should be upcoming treatment strategy for KRAS mutation and squamous cell 

carcinoma. 

Disclosure: T.S.K. Mok: Consultancy with Astrazeneca, Roche, Pfizer, Eli Lilly, 

Merck Serono, Beigene, Eisai, Jannsen, Taiho Speaker engagment with Astrazeneca, 

Roche, Pfizer, Eli Lilly, Merck Serono 

84IN BREAKTHROUGHS IN BASIC RESEARCH 

P.A. Janne 

Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA, 


Over the last few years several basic research studies have led to new therapeutic 

insights into the treatment of patients with advanced non-small cell lung cancer 

(NSCLC). These include genomic studies of lung cancers which have revealed 

novel potential therapeutic targets. One such target is fibroblast growth factor 

receptor (FGFR) 1 which has been found to be amplified in a subset of 

squamous cell lung cancers. Preclinical studies have further demonstrated that 

inhibition of FGFR1 kinase activity using FGFR tyrosine kinase inhibitors (TKIs) 

may be clinically effective in this subset of NSCLC. Clinical trials are now 

underway using FGFR TKIs in this subset of NSCLC. A second example is the 

identification of novel genomic rearrangements of the RET oncogene in NSCLC. 

These rearrangements lead to a fusion gene (KIF5B-RET) which is transforming 

in vitro and in vivo. Several already approved kinase inhibitors, including 

vandetinib, sorafenib and sunitinib, also inhibit RET and may be effective as 

clinical therapies in this subset of NSCLC. In addition, several more potent RET 

TKIs are under preclinical development and undergoing validation in model 

systems. A second recent basic science advance is the use of mouse models of 

lung cancer to mirror ongoing or planned clinical trials. These “co-clinical” trials 

aim to use the murine models to determine if they can predict the outcome of 

human trials and/or be used to further understand the success and limitations of 

the therapeutic approach. A recent example evaluated docetaxel and the MEK 

inhibitor selumetinib compared to docetaxel alone in a genetically engineered 



abstracts

mouse model of Kras mutant NSCLC. In this mouse model the combination led 

to a greater response rate and progression free survival compared to docetaxel 

alone. The result was similar in a recent clinical trial of the same therapeutic 

design in KRAS mutant NSCLC. Interestingly, in the mouse model, those tumors 

with concurrent Lkb1 loss (occurs in about 30% of KRAS mutant NSCLC in 

humans), the combination of docetaxel/selumetinib was significantly less effective. 

These findings open the possibility of evaluating the impact of LKB1 loss in 

KRAS mutant NSCLC patients treated with selumentib/docetaxel and more 

broadly underscore the potential utility of animal models in informing the design 

of human clinical trials. 

Disclosure: P.A. Janne: I have acted as a consultant to Pfizer, Boehringer Ingelheim, 

Astra-Zeneca, Roche, Genentech and Sanofi 

85IN IMPLICATIONS FOR CLINICAL PRACTICE 

M. Reck 

Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, GERMANY 

Treatment of advanced non-small cell lung cancer (NSCLC) has become quite 

complex and differentiated according to a variety of clinical, histological and 

molecular markers. This development does have several implications on diagnosis 

and treatment of patients in clinical practice: • Molecular screening for activating 

EGFR mutations should be routinely performed in patients with advanced non 

squamous NSCLC. In clinical practice intensification of cooperation between 

oncologist and pathologist will be crucial in order to optimize the exchange of 


information and in order to minimize the time to the receipt of the test results. 

For the future sequential biopsies for the identification of resistance mediating 

mechanisms will be of increasing importance and should be integrated in the 

diagnostic algorithm. • In the future a variety of highly specific drugs will be 

available or investigated in patients with molecular oncogenic alterations which do 

occur in NSCLC with frequency of less than 5%. In clinical practice it will be 

essential to create interregional diagnostic and therapeutic networks to be able to 

identify and to treat most of these patients adequately. • By introducing new 

targeted therapies in treatment of Lung Cancer also a variety of specific side 

effects has been established. In clinical practice awareness as well as sufficient 

management strategies will be crucial to facilitate these therapies. • Maintenance 

therapies either by targeted agents of by cytotoxic chemotherapy will be of 

growing importance in the future. Unlike classical cytotoxic chemotherapy these 

treatments are not characterized by a clear and defined number of cycles but by 

duration of treatment according to tumor response and tolerability. This new 

paradigm of treatment does have relevant implication on the interaction and 

communication between patient and physician. • Most of the efficacy information 

does come from highly selected trial populations in good Performance status. 

Unfortunately very few data are available for patients in restricted PS which 

represents a substantial subgroup of patients in daily life. In summary the 

integration of new agents and new strategies offers a great chance to improve 

outcomes of lung cancer patients but changes in diagnosis and treatment 

schedules will have great implications in clinical practice. 

Disclosure: M. Reck: Member of Advisory Board (compensated): Hoffmann-La 

Roche, Lilly, AstraZeneca, Daiichi-Sankyo, BMS Honoraria for lectures: Hoffmann-La 

Roche, Lilly, AstraZeneca, Daiichi-Sankyo 


evidence based answers to critical 

questions on cancer screening 

and prevention 

86IN HPV ELIMINATION OF CERVICAL CANCER: THE NOVEL 

OPTIONS IN VACCINATION AND SCREENING 

J. Cuzick 

Centre for Cancer Prevention, Queen Mary University of London, London, 


The recognition that infection with certain human papillomavirus (HPV) types 

is a necessary cause of cervical cancer has opened new fronts for the prevention 

of this disease. Primary prevention is now possible via immunization and 

secondary prevention has gained impetus with the availability of HPV DNA 

testing. Although universal vaccination of teenagers and young women is a 

desirable policy, even with high uptake a substantial reduction in the burden of 

cervical cancer is unlikely for at least 10–15 years. To achieve cost-effective 

reductions, screening and immunization must be considered as integrated 

approaches. Several novel options are possible. If the nonavalent vaccine proves 

to be effective, a screen and vaccine strategy in older women is attractive, and 

raises the possibility of virtually eliminating cervix cancer in 5-10 years. New 

approaches for triage following primary HPV-based screening are also being 

developed and promise to substantially reduce referrals for non-progressive 

infections. These include HPV typing, p16 and methylation of viral and human 

genes. Lastly, the use of self sampling is likely to increase in vaccinated women 

with less frequent HPV-based tests. New collection devices and transport media 

will be needed to facilitate this. 

Disclosure: J. Cuzick: Advisory boards for Abbott, Becton-Dickinson, Roche, 

GenProbe, Qiagen, Glaxo Smith Kline, Merck. 

87IN PROSTATE CANCER: WHAT ARE THE PROSPECTS AND 

GUIDELINES FOR SCREENING AND PREVENTION? 

H. De Koning 

Public Health, Erasmus MC, Rotterdam, NETHERLANDS 

The European Randomized Study of Screening for Prostate Cancer (ERSPC) 

showed a significant prostate cancer mortality reduction in the screening group of 

21% after a median follow-up of 11 years, and of 29% in screened men when 

adjusted for selection bias. However, PSA screening is associated with considerable 

unfavorable effects. In the ERSPC screening group, cumulative incidence of 

prostate cancer was 7.4%, versus 5.1% in the control group. A proportion of the 

screen-detected tumors (10-56%) would never have led to clinical symptoms but 

these over-diagnosed cancers are frequently treated with associated risks of adverse 

effects. Furthermore, because of a long lead-time, estimated 5-12 years, men have 

to live longer with those effects. Two specific studies on quality of life after 

prostate cancer treatment have been performed for men participating in 

Rotterdam and Sweden. Pre-operatively 1-2% of the men were incontinent and 

31-40% impotent. After 18-52 months 6-16% of the radical prostatectomy patients 

and 3% of the radiation therapy patients were incontinent. Six to 52 months after 

radical prostatectomy, 83-88% of pre-operatively potent men became impotent, 

compared with 42-66% of the men receiving radiation therapy. In this lecture the 

effects of screening strategies on prostate cancer mortality and quality of life will 

be quantified, using the well-validated MISCAN-model, developed by our institute, 

and hereby using results from the ERSPC. The implications of our results are that 

the benefit of PSA screening is diminished by loss of QALYs, that is dependent 

primarily on post-diagnosis long-term utility assumptions. Longer follow-up data 

from both the ERSPC and quality of life and cost-effectiveness analyses are 

essential for making universal recommendations regarding screening, but it is 

possible that limited testing of middle-aged men with relatively long intervals is a 

cost-effective public health policy. 




88IN SCREENING FOR COLORECTAL CANCER: EUROPEAN 

GUIDELINES 

N. Segnan 1 , J. Patnick 2 , L. von Karsa 3 

1 Head, Department of Cancer Screening and Unit of Cancer Epidemiology, CPO 

Piemonte and S.Giovanni University Hospital, Turin, ITALY, 2 Nhs Breast 

Screening Programme, Oxford University, Sheffield, UNITED KINGDOM, 3 Quality 

Assurance Group, International Agency for Research on Cancer, Lyon Cedex, 

FRANCE 

Screening for colorectal cancer: European guidelines for quality assurance According 

to the most recent estimates by the International Agency for Research on Cancer 

(IARC) colorectal cancer (CRC) is the most common cancer in Europe and it is one 

of the most causes of cancer death in Europe. Worldwide CRC ranks third in 

incidence and fourth in mortality with an estimated 1.2 million cases and 0.6 million 

deaths annually. In the 27 Member States of the European Union (EU), CRC ranks 

first in incidence and second in mortality in both sexes, with approximately 334 000 

new cases and 149 000 deaths estimated for men and women combined in 2008. 

Even in those Member States in the lower range of age-standardised rates of CRC, 

the burden of disease is significant compared to other regions of the world. CRC is 

therefore an important health problem across the EU. Screening is an important tool 

in cancer control in countries with a significant burden of CRC, provided the 

screening services are of high quality. The EU recommends population-based 

screening for breast, cervical and colorectal cancer using evidence-based tests with 

quality assurance of the entire screening process including diagnosis and 

management of patients with screen-detected lesions. In this context, 

multidisciplinary evidence-based guidelines for quality assurance in colorectal cancer 

screening and diagnosis have been developed by experts in a project coordinated by 

the IARC. The full guideline document covers the entire process of population-based 

screening. It consists of 10 chapters and over 250 recommendations, graded 

according to the strength of the recommendation and the supporting evidence. The 

450-page guidelines and the extensive evidence base have been published by the 

European Commission. The content of the executive summary is presented here to 

promote international discussion and collaboration by making the principles and 

standards recommended in the new EU Guidelines known to a wider professional 

and scientific community. Following these recommendations has the potential to 

enhance the control of colorectal cancer through improvement in the quality and 

effectiveness of screening programmes and services. 


89IN CANCER REGISTRIES IN SUPPORT OF PLANNING AND 

ASSESSING POPULATION BASED ONCOLOGY OUTCOMES 

J.W. Coebergh 

Department of Public Health, Erasmus MC, Rotterdam AND Comprehensive 

Cancer South (IKZ) Eindhoven, NETHERLANDS 

The about 200 population-based cancer registries in Europe are currently in an 

upswing thanks to an ERA-net FP7 project named EUROCOURSE www.eurocourse. 

org that aims to strengthen their infrastructure in order to better serve the clinical 

oncology and public health communities and policymakers to solidify & improve 

prevention (primary and through mass screening), cure (including quality of care) 

and care (both survivorship and palliative) in various ways: - clarifying widely 

diverging governance and budgets, despite uniform operational methodology and 

training needs of both data collectors and data analysts, which warrants valid, 

neutral, safe and integer data gathering and timely information ‘production’ on all 

aspects of incidence and prognosis of the cancers ‘that be’ both through on-line and 

peer-reviewed reporting and with a new European dataportal at IARC - promoting 

enrichment by linkages with other data sources, e.g. vital statistics and research, e.g. 

EPIC-study, and occupational, screening and clinical cohorts, with due attention to, 

traditionally very well kept, data protection (alas hampered by unwarranted obstacles 

in certain memberstates (a sequel from an unfortunate dictatorial past + incorrect 

interpretation of EU directive 95/46). - allowing registries to be sampling frame for 

in-depth studies of quality of care (adherence to guidelines/best practice?) both 

process and outcome carried out with more speed/urgency than usual because also 

needed in areas/parts of Europe without registry coverage, i.e. in or within more than 

50% of the EU, especially in larger memberstates) not only of first line treatments 

due to increasing application of targeted drugs and survivorship in the various 

phases of the disease - allowing depth via strategic collaborations with clinical, 

etiological, screening databases (stakeholders), promoting the cost-effectiveness of a 

rich infrastructure serving many users (Nordic ‘model’) versus the current threat of 

fragmentation by tumourspecific clinical databases (at risk for becoming data 

cemetaries) With the tree as metaphor a landscape of registries is shown, remaining 

close to its clinical roots. Major European references Comment: Lancet Oncology 

2005;6:193-5 Trends: Eur J Cancer 2008;44:1345-89 Recent data: Eur J Cancer 

2010;46:765-81. 



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abstracts

abstracts 

subtyping soft tissue sarcomas for 

treatment approaches 

90IN WHY WERE IGF-1R INHIBITORS DISAPPOINTING? CAN WE 

IMPROVE ACTIVITY BY BETTER PATIENT SELECTION OR USE 

OF COMBINATIONS? 

I. Judson 

Sarcoma Unit, Royal Marsden Hospital, London, UNITED KINGDOM 

It is been known for many years that the insulin-like growth factor (IGF) signalling 

pathway is important in human cancer. The IGF-1 receptor (IGF-1R) is upregulated 

in colorectal, breast, prostate and lung cancers. It was also known to be a potential 

target in Ewing’s sarcoma. The advent of specific monoclonal antibodies and small 

molecule tyrosine kinase inhibitors of IGF-1R led to many clinical trials. A 

combination of figitumumab with platinum doublet chemotherapy resulted in a 

higher response rate and improved progression-free survival (PFS) in phase II, but a 

phase III trial was negative. In Ewing’s sarcoma activity was seen with R-1507, 

figitumumab and other agents. However, response rates in phase II studies were 

generally low, 14.2% with figitumumab, and duration generally short, e.g. with 

figitumumab median PFS 1.9 months, median survival 8.9 months. Occasionally, 

durable responses have been seen lasting for several years. Could better selection by 

the use of circulating biomarkers, e.g. IGF-1, or IGF binding proteins, be useful or 

does the answer lie with combinations? Laboratory studies suggest that combining 

IGF-1R inhibitors with inhibitors of AKT/mTOR, EGFR or MEK, could help to 

overcome resistance. Given the dearth of new agents for Ewing’s sarcoma it is to be 

hoped that continued access to these agents will enable further work on mechanisms 

of resistance and appropriate combination phase I/II studies to be performed. The 

book is not yet closed on IGF-1R as a target. 


91IN SUCCESSFUL TARGETING OF VEGFR IN SOFT TISSUE 

SARCOMAS 

W.T.A. van der Graaf 

Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen, 

NETHERLANDS 

Successful targeting of VEGFR in soft tissue sarcomas Increasing evidence suggests 

that angiogenesis plays an important role in the biology of the heterogeneous group 

of soft tissue sarcomas (STS). During the last years clinical studies have shown the 

importance of targeting angiogenesis in STS. Most attention has been paid to 

pazopanib, a tyrosine kinase inhibitor, known for its activity in renal cell cancer. 

Pazopanib targets multiple kinases, including vascular endothelial growth factors 

(VEGFR1-3), and platelet derived growth factors. In a previous phase 2 study in 

relapsed or metastatic STS (EORTC study 62043) the progression free rate at 12 

weeks was promising in the strata of leiomyosarcoma, synovial sarcoma, and other 

types of STS, but was disappointing in liposarcoma patients. In the subsequent phase 

3 study which consisted of 372 metastatic STS patients, pazopanib was compared 

with placebo in a 2:1 fashion in patients with progressive non-adipocytic STS, who 

had had anthracyclines and all locally available systemic treatment options. The 

results of this so-called PALETTE trial (EORTC study 62072), which allowed no 

crossover, showed a statistically significant improvement in PFS of 3 months: 4.6 

months with pazopanib compared to 1.6 month with placebo. The final overall 

survival did not show a significant improvement, being 12.5 months with pazopanib 

and 10.7 months with placebo. Pazopanib was generally well tolerated. Most 

common adverse events were fatigue, diarrhea, nausea, weight loss and hypertension. 

The effect of pazopanib was observed in all subgroups of STS, which suggests a 

universal important role of VEGFR, but whether this is the driving force in the 

pathogenesis of all STS is unknown. Based on the positive results of the PALETTE 

study pazopanib has recently been approved by FDA and EMA for the treatment of 

patients with advanced STS who have received prior chemotherapy. GIST and 

liposarcoma were not part of this registration. Apart from VEGFR also VEGF has 

been the target of a couple of clinical studies in STS, either as single agent or as 

combination therapy. With the success of pazopanib in STS the pathogenic role of 

the VEGF-VEGFR pathway in STS becomes even more of interest than has been 

before and the challenge will be to further explore the success of targeting this 

pathway in future clinical studies. 




92IN TREATING SARCOMA (INCLUDING GIST) SUBTYPES BASED 

ON MOLECULAR CHARACTERISTICS 

J-Y. Blay 

University Claude Bernard Lyon I, Centre Léon Bérard, Lyon, FRANCE 

Recent progress in the understanding of the biology of soft tissue sarcomas and 

locally aggressive connective tissue tumors have enabled the identification of distinct 

molecular and pathological entities: six molecular subgroups of connective tissue 

tumors may be distinguished: 1) sarcoma with specific translocations generating 

fusion gene whose protein products modulate transcription or may act as growth 

factors (e.g. EWS/Fli1 in Ewing sarcomas, PDGF-col1a1 in DFSP); 2) sarcomas with 

mutated activated kinases (KIT in GIST); 3) sarcomas with deletion of tumor 

suppressor genes such as NF1 sarcomas, or rhabdoid tumors (INI1); 4) Sarcomas 

with simple genetic alterations (mdm2/cdk4 amplification in WD/DD liposarcomas; 

5) Sarcomas with gross genetic alterations (e.g. leiomyosarcomas); 6) Tumors with 

alterations of the intercellular adhesion pathways (aggressive fibromatosis with APC 

deletion or b catenin mutations). These classifications are rapidly evolving. The 

identification of the “driver” mutation in some of these diseases paved the way for 

the selection of efficient targeted therapies in sarcomas and locally aggressive 

connective tissue tumors such as GIST, DFSP, PEComas, PVNS … Even though the 

driving molecular event is not known, giant cell tumors of the bone fit in this 

category. Interestingly, with the refinement of molecular typing, even rare nosological 

entities evolve towards further fragmentation: the identification of KIT and PDGFRA 

mutations, then Raf, NF1, SDH mitated in GIST led to a rapid development of 

imatinib, sunitinib, and regorafenib, but with the more recent characterization of Raf, 

NF1, SDH gene muations, it is now recognized that GIST gathers probably 10 

different molecular entities with different therapeutic rules and prognosis in localized 

and advanced phase. Recently, it was shown that targeting MdM2/p53 interaction in 

sarcomas with MDM2 amplification can lead to an efficient reactivation of p53 and 

biological response in tumor cell. Targeting CDK4 may also be worth exploring in 

similar context. Targeting a pathway downstream of the driver mutation can however 

be more challenging: in Ewing sarcoma, whose fusion gene product regulates 

IGFBP3, anti–IGF1R Ab yielded responses in now several phase I and II trials but 

only in a small proportion of patents for reasons yet unknown. In addition to these 

examples, more empiric approaches have been successfully developed, with 

anti-angiogenics (pazopanib) and mTOR inhibitors (ridaforolimus) showing efficacy 

in phase III trials, in a broader group of sarcoma subtypes. Treating sarcoma 

subtypes according to their molecular characteristics is critical for the development 

of new treatments, and will also be essential to understand the biological 

mechanisms of response and resistance. 

Disclosure: J. Blay: Suppoted by grants from Novartis, GSK, Roche, Pharmamar 

93IN TARGETING HDM2 (HUMAN MDM2) IN SARCOMAS 

R.G. Maki 

Pediatrics, Medicine and Orthopaedics, Mount Sinai School of Medicine, NEW 

YORK, NY, UNITED STATES OF AMERICA 

Liposarcomas represent three families of genetically distinct cancers. The most 

common of these is well-differentiated / dedifferentiated liposarcoma (WD-DD LS), 

which represents half of the liposarcomas with an incidence of 4–5 per million 

people. The well differentiated version of the tumor appears somewhat like fat, while 

dedifferentiated liposarcomas have typically lost most or all ability to store lipids. 

WD-DD LS is a unique entity with high copy number amplification of chromosome 

12q, followed by loss of portions of other chromosomes, such as 19q13, in more 

aggressive tumors, which notably is the locus for CEBPA, a key main adipocytic 

differentation gene. On chromosome 12q are located important genes in maintaining 

cell survival, such as CDK4 and HDM2 (the human version of MDM2) and 

YEATS4. Recent data also show epigentic effects to turn off adiopocytic 

differentiation genes. The presence of the amplified genes such as those above as well 

as AURKA nearby suggests inhibitors of these proteins may be useful to trigger 

dysregulation and cell death of these tumors cells with highl abnormal genomes. 

CDK4 inhibitors and HDM2 inhibitors are now being examined in phase I-II clinical 

trials in WD DD LS patients. In this talk, the biological background for examining 

HDM2 inhibitors in WD DD LS patients is discussed, as well as the potential role 

for these inhibitors both in cancers with wild type p53 as well as those with 

genetically altered p53. There may not be the need to limit the examination of 

HDM2 inhibitors to WD DD LS, although issues remain regarding the toxicity 

observed with these compounds to date. 

Disclosure: R.G. Maki: Consulting fees: GlaxoSmithKline, Bayer, Sanofi, Lilly, 

Morphotek, Eisai, Pfizer Research Support: Eisai, Ziopharm, Roche Honoraria: 

Ziopharm, Novartis Unpaid consulting: n-of-one, 23 & Me 


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94IN PERSPECTIVES OF SUBTYPING IN SOFT TISSUE SARCOMAS: 

THE RELEVANCE FOR CLINICAL TRIAL DESIGN 

J. Verweij 

Department of Medical Oncology, Erasmus University Medical Center – Daniel 

den Hoed Cancer Center, Rotterdam, NETHERLANDS 

In the relatively recent past soft tissue sarcomas were lumped together for the 

purpose of studying treatment effects in clinical trials. This has clearly served a 

purpose in the development of non-specific cytotoxic agents. But even for 

cytotoxic agents more recently hints of selective sensitivity of sarcoma subtypes 

emerged. So one can state in general that using unselected populations in soft 

tissue sarcoma trials increases the ease of patient accrual, but at the same time 

diminishes the chance of achieving a statistically significant clinical benefit. The 

identification of KIT as a single tumor growth driver in Gastrointestinal stromal 

tumor (GIST), and its subsequent effective inhibition with imatinib, have further 

strengthened the realization that the various subtypes of soft tissue sarcomas 

should each be considered as unique diseases. Because of the rarity of soft tissue 

sarcomas in general and the linked limited number of patients for each individual 

sarcoma subtype, the now required further subsetting creates a challenge for 

current and future trial design. Evidence from recent trials suggests that, if they 

are based on well-characterized preclinical data and/or clinical observations, 

performance of trials in select histologic subtypes should be pursued and is 

feasible; at least for tumor cell related targeted therapeutic approaches. For targets 

in the tumor environment there are also signals that subsets may be more 

sensitive, although this does not ensure that the other subsets are totally 

insensitive. There seems to be a gradual differentiation of sensitivity. For several 

agents the sensitivity of subsets could be predicted with predictive biomarkers, but 

biomarkers were of more limited value of biomarkers in assessing individual 

clinical benefit. This yields yet another challenge, certainly for agents 

where growth inhibition rather than tumor regression is expected. All of these 

aspects are guiding us towards new trial approaches that will shortly 

be discussed. 



abstracts 

key topics in supportive care 

95IN PREVENTION AND TREATMENT OF OSTEONECROSIS 

C.A. Migliorati 

Diagnostic Sciences and Oral Medicine, University of Tennessee Health Science 

Center College of Dentistry, Memphis, TN, UNITED STATES OF AMERICA 

Jaw osteonecrosis associated with medications (JOM) is a significant oral 

complication of antiresorptive drugs (intravenous bisphosphonates and denosumab) 

used in the treatment of cancer patients with metastatic bone disease and multiple 

myeloma. This complication also develops in individuals with advanced cancers such 

as metastatic colorectal cancer, advanced nonsquamous non-small cell lung cancer, 

metastatic kidney cancer, glioblastoma, GIST, and advanced renal cell carcinoma 

treated with antiangiogenics (bevacizumab and sunitinib). There is also evidence that 

the use of these medications in combined protocols can increase the risk of JOM. 

The management of JOM is difficult and patient’s quality of life can be 

compromised. Literature has suggested that the diagnosis and stabilization of dental 

disease aiming risk minimization prior to starting antiresorptive or antiangiogenic 

therapy can prevent or reduce the incidence of JOM. Thus, referring patients for 

dental exam prior to initiating therapy with these drugs is recommended. 

Conservative dental therapy was the standard of care for JOM. The clinical progress 

of invasive dental therapy to eliminate necrotic bone was unfavorable with observed 

aggravation of the clinical defect and with the development of additional necrosis. 

Recently, more aggressive surgical protocols have been successful when using wide 

resection of necrotic bone, primary closure of the extraction site and a combination 

of topical and systemic antibiotics. The objective of this presentation is to update 

professionals who treat patients with solid tumors with bone metastasis such as 

breast, prostate and lung cancer, and bone malignancy like multiple myeloma, on the 

new definition of JOM, clinical characteristics of the lesion, prevention and patient 

management. Good communication between oncologists and dental professionals is 

critical for the success of patient management. We expect to demonstrate that this 

new oral complication could be used as an example to alert health care professionals 

working in oncology of the importance of maintaining strict surveillance of possible 

new complications that can develop with the use of new oncologic treatment, a fast 

developing field. 


96IN HOW TO DEAL WITH PATIENTS WITH ACTIVE 

HEPATITIS B & C 

J. Lubel 

Gastroenterology, Eastern Health, Melbourne, VIC, AUSTRALIA 

Chronic viral hepatitis is a global problem with approximately 350 million people 

infected with hepatitis B virus (HBV) and 170 million people infected with 

hepatitis C virus (HCV) worldwide. It is estimated that one-third of the worlds 

population (over 2 billion people) have been infected with HBV. In Europe the 

prevalence of HBV ranges between 0.1% and 7% whereas the prevalence of HCV 

ranges between 0.4% and 22%. These two viruses account for the majority of cases 

of chronic viral hepatitis and contribute to the development of cirrhosis and 

hepatocellular carcinoma, yet differ markedly in virology, natural history and 

management. In chronic viral hepatitis, equilibrium exists between the host’s 

immunity and viral replication. Immunosuppression allows viral replication to 

continue unchecked. In non-cirrhotic patients with HCV infection this rarely 

results in significant clinical sequelae and patients embarking on 

immunosuppressive therapy can generally be monitored. In contrast, patients 

infected with hepatitis B may have significant hepatitis ‘flares’ following periods of 

immunosuppression which can result in hepatic failure, need for liver transplant 

and occasionally death. The hepatitis B virus itself is not cytopathic; hepatic 

inflammation occurs as a result of immune-mediated injury and therefore generally 

occurs after maximal immunosuppression. The cornerstone to management of 

HBV in patients receiving chemotherapy is identification of currently or previously 

infected patients with appropriate requesting and interpretation of hepatitis B 

serology. In order to prevent HBV reactivation, all patients with chronic hepatitis 

B (CHB) should be started on antiviral prophylaxis before commencing 

immunosuppressive chemotherapy and for a period of 12 months after 

chemotherapy has been completed. In patients with high viral loads the use of 

antiviral agents with a high genetic barrier to resistance should be considered (eg 

entecavir and tenofovir). In those with low or undetectable viral loads lamivudine 

is an acceptable alternative. In patients who have apparently cleared hepatitis B 

(surface antigen negative, core antibody positive), HBV can reactivate with 

subsequent reappearance of surface antigen (seroreversion). This can be followed 

by clinically significant HBV flares. The risk of this occurring seems particularly 

high for regimens containing Rituximab. Patients unable to be monitored closely 

for reactivation with monthly HBV DNA quantification and liver function tests 

should receive antiviral prophylaxis. 


97IN INFLUENZA VACCINATION IN CANCER PATIENTS 

F. Menichetti 

Cisanello Hospital, Infectious Diseases Unit, Pisa, ITALY 

Seasonal influenza virus infections are an important cause of respiratory disease and 

cancer patients are at increased risk of complications. The CDC recommends annual 

vaccination with inactivated viral vaccine for immunosuppressed hosts including 

cancer patients. Limited data are available on the safety and immunogenicity of 

vaccination programs in this setting, especially for the optimal timing of vaccination 

during ongoing chemotherapy and the overall rate of influenza vaccination in cancer 

patients is quite low (30%). Mulder et al. (2001) reported similar seroprotection rate 

after seasonal flu vaccine for patients treated with tyrosyne kinase inhibitors and 

control group. Eggink et al. (2011) reported a lower response rate to flu vaccine in 

breast cancer patients compared to healthy controls; a trend toward better resoponse 

was documented in patients receiving vaccine early during chemotheraspy (day 4) 

compared to those vaccinated during the last week (day 16). In the VACANCE study, 

cancer patients receiving 2 doses of an adjuvated H1N1 vaccine developed an higher 

seroconversion rate with respect the single dose (73% vs. 44%). Mackay et al. 

reported a lower rate of seroconversion and seroprotection after H1N1 vaccination in 

hematological patients with respect to solid tumors patient; rituximab combined to 

chemotherapy was associated with the lower response rate to the flu vaccine. In 

summary, there is the need for further studies to optimize flu vaccine programs 

(patients selection, timing related to chemotherapy, dose schedule) in cancer 

patients. 


98IN THROMBOSIS IN CANCER PATIENTS 



M.A. Dicato 

Hematology- Oncology, Centre Hospitalier de Luxembourg, Luxembourg, 

LUXEMBOURG 

Arterial thrombosis is not a specific cancer related disorder except in some patients 

on some antiangiogenic drugs, but remains an infrequent event compared to venous 

thromboembolism (VTE). VTE is the second most frequent cause of death in cancer 

patients and is a predictor of mortality in hospitalized cancer patients. The death rate 

is about 30% in cancer patients when VTE occurs within 3 months of diagnosis. 

About 15% of patients suffering from cancer will have a VTE during the course of 

their disease and about 10% of patients with an idiopathic (?) VTE develop a cancer 

in the following two years. Risk factors for VTE in oncology are patient dependent, 

treatment dependent, type of cancer and stage dependent, The pathophysiology of 

VTE is complex. In addition to the standard causes, biomarkers and a clinical risk 

assessment score can be useful in deciding on time and duration of VTE prophylaxis 

and treatment. Prophylactic treatment in the ambulatory cancer patient needs to be 

discussed as newer anticoagulants like ultra low molecular weight heparin have been 

used recently in clinical trials and other novel agents (dabigatran, rivaroxaban and 

apixaban) marketed for orthopedic surgery and atrial fibrillation have become 

routine. The latter drugs are given orally, have negligeable interference with other 

medications or with foodstuffs and do not need laboratory surveillance. Approval for 

market release in VTE therapy in the general medical situation is pending and will 

certainly be used in the oncological setting if cost compatible. Various guidelines 

(ESMO, ASCO, NCCN …) are concurrent in their recommendations depending on 

disease activity, anti-cancer treatments (surgery, chemotherapy …) and the patient’s 

clinical situation. These will be discussed in regards to the ambulatory and 

hospitalized patient, for first episode and for recurrent VTE. Some data are available 

though not presently recommended, for anticoagulant therapy in oncology for 

improving survival. 




ESMO-ASCO Joint Symposium: 

Genomics in breast cancer: Opening 

new doors 

99IN NEXT GENERATION DNA SEQUENCING: FIRST RESULTS IN 

BREAST CANCER 

P. Campbell 

Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UNITED 

KINGDOM 

Cancer is driven by mutation. Using massively parallel sequencing technology, we 

can now sequence the entire genome of cancer samples, allowing the generation of 

comprehensive catalogues of somatic mutations of all classes. Bespoke algorithms 

have been developed to identify somatically acquired point mutations, copy number 

changes and genomic rearrangements, which require extensive validation by 

confirmatory testing. The findings from our first handful of breast cancer genomes 

illustrate the potential for next-generation sequencing to provide unprecedented 

insights into mutational processes, cellular repair pathways and gene networks 

associated with cancer development. I will also review possible applications of these 

technologies in a diagnostic and clinical setting, and the potential routes for 

translation. 


100IN GENE EXPRESSION PROFILING OF BREAST CANCER: PAST 

AND FUTURE 

C. Sotiriou, D. Fumagalli 

Breast Cancer Translational Research Laboratory, Institute Jules Bordet, 

Brussels, BELGIUM 

It is intuitive that a high-throughput technology able to define the expression 

level of thousands of genes at once is more suited to investigate the complexity 

of cancer compared to the evaluation of single genes’ expression. This explains 

why the advent of microarray technology has had a profound impact on the way 

the nature and the clinical evolution of breast cancer (BC) are now perceived 

and investigated. Several studies have demonstrated that BC consists of different 

diseases with specific molecular profiles and clinical behaviors that can help 

selecting patients for enrollment in clinical trials and orienting therapeutic 

approaches. Microarrays have also been used to identify gene expression 

signatures (GS) with a prognostic and/or predictive value. After a wave of “first 

generation signatures” mostly based on the ability of proliferation to discriminate 

which patients can be spared aggressive treatments, signatures of “second 

generation” have explored the prognostic value of gene related to immune 

response and stromal compartment. Multigene classifiers have also been 

developed to predict response to either generic or specific endocrino- or 

chemotherapies. Despite the reliability of microarray technology has been 

demonstrated, the clinical implementation of GS is still limited mostly in relation 

to the uncertainty of their added value compared to standard 

clinical-pathological factors. While the results of two big randomized trials will 

help establishing the clinical role of these GS, the evolution of molecular 

technologies is setting the stage for a new interpreter. Next generation 

sequencing technologies are in fact providing an incredible amount of data that 

is revealing new insight in the complexity of BC nature and evolution. When 

compared to microarrays, the ability of RNA sequencing to quantify the level of 

expression of genes seems to be highly correlated for both single genes and gene 

signatures. Moreover, RNA sequencing has the advantage of identifying 

additional molecular events such as editing, which can have a major impact on 

cancer evolution. Even if more data are needed to set the role of this technology, 

RNA sequencing holds the potential to complement and increase the knowledge 

acquired so far with microarrays. 




101IN PUTTING GENOMICS INTO CLINICAL PRACTICE 

A.M. Gonzalez-Angulo 

Department of Breast Medical Oncology and Dept. of System Biology, The 

University of Texas, Houston, TX, UNITED STATES OF AMERICA 

Over the last decade we have seen advances in breast cancer including the realization 

that breast cancer is not a homogenous disease but rather a conglomeration of a 

number of subtypes including luminal A, luminal B, HER2 enriched and basal like 

subtypes; each associated with a different prognostic outcome. The development of 

high-throughput techniques such as gene expression profiling platforms that are able 

to not only predict prognostic outcome but also, as the data indicate, predict for 

responsiveness to chemotherapy and thus being able to identify groups who may not 

require chemotherapy. Such data led to the endorsement for the use of Oncotype DX 

RS by ASCO and NCCN as both a prediction and prognostic tool among women with 

estrogen receptor-positive node negative breast cancer. The two prototypes that have 

the most clinical data reported and are being evaluated in prospective clinical trials are 

MammaPrint (Agendia, Inc., Amsterdam, The Netherlands) and Oncotype DX 

(Genomic Health, Inc., Santa Clara, CA). However the question remains as to whether 

such tools would be useful among women with node-positive disease. Women with 

node-positive disease have traditionally been considered to be at highest risk of 

recurrence. However, multigene assays may be able to identify a group of women with 

endocrine responsive, node positive disease that may not require chemotherapy thus 

avoiding the associated toxicities. Prospective trials will be essential to accurately 

identify the groups that will and will not benefit from chemotherapy. Until results of 

such studies are available the current guidelines still endorse the use of adjuvant 

chemotherapy among all women with node positive disease. 


102IN WHOLE GENOME SEQUENCING FOR LUMINAL-TYPE 

BREAST CANCER 

M.J. Ellis 

Siteman Cancer Center Breast Cancer Program, Washington University School 

of Medicine, St Louis, MO, UNITED STATES OF AMERICA 

Whole genome sequencing is an unbiased approach to detect all classes of somatic 

mutation in a cancer. To correlate the variable clinical features of 

oestrogen-receptor-positive breast cancer with somatic alterations, we applied this 

technique to pre-treatment tumour biopsies accrued from patients in two studies of 

neoadjuvant aromatase inhibitor therapy. Eighteen significantly mutated genes were 

identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously 

linked to haematopoietic disorders. These findings suggest that breast cancer, like 

leukaemia, can be viewed as a stem-cell disorder that produces indolent or aggressive 

tumours that display varying phenotypes depending on differentiation blocks 

generated by different mutation repertoires. Mutant MAP3K1 was associated with 

luminal A status, low grade histology and low proliferation rates, whereas mutant 

TP53 associated with the opposite pattern. Moreover, mutant GATA3 correlated with 

suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis 

demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar 

perturbations as MAP3K1 loss. These analyses also identified transcriptional 

associations to Ki67 response reside in a connected network under the control of 

several key ‘hub’ genes including MYC, FYN and MAP kinases, among others. 

Targeting these hubs in resistant tumours could produce therapeutic advances. Aside 

from the common PIK3CA mutations, druggable mutations were relatively 

uncommon, but were observed in HER2, KIT, PDGFA, DDR1/2, MET, JAK1, 

CSFR1, LTK, BRAF and AKT1/2. If these mutations are activating and drug sensitive 

these are significant findings since breast cancer is so common that drug sensitizing 

mutations with a 1% prevalence represents a population with a similar magnitude to 

CML and PML, diseases in which a randomized trials are feasible. Distinct 

phenotypes in oestrogen-receptor-positive breast cancer are associated with specific 

patterns of somatic mutations that map into cellular pathways linked to tumour 

biology, but most recurrent mutations are relatively infrequent. Prospective clinical 

trials based on these findings will require comprehensive genome sequencing and 

large mutation screening programs. 



ESMO-CSCO Joint Symposium: 

Building the clinical trials of the future 

103IN IS THE NEOADJUVANT MODEL AN ACCELERATED PATH 

TOWARDS BREAST CANCER TREATMENT TAILORING? 

EXPERIENCE OF THE NEOALTTO TRIAL 

M. Piccart 1 , H.A. Azim, Jr 2 

1 Head of The Chemotherapy Department, Jules Bordet Institute, Brussels, 

BELGIUM, 2 Breast Cancer Translational Research Laboratory, Institute Jules 

Bordet, Brussels, BELGIUM 

Around 5% of oncology agents in the development pipeline receive regulatory 

approval. This procedure is very long and expensive, which results in delaying the 

availability of effective therapies to patients. Furthermore, one available, they are 

provided at a considerably high cost to compensate for the exhaustive development 

process. What is more frustrating is that after such a process we still have a crude 

idea on the subsets of patients who will “truly” benefit a given agent. Hence, there is 

a need to adopt innovative strategies to accelerate drug development in a more 

efficient and targeted way. In breast cancer (BC), the neoadjuvant setting emerge as 

an excellent opportunity to incorporate biomarkers within the drug development 

process, taking the advent of the presence of a robust short term surrogate endpoint, 

like pathological complete response (pCR). It also allows interrogating the effect of 

novel therapies on BC biology, via the collection of samples pre and post therapy. 

These advantages would help in accelerating drug and biomarker development via 

the conduction of trials that are relatively small in size and short in duration. This 

would possibly have a positive impact on the health-care economics dimension as 

well. NeoALTTO is a phase 3 trial, which included 455 patients with HER2-positive 

non-metastatic BC. Patients randomized to lapatinib and trastuzumab in 

combination with paclitaxel had nearly double the pCR rate compared to those 

randomized to paclitaxel with either drug alone. A similar trial but in the adjuvant 

setting (ALTTO) including nearly 8,000 patients has recently completed accrual. If 

the higher pCR rate in the NeoALLTO trial translated into improved long term 

outcome and this was confirmed in ALTTO, this could represent an important 

milestone in the way we develop targeted agents in BC, and hence conducting huge 

trials like ALTTO might not be needed in the future. The NeoALTTO trial also had 

an extensive translational research and molecular imaging programs with their results 

expected to be available very soon. It is fascinating to see the tremendous amount of 

information that can be generated and the possible impact this might have on patient 

care, with a study that included less than 500 patients. Hence, this model encourages 

the adoption of the neoadjuvant setting in investigating novel agents/treatment 

strategies, which could represent a smart, fast and cheap way in obtaining regulatory 

approval of effective agents. 


104IN CHINA’S EXPERIENCE IN JOINING THE LARGE ADJUVANT 

ALTTO TRIAL 

Z.F. Jiang 

307 Hospital Amms China, Beijing, CHINA 

The ALTTO study is a randomized, open label multi-center phase III study 

comparing the activity of lapatinib alone versus trastuzumab alone versus 

trastuzumab followed by lapatinib versus lapatinib concomitantly with trastuzumab 

in the adjuvant treatment of patients with ErbB2 overexpressing and/or amplified 

breast cancer. Patients will be enrolled according to one of two design schemas and 

will be randomized to one of four treatment regimens within each design schema. 

The primary objective of this study is to compare disease-free survival (DFS) in each 

treatment regimen. There were 5 sites in China which participated in the ALTTO 

study. From March 2008 to April 2010, a total of 441 patients were randomized to 

one of four treatment regimens within two design schemas (Design 2B was not 

applicable in China). The table shows 100 patients from our cancer center. 


Group Number Withdraw* Recurrence 

Trastuzumab alone 26 1 3 

Lapatinib alone ** 23 2 0 

Lapatinib + Trastuzumab ** * 25 2 0 

Trastuzumab → Lapatinib 26 0 0 

• * 3 subjects due to AE, 2 subject due to Personal reason • ** 2 subjects transfer to 

Trastuzumab alone therapy due to AE • ** * 1subjects transfer to Trastuzumab alone 

therapy due to AE All the subjects in China have finished study treatment and are 

now in follow up. 

105IN LUNG CANCER: THE EUROPEAN THORACIC ONCOLOGY 

PLATFORM 

R.A. Stahel 

Labor für Molekulare Onkologie, Universitätsspital, Zurich, SWITZERLAND 

The European Thoracic Oncology Platform (ETOP) is a foundation with the purpose to 

promote exchange and research in the field of thoracic malignancies. It was founded in 

2009 and continuous to enlarged its membership to now comprise more than 40 members, 

including groups and institutions from most parts of Europe, as well as one large cancer 

center in the USA and China, respectively (www.etop-eu.org). ETOP promotes exchange of 

information and research. This is done be an active web-site, a yearly ETOP meeting for 

associated members and their investigators, and by a residential workshop aimed at 

fostering the research activity of younger investigators. Lungscape is a large translational 

research project designed by ETOP. It aims to coordinating the research of a group of lung 

cancer specialists working in translational research across Europe. This initiative has the 

potential to facilitate more rapid translation of biomarker knowledge to the clinic. 

Lungscape is evolving in step-wise fashion, starting with a retrospective analysis of up to 

2400 completely resected NSCLC from 16 institutions. The fundamental approach of 

Lungscape was to build a decentralized iBiobank of samples from lung cancer patients with 

annotated clinical and pathological data and at least three years of documented follow-up. 

The virtual nature of iBiobank and the introduction of standardized biomolecular 

assessments - in which samples are tested using identical protocols across local 

laboratories- removes the need of transferring samples to a central location for evaluation. 

ETOP has also initiated two clinical trials with biomarker components. BELIEF is phase II 

trial with erlotinib and bevacizumab for patients with non-squamous cell lung cancer and 

activating EGFR mutation stratified by the presence of T790M mutation as determined 

centrally by a very sensitive methodology. This is done on preclinical evidence suggestion 

synergy between EGFR TKI and antiangiogenetic therapy for tumors in case of activating 

mutation and the presence of T790M. The EMPHASIS lung is a phase III trial comparing 

erlotinib and docetaxel in second line for squamous cell lung cancer. The study will allow 

determining the predictive role of a serum proteomic classifier called VeriStrat for a 

beneficial effect of erlotinib. Other trials are in preparation. 


106IN LUNG CANCER ASIA STUDY GROUP EAST 

Y. Wu 

Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) & 

Guangdong Academy of Medical Sciences, Guangzhou, CHINA 

Over the past 10 years, there have been significant advances in clinical trials and 

translation research on lung cancer in China. The significant event was the discovery of 

EGFR mutation in 2004. The first international clinical trial involved in Chinese 

investigators was INTERESTIN that compared gefitinib with docetacel in second lint 

treatment for advanced NSCLC. The most important international trial in China was 

IPASS. Sixteen centers from China contributed 31% cases (372/1217). On the above basis 

the Chinese Thoracic Oncology Group (CTONG) was found in 2007. CTONG’s mission 

is to design and develop multicenter clinical trials and provide a high level of evidence 

for clinical practice. Now the CTONG has 23 active centers. There are more 10 thousand 

new lung cancer cases per year in CTONG centers. 

As the first national cooperative group CTONG has led some important trials that had 

changed clinical practice. CTONG 0802 (OPTIMAL) established the role of erlotinib in 

first line setting for patients with advanced NSCLC and EGFR mutation. Its results have 

helped to register erlotinib as first-line therapy in China and Europe. The CTONG 0804 

(INFORM) is the first maintenance study on gefitinib, and published on Lancet Oncology. 

The table lists the ongoing CTONG studies that focus on biomarker driven clinical trials. 

CTONG trials focusing on biomarkers. 



Study number 

NCT 

number Title Status 

CTONG 0806 00891579 Pemetrexed versus Gefitinib in Patients with 

EGFR wild type and metastatic NSCLC who 

failure to platinum-based chemotherapy 

Recruiting 

CTONG 0901 01024413 Erlotinib versus Gefitinib in Advanced NSCLC 

with Exon 19 or 21 Mutations 

Recruiting 

CTONG 1002 01236716 Nab-Paclitaxel Treatment in Advanced Recruiting 

Squamous Cell Carcinoma of the Lung 

CTONG 1103 01407822 Erlotinib versus chemotherapy as neoadjuvants 

in IIIA-N2 NSCLC with EGFR mutations in 

Exon 19 or 21 (EMERGING) 

CTONG 1104 01405079 Gefitinib versus Vinorelbine/Platinum as 

adjuvant treatments in Stage II-IIIA 

(N1-N2) NSCLC with EGFR Mutations 

(ADJUVANT) 

Recruiting 

Recruiting 

Chinese investigators are also very active in molecular biomarker researches. The 

tumor bank of lung cancer with more 4000 sample was set up. Extensive translational 

works on EGFR mutations including EGFR heterogeneity and mutation profile on 

lung adenocarcinoma were investigated. More high-quality translational research is 

expected in the future. 



ESMO-EACR Joint Symposium: 

Targeted therapies: Promises, 

successes and failures 

107IN HARNESSING CELLULAR SENESCENCE FOR CANCER 

PREVENTION AND THERAPY 

P.P. Pandolfi 

Medicine, BIDMC/Harvard Medical School, Boston, MA, UNITED STATES OF 

AMERICA 

We will present exciting new progress at developing what we regard as a new 

concept, which we refer to as “pro-senescence therapy”, that aims at utilizing cellular 

senescence, a built-in failsafe mechanism in mammalian cell evoked by oncogenic 

stress, for cancer prevention and treatment. 

We will discuss how this analysis allowed us to identify novel and therapeutically 

relevant molecular and biological types of cellular senescence that can be evoked and 

potentiated pharmacologically, in turn allowing the targeting of cancer stem cells as 

well as the “quiescent” cancer stem cell pool for therapy. 

We will analyze how these new concepts emerged from our analysis and systematic 

deconstruction of the molecular genetics of human cancer as studied in vivo in 

faithful mouse models, with particular emphasis on the role of aberrant PTEN/PI3K/ 

AKT/mTOR signaling in tumorigenesis. 


108IN PI3K AND/OR MTOR INHIBITORS: CURRENT STATUS, 

FUTURE DIRECTIONS 

S. Loi 

Breast International Group (BIG), Institute Jules Bordet, Brussels, BELGIUM 

The high incidence of molecular aberrations that target the phosphatidylinositol-3 

kinase (PI3K) pathway in cancer, as well as the demonstration that many resistance 

mechanisms to drugs also involve this pathway, has unsurprisingly led to high 

interest in the development of agents to inhibit PI3K signaling. Currently, many 

PI3K targeted agents are in phase I/II testing, alone and in combination with 

agents that are usual standard of care as well as those that target potential 

resistance pathways such as MEK/ERK. Some agents are about to commence phase 

III evaluation. Thus far in phase I, there have been signs of activity in the advanced 

setting for multiple tumor types but surprisingly yet no strong association with 

PI3K pathway aberrations such as PIK3CA mutations have been seen. Toxicities 

have been reasonably predictable and on-target, including hyperglycaemia, 

diarrhea, skin rash, nausea, fatigue and transaminitis Issues that are currently 

critical for optimal development in this field are: 1. understanding of who will 

benefit- thus far the relationship between PIK3CA, AKT1 mutations, PTEN loss 

and response to PI3K inhibitors has been not as clear as other targets such as 

BRAF mutants, EML4-ALK rearrangements and HER2 amplification. Activity has 

also been observed in genetically unselected cancer populations, though toxicity 

may preclude its acceptance in unselected populations if large and meaningful 

benefit cannot be shown; 2. Understanding the role of dual versus single versus 

isotype specific compounds- this may also depend on the genetic aberration and 

clinical setting; 3. prospective upfront stratification and power to look at mutated 

(as well as wild-type) subsets, particularly in early phase clinical trials; 

4. Determining rationale combinations with PI3K targeted therapy, which will 

undoubtedly depend on the setting and cancer type. Addressing these issues, along 

with adequate genotyping of the tumor, will ensure that we get a clear picture of 

the molecular background of which patients, tumor types and clinical setting 

benefits. 


109IN CANCER: AN ANGIOGENIC DISEASE? 



M. Neeman 

Faculty of Biology, Weizmann Institute of Science, Rehovot, ISRAEL 

The angiogenic switch proposed by Folkman provided a compelling theory for the well 

recognized phenomenon of tumor dormancy, where tumors show prolonged growth 

arrest and remain as microscopic nodules, sometimes for decades before converting into 

rapidly progressing cancer. At the basis of this theory is the idea that diffusion of 

nutrients limits growth to a few cell layers, and perfusion, via sprouting of new blood 

vessels is required for sustained progression. Hypoxia was recognized as a potent 

microenvironmental stimulator of angiogenesis. Hypoxia stabilizes HIF1 alpha resulting 

in induced expression of VEGF, a potent vascular permeability factor and the central 

inducer of angiogenesis. Hypoxia, which affects genetic instability and selection for cells 

resistant to apoptosis, is thus also tightly linked with angiogenesis. Angiogenesis, 

induced by VEGF is accompanied by rapid elevation of vascular permeability. This 

acute effect of VEGF affects tumors in many ways. Extravasated plasma proteins result in 

extensive ECM remodeling to form a reactive stroma which supports Inflammation and 

tumor cell invasion. Elevated permeability enhances interstitial fluid pressure, limiting 

drug delivery. On the other hand, elevated vascular permeability provides thus far one of 

the most sensitive means for rapid detection and non invasive monitoring of cancer, as 

it results in accumulation and retention of contrast media and tumor enhancement on 

MRI and CT scans. Angiogenesis provides tumor cells with routes for metastatic spread 

to the blood circulation, and provide also the pressure gradient which drives interstitial 

fluid pressure and lymphatic drain and thereby facilitates colonization of sentinel lymph 

nodes. Despite the very strong support for the tight association of tumor progression 

with induction of angiogenesis, the experience with targeting angiogenesis in cancer 

therapy has been relatively disappointing, and antiangiogenic therapy is so far nor the 

magic bullet as hoped. Thus clearly it is important to study the mechanisms by which 

tumors escape from antiangiogenic therapy. 


110IN ANTIANGIOGENIC THERAPIES IN THE CLINIC: A 

DOUBLE-EDGED SWORD? 

D. Miles 

Medical Oncology, Mount Vernon Cancer Center, Northwood, UNITED 

KINGDOM 

Despite the initial promise originally proposed by Judah Folkman and others, 

strategies aimed at tumour vasculature have met with variable success in the clinic. 

Antibodies and tyrosine kinase inhibitors targeting Vascular Endothelial Growth 

Factor (VEGF) are among the most highly developed agents targeting angiogenesis. 

In indications such as renal cell cancer, where alterations in VEGF are regarded as 

the principle oncogenic driver, VEGF inhibition has lead to clinically meaningful 

improvements in progression-free and overall survival. In more common epithelial 

malignancies, the efficacy VEGF inhibition has been more modest, possibly as a 

consequence of redundancy in the angiogenic process. The inherent complexity of 

the angiogenic response has also made it difficult to identify markers of efficacy, with 

a myriad of DNA, serological and dynamic (imaging) metrics being implicated in 

prognosis as well as prediction of treatment efficacy and toxicity, e.g., a 

second-generation assay of plasma VEGF appears to be of predictive benefit in a 

retrospective analysis of two studies in metastatic breast cancer and its use is being 

tested prospectively. The controversy surrounding the use of anti-angiogenic 

approaches in terms of efficacy and regulatory considerations, underscores the 

challenges in their development: e.g., simple clinical observations that in 

malignancies with a relatively long natural history, attributable alterations in 

progression-free survival are unlikely to be a surrogate for overall survival. Similarly, 

while the available data for the use of anti-angiogenic agents in the adjuvant 

treatment of cancer is clearly disappointing it is not perhaps surprising, given the 

likely lack of VEGF dependency of what we understand to be micro-metastatic 

disease. A clearer understanding of angiogenesis and its modulation will enable 

further rational development of this important modality. 



ESMO-EANM-ESR Joint Symposium: 

Imaging biomarkers in the era of 

targeted therapies 

111IN STATISTICIAN – THE BASIS OF RECIST1.1 

J. Bogaerts 

Statistics Dept, EORTC, Brussels, BELGIUM 

Since its first publication in 2000 (Therasse et al., JNCI 2000) RECIST has become a 

widely applied method to assess solid tumor response and tumor progression. 

Advantages include its relative simplicity, the assurance that comparisons between trials 

can be reasonably applied, and the acceptance of its use in submitted data by regulators. 

Disadvantages include the difficulty to apply it in several tumor types and the generality 

of the method which does not have tumor type dependent adjustments. 

In 2009 (Eisenhauer et al, EJC 2009) version 1.1 of RECIST was published, with as key 

updates the restriction of the number of targets to a maximum of five, special 

considerations for lymph nodes, a minimum increase in the sum of target diameters by 

5 mm as an added requirement for progressive disease and a host of further 

specifications and clarifications. A first limited inclusion of FDG-PET data was also 

made, but still requiring CT scan confirmation. 

Today work on RECIST continues, with extensive statistical analysis ongoing on the existing 

EORTC RECIST database, as well as efforts to collect FDG-PET data for evaluation of 

FDG-PET into the methodology. An overview of this work will be presented. Also, many 

questions exist in the community that may all have an impact on how RECIST should be 

modified: 3D imaging, the relatively new phenomenon of flare progression caused by some 

drugs, the extensive use of (RECIST based) progression free survival as a Phase III primary 

endpoint, the use of some new drugs beyond progression and the multitude of various 

imaging techniques in various stages of development. 

We will also report on the outcomes of an ongoing survey that queries the community for 

what are seen as the most important items to be addressed by future versions of RECIST. 


112IN RADIOLOGIST - HOW TO PERFORM CORRECT RECIST 

ASSESSMENT (CLINICAL TALK) 

Y. Menu 

Department of Radiology, Saint Antoine Hospital, Paris, FRANCE 

RECIST is a universal standard in tumour response evaluation. Therefore, it is of utmost 

importance that imaging technique and radiological reports are compliant with the 

recommendation. Advantages of standardization comprise the comparability of different 

examinations in the same patient, and responses in a cohort. Precise definition of 

response or progression makes possible to evaluate the accuracy of a specific treatment. 

Another advantage is that structured reporting is easier to perform, improving efficiency 

and communication. Technical requirements are important though easily achievable: 

slice thickness of 5 mm or less reconstructed in the axial plane, contiguous slices (on CT, 

minimal gap on MRI), robust and reproducible contrast injection with similar delay and 

injection rate, similar coverage ensure proper comparison of images and clear basis for 

decision making. Thinner slices, alternative planes, specific contrast media and/or 

customized MRI sequences are optional, and should not replace basic techniques. 

Interpretation of baseline images requires a perfect knowledge of the method for 

measurement of the largest diameter, identification of targets and non targets. 

Interpretation of evaluation examinations needs iterative comparison with Baseline and 

Nadir examinations, and identification of unequivocal new lesions. Obviously, a universal 

standard does not fit all oncology cases. It appears that some tumours like GIST or HCC 

may need adapted criteria in addition to RECIST. PET is only mildly included among 

the criteria, although it proves to be an important method for evaluation. Finally, 

morphology does not summarize tumour biology. Besides RECIST, the addition of 

structural, metabolic and/or functional information would be desirable. 


113IN ONCOLOGIC IMAGING 2012: FROM MORPHOLOGY TO 

FUNCTION 

A. Graser 

Head of Oncologic Imaging, University of Munich, Munich, GERMANY 

Purpose: To demonstrate new trends and developments in oncologic imaging in 2012. 

To show how functional imaging influences treatment decisions in patients with 

malignancy. 

Summary: In oncologic patients, imaging is the most important biomarker determining 

the stage and spread of disease as well as treatment success. Novel targeted therapies lead 

to delayed or absent changes in size of tumors and metastatic lesions. New strategies in 

imaging are needed to depict treatment effects with respect to lesion vascularity and 

vessel density. Functional imaging tests aim at the determination of these changes rather 

than at the depiction of morphologic alterations of lesions. Modalities used for 

functional imaging include time-resolved perfusion CT, dual energy CT, diffusion 

weighted MRI and perfusion MRI. To date, only few studies investigate the usefulness of 



these tests in patients on targeted therapies. This presentation will feature information on 

the technical background of functional CT and MRI and assess their use in patients that 

are treated with antiangiogenic drugs. Both animal and human studies will be presented 

and the importance of early response imaging will be highlighted. The role of radiology 

as essential link between different medical fields becomes more and more important in 

the era of personalized medicine, and radiologists, nuclear medicine physicians, and 

oncologists have to be aware of specific imaging characteristics of findings in functional 

imaging tests.This presentation will include methodological and educational content as 

well as interesting case studies highlighting the importance of the most advanced 

imaging strategies to aid treatment decisions. 

Disclosure: A. Graser: Disclosures: Speaker’s Bureau, Siemens Healthcare and Bayer 

Healthcare 

114IN MOLECULAR IMAGING WITH PET/CT: FDG AND BEYOND 

S. Fanti 

Department of Nuclear Medicine, University of Bologna, Bologna, ITALY 

Molecular imaging has rapidly acquired importance for the evaluation of cancer patients, 

being complementary to conventional imaging methods as CT, MR and US. Among 

molecular imaging procedures, Positron Emission Tomography (PET) is the most diffuse 

and rapidly growing, and at present it is routinely used in patients affected by a large 

variety of malignant neoplastic diseases. Many papers in the literature have already 

demonstrated the utility of this imaging technique whose capabilities have been 

furthermore developed by the introduction of hybrid scanners, particularly PET-CT. The 

combination of functional data (given by PET) and anatomic details (provided by CT) 

allows to significantly increase diagnostic accuracy, essentially due to a better specificity. 

The usefulness of PET relies on its capability of investigating molecular processes by 

means of specific radiotracers, with the most employed being 18F-DeoxyGlucose (FDG). 

FDG PET scans give important information about tissues glucose consumption, usually 

very increased in the great majority of solid malignancies. A number of indications for 

PET use in clinical oncology have already been validated. Main indications are: 

characterization of uncertain lesions; staging; early evaluation of response to therapy; 

evaluation of residual disease at therapy completion and identification of relapse during 

follow-up. 

Despite FDG scans represent more than 90% of all PET scans, other positron emitter 

tracers are available and each one may be specific for different neoplastic diseases. In fact 

some malignancies do not show increase in glucose consumption and are almost 

invisible with FDG: therefore other tracers have been developed to study other metabolic 

pathways. Tracers already in clinical use include Choline (labeled with 11C or 18F), a 

marker of cell membrane metabolism particularly useful for prostate cancer detection; 

18F-Tyrosine and 11C-Methionine, which enable to study proteic metabolism and are 

successfully employed for CNS neoplastic diseases; 18F-DOPA and 68Ga-DOTA-NOC, 

useful in neuroendocrine tumors. 


115IN ADDRESSING CLINICAL CHALLENGES IN TARGETED 

THERAPIES WITH ADVANCED IMAGING 

W.J.G. Oyen 

Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, 

Nijmegen, NETHERLANDS 

Advanced imaging techniques are being developed to provide information relevant for 

patient management beyond changes in tumor size. Treatment with novel targeted 

therapies showed that conventional RECIST measurements are insufficient to assess 

response as changes in tumor size occur relatively late, if at all. It has been shown that 

molecular imaging techniques provide predictive and prognostic information at baseline 

or by comparing baseline scans to scans obtained very early after the start of treatment. 

It aims at the (very) early identification of responders before tumor shrinkage occurs, but 

also indicating a high likelihood of relapse even before tumor growth is apparent. 

Furthermore, molecular imaging with radiopharmaceuticals may aid in identifying 

receptor overexpression or pathway activation in tumors before treatment with targeted 

therapies is initiated. The ability of FDG-PET to predict response of metastatic GIST to 

imatinib became the role model for the potential of molecular imaging to provide 

clinically relevant answers within days after the start of treatment. Since the introduction 

of integrated PET/CT the acceptance of the technology enormously increased. A large 

number of PET/CT studies was performed in patients treated with various targeted 

therapies (both antibodies and TKIs) in a wide variety of tumor types with both FDG 

and other radiopharmaceuticals such as FLT, a marker of proliferation. Similary, 

advanced CT (perfusion) and MRI (dynamic MRI, DWI, MRS) techniques have taken 

advantage of the development of technology. Following the introduction of therapeutic 

monoclonal antibodies such as bevacuzimab and trastuzumab, studies with the 

radiolabeled derivatives have been used to image the tumor-associated factors and 

receptors, targeted by these antibodies (immunoPET and immunoSPECT). It has been 

shown that this approach could successful visualize the antibody targets. More recently, 

small molecules (e.g. paclitaxel, lapatinib) have been radiolabeled and used in clinical 

studies. Following the numerous proof of principle and translational research studies, the 

time has come time to develop the role of the advances towards evidence-based imaging 

in clinical practice by systematically positioning advanced imaging for treatment 

selection in clinical trials. 



ESMO-ESP Joint Symposium: 

Molecular diagnostics for personalized 

cancer treatment 

116IN NEXT GENERATION SEQUENCING IN THE CONTEXT OF 

CURRENT CLINICAL PRACTICE: IMPLEMENTATION AND 

CHALLENGES 

H. Morreau 

Leiden University Medical Center, Leiden, NETHERLANDS 

In the era of personalized medicine next generation sequencing (NGS) of normal 

and/or tumor DNA has already proven its value in the discovery phase of novel 

molecular defects associated with human disease. Different levels of information can 

be obtained from transcriptome sequencing, whole genome sequencing, exome 

sequencing, and sequencing of DNA enriched for methylated DNA. It is expected by 

many that soon the NGS sequencing will take its place in current clinical practice 

giving diagnostic, prognostic or predictive information. The complex biology 

underlying human disease is however now more and more surfacing. Already from 

the relatively simple tests using single biomarker sets, but now also from the 

discovery phase NGS reports, it became clear that tumor heterogeneity is a major 

issue in clinical practice. Although some advocate that the solution should be to 

screen all metastasized lesions, obtaining those will be burdensome for patients. How 

to use such knowledge on heterogeneous DNA alterations in metastatic lesions for 

clinical decision making is also not so easily answered. In current clinical practice we 

see that with the success of neo-adjuvant therapies for rectum-, esophagus-, stomach 

and breast cancers much of the molecular analyses should be done on limited 

material. With innovative methods, such as ultrasound guided trans-bronchial or 

trans- esophageal needle aspiration for staging of lung cancer combined with 

molecular analysis on very limited amounts of cancer cells, a similar trend can be 

seen. Although technical advances coming from e.g. single cell sequencing efforts can 

be applied it should be realized that such approaches can lead to diagnostic errors in 

true clinical practice. Therefore major quality assurance programs should be initiated 

before NGS can truly take its predicted role. 


117IN BIOMARKER DEVELOPMENT NEEDS TISSUE 

REPOSITORIES: NO HONEY WITHOUT BEES 

H. Lehr 

IUP Institut Universitaire de Pathologie de Lausanne, Lausanne, SWITZERLAND 

Pathologists have traditionally archived the tissues on which they have established the 

diagnoses for their patients. Like many other professional societies, the Swiss Society 

for Pathology has recommended that paraffin blocks be retained for a minimum of 

20 years (40 years for pediatric tumors). In addition to paraffin blocks, fresh tumor 

and non-tumorous tissues can be frozen rapidly and kept for many years in freezers 

at -80°C or in nitrogen tanks. The research value of these archived tissues depends 

largely on the disposition of clinical information, on patient survival, and – ideally – 

on data concerning tumor response to treatment (chemotherapy, targeted 

treatments). With this information, combined with the modern tools of molecular 

pathology, notably deep sequencing, novel cancer markers with prognostic and/or 

predicitve values can be detected in historic cohorts and verified in independent 

historic cohorts, before ultimately being tested prospectively in “new” cancer patients 

(the “honey”). Certainly, this can only be successful, (i) if the material is adequately 

stored and quality-controlled (is there truely invasive carcinoma in the tissue block 

?), (ii) if the logistics for clinical data management is professionally organized, and 

(iii) if there exists an understanding and a consent of the patients whose tissues are 

to be used for research. The first two tasks lay in the hands of professionals who run 

the bank (pathologists, technicians, data managers), and have to be compensated for 

their work (the “bees”). The third task needs to be solved at the level of the general 

population. The last few years have seen many fruitful discussions and conferences 

dedicated to establishing a consensus between the general population (patients) and 

the scientific community (researchers). A recent survey among 1600 French- and 

German-speaking Swiss citizens has shown that the population is highly- and quite 

unconditionally - in favor of biobanking for research, provided that patients are 

properly informed and that their (written) consent is asked. 


118IN KRAS AND COLORECTAL CANCER: WHAT’S NEXT? 




119IN MOLECULAR TYPING OF LUNG CANCER: MORE PIECES TO 

THE PUZZLE 

S. Peters 

Oncology, Centre Hospitalier Universitaire Vaudois - CHUV, Lausanne, 

SWITZERLAND 

Distinct subtypes of NSCLC, so-called “oncogene addicted”, are driven by a specific 

genetic alteration sustaining tumor proliferation and survival – and are thus sensitive 

to inhibition of the corresponding activated pathway. This new paradigm has 

substantially impacted treatment from standard chemotherapy customized patient 

characteristics, expected toxicity and histological subtype to molecularly driven 

approaches in advanced NSCLC. Nowadays, adenocarcinoma - but also squamous 

carcinoma in recent reports - can be further subdivided into numerous clinically 

relevant molecular subsets. EGFR activating mutations or EML4-ALK translocation 

have been shown to be associated with better outcome when targeted by dedicated 

molecules. Treatment of patients with EGFR activating and sensitizing 

mutations-driven NSCLC with EGFR tyrosine kinase inhibitors (TKIs) results in an 

unprecedented response rate (RR) of 60-80%, a median progression free survival 

(PFS) of approximately 8-13 months, as well as an improved quality of life (QoL) 

compared to chemotherapy. This was the first and a strong illustration of the 

therapeutic relevance of molecular classification of NSCLC. In NSCLC, ALK 

rearrangement has at least 3 reported fusion partners: EML4, KLC1, and KIF5B. In 

these tumors, ALK is the sole determinant of critical growth pathways, resulting in 

activation of downstream canonical PI3K/AKT as well as MAPK/ERK pathways. 

Within the pivotal phase 1/2 clinical trial, treatment of 82 EML4-ALK positive 

patients with crizotinib resulted in a 57% RR and median PFS was 10 months. The 

kinetics of clinical response were comparable to previous experiences with EGFR 

TKIs in EGFR-mutated NSCLC. Other transforming genetic alterations have been 

identified such as MET, Her2 and FGFR1 amplification, KRAS, NRAS, BRAF, MEK1, 

AKT1, PIK3CA, AKT, FGFR2, DDR2, PTEN and HER2 mutations, RET, ROS1 and 

ALK rearrangements. While every distinct alteration remains a rare event per se in 

our NSCLC population, their frequency was shown to vary according to histological 

subtype, and defined clinical characteristics including smoking history, gender and 

ethnicity. All of them have to be subject of future epidemiological, fundamental, 

translational as well as clinical research in order to propose more active treatments to 

patients in the future. 



ESMO-ESTRO Joint Symposium: 

Innovative approaches to the treatment 

of brain metastases 

120IN HOW NEW INSIGHTS IN THE BIOLOGY OF BRAIN 

METASTASES MAY LEAD TO THE IDENTIFICATION OF NEW 

EFFECTIVE MEDICAL THERAPIES 

B. Gril 

Women’s Cancer Section, Laboratory of Molecular Pharmacology, National 

Cancer Institute, National Institutes of Health, Bethesda, MD, UNITED STATES 

OF AMERICA 

Brain metastases are a devastating event in the progression of cancer and are 

expected to increase in incidence as chemotherapies improve and lead to better 

systemic disease control. The brain offers unique environment as it is protected by 

the blood–brain barrier, which strongly limits the penetration of drugs. Using a 

quantitative model system for experimental breast cancer brain metastasis, vascular 

permeability was heterogeneous in brain metastases, with only 10% of lesions 

exhibiting sufficient permeability to mount an apoptotic response to taxol, suggesting 

that inadequate chemotherapeutic drug distribution accounts for a lack of efficacy. 

We have tested 18 compounds, both traditional chemotherapeutics and small 

molecule inhibitors, for efficacy in an experimental brain metastasis model. 

Prevention of the development of brain metastases was observed using vorinostat, 

lapatinib, pazopanib, TPI-287, gemcitabine and irinotecan. No drug effectively 

shrunk already established metastases. Our work strongly suggests that preventive 

approaches for the development of brain metastases constitutes a feasible clinical 

goal. We advocate the use of “secondary brain metastasis prevention” trials, in which 

patients with limited, treated brain metastases (without whole brain radiotherapy) are 

randomized to a preventive or placebo, with time to the development of a new 

metastasis as an endpoint. Close collaboration between researchers and medical 

oncologists will be needed to address these challenges brought on by this growing 

and incurable disease. 

Disclosure: B. Gril: Dr. Patricia Steeg received research founding from Glaxo Smith 

Kline (for lapatinib, pazopanib and PLK inhibitor) and from Millennium 

Pharmaceuticals (for TAK-285). 

121IN PUTTING DRUGS AT WORK AGAINST BRAIN METASTASES 

IN HER2 POSITIVE BC: RESULTS OF THE LANDSCAPE TRIAL 

T. Bachelot 1 , G. Romieu 2 , C. Cropet 3 , M. Campone 4 , V. Diéras 5 , M. Jimenez 6 , 

F. Dalenc 7 , E. Le Rhun 8 , C. Labbe-Devilliers 4 

1 Département De Cancérologie Médicale, Centre Léon Bérard, Lyon, FRANCE, 

2 Oncologie Médicale, Centre Val d’Aurelle, Montpellier, FRANCE, 3 Unité De 

Biostatistique Et D’evaluation Des Thérapeutiques, Centre Léon Bérard, Lyon, 

FRANCE, 4 Medical Oncology, Centre René Gauducheau (ICO) Institut de 

Cancerologie de l’Ouest, St Herblain, FRANCE, 5 Department of Medical 

Oncology, Clinical Trial Unit, Institut Curie, Paris, FRANCE, 6 R&d, Unicancer, 

Paris, FRANCE, 7 Oncologie Médicale, Centre Claudius Regaud, Toulouse, 

FRANCE, 8 Département De Sénologie, Centre Oscar LAMBRET, Lille, FRANCE 

Background: Brain metastases (BM) occur in 30 to 50% of metastatic breast cancers 

(MBC) overexpressing HER2. In case of diffuse BM, current treatment is primarily 

based on whole brain radiotherapy (WBRT). Few systemic options are available. 

Lapatinib (L) has shown some activity in association with capecitabine (C) after 

previous WBRT. The LANDSCAPE study assessed the efficacy of the association 

before any local treatment. 

Methods: Eligible pts had HER2+ MBC with BM not previously treated with WBRT, 

C or L. They received lapatinib 1,250 mg once daily and oral capecitabine 2,000 mg/ 

m 2 from day 1 to day 14, every 21 days. The primary endpoint was the rate of central 

nervous system objective responses (CNS-OR) defined as a ≥50% volumetric 

reduction of CNS lesions in the absence of all the following: increasing steroid use, 

progressive neurologic symptoms, or progressive extra-CNS disease. Secondary 

endpoints included time to progression (TTP), time to WBRT, and toxicity. 

Findings: From April 2009 to August 2010, forty-five patients were included in the 

study. 44 patients were evaluable for efficacy, with a median follow-up of 21.2 

months (range 2.2-27.6).The CNS-OR rate was 67.4% (95% CI: 51.5%-80.9%). 

Thirty-seven patients (86%) exhibited a reduction in tumor volume. Median time to 

progression was 5.5 months (95% CI: 4.3-6). At the time of analysis, 81.8% of 

patients had received brain radiotherapy, median time to radiotherapy was 8.3 

months (95% CI: 5.4-9.1). Most adverse events (AE) were grade 1-2 as already 

reported for this association, 22 patients (49%) experienced grade 3 or 4 treatment 

related toxicity and 14 patients presented at least one SAE; treatment was 

discontinued due to toxicity in 4 pts 

Interpretation: The association of L and C is effective in the treatment of BM of 

HER2 positive BC. Our data suggest that this regimen might be used right away at 

diagnosis of BM. This approach might change the management of selected patients 

with BM, allowing a delayed WBRT. This strategy deserves further evaluation to 

confirm the clinical benefits for patients in terms of survival, cognitive functions and 

quality of life. We are currently planning such a randomized clinical trial. 

Disclosure: T. Bachelot: GSK: Board member Travel accommodation Reaserch grant, 

M. Campone: GSK: Board Member, V. Diéras: GSK: Board Member. All other 

authors have declared no conflicts of interest. 

122IN DOES IMRT, IMAT, TOMOTHERAPY REDUCE THE 

NEUROTOXICITY OF WHOLE BRAIN RADIOTHERAPY? 




123IN THE BIOLOGICAL RATIONALE AND POTENTIAL ROLE OF 

RADIATION DOSE ESCALATION IN PATIENTS WITH BRAIN 

METASTASES 

F.J. Lagerwaard 

Radiation Oncology, Vrije University Medical Centre (VUMC), Amsterdam, 

NETHERLANDS 

The majority of patients with BM from solid tumors have a prognosis of only a few 

months based on extracranial tumor activity and performance status. The standard of 

care for these patients consists of palliative treatment with steroids, and, if 

appropriate, a short course of whole brain radiotherapy (WBRT). Several prognostic 

classification systems such as the RPA classification [Gaspar 1997] or the DS-GPA 

[Sperduto 2008] enable identifying a subset of patients that may have long-term 

survival, provided that the BM are treated aggressively. 

Although neurosurgery is the traditional treatment for single BM at an accessible 

location, radiosurgery (RS) has been established as a non-invasive alternative. RS 

involves high-precision delivery of a single fraction of approximately 20 Gy directed 

to the lesion, resulting in local control rates of 60-90%, dependent on the size and 

aspect (poorer control for necrotic lesions). The survival benefit of RS has only been 

confirmed for a single BM in a randomized study [Andrews 2004], but improved 

functional autonomy was observed in all groups with 1-3 BM. The question whether 

WBRT should be added to RS has been a long-standing unresolved issue with 

proponents highlighting the better intracranial control, and opponents pointing out 

the neurocognitive toxicity of WBRT and available salvage options. As the risk of 

developing new BM following RS alone is not only dependent on extracranial tumor 

activity (reseeding) but also on the number of initially treated BM (misdiagnosis of 

occult BM), a more differentiated approach may be better suited. 

A well selected patient group with multiple BM in good performance status and 

absent progressive extracranial disease may be candidates for recently developed 

advanced radiation planning and delivery. Techniques such as volumetric 

intensity-modulated arc therapy (VMAT, RapidArc) or Tomotherapy have enabled 

fast and accurate delivery of fractionated stereotactic integrated boosts to multiple BM 

in combination with WBRT. The integrated approach of this technique allows steep 

dose gradients outside the BM, thereby minimizing toxicity. Early experiences with 

this technique have reported relatively high intracranial control rates. 

Disclosure: F.J. Lagerwaard: The Department of Radiation Oncology has research 

agreements with Varian medical systems and BrainLAB AG. The author has received 

honoraria for presentations from Varian medical systems and BrainLAB AG 


ESMO-JSMO Joint Symposium: 

Recent advances in the treatment of GI 

tract and liver cancer in the EU and 

Japan 

124IN HEPATOCELLULAR CARCINOMA: PRESENT TREATMENT 

STRATEGY IN JAPAN 

J. Furuse 

Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, 

JAPAN 

Hepatocellular carcinoma (HCC) develops mainly from liver cirrhosis due to 

hepatitis B or C virus infection. A screening system in patients with cirrhosis is 

important to diagnose HCC at as earlier a stage as possible. As a result, in Japan, 

approximately 90% of HCC patients successfully undergo local therapies including 

hepatectomy, local ablation, and transcatheter arterial chemoembolization (TACE). 

However, many patients develop recurrences or progression after these treatments, 

and an effective systemic therapy is needed to improve the survival. 

Sorafenib is the first agent which demonstrated survival benefits in patients with 

unresectable advanced HCC that was approved for HCC in Japan in May, 2009, and 

more than 13,000 patients have received systemic therapy using sorafenib. In a survey 

by the Study Group on New Liver Cancer under the auspices of the Health and 

Labour Sciences Research Grant in Japan, 264 patients treated with sorafenib were 

analyzed and 90% of these patients treated with sorafenib received prior treatments 

including hepatectomy, local ablation and/or TACE. Common adverse events were 

hand-foot skin reaction, rash and diarrhea. The median overall survival was 11.0 

months. These results were comparable with those of a large phase III trial of 

sorafenib, the SHARP trial. 

Following sorafenib, several targeted agents are currently under investigation in the 

treatment of HCC at various stages. Large randomized control trials are needed to 

establish new standard treatments, and most trials have been conducted in 

international collaboration including Japan. On the other hand, some trials are 

conducted only in Japan, for example combination of hepatic arterial infusion 

chemotherapy with sorafenib. 

In this presentation, the outcomes of sorafenib treatment in Japan and recent clinical 

trials in chemotherapy are summarized and discussed. 

Disclosure: J. Furuse: I received honoraria and consulting fee from Bayer, Eli Lilly, 

Taiho, Chugai and Eisai. 

125IN HEPATOCELLULAR CARCINOMA IN THE EU 

J. Bruix 

Liver Unit, Hospital Clinic y Provincial de Barcelona, University of Barcelona, 

Barcelona, SPAIN 

The incidence of liver cancer varies across Europe. However, while figures have 

stabilised in Italy and Spain, Northern countries present a slight increase in recent 

years. In most cases, liver cancer appears in the background of chronic liver disease 

related to hepatitis C or B, infection and alcoholism, among other risk factors. 

Current data show that hepatocellular carcinoma is the leading cause of death in 

patients with cirrhosis and that the incidence of intrahepatic cholangiocarcinoma is 

on the rise. Because of its clinical relevance all scientific associations have developed 

practice guidelines to inform patients, physicians and regulatory agents about the 

established diagnostic and therapeutic procedures. Non-invassive diagnostic criteria 

have been accepted and in almost all documents the recommended strategy for 

staging and treatment indication is the BCLC model. Following it, patients diagnosed 

with HCC are stratified into stages for which different treatment options are to be 

considered. 

References 

1. Jelic S, Sotiropoulos GC; ESMO Guidelines Working GroupHepatocellular 

carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and followup. 

Ann Oncol. 2010 ;21 Suppl 5:v59–64 

2. Bruix J, Sherman M. Management of hepatocellular carcinoma: An update. 

Hepatology. 2011 Mar 1;53 (3):1020–2. 

3. EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular 

carcinoma. J Hepatol. 2012 Apr;56 (4):908–43. 

4. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379 

(9822):1245–55. 




126IN COLORECTAL CANCER: A NEW ORAL CYTOTOXIC AGENT 

REAPPEARS 

T. Yoshino 

Department of Gastroenterology & Gi Oncology, National Cancer Center Hospital 

East, Kashiwa, JAPAN 

Cytotoxic agents, such as fluoropyrimidine, irinotecan, and oxaliplatin and antibodies 

such as bevacizumab, and cetuximab and panitumumab have been shown to 

significantly improve the survival of patients with unresectable metastatic colorectal 

cancer (mCRC). Although many patients have a good long-term performance status, 

a standard therapy for patients refractory to or unable to tolerate these agents does 

not currently exist. TAS-102 is a novel oral nucleoside antitumor agent consisting of 

trifluorothymidine (FTD) and 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4 

(1H,3H)-pyrimidinedione hydrochloride (TPI) at a molar ratio of 1 to 0.5. TAS-102 

possesses a mechanism of action different from that of other antitumor agents, 

including fluoropyrimidine, irinotecan and oxaliplatin. Based on a phase I clinical 

trial in Japan, the recommended dose of TAS-102 (35 mg/m 2 /b.i.d) twice daily 

administered orally in days 1-5 and 8-12 of a 28-day cycle was determined. These 

results indicated that TAS-102 was expected to further improve the outcomes of 

patients with unresectable mCRC. We conducted randomized, double-blind phase II 

trial as a placebo-controlled study to evaluate the efficacy of TAS-102. A total of 172 

colorectal cancer patients who were refractory or intolerable to 2 or more regimens of 

standard chemotherapy with a fluoropyrimidine, irinotecan, and oxaliplatin 

underwent either TAS-102 plus best supportive care (BSC) (114 patients) or placebo 

plus BSC (58 patients) with the primary endpoint of overall survival. TAS-102 

significantly decreased death risk compared to placebo (hazard ratio, 0.56; 95% 

confidential interval [CI], 0.39-0.81; P = 0.0011). The median overall survival was 9.0 

months in the TAS-102 group and 6.6 months in the placebo group. TAS-102 

significantly improved progression-free survival (median, 2.0 months vs 1.0 month; 

hazard ratio, 0.41; 95% CI, 0.28-0.59; P < 0.0001). TAS-102 was effective regardless of 

KRAS mutational status. Grade 3 or higher adverse events observed in the TAS-102 

group were neutropenia (50.4%), leucopenia (28.3%), and anemia (16.8%). There 

were no treatment-related deaths. An international phase III trial is ongoing to 

confirm the clinical benefits of TAS-102 worldwide. 

Disclosure: T. Yoshino: I have honoraria with Chugai, Takeda, Bristol-Myers Squibb, 

Yakult and Merck Serono. I have research funding from Bayer, Taiho, Daiichi-sankyo 

and Quintiles. I have received consulting fee from Takeda. 

127IN CAN PET IMAGING HELP INDIVIDUALIZE THE TREATMENT 

OF COLORECTAL CANCER PATIENTS? 

A. Hendlisz 

Medicine Department, Institut Jules Bordet, Brussels, BELGIUM 

While the science of medicine tries to understand the rules and hidden laws behind 

diseases and their management, the art of medicine aims to treat individual patients 

by matching clinical observations and existing knowledge. The ambiguity between the 

art and the science of medicine has never been so obvious than in our attempts to 

tailor cancer treatment to individual patients: the growing evidence of tumor 

heterogeneity makes understanding a patient’s disease increasingly complex, especially 

when one considers the inadequacy of current assessment tools, which is becoming 

more apparent each day. In the setting of advanced colorectal cancer (aCRC), three 

main clinical situations coexist: metastasis that is immediately resectable with curative 

intent, borderline resectable disease and definitively non-resectable disease. Despite 

broad parameters within which to treat disease, clinicians lack tools that can rapidly 

and reliably point out treatment inefficiency in order to allow a therapeutic strategy to 

be quickly stopped or adapted. The usual endpoints of prospective randomized trials, 

which form the basis of the science of medicine, are seldom usable at the bedside to 

exercise the art of medicine. Death (overall survival) and progression (progression-free 

survival) both occur too long after the beginning of a treatment, and quality of life is 

much too subjective. The RECIST-based response rate is more readily available and 

relatively well standardized, but careful analysis reveals a definite but only small 

correlation with survival outcome in the aCRC setting. Several alternates for tumor 

response assessment have been studied: plasma tumor markers, circulating tumor cells, 

and functional imaging, notably the FDG-PET scan. However, few data from 

well-structured studies are available, and they are sometimes discordant. Among these 

alternatives, metabolic imaging by FDG-PET appears to be the most promising, 

bearing the highest and the most reproducible negative predictive value. This means 

that it could become useful both in the daily clinic and to develop new concepts for 

clinical trials. The aim of this review is to present the available evidence, point out 

areas of weakness, and consider how current findings might shape the future 

development of both FDG-PET techniques and study designs. 



ESMO-MASCC Joint Symposium: 

Integration between medical oncology 

and supportive care: Two sides of the 

same coin 

128IN SUPPORTIVE AND PALLIATIVE CARE: CORE ELEMENTS OF 

QUALITY CANCER CARE 

N.I. Cherny 

Dept Medical Oncology, Shaare Zedek Medical Centre Oncology Institute, 

Jerusalem, ISRAEL 

There has been much confusion regarding the definitions of supportive care (SC) 

and palliative care (PC) and many authorities use the terms interchangeably. Both 

MASCC and ESMO are among the minority of professional organizations that 

distinguish between the two. SC is defined as care that facilitate safe and effective anti 

cancer care, minimizing toxicity and optimizing physical, psychological and social 

function of patients undergoing disease management strategies. SC facilitates the 

ability to deliver optimal anti cancer care and it has a particular focus on side effect 

prevention and management. All cancer patients undergoing treatment need SC and 

this is equally true for those undergoing curative treatments as it is for those 

undergoing treatment to mitigate the trajectory and consequences of advanced and 

incurable cancer. PC optimizes the comfort, function and social support of the 

patient and their family when cure is not possible. The context of incurability, with 

all of its implications for the patent and family, that grounds palliative care as a 

special entity. “End of life care” or “terminal care” is defined as PC when death is 

imminent. End-of-life care acknowledges that the intensity of physical, psychological, 

existential, spiritual and family issues may be magnified by the patient’s approaching 

death. Patients with incurable cancer receiving antitumor therapies will often need 

both S + PC. 

Conclusion: The delivery of high quality S + PC are core elements of quality 

oncological service and it is incumbent upon clinicians to be adequately skilled, to 

tend to these needs with due diligence and to promote the development of effective 

service delivery frameworks to ensure that patients receive these vita elements of 

quality care. 


129IN ANTIEMETICS: A WINDOW TO TRANSLATIONAL MEDICINE 

S. Grunberg 

Hematology/Oncology, University of Vermont, Burlington, VT, UNITED STATES 

OF AMERICA 

The concepts of targeted therapy, molecular pharmacology, and population genetics 

are not new to the field of clinical antiemetic care. The most basic principle of 

antiemetic care is to identify and target neurotransmitter/neurotransmitter receptor 

pairs within the emetic reflex arc that can be suppressed without causing severe 

disruption of physiologic function. Early research focused on dopamine (D2) 

receptors led to effective antiemetics but also resulted in significant antidopaminergic 

toxicity. Identification of serotonin (5HT3) receptor pathways with similar 

emetogenic activity provided a target that could be effectively suppressed without 

antidopaminergic toxicity. Appreciation of the role of neurokinin (NK-1) receptors 

in delayed emesis complements previous knowledge and allows for more effective 

suppression of emesis throughout the period of emetic risk. More recently genetic 

mutations that alter these neural pathways as well as the metabolic pathways of 

antiemetic agents have been appreciated. Over-expression of the CYP 2D6 pathway 

increases metabolism of some serotonin antagonist antiemetics and has been shown 

to decrease the efficacy of these agents. A mutation in the 5-HT3B subunit of the 

serotonin (5HT3) receptor itself can also alter sensitivity to emetogenic 

chemotherapy and to antiemetic agents. Appreciation of the role of genotype and 

phenotype in the response of different ethnic groups to therapy has now allowed 

correlation of lessons from population science with clinical treatment. A study from 

Malaysia comparing Chinese, Malay, and Indian populations receiving similar 

chemotherapy and similar antiemetics has demonstrated an increased emetic 

response in the Chinese population. A study from the United States similarly 

demonstrated increased emetic response in a Chines population compared to a 

Caucasian population. Whole genome analysis to identify differences between these 

ethnic groups may therefore lead back to genetic foci of interest that will in turn 

affect the clinical science of antiemetic protection. Such translational and 

multidisciplinary efforts increase knowledge of the basic mechanisms of disease and 

treatment while simultaneously improving patient quality of life. 

Disclosure: S. Grunberg: I have served as a consultant to Helsinn, Merck, Tesaro, AP 

Pharma, and Prostrakan. I also am a stockholder in and have received honoraria 

from Merck. 



130IN GASTROINTESTINAL TOXICITY IN ONCOLOGY: 

EVOLUTIONARY SCIENCE 

D. Keefe 

Medicine, University of Adelaide, Adelaide, SA, AUSTRALIA 

Proper practice of Medical Oncology requires an understanding of the science of 

regimen-related toxicity (RRT); and as treatment regimens evolve, so too does that 

science. Mouth ulcers, pain, diarrhea and constipation are among the common side 

effects of chemotherapy and hinder our ability to give adequate, perhaps curative, 

doses. As we increase our understanding of toxicity mechanism, so we slowly 

improve its prevention and treatment. However, this must not come at the cost of 

tumour-response, thus requiring understanding of the interaction between 

mechanism of action and of toxicity. Animal models have become increasingly 

sophisticated, and are used to screen for interventions that reduce toxicity without 

affecting tumour response. The introduction of the targeted anti-cancer (TAT) agents 

has further complicated the picture, with GI toxicity being a major, and not always 

predicted effect. The mechanism of toxicity is often the same as the mechanism of 

action, making successful management difficult. Each new class of TAT has a new 

mechanism, epidemiology and presentation of toxicity, so we constantly need to 

update our understanding of the science. A mouth ulcer caused by methotrexate is 

not the same as one caused by an mTOR inhibitor. There has been a corresponding 

evolution in the doctor-patient relationship surrounding toxicity, as we have moved 

from the paternalistic relationship to a partnership, with Patient Reported Outcomes 

(PROs) increasingly important. Clinicians will usually rate a given toxicity less 

severely than will the patient; the message being that we need to listen to the patient. 

Risk prediction is receiving more attention, with Oncologists now talking about 

response prediction and risk prediction as two sides of the same coin, aiming to offer 

treatment to non-toxic responders, treatment with toxicity interventions to toxic 

responders, and completely avoid ineffective treatment for non-responders. We have 

moved from the simplistic risk prediction of age, sex, comorbidity and drugs, to 

complex gene and SNP analysis using modern bioinformatics. However, given the 

common lag between drug development and successful toxicity interventions, toxicity 

specialists should be involved earlier in drug development. The science will continue 

to evolve as long as cancer treatment evolves. 

Disclosure: D. Keefe: Prof Keefe works with many companies in the development of 

agents in the field of GI toxicity. These include: Helsinn, Entera Health, Pfizer, GSK 

and Merck. 

131IN DEVELOPMENT OF RATIONAL THERAPEUTIC STRATEGIES 

FOR PATIENTS WITH PRE-CACHEXIA AND CACHEXIA 

THROUGH THE INTEGRATION OF ONCOLOGY AND 

PALLIATIVE CARE AND COLLABORATIVE CLINICAL TRIALS 

(EAPC-RESEARCH NETWORK) 

F. Strasser 

Oncological Palliative Medicine, Cantonal Hospital, St.Gallen, SWITZERLAND 

Nutritional issues are frequent but underestimated in advanced, incurable cancer 

patients (pts), impacting patients’ tolerability of anticancer treatment, quality of 

life, physical (and social) function, effective health services use and family 

members. The new cancer cachexia framework (Fearon & Strasser, Lancet 

Oncology 2011) separating simple starvation from cachexia, facilitates the 

development of both effective nutritional, multimodal and tailored treatments. 

Collaborative, international efforts and EU-funding made this framework possible. 

Cachexia is defined by muscle loss relevantly impacting physical function, which is 

not reversible by nutrition only, and is caused by a combination of dysregulated 

eating ability and a dysbalanced catabolic and anabolic metabolism. To identify 

such pts in clinical practice, monitoring of % weight loss in the last 6 months and 

asking pts about appetite and eating shall become a standard procedure. The 

clinical assessment will diagnose cachexia, then classify pts for the phase 

(pre-cachexia, cachexia, refractory cachexia), main domains (stores, intake, 

potential, performance), and severity. Currently a consensual cachexia assessment is 

developed involving various professional groups. For pre-cachexia and cachexia 

there is currently no established therapeutic intervention. Clinical trials 

investigating increase of nutritional intake (oral, enteral, parenteral) focus on 

patient populations having simple starvation. For cachexia treatment a multimodal 

approach is mandatory, tackling in a combined strategy its main causes of 

decreased eating ability, catabolism, decreased anabolism, and impaired 

neuro-muscular function. Preclinical studies and several clinical trials document the 

potential of such interventions. A sentinel next step however, is the conduct of well 

powered, multimodal phase III trials in pre-cachexia and cachexia. For refractory 

cachexia, efforts concentrate to characterize these pts and develop psychosocial and 

other symptom alleviating interventions. Currently guidelines on treatment are 

updated, applying the procedures of ESPEN. Educational initiatives emerge. All 

these efforts mandate collaboration of professionals and working groups of involved 

societies (e.g., EAPC-RN, ESPEN, MASCC, ESMO PCWG, SCWD). 

Disclosure: F. Strasser: Unrestricted grants: Celgene (NCT01127386), Fresenius 

(http://www.surveymonkey.com/s/XBT6HQW.). Participation BYM338 trial 

(NCT01433263). Occasional Advisor: Baxter, Danone, Fresenius, Helsinn, Novartis, 

X-Biotech. 


ESMO DCTF-AORTIC-SLACOM-UICC- 

WHO Joint Symposium: 

Independent and publicly funded 

research: A new global model 

132IN GLOBAL CANCER RESEARCH; CURRENT SITUATION AND 

CHALLENGES 

E.L. Cazap 

Latinamerican & Caribbean Society for Medical Oncology (SLACOM), Buenos 

Aires, ARGENTINA 

Clinical research is vital to the development and improvement of methods to prevent, 

detect and treat cancer. The majority of clinical trials take place in the developed world 

through sponsored pharmaceutical company research. The corresponding lack of 

research in developing countries results in two unmet needs related to cancer 

treatment in the developing world. First, recommended treatments do not reflect 

ethnic (genetic), cultural and resource differences between developed countries and 

developing countries that are not subject to clinical research. Second, there is little 

research conducted on those cancers that are primarily found in developing countries. 

Thus the ability to diagnose and treat these diseases is impaired. This general picture 

reflects today’s situation globally, then it is critical to promote clinical research in 

developing countries mainly with training of all levels of research professionals (data 

managers, research nurses, etc.) in a local context, and training on identifying 

resources to fund research outside of pharmaceutical company sponsorship. 

Disclosure: E.L. Cazap: Leadership Position SLACOM, ASCO, UICC Consultant: 

Bayer; Schering Pharma Honoraria: Bayer; Bristol-Myers Squibb; Fresenius Research 

Funding: Poniard Pharmaceuticals; Daiichi Sankyo Pharma; Breast Cancer Research 

Foundation (BCRF). 

133IN INDEPENDENT CANCER RESEARCH IN LATIN AMERICA: A 

NEW MODEL 

C. Vallejos-Sologuren 

Division of Research, Oncosalud SAC, Lima, PERU 

It is well known that pharmaceutical Industry leads the cancer research in Latin America, 

but also is well known that there is a large pool of well-trained oncologists and basic 

scientists able to lead successfully scientific research of complex designs. A recent survey 

by Gomez et al (presented in the extended educational session at ASCO Annual Meeting 

2011), that involved the perception of oncologist from low income countries; reveals the 

desires of Latin American medical oncologists to participate in clinical research from the 

international cooperative groups. We - the Latin-American researchers- have learned that 

the academical investigation and the participation in the concept of study and research 

design is the best way to achieve academicals status. We have bet in the formation of local 

and regional cooperative groups, and we are doing efforts to implement research sites of 

excellence, improve our quality of data and seeking for collaboration of scientist from 

more developed countries to perform research involving complex procedures (eg. 

molecular analysis). Nowadays, the goal for our young researchers is get trained in 

renamed international institutions and establish strong links with other worldwide 

scientists. The future of research in our region reveal a landscape where we work together 

to fight the cancer in benefit of our patients. 


134IN WHO AND CANCER RESEARCH 


135IN CANCER RESEARCH IN AFRICA 

I. Adewole 

Obstetrics and Gynaecology, College of Medicine, University of Ibadan, Ibadan, 

NIGERIA 

Cancer remains a public health challenge worldwide, and its fast rising nature in 

Africa is occasioned by the changing demographic and environmental characteristics. 

The epidemic is further propelled by HIV/AIDS, poverty and ignorance within the 

continent. At the moment, cancer is currently responsible for more than 7 million 

deaths per year. By 2030, it is projected that cancer alone will account for about 1.27 

million new cases and about a million deaths per annum. 

Disease prioritization is often a product of cutting edge research, and it is also a driver 

for follow-up implementations. The differential opportunity for sound translational 

research between developed countries and Africa is one of the key causal factors 

responsible for disease outcome between the two settings. At moment, the quality of 

cancer research is yet to offer the much-needed platform to generate a momentum for 

cancer prioritization in Africa. Cancer research from Africa is mostly donor funded, 

lacks depth of contextual framework - sociocultural, minimal multi-national outlook, 

lean basic science component, and low translational potential. Other challenges 

include poor research friendly environment (laboratory, incentives and recognition); 

lack of mentoring programs, public funding comparable to NIH is non-existence, lack 

of robust cancer registry with necessary resources, and poor political support. The 

African Organisation for Research and Training in Cancer (AORTIC) has the vision of 

transforming the orientation of cancer researchers within the continent through 

provision of research capacity building opportunities, generation of a critical mass of 

cancer researchers that will form the core of the network, leading advocacy for local 

funding of cancer research in Africa, and promotion of center of excellence in cancer 

research at national and sub-regional level. It is imperative that cancer research in 

Africa charts a course that is visionary, pragmatic, multidisciplinary and sustainable as 

well as avoiding a “one perch approach”. A holistic approach to cancer research that 

will use both inductive and deductive reasoning philosophy is hereby advocated. 


136IN INTERNATIONAL RESEARCH 



T. Cufer 

Department of Medical Oncology, University Clinic Golnik, Golnik, SLOVENIA 

Substantial increase in international clinical cancer research (CCR) observed during 

the last decade is due to fragmentation of major cancer types in biological subtypes 

with plethora of new treatment agents, both requiring a larger number of CCR 

participants, as well as to improved infrastructure and skills needed to perform CCR 

in developing countries. Based on ClinicalTrials.gov registry approx. one third of both 

academia- and industry-driven CCR is running on international basis nowadays: and 

the number of countries serving as trial sites in CCR reports published in prestigious 

journals doubled during the last decade. The scientific and logistical imperative for 

international CCR is clear, it shortens the time for clinical testing, offers an early 

access to new treatment strategies worldwide and lowers costs by establishing 

international networks of CCR. Clinical trials cooperative groups, already established 

as regional international groups (e.g. NCI-CTG, RTOG, NCIC, EORTC, CECOG, 

BIG, etc.), offer an excellent platform for exchange of scientific ideas, avoid 

unnecessary duplication of trials and represent a solid base for expanding international 

collaboration. But, there are still a lot of regulatory, logistical, financial and scientific 

issues to be solved to further improve international CCR and maximize its outcome. 

Regulatory requirements and oversight of the CTs need to be harmonized with data 

and tissue handling representing one of the main issues. Protection of publication 

rights and access to trial data is of upmost importance for transparency of CCR in 

developing countries. The drugs being evaluated in CCR must be available in 

participating countries, when approved. Formal training programs in CCR and ethics 

intended to future CCR leaders in developing countries, such as ICTW courses 

organized by ASCO and other academia organized GCP courses, need to be 

promoted. Effective collaboration between industry and cooperative groups has to be 

established. Our ability to establish international collaboration in CCR will results in 

maximization of our resources and patients, thus permitting international community 

to further improve cancer control globally through effective CCR. 



ESO Society Symposium: 

Celebrating 30 years of ESO and 50 

issues of Cancer World. Cancer 2020: 

The road to personalized cancer care 

137IN CAN WE WIN THE WAR ON CANCER GLOBALLY? 

F. Cavalli 

Oncology Institute of Southern Switzerland, Bellinzona, SWITZERLAND 

In the last 15 years our understanding of the biology of cancer has increased tremendously 

and the speed, with which we acquire new knowledge about the basic biology of neoplastic 

diseases is currently increasing even further. Thanks to the development in the field of 

translational research, some of this knowledge has been transferred into new and more 

efficacious treatments. Together with intensified preventive efforts and some improvements as 

regards early detection, these new treatments have contributed to the relative decline of the 

overall cancer mortality, which we are currently witnessing at least in the most developed 

countries. Even here, however, costs of new treatments have reached a level which is no longer 

sustainable for most of the health care systems. Moreover, on a global scale, the situation 

looks quite worrysome. Mainly because of an explosion of new cancer cases in low- and 

middle income countries we are witnessing a rapid increase of the worldwide burden as 

demonstrated by following numbers: in the year 2000 there were 11 millions new cancer 

diagnosed and 7 millions cancer deaths. If current trends will continue, in 2030 we will have 

27-28 millions new cancer diagnosed and 16-17 millions cancer deaths. Reasons for this 

evolution and possibilities to tackle this looming disaster will be presented. This situation will 

be at the centre of the discussions, which will take place in Lugano (26-27 October 2012) at 

the World Oncology Forum (WOF), which will be organized by ESO with the title “Are we 

winning the war on cancer?”. Our current hypothesis is that, although we are about to win the 

battle from a medical and scientific point of view, we might lose the war on a global scale, if 

we will not be able to implement radical changes in the social/political environment. 


138IN PERSONALIZED THERAPY IN LUNG CANCER: THE PROMISE 

FOR THE FUTURE 

R.A. Stahel 

Labor für Molekulare Onkologie, Universitätsspital, Zurich, SWITZERLAND 

Chemotherapy has improved the outcome of patients with non-small cell lung cancer with 

prolonged survival rates in advanced disease and higher cure rates in combination with 

surgery or radiotherapy for earlier stages of disease. With the exception of maintenance 

therapy, the most recent advances have been achieved in patients with selected molecularly 

defined subgroups of non-small cell lung cancer. The area of personalized therapy for lung 

cancer started in the year 2004 with the identification of activating EGFR mutations in lung 

adenocarcinoma being associated with striking clinical responses to EGFR tyrosine kinase 

inhibitors. Subsequent clinical studies lead to the approval of EGFR tyrosine kinase inhibitors 

gefitinib and erlotinib as fist line therapy for this group of patients. These developments were 

followed by the discovery of ALK rearrangements as oncogenic driver for another subgroup 

of lung adenocarcinoma and the demonstration of selective activity of the tyrosine kinase 

inhibitor crizotinib. Since, the field has developed rapidly with the detection of other 

potentially actionable mutations and genetic rearrangements in lung adenocarcinoma and 

lung squamous cell carcinoma. The consequence – at present restricted to patients with 

advanced disease – it a transition from empiric clinical trials based on patient characteristics 

to molecularly-driven clinical trials and - in clinical practice - a transition from a 

standardized therapeutic approach to a personalized approach based on molecular tumor 

characteristics. There is evidence that the integration of EGFR tyrosine kinase inhibitors into 

the treatment of patients with tumors harboring an activating EGFR mutation is associated 

with more than a doubling of the time of survival as compared to treatment with 

chemotherapy alone – no doubt a significant clinical improvement. However, the fact 

remains, that eventually tumors become resistant also to targeted therapy. In consequence 

chemotherapy is likely to stay as a treatment option for the future and research into how to 

counteract resistance will gain in importance. The major challenge however will be on how to 

optimally deal with new the opportunities. How to move from standardized medicine to 

personalized medicine will become a priority issue in health care delivery. 


139IN MELANOMA AS A PARADIGM MODEL TO DISCUSS THE 

OPPORTUNITIES AND LIMITATIONS OF REALIZING 

PERSONALIZED CANCER MEDICINE 


140IN DEVELOPING PATIENT-CENTRIC CANCER SERVICES FOR 

THE 21ST CENTURY 

A. Buzyn 

Institut National du Cancer, Boulogne Billancourt, FRANCE 

The future of cancer control may well involve personalized approach, although considering 

both the patient and the tumour uniqueness remains challenging. The wealth of 



technological progress, improved research coordination and political willingness through 

cancer control plans are nevertheless convergent towards tailoring patient care. Nationwide 

access to innovation for better care is among INCa’s priorities. Researchers are mobilised to 

reduce health inequalities and to decipher the links between environment, behaviour and 

cancer occurrence. INCa’s actions towards personalised medicine include funding 28 

molecular genetics platforms since 2006. They perform predictive tests on tumour samples 

for targeted therapies nationwide. In 2010, molecular testing was performed for 17,000 lung 

and 19,000 colon cancer patients. Collaboration with the pharmaceutical industry allows 

anticipating the release of new targeted therapies. This organisation has proved to be cost 

effective for the health insurance. Its impact on therapeutic decision is currently being 

assessed. Regarding the organisation of care, INCa helps structuring a care pathway that 

guides patients through a unique path from diagnosis stage to survivorship (including social 

or psychological conditions, return to employment), through 35 pilot projects. INCa also 

contributes to the implementation of specialised care networks: 17 networks of national 

expert centres combine expertise and proximity for adults with rare cancer, 15 coordination 

units specialised in geriatric oncology link geriatricians and oncologists, 8 experimental 

interregional appeal organisations promote integrated care for teenagers and young adults. 

Personalised medicine applied to cancers prevention and early detection is also considered. 

Personalized medicine in the 21th century is in progress, taking into account tumour or 

genetic specificities while placing individuals in the centre of the health care system. 


141INIS PERSONALISED CANCER CARE AFFORDABLE? 

R. Sullivan 

Institute of Cancer Policy, Kings Health Partners Integrated Cancer Centre, 

London, UNITED KINGDOM 

Is Cancer Care and Research Becoming a Luxury Good? Affording Cancer in the 21 st 

Century Cancer has become one of the most intractable global diseases in both high income 

and increasingly in emerging economies. This complex and complicated disease has been a 

major focus for R&D since the 1970’s. Global public sector spend on cancer R&D has 

reached over 16.5 billion euros and disease specific R&D activity in cancer dominates all 

other areas with over 14% of total global activity. Within this research activity translational 

cancer medicine has expanded in only 20 years to account for nearly 40% of research 

outputs. In parallel the direct healthcare costs of cancer now consume between 5 and 10% 

of high income healthcare budgets, with particular areas such as imaging and 

pharmaceutical costs growing at an average annual rate of over 10%. The costs of both care 

and research are growing beyond the ability of countries to manage and deliver cost effective 

R&D and national cancer plans. The vast expansion in new technologies in cancer (NME, 

procedures, biomarkers, etc) coupled to rapid macro-economic (especially pricing) and 

socio-demographic measures is overwhelming the ability of national and trans-national 

systems to, a) effectively translate research through appropriately powered clinical trials, and 

b) deliver sufficient improvements in outcomes to merit the prices now being demanded. 

Cancer has reached both a crossroads and is on an apparent trajectory that could see the 

best care and fruits of research only available to affluent sectors of society. In this lecture we 

will explore the roots, trajectory and solutions to this convergent crisis and ask whether 

cancer care will become a luxury good; and whether the p-medicine agenda really can 

deliver tomorrows solutions or whether this is rapidly becoming a morally bankrupt 

paradigm that no-one will be able to afford. 


142IN PERSONALIZED CANCER CARE: EMPOWERING THE 

PATIENT 

K. Redmond 

Cancer World Magazine, European School of Oncology, Montagnola, 

SWITZERLAND 

The shift from the traditional “one size fits all” approach to treating cancer to a more 

“personalised” model where treatment is customised to the individual is good news for 

cancer patients. Potentially personalised cancer care will result in more optimal use of 

available treatments and less treatment-related side effects. Consequently patient outcomes 

should be improved. Cash-strapped health services are also set to benefit because resources 

should be used more efficiently to deliver more effective care. However, given that there are 

many different cancers and cancer subtypes, and the fact that scientific advances cannot be 

applied equally across all cancers, it is unrealistic to think that every cancer patient will 

benefit from personalised cancer care over the coming decade. Moreover, there is no 

guarantee that even those patients with cancers where there is strong evidence that 

treatment should be customised according to tumour characteristics will gain access to more 

personalised treatments. This is because cancer patients’ right to receive care that is 

appropriate to their needs is not always upheld. Although numerous factors contribute to 

this situation; empowerment represents a key means for patients to realise their rights. 

Empowering cancer patients to be more involved in decision making can be challenging 

because of entrenched attitudes and beliefs, unrealistic expectations, cultural norms and 

literacy levels. Innovative communication technologies offer a novel way to empower 

patients but care is required to ensure that those who are less “technology savvy” are not 

discriminated by their lack of skills in using this media. The cancer community needs to 

engage closely with the media to ensure that coverage on the potential of personalised 

cancer care is balanced and does not generate unrealistic expectations. The media also has 

an important role to play to counteract negative attitudes about cancer. 



asic science 

143PD MET ACTIVATION BY AUTOCRINE LOOP RESCUES COLON 

CANCER CELLS FROM SENSITIVITY TO EGFR INHIBITION 

T. Troiani, D. Vitagliano, S. Napolitano, F. Morgillo, A. Capasso, V. Sforza, 

A. Nappi, L. Berrino, F. Ciardiello, E. Martinelli 

Division of Medical Oncology, Department of Experimental and Clinical Medicine 

and Surgery “F. Magrassi and A. Lanzara”, Second University of Naples, Naples, 

ITALY 

Background: Cetuximab, a monoclonal antibody targeting the epidermal growth 

factor receptor (EGFR), is active in K-RAS wild type colorectal cancer (CRC). 

However, initially in responding patients cancer cells would become resistant to 

EGFR inhibition by the activation of alternative growth controlling pathways 

including the hepatocyte growth factor (HGF)/MET-dependent signal. 

Methods: mRNA expression profiles of cetuximab-sensitive human GEO colon 

cancer cells and of their cetuximab-resistant derived GEO-CR cells were analyzed by 

microarrays. Protein expression levels were evaluated by western blot (WB). Growth 

factors were measure in the culture medium by Luminex technology. The in vitro 

antitumor activity of MET inhibitor (METi), was tested in a panel of ten human 

colon cancer cell lines by MTT assay. 

Results: Evaluation of gene expression profile identified a series of genes that were 

up-regulated in GEO-CR cells possibly involved in acquired resistance to EGFR 

inhibition. Among these we found several genes involved in the MET pathway. WB 

analysis detected activated, phosphorylated MET in GEO-CR but not in GEO and in 

the other colon cancer cell lines tested. We also found in GEO-CR cells up-regulation 

of EGFR ligands such as transforming growth factor – α (TGFa) and Heparin 

Binding- Epidermal Growth Factor (HB-EGF). We further observed expression of 

HGF in GEO-CR cells, supporting HGF/MET autocrine activation following acquired 

resistance to cetuximab treatment. In fact, the RAS/RAF/MEK/MAPK pathway was 

constitutively active despite of EGFR inhibition by cetuximab in GEO-CR cells 

possibly due to HGF-induced MET activation. Treatment with a potent and selective 

METi was able to overcome cetuximab resistance in GEO-CR cells and causes cell 

growth inhibition. 

Conclusion: These results suggest that autocrine activation of HGF/MET could be a 

relevant therapeutic target in colorectal cancer patients that become resistant to 

anti-EGFR treatment. 


144PD OPTIMIZING GEMCITABINE EFFICACY THROUGH 

DEGRADATION OF RRM1 

G. Bepler, Y. Zhang, X. Li 

Karmanos Cancer Institute and Wayne State University, Detroit, MI, UNITED 


Objectives: RRM1 (ribonucleotide reductase M1) is the molecular target and key 

efficacy determinant of gemcitabine. Gemcitabine binds directly to active sites 

resulting in irreversible inactivation. Mechanisms that control RRM1 abundance are 

largely unknown, but may provide an opportunity for optimization of gemcitabine 

efficacy. 

Methods and results: We have identified that the E3 ubiquitin-protein ligases RNF2 

(RING finger protein 2, Ring1B) and Bmi1 (B cell-specific moloney murine leukemia 

virus insertion site 1) interact with RRM1 using yeast two-hybrid screening. We 

confirmed that RNF2and Bmi1 interact with RRM1 in vivo by immunoprecipitation. 

Confocal immunofluorescence microscopy revealed that RNF2 and Bmi1 completely 

co-localized with RRM1 in nucleus. RRM1 undergoes proteasome-mediated 

polyubiquitination and degradation. The proteasome inhibitor MG132 blocked the 

turnover of RRM1. We found that RNF2 and Bmi1 can induce polyubiquitination of 

RRM1 in vitro and in vivo. Lysine (K) 548 and 224 are major polyubiquitination 

sites of RRM1. Substitution of the lysine residues 548 and 224, either alone or 

together, significantly reduced RRM1 polyubiquitination. Depletion of RNF2 and 

Bmi1 by siRNA increased RRM1 protein level and promoted chemoresistance to 

gemcitabine in vitro. 

Conclusions: These results establish that RNF2 and Bmi1 are E3 ubiquitin ligases of 

RRM1 that regulate RRM1 ubiquitination, degradation, and cellular response to 



gemcitabine. This suggests that RNF2 and Bmi1 might be attractive therapeutic 

targets to overcome gemcitabine resistance in malignancies. 


145P ZEB1 AND ZEB2 MEDIATE PANCREATIC FIBROBLAST 

INDUCED EPITHELIAL-TO MESENCHYMAL TRANSITION 

(EMT) IN PANCREATIC CANCER 

L. Visa 1 , E. Samper 2 , M. Rickmann 2 , A. Postigo 3 , E. Sanchez-Tilo 3 , 

L. Fernandez-Cruz 4 , J. Maurel 5 , X. Molero 6 , E.C. Vaquero 2 

1 Department Medical Oncology, Hospital Clinic Barcelona, Barcelona, SPAIN, 

2 Gastroenterology Department, Hospital Clinic, Barcelona, SPAIN, 3 Oncology 

and Hematology, IDIBAPS, Barcelona, SPAIN, 4 Surgical Department, Hospital 

Clinic, Barcelona, SPAIN, 5 Medical Oncology, Hospital Clinic i Provincial, 

Barcelona, SPAIN, 6 Gastroenterologist, Hospital Vall Hebron, Barcelona, SPAIN 

EMT renders neoplastic cancer cells the ability to migrate and to invade distant 

organs. The hallmark of EMT is the loss of E-cadherin, which is a prerequisite for 

epithelial tumor cell invasion. In pancreatic cancer, loss of tumor E-cadherin is an 

independent predictor of poor outcome.AIMS: To analyze the effect of pancreatic 

fibroblasts (PF) on inducing EMT in pancreatic cancer cells and to identify the 

transcription factors (Snail, Slug, ZEB1, ZEB2) that mediate EMT process. 

Methods: Human PFs were isolated from human pancreatic specimens obtained 

from chronic pancreatitis and from unaffected margins of pancreatic adenocarcinoma 

and serous cistoadenoma. PF were cultured until complete cellular activation, as 

assessed by expression of a-smooth muscle actin, vimentin and fibronectin. 

Human pancreatic cancer cells Panc-1 were exposed to PF conditioned medium 

(PF-CM) and EMT analyzed by cell morphology, migration, and E-cadherin 

expression (quantitative RT-PCR and immunoblot). Gene expression of Snail, Slug, 

ZEB1, and ZEB2 was analyzed by quantitative RT-PCR, and their activity modulated 

by siRNA. 

Results: Conditioned media from all types of activated PFs induced EMT changes in 

Panc-1 cells, as shown by 1) morphological transition from cobblestone shaped to 

fibroblast-like cells, 2) stimulation of cell migration, and 3) E-cadherin down– 

regulation; mRNA expression of Snail transiently increased at 30 min after exposure 

to PF returning to basal levels afterwards; mRNA levels of ZEB1 were not 

up-regulated upon exposure to PF-CM. However, ZEB1 protein greatly accumulated 

after 48h incubation with PF-CM, suggesting that PF prevent ZEB1 degradation in 

Panc-1 cells. Combined RNA downregulation of ZEB1 and ZEB2, but not of Snail 

and/or Slug, suppressed E-cadherin repression induced by PF. 

Conclusion: Activated PFs promote the invasive phenotype of pancreatic cancer cells 

through ZEB1 and ZEB2 activation. 


146P THE PROGNOSTIC VALUE OF MMP-9, MMP-2, TIMP-1 AND 

TIMP-2 IN BREAST CANCER AFTER TWELVE YEARS OF 

INITIAL INVESTIGATION 

D.C. Jinga 1 , A. Blidaru 2 , I. Condrea 3 , C. Ardeleanu 4 , D. Median 5 , 

M. Stefanescu 6 , C. Matache 6 

1 Medical Oncology, University Bucharest Hospital, Bucharest, ROMANIA, 

2 Surgical, “Al.Trestioreanu” National Institute Of Oncology, Bucharest, ROMANIA, 

3 Pathology, “Al.Trestioreanu” National Institute of Oncology, Bucharest, 

ROMANIA, 4 Pathology, Victor Babes National Institute, Bucharest, ROMANIA, 

5 Medical Oncology, Institute of Oncology Bucharest, Fundeni Clinical Hospital 

Alexandru Treistoreanu, Bucharest, ROMANIA, 6 Immunology, Cantacuzino 

National Research for Microbiology and Immunology, Bucharest, ROMANIA 

Background: The aim of this study was to investigate the prognostic power of 

matrixmetalloproteinases (MMP-9, MMP-2) expression and activity as well as their 

natural inhibitors (TIMP-1, TIMP-2) expression in breast cancer tumours. 

Patients and methods: All of the experimental parameters were evaluated in fresh 

tumour tissue samples from thirty-two consecutive patients with primary invasive 

breast carcinomas collected between 2001-2002. Gelatinase activity (MMP-9 and 

MMP-2) was analysed by zymography while the expression level of MMP-9, MMP-2, 

TIMP-1 and TIMP-2 was quantified by commercial ELISA kits in 1% Triton-X 100 

tumour extracts. The Mann-Whitney U test and Spearman’s coefficient where 

calculated in order to establish the correlation of the experimentally determined 

parameters with relapse free survival (RFS), overall survival (OS) and the presence of 

metastasis and death (D) at the end of study. 



abstracts

Results: TIMP-1 expression was increased in the groups of patients with RSF < 104 

months, with OS < 113 months and in those who died by comparison with their 

counterparts. These patients, especially the group with OS < 113 months, have also 

the lowest levels of TIMP-2 (p = 0.058). Therefore, MMP-2/TIMP-2 ratio 

distinguished statistically significant the groups of patients with OS greater and lower 

than 113 months (p = 0.051). On the other hand, TIMP-1/TIMP-2 ratio 

distinguished statistically significant groups of patients with RFS more than 104 

months (p = 0.057), with OS more than 113 months (p = 0.068) or alive (p = 0.038) 

of their counterparts. TIMP-1/TIMP-2 ratio directly correlated with the death of 

patients (r = 0.381, p = 0.034), being significantly higher in the group of patients who 

died. 

Conclusions: Our data suggested that as TIMP-1 expression is lower and TIMP-2 

expression is higher, both relapse free survival and overall survival are higher. 

TIMP-1/TIMP-2 and MMP-2/TIMP-2 ratios seemed to be long term prognostic 

markers. These results are consistent with our previous observation that showed a 

direct correlation between MMP-2/TIMP-2 ratio and the value of Nottingham 

Prognostic Index. 


147P HOX GENE EXPRESSION IN OVARIAN CANCER 

Z. Kelly 1 , H. Pandha 1 , K. Madhuri 2 , R. Morgan 2 , A. Michael 3 

1 Department of Microbial and Cellular Science, University of Surrey, Guildford, 

UNITED KINGDOM, 2 Gynaecology and Surgery, Royal Surrey County Hospital, 

Guildford, UNITED KINGDOM, 3 Oncology, University of Surrey PGMS, 

Oncology, Guildford, UNITED KINGDOM 

Background: Ovarian cancer is the leading cause of cancer death among all 

gynaecological cancers. The aggressive nature of ovarian cancer is partly due to its 

heterogeneity and lack of effective treatment strategies other than surgery and 

standard chemotherapy. Further work to understand the molecular changes and 

design more effective drugs is essential. We have studied the expression of HOX 

genes-a family of homeodomain-containing transcription factors that determine cell 

and tissue identity in the early embryo and have been found to be dysregulated in 

cancer. We looked at the HOX gene expression profile of all 39 HOX genes in 

primary ovarian and peritoneal tumours of different histotypes. 

Methods: HOX gene expression profiles were analysed in ovarian tumour samples 

and compared to normal ovarian tissue. RNA was isolated from tumour samples 

using the RNeasy® Plus Mini Kit (Qiagen Ltd) and the relative expression of all 

39HOX genes were determined by quantitative real-time polymerase chain reaction. 

The 2-tailed student’s t-test was applied to determine significant differences between 

tumours and normal ovary. 

Results: We have analysed a cohort of 72 patients with epithelial ovarian cancer-59 

serous, 5 endometrioid, 5 clear cell, 3 MMMT and one mucinous. Dysregulation of 

certain HOX genes expression was found in the majority of ovarian tumour samples 

with little to no expression in normal ovarian epithelium. By comparing HOX genes 

from all histotypes with normal ovarian tissue, 28 HOX genes were found to be 

upregulated in the tumours with P-values < 0.0001 for 20 genes. Expression of 

HOXB1, B2, B3, B7, B13, C11 and D12 were only seen in cancer tissue. HOXA9 and 

HOXB5 were found to be most highly expressed. The expression of HOXB5 was seen 

in 98% of the cancers analysed as compared with the normal ovarian tissue. The 

expression did not correlate with the clinical stage or CA-125 levels at presentation. 

The median follow up of the cohort was 26 months and median survival has not 

been reached. 

Conclusion: HOX genes were shown to be dysregulated in ovarian tumours, with a 

number of genes showing significant upregulation compared to normal ovarian 

epithelium. HOXB5 and HOXA9 are the most highly up-regulated. This suggests 

that HOX genes may have a role in ovarian cancer oncogenesis. 


148P TARGETING NFKB IN CISPLATIN RESISTANT NSCLC 

K.A. Gately 1 , S. Heavey 1 , P. Godwin 1 , M. Barr 2 , K.J. O’Byrne 3 

1 Clinical Medicine, Trinity College Dublin/St James Hospital, Dublin, IRELAND, 

2 Clinical Medicine, Trinity College Dublin, Dublin, IRELAND, 3 Hope Directorate, St 

James’s Hospital, Dublin, IRELAND 

The most effective systemic chemotherapy for Non Small Cell Lung Cancer (NSCLC) 

is cisplatin-based combination treatment. However, chemoresistance is a major 

therapeutic problem with the patients’ tumours either de novo resistant to therapy or 

ultimately developing resistance to cisplatin. Understanding the mechanisms 

underpinning cisplatin resistance (CR) may lead to the development of predictive 

biomarkers and novel therapies for NSCLC and other platinum treated tumours in 

the future. The NF-κB pathway has been implicated in tumour initiation, 

progression, and resistance to chemotherapy. Although small-molecule inhibitors of 

NF-κB have been proposed as single-agent therapies for cancers with aberrant 

NF-κB activity, most classic NF-κB inhibitors are poorly selective and result in 

off-target effects. Dehydroxymethyl-epoxyquinomicin (DHMEQ) is an inhibitor of 


low molecular weight designed from the structure of the antibiotic epoxyquinomicin 

C. The aim of this study is to investigate the role of the PI3K-NFκB pathway in 

resistance to cisplatin in NSCLC and assess the effect of NF-κB inhibition by 

DHMEQ in cisplatin sensitive and resistant cell lines. A panel of cisplatin resistant 

NSCLC cell lines (H460, SKMES1, A549) were developed in our laboratory. H460 

parent & resistant cell lines were screened for changes in mRNA expression using the 

PI3K Profiler array (SABiosciences). Changes in gene expression were validated by 

QPCR and protein expression by Western blot and HCA. IkBa exons 3-5 were 

screened for mutations by sequencing. The effect of DHMEQ (inhibitor of NF-κB 

translocation) was assessed by HCA assays. An 11.99 fold increase in IkBa mRNA 

expression was identified in the cisplatin resistant H460 cells compared to parent 

cells. QPCR, Western blot and HCA confirmed this overexpression of IkBa. No 

mutations were identified in exons 3-5 of the IkBa gene. Inhibition of NF-kB by 

DHMEQ led to increased apoptosis and decreased proliferation in cisplatin resistant 

cells versus parent cells implying NF-kB plays a significant role in cisplatin 

resistance. We are evaluating the synergistic effects of DHMEQ and cisplatin both in 

vitro and in vivo on tumour growth and spontaneous lung metastasis in athymic 

nude mice. DHMEQ may provide a beneficial treatment strategy for NSCLC patients 

who progress on cisplatin. 


149P MICRORNA PROFILING AND CDDP-GPG DNA ADDUCT 

FORMATION ANALYSIS IN A PANEL OF CISPLATIN 

RESISTANT NON-SMALL CELL LUNG CANCER CELL LINES 

M. Barr 1 , S.G. Gray 2 , D.A. Fennell 3 , J.J. O’Leary 4 , D. Richard 5 , J. Thomale 6 , 

A.C. Hoffmann 7 , K.J. O’Byrne 1 

1 Clinical Medicine, St James’s Hospital, Dublin, IRELAND, 2 Clinical Medicine, 

Trinity College Dublin, Dublin, IRELAND, 3 Centre for Cancer Research and Cell 

Biology, Queen’s University Belfast, Belfast, UNITED KINGDOM, 

4 Histopathology, St James’s Hospital, Dublin, IRELAND, 5 Queensland University 

of Technology, Institute of Health and Biomedical Innovation, Brisbane, 

AUSTRALIA, 6 Cancer Research, Institute for Cell Biology, University Hospital 

Essen, Germany, Essen, GERMANY, 7 Internal Medicine (Cancer Research), 

Molecular Oncology Risk-Profile Evaluation (M.O.R.E) University Hospital Essen, 

Germany, Essen, GERMANY 

Introduction: The outcome of cisplatin therapy in NSCLC has reached a plateau, 

with the development of resistance being a major obstacle in the use of this drug. 

Understanding the molecular mechanisms underlying this resistance phenotype may 

aid in the development of novel agents that enhance the sensitivity of cisplatin. In 

this study, we examined the microRNA profile and levels of cisplatin-DNA adduct 

formation in a panel of cisplatin resistant NSCLC cell lines. 

Methods: We have previously generated a panel of cisplatin resistant (CisR) cell lines 

(MOR, H460, A549, SKMES-1, H1299) from original, age-matched parent (PT) cells 

and extensively characterised these based on a number of functional assays including 

proliferation (MTT), apoptosis (FACS), cell cycle arrest (PI staining), survival ability 

(clonogenic assay), DNA copy number gains and losses (CGH arrays) and cancer 

stem cell marker expression (CD44, CD133, ALDH1, Nanog, Sox-2 and Oct-4) by 

FACS and Western blot analysis. MicroRNA profiling was carried out using the 

nCounter miRNA Expression Assay consisting of 749 target miRNA’s. 

Immunofluorescence staining and measurement of specific DNA platination 

products (CDDP-GpG DNA adducts) was performed at 0, 4, 12 and 24h using 

immunofluorescence microscopy and quantitative digital image analysis using the 

ACAS 6.0 CytometryAnalysis System, respectively. 

Results: In a panel of five NSCLC cell lines exhibiting a cisplatin resistant phenotype, 

a 3- and 13-miRNA signature was deduced, based on differential expression of 3 

miRNA’s (5/5 cell lines) and 13 miRNA’s (4/5 cell lines) in the CisR cell lines 

relative to their parent counterparts. Levels of CDDP-GpG adducts were greatly 

reduced in resistant cells up to 24h in response to cisplatin compared to that 

observed in corresponding parent cells. 

Conclusion: We have identified a distinct miRNA fingerprint in a clinically relevant, 

isogenic model of cisplatin resistance that may predict resistance to cisplatin in lung 

cancer. Furthermore, as cisplatin-DNA adducts correlate with cisplatin resistance in 

vitro, these may be used as a potential predictive marker in patient response to 

platinum therapy in NSCLC. 


150P IL-23 IS EPIGENETICALLY REGULATED AND INDUCED BY 

CHEMOTHERAPY IN NSCLC 

A. Baird, J. Leonard, L. Kilmartin, É. Dockry, K.J. O’Byrne, S.G. Gray 

Clinical Medicine, Trinity College Dublin/St. James’s Hospital, Dublin, IRELAND 

Introduction: Inflammation plays a role in many malignant states including lung 

carcinogenesis. IL-23A is one such inflammatory mediator which may have a role in 

lung cancer. It is a hetero-dimeric cytokine composed of two covalently linked 

subunits consisting of p19 and p40. IL-23A plays a key role in chronic inflammation 

and angiogenesis through the promotion of IL-17 production by T helper 17 cells via 



the STAT signalling pathway and NF-κB. This study sought to determine the 

expression and regulation of IL-23A in NSCLC. 

Methods: IL-23A expression levels were determined in a series of 34 tumour 

specimens with matched normal tissue taken from patients presenting with NSCLC. 

Basal expression levels were also examined in a panel of normal and NSCLC cell 

lines at the mRNA level. Using histone deacetylase (HDi), DNA methyltransferase 

(DNMTi) inhibitors and a ChIP assay it was determined if IL-23A was subject to 

epigenetic regulation in NSCLC cell lines (adenocarcinoma and squamous cell 

carcinoma). The effect of Gemcitabine on IL-23A expression was also studied. In 

addition, the effect of recombinant IL-23 treatment on NSCLC cell line proliferation 

was examined. 

Results: In a cohort of NSCLC patients, IL-23A expression levels were significantly 

elevated in tumour tissue compared with normal (p < 0.05). This elevation was also 

evident within the NSCLC sub types. Treatment with TSA (p < 0.05) and SAHA 

(p < 0.05) induced the expression of IL-23A in the A549 and SK-MES-1 cell lines. A 

ChIP assay confirmed dynamic remodelling of the IL-23A promoter region. 

Significant induction of IL-23A was also evident post treatment with a DNMTi 

(5-Aza-2’-Deoxycytidine) and Gemcitabine. Furthermore, treatment with 

recombinant IL-23 increased cellular proliferation in NSCLC cell lines that express 

functional IL-23R receptors. 

Conclusion: IL-23A was significantly elevated in a cohort of NSCLC patient tissues 

and is epigenetically regulated through histone post-translational modifications and 

DNA CpG residue methylation. The chemotherapy agent, Gemcitabine, also induced 

IL-23A expression. Additionally, IL-23 promoted NSCLC cell line proliferation. 

These results may have important implications for treating NSCLC patients with 

epigenetic targeted therapies or Gemcitabine. 


151P INTRATUMOR HETEROGENEITY OF ER STATUS IS A 

FEATURE OF INTERACTION BETWEEN MAMMARY 

CARCINOMA CELLS AND MICROENVIRONMENT 

I. Boichuk 1 , D. Burlaka 2 

1 Department of Cancer Experimental Therapeutics, R.E. Kavetsky Institute of 

Experimental Pathology, Oncology and Radiobiology, Kyiv, UKRAINE, 

2 Biotechnical Problems of Diagnostic, Institute Problems of Cryobiology and 

Cryomedicine of the National Academy of Sciences (IPCC), Kiev, UKRAINE 

The growth and survival of mammary carcinoma cells often depend on their 

estrogen sensitivity proving a rationale for targeted therapy. The relationship between 

tumor growth and changing hormonal environment is demonstrated both in 

experiment and in clinical setting (age-related difference in breast cancer prognosis, 

changing estrogen and progesterone receptor patterns in breast carcinoma during the 

menstrual cycle and menopause, etc.). The aim of this study was to analyze the 

effects of the changing hormonal environment in the setting of the oestrus cycles on 

tumor growth and levels of estrogen receptors (ER) in murine mammary tumors. 

Methods: The dextran-coated charcoal radioactive ligand-binding ER assay method 

was used followed by Scatchard analysis. 

Results: The increment of tumor volume in mouse with mammary carcinoma is not 

a linear one but followed the pattern of changing hormonal levels within 4-day 

oestrus cycle in a wave-shaped manner. Upon the plateau of tumor growth, receptors 

are lost in half of cells. Thus, the population becomes heterogeneous in ER content. 

The widely accepted hypothesis that the interaction of estrogen with cellular ER 

determines the hormone dependency of mammary tumors should now be challenged 

on the basis of the following observations: a) tumors arising in experimental animals 

with permanent high estrogen levels are receptor-positive and that with low estrogen 

levels are receptor-negative; b) tumors regrowing after complete or partial regression 

as a result of endocrine ablation or hormone administration are considered to be 

environment dependent rather than autonomous or hormone dependent; c) 

mammary tumors growing in the setting of cyclically changing hormonal level 

become heterogeneous. 

Conclusion: Tumor cells are highly sensitive to alterations in hormonal background. 

The adaptation to the altered microenvironment could promote metastases, tumor 

heterogeneity, and, oddly enough, transform the tumors into a nonmalignant state. 


152P BONE MARROW TRANSPLANTATION RESCUES INTESTINAL 

MUCOSA AFTER WHOLE BODY RADIATION VIA PARACRINE 

MECHANISMS 

H. Chang 1 , Y.H. Chang 1 , L. Lin 1 , C. Lou 1 , C. Chou 2 

1 National Institute of Cancer Research, National Health Research Institutes, 

Tainan, TAIWAN, 2 National Laboratory Animal Center, National Applied Research 

Laboratories, Taipei, TAIWAN 

Background: Our previous study reveals BM transplantation (BMT) triggers 

trafficking of host CD11b(+) myelomonocytic cells from the host marrow to the 

radiation-injured intestinal mucosa, enhancing the proliferation of intestinal stroma 

cells, leading secondarily to epithelial regeneration. In this study, we propose that 

BMT ameliorates intestinal damage via paracrine mechanisms. 

Materials and methods: Mouse survival, intestine microcolony assay, angiogenic 

cytokine array, immunonhistochemical studies of both intestine and BM were 

evaluated in mice after WBI and BMT. Epithelial and stromal components within 

intestine mucosa were measured by immunoblotting and flowcytometry. BM 

conditioned medium (BMCM) with or without treatment with neutralizing 

antibodies to angiogenic cytokines were continuously infused to mice after WBI or 

whole abdomen irradiation. Carrageenan was used to deplete myelomonocytic cells 

of recipient mice. 

Results: BMT increases VEGF, bFGF and other angiogenic cytokines within intestine 

mucosa within 24 hrs after WBI. Continuous infusion of BMCM alone ameliorated 

radiation-induced intestine damage and improved survival of mice. Proliferation 

index, endothelial cells, myofibroblasts as well as myelomonocytic cells within 

intestine were increased by BMCM within one week after radiation. Neutralization of 

bFGF, PDGF and other angiogenic cytokines within BMCM abolished the mitigating 

effect to intestine. Pretreatment of carrageenan to recipient mice depleted CD11b(+) 

myelomonocytic cells and reversed some of the angiogenic cytokine levels, including 

VEGF, within intestine mucosa after BMT from healthy donors. 

Conclusions: Our results suggest that BMT recruits host CD11b(+) myelomonocytic 

cells and enhances intestine stroma proliferation by secreting angiogenic cytokines 

including PDGF, bFGF. Host CD11b(+) myelomonocytic cells further uplift the 

angiogenic effect via cytokines including VEGF. 


153P TOCILIZUMAB CAN ENHANCE THE ANTI-TUMOR EFFECT OF 

IFN-α IN RENAL CELL CARCINOMA 

T. Oguro 1 , K. Ishibashi 1 , T. Sugino 2 , S. Kumagai 1 , N. Takahashi 1 , N. Haga 1 , 

T. Yanagida 1 , K. Aikawa 1 , O. Yamaguchi 3 , Y. Kojima 1 

1 Urology, Fukushima Medical University, Fukushima, JAPAN, 2 Pathology, 

Fukushima Medical University, Fukushima, JAPAN, 3 Bioenginnering, Nihon 

University, Koriyama, JAPAN 

Background: Interleukin 6 (IL-6), one of the proinflammatory cytokines, contributes 

to the onset and maintenance of various types of cancer. IL-6 signaling induces 

up-regulation of SOCS3, which leads to interferon (IFN) –α resistance in renal cell 

carcinoma (RCC) cells. To propose a new treatment for mRCC, we investigated the 

effect of combination therapy with IFN-α and humanized antihuman IL-6R 

antibody, tocilizumab. 

Material and methods: Real time PCR (RT-PCR) was used to analyze gene 

expression of IL-6 and SOCS3 after IFN stimulation and ELISA were used for IL-6 

secretion in RCC cell lines. These expression levels were compared among the RCC 

cell lines, i.e., ACHN, Caki-1, TUHR3TKB, TUHR4TKB and 786-O. 

Phosphorylation of STAT-1, STAT-3 and ERK were investigated by Western blotting 

(WB) analysis. We investigated alteration of IL-6 signaling by tocilizumab, and 

analyzed its impacts on the susceptibility to IFN-α in RCC cells by MTT assay. The 

effects of tocilizumab on in vivo growth on 786-O xenografts were determined by 

SOCS3 expression, morphological observation and tumor volume. 

Results: Among the RCC cell lines, the expression levels of IL-6, SOCS3 in RT-PCR 

and the production level of IL-6 were highest in 786-O. These results revealed a 

correlation between the expression levels IL-6 and SOCS3 (P = 0.0001, r = 0.99974). 

Although the 786-O cells had IFN-α resistance, MTT assay showed that the 

tocilizumab induced a growth inhibitory effect of IFN-α. WB analysis showed that 

phosphorylation level of STAT-1 was increased and the levels of STAT-3 and ERK 

were decreased with the simultaneous use of tocilizumab in 786-O cells. An in vivo 

study demonstrated that tocilizumab promoted IFN-α-induced cell death and growth 

suppression in 786-O cell xenograft in nude mice. 

Conclusions: IL-6 could be a key component in the resistance to IFN-α treatment of 

renal cell carcinoma. Antihuman IL-6R antibody can be an effective strategy to 

enhance the anti-tumor effect of IFN-α, and probably, the effect of angiogenic 

inhibitors, in human RCC cells. 


154P CO-TARGETING THE PI3K-MTOR & MEK PATHWAYS IN 

NSCLC 

S. Heavey, M. Barr, A. Ahmad, A. Davies, K.J. O’Byrne, K.A. Gately 

Clinical Medicine, Trinity College Dublin, Dublin, IRELAND 

The PI3K/Akt/mTOR and MAP/ERK kinase (MEK) pathways regulate cell growth 

and proliferation and are often dysregulated in cancer due to mutation, amplification, 

deletion, methylation and post-translational modifications. We and others have 

shown that activation of the PI3K pathway in Non Small Cell Lung Cancer (NSCLC) 

leads to a more aggressive, drug-resistant disease which correlates to poor prognosis 

for patients. Combinations of PI3K and MEK and inhibitors have shown promise in 

preclinical cancer models, leading to the initiation of clinical trials cotargeting these 

two key cancer signalling pathways. The selection of appropriate patient cohorts who 


will benefit from this targeted therapy, using biomarkers, is key to the success of 

these inhibitors. GDC-0941 is a PI3K targeted inhibitor which is currently in phase 

II trials for combination treatment with carboplatin, paclitaxel and bevacizumab in 

patients with previously untreated advanced or recurrent NSCLC. GDC-0980 is a 

selective dual inhibitor of PI3K and mTOR, which is currently in phase I trials for 

combination treatment with bevacizumab, trastuzumab and capecitabine in solid 

tumours. GDC-0973 is a MEK targeted inhibitor which is currently in Phase I 

clinical trials for treatment of patients with solid tumours in combination with 

GDC-0941. The aim of this study is to investigate the effects of GDC-0941, 

GDC-0980 and GDC-0973 alone and in combination on a panel of NSCLC cell lines 

and to develop cell line models resistant to dual inhibitor GDC-0980 which will then 

be characterised to elucidate mechanisms involved in acquired resistance. The effects 

of GDC-0941 and GDC-0980 on pAkt, pS6 and cPARP levels, and the effects of 

GDC-0973 on MAPK and Bim levels were analysed by Western blot. The effects of 

these inhibitors alone and in combination on cell proliferation and apoptosis were 

analysed by BrdU assay and by multiparameter apoptosis assays (using High Content 

Analysis) respectively. The results varied across the panel of cell lines, however the 

dual inhibitor GDC-0980 demonstrated more significant anti-proliferative and 

pro-apoptotic effects than PI3K inhibitor GDC-0941. IC50 values for GDC-0980 are 

currently being used to treat the panel of cell lines in order to develop cell line 

models of resistance. 


155P EFFECT OF BEVACIZUMAB ON TUMOUR 5-FLUOROURACIL 

CONCENTRATION AND MICROCIRCULATORY PARAMETERS 

OBTAINED BY DYNAMIC CONTRAST-ENHANCED MRI IN A 

HEPATOCELLULAR CARCINOMA XENOGRAFT MODEL 

S. Mikulski 1 , L. Wang 2 , S. Hartono 3 , L. Martarello 4 , T.S. Koh 5 , B.C. Goh 2 , 

C.H. Thng 5 , Q.S. Ng 6 

1 Graduate Medical School, Duke-NUS, Singapore, SINGAPORE, 2 Cancer 

Science Institute of Singapore, National University of Singapore, Singapore, 

SINGAPORE, 3 School of Electronic & Electrical Engineering, Nanyang 

Technological University, Singapore, SINGAPORE, 4 Roche Translational Medicine 

Hub, SingHealth, Singapore, SINGAPORE, 5 Department of Oncologic Imaging, 

National Cancer Centre, Singapore, SINGAPORE, 6 Department of Medical 

Oncology, National Cancer Centre, Singapore, SINGAPORE 

Introduction: Vascular endothelial growth factor (VEGF) is expressed by tumours to 

promote angiogenesis. Clinical trials of anti-VEGF therapy combined with 

chemotherapy demonstrate improvement in survival. We investigate the effect of 

bevacizumab (bev), a humanized monoclonal antibody that inhibits VEGF-A, on 

tumour 5-fluorouracil (5FU) concentration in a hepatocellular carcinoma (HCC) 

xenograft model, together with changes in tumour microcirculatory parameters 

obtained by dynamic contrast-enhanced (DCE) MRI. 

Methods: 48 immunodeficient mice implanted with subcutaneous HCC xenografts 

were first injected with bev (1mg/kg or 10mg/kg) or omalizumab (control). 1 day 

later, they received 5FU and were sacrificed. Tumour and plasma 5FU concentration 

was measured by liquid chromatography-mass spectrometry. A subset of 17 mice 

underwent DCE MRI with gadolinium contrast at baseline and one day after bev/ 

omalizumab injection. Scans employed a three-dimensional spoiled gradient recalled 

sequence with tracer concentration estimated using variable flip-angle technique. 

Data analysis employed a conventional two-compartment tracer kinetic model. 

Results: Tumour 5FU concentration (µg/g) was significantly lower 1 day after bev 

(10mg/kg) compared to control (8.4 vs 21.6, p = 0.027). However, there was no 

significant difference in plasma 5FU concentration between the bev and control 

groups. Following bev (10mg/kg), DCE MRI measurements of tumour intravascular 

blood volume reduced by 38.3% (p = 0.01); there was no significant change in 

DCE-MRI parameters in the control group. Following bev (1mg/kg), tumour 

permeability-surface area product (ml/100ml/min) correlated with tumour 5FU 

concentration (r 2 = 0.84, p = 0.01). 

Conclusion: Bev causes vascular shutdown consistent with its anti-angiogenic mode 

of action. Reduced tumour 5FU concentration suggests that the reported synergism 

between anti-VEGF and chemotherapy may not be attributable to improved drug 

delivery at this early time point. DCE-MRI may play a role as a biomarker for 

tumour drug concentration following anti-VEGF therapy. 


156P TARGETING HSP90 IN IRRADIATED CANCER CELLS BLOCKS 

DNA-REPARATIVE, ANTIAPOPTOTIC AND ANGIOGENIC 

PATHWAYS 

V. Kudryavtsev, A. Demidkina, A. Kabakov 

Department of Radiotherapy, Medical Radiology Research Center, Obninsk, 

RUSSIAN FEDERATION 

Introduction: Human tumors are often resistant to radiotherapy; therefore, 

radiosensitization of them is of importance. We explored how 

17-N-allilamino-17-demethoxygeldanamycin (17AAG), an inhibitor of the heat 

shock protein 90 (Hsp90) chaperone activity, affects radiation response of breast 

cancer cells. In addition, we examined effects of 17AAG on the angiogenic signaling 

because tumor-stimulated angiogenesis is a factor decreasing the efficacy of 

radiotherapy. 

Methods: MCF-7 cells cultured from human breast carcinoma were exposed to 

clinically relevant doses (2-5 Gy) of gamma-radiation, while some samples were 

co-treated with 10-500 nM 17AAG. The cell death/survival was assessed in 

annexin-V staining and clonogenic assays. Certain cell death-, DNA repair- and 

angiogenesis-related proteins were probed by immunoblotting. The p53 and ATM 

patterns were visualized by immunofluorescence. 

Results: In the breast cancer cells, 40-150 nM 17AAG inhibited the Hsp90 

chaperone function and down-regulated the Akt, survivin, HIF-1alpha, VEGF and 

Bcl-2 levels. The phosphorylation of Akt and its down-stream targets such as Bad, 

XIAP, GSK-3 or MDM2 became impaired. Enhanced activation of p53 and its longer 

up-regulation together with the inhibition of phosphorylation and nuclear 

translocation of ATM were found in the cells irradiated at 2-5 Gy after incubation 

with 40-150 nM 17AAG. The cells co-treated by such a way exhibited massive 

apoptosis and sharply decreased clonogenicity, whereas the same irradiation without 

17AAG induced the less cytotoxicity. This radiosensitization seems to be due to (i) 

down-regulation or inactivation of antiapoptotic proteins (Akt, Bcl-2, survivin, 

XIAP), (ii) activation of pro-apoptotic proteins (Bad, GSK-3) and (iii) switching the 

MDM2/p53/ATM-mediated DNA damage response from DNA repair to apoptosis. 

Besides the enhancement of radiation-induced killing of the cancer cells, 40-150 nM 

17AAG impaired their angiogenic potential that was revealed on down-regulation of 

HIF-1alpha and VEGF. 

Conclusion: Clinically achievable concentrations of 17AAG allow to enhance the 

radiation response of human breast tumors and to suppress the tumor-stimulated 

angiogenesis. 


157P RITUXIMAB INDUCED INTERNALISATION OF B-CELLS CD20 

RECEPTOR IS INDEPENDENT OF THE INHIBITORY FC 

RECEPTOR (CD32B) INTRACELLULAR CELL SIGNALLING 

V. Shah, A. McIntosh, C.H.T. Chan, S.H. Lim, A.T. Vaughan, M.J. Glennie, 

A. Roghanian, M.S. Cragg 

Antibody and Vaccine Group, Cancer Sciences Unit, Southampton University 

Faculty of Medicine, University of Southampton, Southampton, UNITED 

KINGDOM 

The anti-CD20 monoclonal antibody, rituximab, has improved treatment outcomes 

in B-cell malignancies. However, several B-cell lymphomas either do not respond to 

rituximab or develop resistance. Internalisation of rituximab may be partly 

responsible for this resistance. We recently showed that the level of the inhibitory Fc 

receptor (CD32B) at the cell surface controls the rate of rituximab internalisation. 

However, the precise mechanism involved has not been elucidated. Different isoforms 

of CD32B exist (B1 and B2), only one of which (B2) has previously been associated 

with an ability to internalise after engagement of immune complexes. The B1 form 

in contrast contains an additional intracellular region that makes it more resistant to 

internalisation. We therefore investigated the role of the two different CD32B 

isoforms (B1 and B2) and the associated intracellular tail on rituximab 

internalisation. CD32B1 and CD32B2 isoforms were stably transfected into 

CD32B −ve mouse IIA1.6 and human Ramos lymphoma cells, and flow cytometry was 

then used to determine the relative rates of CD32B and CD20 internalisation. 

Additionally, we generated mutant versions of the CD32B receptors, including those 

lacking the entire cytoplasmic domain to assess the importance of intracellular 

signalling. In contrast to expectations both B1 and B2 CD32B isoforms were 

downregulated upon engagement with CD32B mAb as a surrogate for immune 

complexes, although in agreement with earlier reports the CD32B2 isoform 

internalised more extensively. However, the rate of rituximab internalisation occurred 

equally with both isoforms and was dependent on relative expression of CD32B and 

the CD20:CD32B ratio at the cell surface rather than any specific activity imparted 

by the CD32 intracellular domain. These studies suggest that the intracellular part of 

CD32B is redundant for rituximab-induced CD20 internalisation and imply that 

internalisation is augmented by CD32B through its physical ability to bind the Fc 

region of rituximab at the cell surface. 


158P TARGETING EFFICIENCY AND BIODISTRIBUTION OF 

EGFR-CONJUGATED MESOPOROUS SILICA NANOPARTICLES 

FOR CISPLATIN DELIVERY IN NUDE MICE WITH LUNG 

CANCER 

S. Sundarraj 

Zoology, Bharathiar University, Coimbatore, INDIA 


Lung cancer is the most malignant cancer today; in order to develop an effective 

drug delivery system for lung cancer therapy In this study, an efficient approach for 



tumor-targeted drug delivery was developed with non-small cell lung cancer as the 

targeting vehicle and a mesoporous silica nanoparticle as the drug carrier. A 

mesoporous silica nanoparticle-cisplatin drug delivery system was efficiently 

anchored to non-small cell lung cancer by specific EGFR recognitions at the 

cytomembrane interface without any cell preconditioning. By the in vitro cell culture 

test, EGFR-MSN-cisplatin resulted in higher entrance efficiency on adenocarcinoma 

cells (A549) than that on normal lung cells (L-132) because A549 possessed greater 

amounts of EGFR. High levels of nanoparticles were uptake to each MSCLC cell with 

high cell viability and tumor-tropic ability. The intracellular retention time of the 

MSN was no less than 48 h, which is sufficient for cell-directed tumor-tropic 

delivery. In vivo experiments proved that the burdened NSCLC can track down the 

more efficiently and deliver cisplatin with wider distribution and longer retention 

lifetime in tumor tissues compared with free cisplatin and EGFR-MSN-cisplatin. The 

increased and prolonged cisplatin intratumoral distribution further contributed to 

significantly enhanced tumor-cell apoptosis. This strategy has potential to be 

developed as a robust and generalizable method for targeted tumor therapy with high 

efficiency and low systematic toxicity. 


159P DEAD/H (ASP-GLU-ALA-ASP/HIS) BOX POLYPEPTIDE 3, 

X-LINKED PLAYS AN ONCOGENIC ROLES TO INDUCE 

CANCER STEM CELL-LIKE PROPERTIES 

K. Nozaki 1 , H. Kagamu 1 , K. Ichikawa 1 , J. Koshio 1 , Y. Saida 1 , T. Tanaka 1 , 

S. Miura 1 , S. Watanabe 2 , H. Yoshizawa 2 , I. Narita 1 

1 Division of Respiratory Medicine, Graduate School of Medical and Dental 

Sciences, Niigata University, Niigata, JAPAN, 2 Bioscience Medical Research 

Center, Niigata University Medical and Dental Hospital, Niigata, JAPAN 

Background: DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 3, X-linked 

(DDX3X) is a member of the DEAD-box family of ATP dependent RNA helicase. 

DEAD-box helicases have multiple functions including RNA splicing, mRNA export, 

transcriptional and translational regulation, RNA decay, and ribosome biogenesis. In 

the last ESMO meeting, we demonstrated that DDX3X is one of 4 proteins that are 

specifically expressed in CD133+ B16 melanoma cells, which possess cancer stem cell 

(CSC) properties and that a DDX3X vaccination induced antitumor therapeutic 

immunity against parental melanoma. DDX3X is evolutionarily well conserved from 

yeast to humans, suggesting that it is essential for cell survival. In humans, DDX3X 

deletion or dysfunction results in genetically related primary amenorrhea and 

impaired female fertility. Although DDX3X was originally reported to suppress 

growth by modulating p21waf/cip1 gene expression, it has been recently shown that 

DDX3X is directly correlated with oncogenesis. Furthermore, it has been shown that 

DDX3X over-expression in breast cancer cells facilitates β-catenin signal transduction 

and induces epithelial mesenchymal transition (EMT), a known feature of CSC. 

However, a precise mechanism how DDX3X, a RNA helicase, plays an oncogenic 

role to induce CSC features is still uncertain. 

Results: Immunoblotting analyses revealed that all of the examined cancer cells, 

including lung cancer, colon cancer and breast cancer cells expressed DDX3X, while 

normal human epidermal keratinocytes (NHEK), human microvascular endothelial 

cells (HMEC), and normal human bronchial epithelial cells (NHBE) faintly expressed 

DDX3X. Moreover, putative CSC marker positive cancer cells, such as 87.5, HCT116, 

and MCF7, strongly expressed DDX3X. HCT116 cells, which have CD133 and strong 

DDX3X expression, exhibit CSC like properties, such as high tumorgenicity, growth 

as non-adherent spheres, and aggressive invasion ability. Knockdown of DDX3X 

resulted in loss of CSC-like features. We found that epigenetic regulation by DDX3X 

play a critical role in oncogenesis. 

Conclusion: DDX3X plays an important role in inducing CSC properties. 

Disclosure: H. Kagamu: I received research fund from Otsuka Phamaceutical Co., 

Ltd. All other authors have declared no conflicts of interest. 

160P GLUCOSE AND NKG2D LIGAND EXPRESSION: A LINK 

BETWEEN CELLULAR IMMUNOGENICITY AND WARBURG 

METABOLISM 

M.T. McCarthy 1 , G.E. Moncayo 2 ,C.O’Callaghan 1 

1 Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UNITED 

KINGDOM, 2 Institute for Biomedical Research, Friedrich Meischer Institute, 

Basel, SWITZERLAND 

Natural killer group 2D (NKG2D) is an activating receptor constitutively expressed 

on the surface of human natural killer cells and CD8+ T-lymphocytes. The ligands 

for NKG2D, including MICA, are up-regulated in several pathophysiological settings, 

including cancer, and viral infection. In these contexts, glucose metabolism is often 

perturbed (the Warburg effect) and glucose levels can be low in the tumour 

microenvironment. We hypothesized that low glucose availability would reduce cell 

surface NKG2D ligand expression and lower the immunogenicity of malignant cells. 

Cell lines cultured in different glucose concentrations displayed a direct correlation 

between glucose level and cell surface expression of MICA, a key activating ligand of 

NKG2D. Real-time RT-PCR demonstrated an increase in MICA mRNA transcript 

levels with increasing glucose concentration. Chromium-release cytotoxicity assays 

demonstrated an NKG2D-dependent change in NK cell-mediated killing of target 

cells, in response to changing glucose availability. This suggests that extracellular 

glucose concentration may alter the susceptibility of malignant cells to 

immune-mediated clearance. 

We demonstrate that the contribution of glucose to nucleotide synthesis is necessary 

for the observed increase in MICA expression. In a primary cell-viral infection model 

of NKG2D ligand induction, we demonstrate that glucose availability determines the 

level of NKG2D ligand expression in the transition from healthy to infected cells. As 

with cell line models, reduced glucose availability in this primary cell model limits 

the up-regulation of NKG2D ligands observed in virus-infected cells. These results 

suggest that Warburg metabolism is important to support NKG2D ligand expression 

in these models. The reduction in NKG2D ligand expression in a low glucose 

environment may represent a novel immune-evasion mechanism in aberrantly 

vascularized tumour microenvironments. Further understanding of the downstream 

signaling pathways could lead to the development of novel therapeutic agents. 


161P UTILIZATION OF FORMALIN-FIXED, PARAFFIN-EMBEDDED 

ARCHIVAL TISSUE FOR CYTOGENETIC ANALYSIS OF 

MICROARRAY-COMPARATIVE GENOMIC HYBRIDIZATION 

M. Oikawa 1 ,J.Arai 1 , H. Kondo 2 , M. Nakashima 3 , T. Hayashi 4 , K. Yoshiura 5 , 

H. Yano 1 , T. Nagayasu 1 

1 Surgical Oncology, Nagaski University Hospital, Nagasaki, JAPAN, 2 Biostatistics 

Section, Division of Scientific Data Registry, Nagasaki University Graduate School 

of Biomedical Sciences, Nagasaki, JAPAN, 3 Tumor and Diagnostic Pathology, 

Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JAPAN, 

4 Pathology, Nagasaki University Hospital, Nagasaki, JAPAN, 5 Human Genetics, 

Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JAPAN 

Background: Utilization of formalin-fixed, paraffin-embedded (FFPE) archival tissue, 

which is the most common form of tissue preservation in routine practice, for 

cytogenetic analysis of microarray comparative genomic hybridization (aCGH) 

remains challenging. We searched for predictive factors of FFPE DNA performance 

on aCGH analysis. 

Materials and methods: Tumor DNA was extracted from 63 various types of FFPE 

archival tissues (31 of breast cancer, 24 of lung cancer, and 8 of thyroid tumor) 

followed by aCGH analysis using high-density oligonucleotide microarray. In two 

cases, tumor DNA from a matched frozen sample and tumor DNA after 

whole-genome amplification (WGA) from an FFPE sample were also analyzed. The 

derivative log ratio spread (DLRSpread) was used as a metric to assess the overall 

quality of each aCGH result. 

Results: The DLRSpread was significantly correlated with the double-stranded DNA 

ratio of tumor DNA, storage time, and degree of Cy5 labeling (P < 0.0001; correlation 

coefficients = -0.796, 0.551, and -0.481, respectively). Stepwise multiple linear 

regression analysis revealed that the double-stranded DNA ratio of tumor DNA is the 

most significant predictive factor of the DLRSpread (regression coefficient = -0.4798; 

P < 0.0001). Cytogenetic profiles of FFPE samples and matched frozen samples were 

well concordant. Although the double-stranded DNA ratios were increased after 

WGA, the DLRSpreads were not improved. 

Conclusions: The double-stranded DNA ratio of tumor DNA predicted the 

performance of DNA from FFPE samples on aCGH analysis. Quality control by 

these metrics can utilize valuable FFPE archival tissue on aCGH analysis. 


162P DETERMINATION OF FREQUENCY OF OCCURRENCE OF THE 

VIRUS ASSOCIATED NON-HODGKINS LYMPHOMA (NHL) IN 

DIFFERENT AGE ASPECTS 

S.R. Abdiganieva, D.A. Pulatov, J.M. Ibragimov, D.A. Abdurakhmanov, 

K.K. Tuydjanova 

Chemotherapy, National Cancer Research Center, Thashkent, UZBEKISTAN 

NHL is often characterized by unpredictable clinical course, i.e. patients with the 

same disease stage, morphology, and treatments for this disease can be dramatically 

different. As a consequence, one can remain latent for many years, and others, on 

the contrary, rapidly progressing incurable with the spread of the disease. One 

possible reason for the unexpected course of the disease may be the viral infection. It 

should be noted that such information on the epidemiology of the virus infection in 

the NHL, both scientific and practical information is completely absent. Therefore, 

no evidence of a viral effect of various agents on the clinical course of the NHL, are 

likely to evaluate the contribution to the pathogenesis and in the future to develop 

new approaches to its treatment. The purpose of this research is to study the virus 

infection in patients with NHL using molecular-biological methods of determining 

the frequency depending on the age of the patients. The object of the study served 

the lymph nodes of 27 patients: 20men (65%) and 7 women (35%). To detect 

infection analysis used immunoglobulin genes by PCR diagnostic of human 

papillomavirus general (HPVG), herpes simplex virus I + II (HSV I + II), 


cytomegalovirus (CMV). Analysis of the frequency of common virus infection in 

different age groups showed the presence of two peaks in patients aged 18 to 35years 

(HPVG-37,7%, HSV I + II-19, 1%, CMV-13, 9) and 65-78 years(HPVG-30,7%, HSV 

I + II-29, 1%, CMV-17, 5). In the other age periods were detected less frequently: 

36-45 years (HPVG-23.4%, HSV I + II-12, 1%, CMV-11, 9), 46-55 (HPVG-30.1%, 

HSV I + II-171%, CMV-10, 9), with the lowest frequency in the age of 56-64 years 

(HPVG-17,7%, HSV I + II-11, 1%, CMV-11, 9). From these, the total extent of 

infection by age of patients was as follows: a high degree of infection ranged in age 

from 18 to 35 years (97.2%) and over 65-78 years (86.7%), moderate - 46-55 years 

(71.7%), low infection rates, 36-45 years (53.5%) and 56-64 years(54.5%). Thus, in 

our study, the presence of a virus associated NHL revealed in all cases, with a 

statistically significant increase in the frequency of occurrence of 18 to 44 years and 

over 65 years. Our evidence suggests that virus infection may play an important role 

in the pathogenesis of NHL, and the choice of treatment effectiveness and prognosis. 


163P TESTING AND ANALYSIS OF FLUORESCENT MARKERS 

PANEL FOR T-CELLS’ MULTIFUNCTIONALITY IN 

GLIOBLASTOMA MULTIFORME PATIENTS 

I. Ben-Horin 1 , I. Volovitz 2 , Z. Ram 3 

1 Oncology Devision, Tel Aviv Sourasky Medical Center-(Ichilov), Tel Aviv, ISRAEL, 

2 Cancer Immunotherapy Lab, Tel-Aviv Sourasky Medical Center, Tel-Aviv, 

ISRAEL, 3 Neurosurgery, Tel-Aviv Sourasky Medical Center, Tel-Aviv, ISRAEL 

Introduction: Immunotherapy had only limited success in brain tumors as the brain 

is regarded as an immunologically privileged site. Recently published work on a rat 

model showed that when live, non-attenuated brain tumor cells are injected 

subcutaneously they are first accepted but are later spontaneously rejected. This 

immunologically mediated rejection of the brain tumors cells in peripheral sites leads 

to a similar intra-cranial tumor rejection. Objective: to characterize the different 

immune cell populations found in human glioblastoma multiforme (GBM) and in 

peripheral blood of GBM patients and to develop means to follow immune responses 

in the CNS to anti-tumor therapy. 

Methods: Tumors were broken down and tumor cells isolated. Cultures of tumor 

cells with or without the respective patient’s activated or non-activated lymphocytes 

were prepared, stained with a fluorescent markers panel for T-cells multifuncionality 

and analyzed using flow cytometry. The panel was constructed in our lab with 

markers for CD3 (total T-cells), CD4 (Th cells), CD8 (CTL), IFNγ, TNFα, IL-12 and 

ViViD – a viability marker. 

Results: Our panel succeeded in characterizing the different immune cell 

populations. It also demonstrated that activation of CD4 T-cells increased IFNγ and 

IL12 expression and not TNFα’s expression. CD8 T-cells demonstrated a smaller rise 

in IFNγ and IL12 expression and no expression of TNFα, before or after stimulation. 

Non-activated lymphocytes demonstrated no multifunctionality while activated cells 

exhibited low levels of IFNγ and IL12 joint expression. The extent of 

multifuncionality differed between CD4 and CD8 cells. 

Conclusion: Our panel characterized the different T-cell populations in tumors. It 

demonstrated that only a small percentage of cells exhibited multifuncionality. To the 

best of our knowledge this is the first time T-cells multifunctionality in brain tumors 

has been described. This phenomenon is of importance as it correlates with vaccines’ 

potency. Future work will characterize the difference between peripheral and 

intratumoral T-cells and their interaction with other immune cells populations as we 

aim to understand tumor induced immune system inhibition. 


164 ISOLATION, PROLIFERATION, AND PHENOTYPING OF CANCER 

STEM CELLS FROM PRIMARY BREAST CANCERS: A MODEL 

FOR EVALUATING THE RESPONSE TO ANTI-TUMOR DRUGS 

M.I. Salamoon 1 , M. Al Jamali 2 , L. Youcef 2 , I. Kasem 3 , M. Bachour 1 

1 Medical Oncology, Al Bairouni University Hospital, Damascus, SYRIA, 2 Clinical 

Pharmaceutics, Faculty of Pharmacy, Damascus, SYRIA, 3 Biotech, Technical 

Institution, Damascus, SYRIA 

Background: Recent years have witnessed an increasing interest in the role of cancer 

stem cells (CSCs) because of selfrenewal, promoting metastasis, and resisting radioand 

chemotherapies. In addition, the high levels of CSCs in tumor mass were linked 

to a poor prognosis, relapse and metastasis. For the former reasons SCS is currently a 

main focus of cancer research. 

Objective: This study aims at establishing a CSC cellular model, which might enable 

the testing of new chemotherapeutics and/or combinatorial therapies for currently 

used agents. 

Material and methods: We culture tumor cells obtained from primary breast tumors 

of Syrian patients. This was followed by isolating stem cell population existing in the 

primary tumor by means of serial dilution of cells, and the characterization of these 

cells by flow cytometry based on their morphology, surface antigen profile (CD44 

+ /high/CD24-/low), and their growth and enrichment in both adherent and 


non-adherent conditions. Finally, the viability of CSCs was tested after freezing cells 

in liquid nitrogen. 

Results and discussion: In this study, we were able to isolate CSCs from primary 

breast tumor with high purity exceeding 90%, and we showed their CSC 

characteristics, which included: i) CD44high/CD24-/low profile, ii) their ability to 

form tumorspheres in non-adherent/suspension conditions, iii) and their ability of 

resisting chemotherapeutic agents in comparison with non-purified/non-stem breast 

tumor cells. 

Conclusions: Our results confirm the establishment of a cellular model representing 

the characteristics of cancer stem cell population. This breast CSC model could be 

useful in conducting research enabling the identification of responsible mechanisms 

behind breast cancer resistance to chemotherapeutics. In addition, this model might 

enable the examining of new combinatorial therapeutics by evaluating the effects of 

drug combinations targeting the different and heterogeneous cell populations inside 

breast tumors, both tumor non-stem as well as tumor stem cells, thus, achieving the 

desirable therapy outcomes. 


165 EFFECTS OF IL6 ON STATIN INDUCED APOPTOSIS IN HUMAN 

MELANOMA CELLS 

C. Minichsdorfer 1 , C. Wasinger 2 , E. Sieczkowski 3 , B. Atil 2 , M. Hohenegger 2 

1 Department of Medicine I, Medical University of Vienna, Vienna, AUSTRIA, 

2 Pharmacology, Medical University of Vienna, Vienna, AUSTRIA, 3 Neurology, 

Medical University of Vienna, Vienna, AUSTRIA 

Statins trigger apoptosis in primary cells and tumour cells. In particular, melanoma 

cells have been found to be susceptible to statin-induced apoptosis, although only 

after longer incubation times. Cells derived from metastatic melanoma cell lines 

(A375, 518A2) secrete high amounts of IL-6 in contrast to WM 35 cells which derive 

from an early lesion. However, IL-6 did not ameliorate the statin induced apoptosis 

in A375 and 518A2 cells. Conversely, in WM35 cells IL-6 led to a marked decrease 

in Cyclin D1 levels and enhanced the simvastatin induced apoptosis. Melanoma cells 

from early growth stage are more resistant to simvastatin induced apoptosis than 

metastatic melanoma cells. IL-6 plays a major role in the progression of melanoma. 

Interestingly, IL-6 has no cytostatic effect on metastatic melanoma cells but primes 

WM 35 cells for statin induced apoptosis. These pro-apoptotic stimuli confirm 

possible therapeutic potentials and may guide feasibility for more potent statins in 

anti-cancer strategies and help to understand the dualistic effect of IL-6 during 

melanoma tumorigenesis. This work was supported by Herzfeldeŕsche 

Familienstiftung and FWF (grant P22385). 


166 EFFECT OF NEURAL CELL ADHESION MOLECULE 

EXPRESSION ON GLYCOLYTIC PATHWAY IN MELANOMA 

H.J. Cho1 , M. Choi2 , J.D. Lee2 , C.H. Kim1 1 

Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, KOREA, 

2 

Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, 

KOREA 

Background: Neural cell adhesion molecule (NCAM), a member of the 

immunoglobulin superfamily, has been well characterized in cell-cell adhesion, 

neurite outgrowth, and synaptic plasticity. Recent studies have also shown that the 

expression of NCAM affects tumor progression. Indeed, the expression of NCAM has 

been implicated in the cellular invasion and metastasis of melanoma. Like many 

other malignant tumors, melanomas are dependent on aerobic glycolysis for ATP 

production. Many studies have consistently correlated poor prognosis and increased 

tumor aggressiveness with increased glucose uptake. In this study, we tested whether 

the expression of NCAM influences glycolytic pathways in mouse melanoma cell 

line. 

Methods: We constructed a recombinant viral vector derived from adeno-associated 

virus serotype 2 (rAAV2) that expresses NCAM. Mouse melanoma cell line B16F10 

was transduced with rAAV2. We performed in vitro fluorine-18 fluorodeoxyglucose 

( 18 F-FDG) uptake assay in a gamma counter. In addition, western blot analysis was 

carried out for glucose transporters (GLUT) and hexokinases (HK). 

Results: Transduction of B16F10 cells with rAAV2 NCAM resulted in increased 

18 F-FDG uptake. Western blot analyses demonstrated that the 180-kDa isoform of 

NCAM (NCAM 180) was up-regulated. Expression levels of GLUT1, GLUT2 and 

HK II were elevated. 

Conclusions: Overexpression of NCAM was associated with elevated levels of 

GLUT1, GLUT2, and HK II, which contributes to increased glycolysis. We 

demonstrated that 18 F-FDG uptake might be used as a surrogate marker for assessing 

NCAM expression in melanoma. In terms of monitoring NCAM expression, the 

utility of 18 F-FDG uptake as a prognostic indicator requires further elucidation. 



iomarkers 

167O PREVALENCE AND CLINICAL OUTCOMES FOR PATIENTS 

WITH ALK GENE REARRANGEMENT IN EUROPE: 

PRELIMINARY RESULTS FROM THE EUROPEAN THORACIC 

ONCOLOGY PLATFORM LUNGSCAPE PROJECT 

F. Blackhall 1 , S. Peters 2 , K.M. Kerr 3 ,K.O’Byrne 4 , H. Hager 5 , A. Sejda 6 , 

A. Soltermann 7 , C. Dooms 8 , E. Felip 9 , A. Marchetti 10 , E-J.M. Speel 11 , N. Price 12 , 

S. Savic 13 , J. de Jong 14 , M. Martorell 15 , E. Thunnissen 16 , L. Bubendorf 17 , 

O. Dafni 18 , R. Rosell 19 , R.A. Stahel 20 

1 Medical Oncology, Christie Hospital NHS Foundation Trust, Manchester, 

UNITED KINGDOM, 2 Multidisciplinary Oncology Center, Lausanne Cancer 

Center, Centre Hospitalier Universitaire Vaudois, Lausanne, SWITZERLAND, 

3 Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, UNITED 

KINGDOM, 4 HOPE Directorate, St James’s Hospital, Dublin, IRELAND, 

5 Department of Pathology, Aarhus University Hospital, Aarhus, DENMARK, 

6 Medical University of Gdansk, Gdansk, POLAND, 7 Institut für Klinische 

Pathologie, Universitätsspital Zürich, Zurich, SWITZERLAND, 8 Department of 

Pulmonology, University Hospital Leuven, Leuven, BELGIUM, 9 Medical 

Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN, 10 Center of 

Predictive Molecular Medicine, University-Foundation, Chieti, ITALY, 11 Molecular 

Diagnostics, Department of Pathology, Maastricht, NETHERLANDS, 12 Aberdeen 

Royal Infirmary, Aberdeen, UNITED KINGDOM, 13 Pathology, Institute for 

Pathology, University Hospital Basel, Basel, SWITZERLAND, 14 Pathology, The 

Netherlands Cancer Institute, Amsterdam, NETHLANDS, 15 Consorcio Hospital 

General Universitario de Valencia, Universitat de Valencia, Valencia, SPAIN, 

16 Pathology, Vrije Universiteit Medical Center, Amsterdam, NETHERLANDS, 

17 Division of Cytology, Institute for Pathology, University Hospital Basel, Basel, 

SWITZERLAND, 18 Frontier Science Foundation-Hellas, Athens, GREECE, 

19 Oncology Research, Catalan Institute of Oncology, Hospital Germans Trias i 

Pujol, Badalona (Barcelona), SPAIN, 20 Clinic of Oncology, University Hospital 

Zurich, Zurich, SWITZERLAND 

Background: The prevalence of ALK gene rearrangement (ALK+) in European 

patients with non-small cell lung cancer (NSCLC) is unknown. The Lungscape 

project provides a platform to evaluate its expression and clinical significance in a 

large cohort of patients with resected NSCLC from 13 European sites in 11 

countries. 

Methods: Participating sites retrospectively identified cases of NSCLC with 

clinical demographic and outcome data, and available tissue for research 

according to predefined protocol criteria. Local ethical and regulatory approvals 

were adhered to. Clinical data were entered to a central, secure database. 

Accepted cases on the basis of completeness of clinical data were assessed for 

ALK expression using immunohistochemistry (IHC) using antibody clone 5A4 

(Novocastra) and an H-score modified after Ruschoff et al. All cases were 

analysed at participating clinical pathology laboratories using the same protocol, 

control tissue microarray and after passing an external quality assurance 

exercise. 

Results: To date 998 cases of adenocarcinoma have been accepted to the 

database and ALK IHC results are available for 743 (74%). Positive IHC 

staining is present in 54 cases (7.3%) with IHC 3+ in 17 cases (2.3%), 2+ in 6 

cases and 1+ in 31 cases. The median H-score is 45 (range 1-300) with 

homogeneous staining in 30% of cases and heterogeneous staining in at least 

70% of cases. In total there are 38% women and 62% men, the proportion of 

stage I, II and III is 55, 23 and 22 % respectively, 16% of cases are never 

smokers and 99% Caucasian ethnicity. The median age of all cases (n = 998) is 

65 years (range 23 - 86) and for IHC + 63.2 years. With respect to gender and 

smoking status 11% of women, 5.6% of men, 13% of never-smokers, 5.3% of 

former smokers and 9.3% of current smokers demonstrated positive IHC 

for ALK. 

Conclusions: The preliminary results for this large multicentre European cohort 

demonstrate a prevalence of ALK assessed by IHC of 7.3%, with IHC 3+ 

expression in 2.3% of cases. Correlation of IHC scores with fluorescent in situ 

hybridisation, clinical demographics and outcomes is ongoing and will be 

presented. 




168O QUANTIFICATION OF CELL FREE DNA AS A PROGNOSTIC 

FACTOR IN ADVANCED NSCLC 

A. Dowler Nygaard 1 , K. Spindler 1 , R. Andersen 2 , N. Pallisgaard 2 , A. Jakobsen 1 

1 Department of Oncology, Vejle Hospital, Vejle, DENMARK, 2 Department of 

Clinical Biochemistry, Vejle Hospital Sygehus Lillebaelt, Vejle Sygehus, 

Vejle, DENMARK 

Purpose: To investigate the prognostic importance of baseline circulating cell free 

DNA (cfDNA) in plasma from patients with advanced Non Small Cell Lung Cancer 

(NSCLC) prior to first-line chemotherapy. 

Material and methods: The inclusion criteria were; histopathologically verified 

advanced NSCLC, indication for first-line chemotherapy and performance status (PS) 

0-2. Treatment comprised carboplatin (area under the curve (AUC)5) iv day 1, and 

vinorelbine 30 mg/m 2 iv day 1 and 60mg/m 2 po day 8, q3w. A maximum of six 

courses was given. Plasma was obtained from a pre-treatment EDTA blood-sample. 

The number of cfDNA alleles at baseline was assessed by an in-house quantitative 

polymerase chain reaction (qPCR). 

Results: A total of 246 patients were included, all receiving at least 1 course (median: 

4). The overall response rate was 26%. The number of cfDNA alleles ranged from 

480 to 1048500 per ml with a median value of 3200 and a 75 th percentile of 6040 

alleles per ml. The progression free survival (PFS) by intention to treat (ITT) was 5.4 

months and the overall survival (OS) 8.9 months. The baseline level of cfDNA was 

strongly correlated to outcome. The median PFS was 2.9 months in patients with 

high levels (> the 75 th percentile) compared to 5.7 months in patients with low levels 

(< the 75 th percentile) (HR: 1.83; 95% CI 1.29-2.59; p < 0.0001). The median OS was 

4.9 and 10.3 months, respectively (HR: 2.11; 95% CI 1.47-3.0; p < 0.0001). High levels 

of cfDNA were significantly associated with poor performance status (PS = 2), but 

neither age, gender, stage, histology nor number of metastases showed any 

correlation to the cfDNA-level. A multivariate Cox regression analysis confirmed an 

independent prognostic value of cfDNA in both PFS (p = 0.0002) and OS (p < 

0.0001). PS also remained an independent prognostic marker (p = 0.0003 (PFS) and 

p = 0.002 (OS)). 

Conclusion: High levels of cfDNA seem to have a strong prognostic influence as 

estimated by both PFS and OS in patients with newly diagnosed advanced NSCLC. 

Combined with PS it outlines a group of patients with minimal or no benefit of 

chemotherapy, though further investigations are warranted. 


169O IDENTIFICATION OF ENDOGLIN (CD105) AS AN 

EPIGENETICALLY REGULATED CANDIDATE TUMOUR 

SUPPRESSOR GENE IN LUNG CANCER 

K. O’Leary 1 , A. Shia 1 , V. Haley 1 , F. Cavicchioli 1 , A. Comino 2 , P. Vanella 3 , 

M. Wischnewsky 4 , T. Crook 5 , C. Lo Nigro 3 , P. Schmid 1 

1 Oncology, Brighton and Sussex Medical School, Brighton, UNITED KINGDOM, 

2 Pathology, S. Croce General Hospital, Cuneo, ITALY, 3 Oncology, S. Croce 

General Hospital, Cuneo, ITALY, 4 Escience Lab, University of Bremen, Bremen, 

GERMANY, 5 Dundee Cancer Centre, University of Dundee, Dundee, UNITED 

KINGDOM 

Background: The transforming growth factor-beta (TGF-β) pathway is implicated 

in proliferation, migration, invasion, and metastasis of various cancers. Endoglin, 

a TGF-β accessory receptor which modulates TGF-β signalling, was identified in 

a genome-wide methylation screen for candidate tumour suppressors as a novel 

gene subject to transcriptional silencing in lung cancer. The aim of this project 

was to investigate whether epigenetic mechanisms play a role in loss of Endoglin 

expression in lung cancer and secondly, whether this has an impact on clinical 

outcome. 

Methods: Genome-wide methylation analysis was performed using methylation 

microarrays (Human 450K Methylation BeadChip) and demethylation assays with 

5-aza-2-deoxycytidine treatment coupled with mRNA array (Illumina HumanHT12 

v4 Expression BeadChip Kit) in lung cancer cell lines. Methylation was validated in a 

panel of 21 lung cancer cell lines (16 NSCLC, 6 SCLC), a series of 134 surgically 

resected, stage I or II non-small cell lung cancers and 19 non-malignant lung tissue 

samples using pyrosequencing and methylation-specific PCR (MSP). To assess the 



abstracts

functional consequences of Endoglin methylation in cell lines, expression was 

silenced by transfection with Endoglin-specific siRNA. 

Results: Methylation-dependent transcriptional silencing of Endoglin is a 

frequent event in lung cancer. Pyrosequencing and MSP analyses 

demonstrated dense methylation in the CpG island located in the 5’ 

regulatory sequences of the gene in 20/22 lung cancer cell lines. Methylation 

of Endoglin correlated with absent or down-regulated mRNA and protein 

expression which could be reactivated by demethylation treatment. Using 

pyrosequencing, methylation was detected in 54.5% of lung cancer tissues. 

There was a strong trend for reduced survival in patients with Endoglin 

methylation (HR 1.44, 95%CI 0.74-2.79). 

Conclusion: Our data show that Endoglin is a common target of epigenetic 

silencing in lung cancer and that the resulting loss of expression may be 

associated with shorter survival. Work is ongoing to elucidate the mechanistic 

basis for this and to expand our cohort of patients to explore the value of 

Endoglin as a potential biomarker in lung cancer. 


170O PROGNOSTIC AND PREDICTIVE VALUES OF KRAS IN 

EGFR-BASED SUBGROUPS AND COMBINED WITH P53 IN 

COMPLETELY RESECTED NON-SMALL CELL LUNG CANCER 

(NSCLC): A LACE-BIO STUDY 

P.A. Janne 1 , F.A. Shepherd 2 , C. Domerg 3 , G. Le Teuff 3 , R. Kratzke 4 , P. Hainaut 5 , 

J. Pignon 3 , R. Rosell 6 , J. Soria 7 , M. Tsao 8 

1 Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA, 

UNITED STATES OF AMERICA, 2 Department of Medicine, Princess Margaret 

Hospital, Toronto, CANADA, 3 Oncology, Institut de Cancerologie 

Gustave-Roussy, Villejuif, FRANCE, 4 Oncology, University of Minnesota, 

Minneapolis, MN, UNITED STATES OF AMERICA, 5 Research, International 

Prevention Research Institute, Lyon, FRANCE, 6 Medical Oncology Service, 

Catalan Institute of Oncology ICO Badalona Hospital Germans Trias i Pujol, 

Medical Oncology, Badalona, SPAIN, 7 Dept. of Medicine, Institut de 

Cancérologie Gustave Roussy, Villejuif Cedex, FRANCE, 8 Pathology Department, 

Princess Margaret Hospital, University Health Network, Toronto, CANADA 

Background: We reported previously that KRAS is neither significantly 

prognostic nor predictive of benefit from adjuvant chemotherapy (ACT) in 

NSCLC (Shepherd et al. Proc ASCO 2012). P53 and EGFR mutations are also 

detected in NSCLC and P53 mutations can occur concurrently with KRAS 

mutations. We undertook to evaluate the prognostic and predictive effect of (i) 

KRAS in EGFR Wild-Type (WT) Adenocarcinoma (ADC) patients (pts) and (ii) 

KRAS combined with P53. 

Methods: Analysis included IALT, JBR10, CALGB-9633 and ANITA trials. KRAS, 

P53 and EGFR mutations (exons 19 and 21) were determined in blinded fashion in 3 

laboratories by direct sequencing. KRAS (WT/Mut) and P53 (WT/Mut) were 

combined in 4 groups with WT/WT as reference group. Hazard ratios (HR) and 

95% confidence intervals (CI) were estimated using the multivariable Cox model 

stratified by trial and adjusted on covariates, for Overall (OS) and Disease-Free 

Survival (DFS). 

Results: Among 1543 pts (605 ADC, 938 non-ADC) with documented KRAS 

genotype, EGFR was available in 485/605 ADC (12% of mutations) and P53 in 

1181/1543 (36% of mutations). In EGFR-WT ADC pts (n = 426), KRAS 

mutation, detected in 40%, was neither predictive (p = 0.96) nor prognostic in 

the observation group (OBS) (p = 0.65). In pts with KRAS and P53 status, 16% 

had only KRAS Mut, 32% P53 Mut only and 4% had both. Among pts with 

KRAS/P53 mutations, OS was worse in the ACT group (HR ACT vs. OBS 2.49; 

95%CI 1.10-5.66, p = 0.03) but not in pts with either mutation alone: KRASMut/ 

P53WT HR = 0.73 (0.47-1.13) KRASWT/P53Mut HR = 0.97 (0.73-1.29) and WT/ 

WT HR = 0.82 (0.64-1.06). No significant heterogeneity among these 4 HRs (p = 

0.06) was observed but there was a significant difference when comparing only 

WT/WT and Mut/Mut groups (p = 0.01). The prognostic value of this 

combination was not significant in the OBS group (p = 0.57). Results were 

similar for DFS. 

Conclusions: Patients with both KRAS and P53 mutations have significantly worse 

outcome with ACT compared to those with WT/WT tumors. Further studies are 

needed to understand the biologic basis for this. Supported by unrestricted grants 

from Sanofi Aventis and LNCC. 

Disclosure: J. Pignon: unrestricted research grant from Roche for a meta-analysis on 

bevacizumab in advanced NSCLC. All other authors have declared no conflicts of 

interest. 


171O MONITORING OF METASTATIC BREAST CANCER USING 

CIRCULATING TUMOUR DNA: A COMPARISON WITH 

CIRCULATING TUMOUR CELLS 

S. Dawson 1 , D. Tsui 1 , M. Murtaza 1 , H. Biggs 2 , S. Chin 1 , D. Gale 1 , T. Forshew 1 , 

M. Wallis 3 , N. Rosenfeld 1 , C. Caldas 1 

1 Department of Oncology, Li Ka Shing Centre, Cancer Research UK, Cambridge 

Research Institute Addenbrooke’s Hospital, Cambridge, UNITED KINGDOM, 

2 Oncology, Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge 

University Hospitals NHS Foundation Trust, Cambridge, UNITED KINGDOM, 

3 Department of Radiology, Addenbrooke’s Hospital, Cambridge University 

Hospitals NHS Foundation Trust, Cambridge, UNITED KINGDOM 

Background: Management of metastatic breast cancer (MBC) requires monitoring of 

tumour response to determine treatment efficacy. Imaging is routinely used, but is 

often a poor indicator of dynamic clinical response. Circulating tumour cells (CTCs) 

have been extensively studied but dynamics of cell-free DNA carrying 

tumour-specific alterations (circulating tumour DNA, ctDNA) has only recently been 

demonstrated. We performed the first direct comparison of CTCs and ctDNA in 

relation to medical imaging, to compare the performance of these biomarkers for the 

non-invasive monitoring of MBC. 

Methods: Clinical details, imaging and serial whole blood were collected 

prospectively from women undergoing therapy for MBC. DNA from tumour tissues 

was analysed using targeted and/or whole genome sequencing to identify somatic 

genetic alterations. These were used to design personalised assays to quantify ctDNA 

in plasma using digital PCR. CTCs were quantified at identical time points using the 

CellSearch® system. A blinded review of all imaging was performed according to 

RECIST criteria. 

Results: Concurrent CTC and ctDNA data was available from 16 women across 58 

samples. Elevated CTCs (≥5 cells / 7.5ml blood) and ctDNA were identified in 11 

(69%) and 15 (94%) cases respectively. ctDNA levels were a median of 234-fold 

higher than CTC numbers and showed greater sensitivity for monitoring tumour 

dynamics. In several cases, rising ctDNA was identified months before progressive 

disease was detected by CTCs or imaging. Changes in ctDNA levels were also 

observed in a subset of women with no measurable disease using the other 

modalities. Multiple somatic mutations and structural variants were measured in 

parallel in ctDNA, demonstrating the utility of this methodology to follow clonal 

evolution during treatment. 

Conclusions: ctDNA is a more sensitive biomarker than CTCs for the monitoring of 

MBC and often provides the earliest measure of treatment response. ctDNA has the 

potential to be used as a ‘liquid biopsy’ to directly monitor responses to targeted 

therapies and detect the emergence of resistant mutations. Future work should focus 

on the integration of ctDNA monitoring into multi-centre prospective clinical trials. 


172O ER + /HER2+ AND ER-/HER2+ BREAST CANCERS ARE 

MOLECULARLY DISTINCT BUT IMMUNE GENE SIGNATURES 

ARE PROGNOSTIC AND PREDICTIVE IN BOTH GROUPS 

T. Iwamoto 1 , L. Pusztai 2 , J. Matsuoka 1 , M. Callari 3 , C.M. Kelly 5 ,Y.Qi 6 , 

T. Motoki 1 , N. Taira 1 , L. Santarpia 4 , H. Doihara 1 , L. Gianni 3 , G. Bianchini 3 

1 Breast and Endocrine Surgery, Okayama University Hospital, Okayama, JAPAN, 

2 Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX, UNITED 

STATES OF AMERICA, 3 Breast Medical Oncology, Fondazione IRCCS Istituto 

Nazionale dei Tumori, Milan, ITALY, 4 Oncology, Translational Research Unit, 

Hospital of Prato and Istituto Toscano Tumori, Prato, ITALY, 5 Department of 

Medical Oncology, Mater Misericordiae University Hospital, Dublin, IRELAND, 

6 Department of Bioinformatics and Computational Biology, MD Anderson 

Cancer Center, Houston, TX, UNITED STATES OF AMERICA 

Objectives: We examined if gene expression patterns differ among HER2 positive 

breast cancers by estrogen receptor (ER) status. We also assessed the prognostic and 

chemotherapy response predictive values of over 3000 gene sets separately in the ER 

subsets. 

Methods: Publically available, clinically annotated Affymetrix gene expression data 

of 537 HER+ (ER-/HER2+ n = 278, ER + /HER2+ n = 259) and 2985 HER2- 

(ER thinsp;+ /HER2- n = 1923, ER-/HER2- n = 1062) patients were studied including 

121 node-negative, HER2+ cases with no systemic adjuvant therapy (ER+ n = 61, 

ER- n = 60) and 86 HER2+ patients treated with neoadjuvant taxane or 

anthracycicline chemotherapy (ER+ n = 27 and ER- n = 59). 

Results: Genes that distinguished ER+ from ER- cases differed for HER2+ and 

HER2- cancers. HER2+ cancers showed less difference by ER status compared to 

HER2- cancers (differentially expressed genes by ER status: n = 194 and n = 6750, p < 

1.0E10-6, shared genes 84%). Significant differences were also observed when HER2+ 

and HER2- cancers were compared stratified by ER status (HER2-related 

differentially expressed genes in ER+ n = 242, in ER- n = 1200, p < 1.0E10-6, shared 

genes 20%). In ER + /HER2+ tumors, 67 gene sets (GSs) were associated with good 

prognosis (e.g. B, T and NK cells and interferon-gamma production) and 2 GS with 

poor prognosis (PTEN dependent cell cycle arrest and apoptosis) (p ≤ .001). The 

same GSs were also prognostic in ER-/HER2+ cancers. In the neoadjuvant series, 11 



and 2 GSs were associated in both ER+ and ER-/HER2+ groups with pathologic 

complete response (pCR) (e.g. T-cell activation and differentiation) and residual 

disease (RD) (e.g. Cell-cell junction) respectively (combined p ≤ .001). We also noted 

ER specific associations with pCR or RD. For instance, 18 GSs were associated with 

pCR in ER-/HER2+ (p ≤ .001) but not in ER + /HER2+ tumors (e.g. chemochine 

C-C binding and activity, phospholipid catabolic process). 

Conclusions: Among HER2+ tumors, ER- and ER+ cancers represent distinct 

molecular subtypes. Immune signatures predict for good prognosis and higher 

chemotherapy sensitivity in HER2+ cancers regardless of ER status. 


173O OPTIMIZING THERAPEUTIC COMBINATIONS OF A 

SELECTIVE MEK 1/2 INHIBITOR (PIMASERTIB) WITH PI3K/ 

MTOR INHIBITORS OR WITH MULTI-TARGETED KINASE 

INHIBITORS IN PIMASERTIB-RESISTANT HUMAN LUNG 

AND COLORECTAL CANCER CELLS 

E. Martinelli 1 , T. Troiani 1 , F. Morgillo 1 ,E.D’Aiuto 2 , L. Ciuffrida 3 , S. Costantini 3 , 

L. Vecchione 4 , V. De Vriendt 4 , S. Tejpar 4 , F. Ciardiello 1 

1 Division of Medical Oncology, Department of Experimental and Clinical Medicine 

and Surgery “F. Magrassi and A. Lanzara”, Second University of Naples, Naples, 

ITALY, 2 Immunology Department, Second University of Naples, Naples, ITALY, 

3 Pharmacology Department, Second University of Naples, Naples, ITALY, 

4 Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, BELGIUM 

Background: The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR 

pathways are key intracellular signal transduction pathways for the control of survival 

and proliferation in human cancer cells. Selective inhibitors of different transducer 

molecules in these pathways have being developed as molecular targeted anti-cancer 

therapies. 

Methods: The in vitro and in vivo antitumor activity of pimasertib, a selective MEK 

½ inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR 

inhibitor (everolimus), or with multitargeted kinase inhibitors (sorafenib and 

regorafenib) were tested in a panel of eleven human lung and colon cancer cell lines. 

Results: Following pimasertib treatment, the cancer cell lines were classified as 

pimasertib-sensitive (IC 50 for cell growth inhibition of approximately 0.001 µM) or 

pimasertib-resistant (IC 50 for cell growth inhibition above 3 µM). Evaluation of basal 

gene expression profiles by microarrays identified a series of genes that were 

up-regulated in pimasertib-resistant cancer cells and that were involved in both RAS/ 

RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of 

combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or 

regorafenib were conducted, demonstrating a synergistic effect in cell growth 

inhibition, G1 phase arrest and induction of apoptosis with a sustained blockade in 

MAPK- and AKT-dependent signaling pathways in pimasertib-resistant human 

colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude 

mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the 

combination treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) 

or with sorafenib caused significant tumor growth delays and increase in mice 

survival as compared to single agent treatment. 

Conclusion: These results suggest that it is possible to overcome intrinsic resistance 

to MEK inhibition by the dual blockade of MAPK and PI3K pathways. 


174O VEGF-A-INDUCED TREG PROLIFERATION, A NOVEL 

MECHANISM OF TUMOR IMMUNE ESCAPE IN COLORECTAL 

CANCER: EFFECTS OF ANTI-VEGF/VEGFR THERAPIES 

M. Terme, S. Pernot, E. Marcheteau, O. Colussi, F. Sandoval, N. Benhamouda, 

E. Tartour, J. Taieb 

Parcc-european Georges Pompidou Hospital, INSERM U970, Paris, FRANCE 

Background: Regulatory T cells (Treg) are suspected of hindering an effective 

antitumor immune response in cancer. Multi-target anti-angiogenic tyrosine kinase 

inhibitors (TKI) that are routinely used as first or second line treatment of cancer 

patients, have been shown to decrease Treg proportion in tumor-bearing mice and 

metastatic renal cancer patients. However, the role of VEGF/VEGFR blockade in this 

effect is still debatable, and the direct impact of VEGF-A on Treg has not been studied. 

Methods: Treg proportion, number were analyzed by flow cytometry in peripheral 

blood of metastatic colorectal cancer (mCRC) patients treated with bevacizumab, and 

in CT26 tumor-bearing mice treated with drugs targeting the VEGF axis. The direct 

impact of VEGF on Treg increase in cancer was also studied. 

Results: Sunitinib (a TKI targeting VEGFR, PDGFR, c-kit), and anti-VEGF-A 

antibody both decreased Treg in CT26 tumor-bearing mice. Masitinib, a TKI that does 

not target VEGFR, did not reduce Treg proportion in CT26 bearing mice. 

Bevacizumab, an anti-VEGF-A monoclonal antibody, reduced Treg proportion in 

peripheral blood of mCRC patients. Proliferation of Treg was enhanced in CT26 

tumor-bearing mice compared to tumor-free mice and was decreased after 

anti-VEGF-A treatment. Furthermore, in vitro experiments have shown that VEGF-A 

could directly induce Treg proliferation. VEGFR1 and 2 were expressed on Treg in the 

presence of a tumor. Anti-VEGFR2 antibody administration reduces Treg proportion 

and also proliferation in CT26 bearing mice, but anti-VEGFR1 antibody did not, 

suggesting that VEGF-A-induced Treg proliferation was dependent on VEGFR2 

expression. In metastatic CRC patients, Treg proliferation was also enhanced 

compared to healthy volunteers and was blocked by bevacizumab treatment. 

Conclusions: We identified a new mechanism by which VEGF-A induced by the 

tumor could stimulate Treg proliferation. VEGF-A/VEGFR2 blockade reduced Treg 

proportion and proliferation in tumor-bearing mice and metastatic CRC patients 

suggesting that combination of anti-VEGF-A/VEGFR2 therapies with immunotherapeutic 

approaches in the future might be particularly relevant in CRC patients. 

Disclosure: J. Taieb: advisory role, Roche; research grant, Roche. All other authors 


175PD EFFECTS OF CHEMOTHERAPY ON IPILIMUMAB-MEDIATED 

INCREASES IN ABSOLUTE LYMPHOCYTE COUNT AND 

ACTIVATION OF T CELLS 

S.D. Chasalow 1 , J.D. Wolchok 2 , M. Reck 3 , S. Maier 4 , V. Shahabi 5 

1 Bioinformatics, Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF 

AMERICA, 2 Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, 

UNITED STATES OF AMERICA, 3 Thoracic Oncology, Hospital Grosshansdorf, 

Grosshansdorf, GERMANY, 4 Global Clinical Research, Bristol-Myers Squibb, 

Lawrenceville, NJ, UNITED STATES OF AMERICA, 5 Oncology Biomarkers, 

Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA 

Background: Ipilimumab (IPI) is a fully human monoclonal antibody that binds 

CTLA-4 to augment an antitumor T-cell response. Consistent with the expected 

immune-stimulating effect, increases in absolute lymphocyte count (ALC) and 

activation of peripheral-blood T cells frequently have been observed in patients (pts) 

treated with IPI as monotherapy. Such changes thus appear to be indicators of the 

biological activity of IPI. Combining IPI with other treatments, such as 

chemotherapy (CT), may have the potential to enhance efficacy. However, CT may 

also interfere with the immune-stimulating effects of IPI. The current analysis 

investigated the effect of IPI on ALC and T cell activation in the presence of CT. 

Methods: ALC was measured in 3 trials of IPI + CT (n = 887). In CA184024, IPI or 

placebo (PLB) was combined with dacarbazine (DTIC) in metastatic melanoma 

(MM) pts. In CA184041, IPI in 2 different dosing schedules or PLB was combined 

with carboplatin/paclitaxel (CP) in lung cancer (NSCLC and SCLC) pts. In 

CA184078, IPI was combined with PLB, CP, or DTIC in MM pts. ALC assessments 

from baseline through the end of a 12- or 18-week dosing period were included. In 

CA184078, frequency of peripheral-blood activated (HLA-DR + ) T cells at 0, 3, and 

11 weeks from first treatment was assessed by flow cytometry. Extended linear 

models were used to estimate mean ALC and T cell frequencies as a function of time 

and treatment group. 

Results: In all 3 studies, mean ALC increased significantly (p < 0.0001 to p = 0.027) 

over time after initiation of treatment in the IPI-containing arms, with or without 

CT, but not in the PLB arms. In the IPI arms, mean ALC changes from baseline to 

the end of IPI dosing ranged from 0.45 to 0.75 x 10 9 cells/L. ALC increases were 

temporally associated with IPI, but not CT, dosing. In CA184078, mean relative and 

absolute frequencies of activated CD4 + and CD8 + T cells increased significantly after 

start of IPI treatment similarly in the 3 arms. 

Conclusions: Mean increases in ALC and activated T cells, similar to those seen with 

IPI monotherapy, were observed after treatment with IPI combined with CP or 

DTIC. This suggests that IPI maintains biological activity when administered with 

CT, thus supporting continued clinical evaluation of IPI/CT combination therapy. 

Disclosure: S.D. Chasalow: Employment by Bristol-Myers Squibb, Bristol-Myers 

Squibb stock ownership. J.D. Wolchok: I am a consultant to Bristol-Myers Squibb, 

Merck and Glaxo Smith Kline. I have research support from Bristol-Myers Squibb. 

M. Reck: Consultant/advisor to Bristol-Myers Squibb, Hoffmann-La Roche, Eli Lilly, 

Pfizer, AstraZeneca, and Daiichi Sankyo; compensated, self. S. Maier: Employment 

by Bristol-Myers Squibb, Bristol-Myers Squibb stock ownership. V. Shahabi: 

Employment by Bristol-Myers Squibb, Bristol-Myers Squibb stock ownership. 

176PD PREDICTION OF LATE BREAST CANCER RECURRENCE BY 

THE ROR (PAM50) SCORE IN POSTMENOPAUSAL WOMEN 

IN THE TRANSATAC COHORT 

J. Cuzick 1 , I. Sestak 1 , S. Ferree 2 , J.W. Cowens 2 , M. Dowsett 3 

1 Centre for Epidemiology Mathematics and Statistics, Queen Mary University of 

London, London, UNITED KINGDOM, 2 Nanostring Technologies, NanoString 

Technologies, Seattle, WA, UNITED STATES OF AMERICA, 3 Academic 

Department of Biochemistry, Breakthrough Research Centre, London, UNITED 

KINGDOM 

Background: Adjuvant endocrine therapy beyond 5 years is known to be of benefit 

to some oestrogen receptor (ER) positive breast cancer patients. We have shown 

previously that the IHC4 score and the ROR score are significantly correlated with 

distant recurrence in the cohort from the TransATAC study. Here we assess the 


elationship between the ROR score, RS (Oncotype Dx) and the IHC4 score in 

predicting distant recurrence beyond 5 years. 

Methods: We determined the univariate and multivariate prognostic value of ROR 

score, RS, and IHC4 score for distant recurrence separately in years 0-5 and 5-10 of 

follow up for all patients (N = 940), and for node-negative (N = 683) and 

node-positive (N = 257) patients separately using proportional hazard models for 

time to distant recurrence. 

Results: In years 0-5, all three scores add significant prognostic information on 

distant recurrence in a univariate model (ROR: ΔLR-χ 2 = 41.50, P < 0.0001; RS: 

ΔLR-χ 2 = 23.23, P < 0.0001; IHC4: ΔLR-χ 2 = 36.18, P < 0.0001). When the Clinical 

Treatment Score (CTS) was added to the model, IHC4 added the most prognostic 

information in years 0-5 (ΔLR-χ 2 = 25.22, P < 0.0001). In years 5-10, ROR provided 

the most prognostic information in a univariate analysis although all scores were still 

significant in this time period (ROR: ΔLR-χ 2 = 46.31, P < 0.0001; RS: ΔLR-χ 2 = 10.95, 

P = 0.0009; IHC4: ΔLR-χ 2 = 12.42, P = 0.0004). In the multivariate model, ROR added 

the most prognostic information both overall (ΔLR-χ 2 = 16.66, P < 0.0001) and in 

node-negative patients (ΔLR-χ 2 = 8.82, P = 0.003). For all patients, smaller 

contributions were seen for RS (ΔLR-χ 2 = 5.42, P = 0.02) and IHC4 (ΔLR-χ 2 = 7.12, P 

= 0.008) and neither added significant information in node-negative patients. For 

node-positive patients, ROR added most information in years 5-10 in both the 

univariate and multivariate model. 

Conclusion: Overall, all three scores provided significant additional prognostic 

information in the 5-10 year period, but ROR added most prognostic information in 

both the univariate and multivariate analysis and in node-negative patients. These 

results may be used to select patients who could benefit from hormonal therapy 

beyond 5 years. 

Disclosure: J. Cuzick: Dr. Cuzick disclosed that he received grant support from and 

is a consultant for AstraZeneca. S. Ferree: Dr. Ferree disclosed that he is an employee 

of and shareholder in NanoString Technologies. J.W. Cowens: Dr. Cowens disclosed 

that he is an employees of and shareholder in NanoString Technologies. M. Dowsett: 

Dr. Dowsett disclosed that he received grant support from and is on the speaker’s 

bureau, has received grant support and provided legal advice for AstraZeneca and 

has sponsored IHC4 in a NICE assessment. All other authors have declared no 

conflicts of interest. 

177PD EXOSOMAL LONG NON-CODING RNA (LNCRNA) IN LUNG 

CANCER 

G. Kloecker 1 , C. Taylor 2 , N. Vinayek 1 , D. Taylor 2 

1 Dept. Medical Oncology & Hematology, Brown Cancer Center University of 

Louisville, Louisville, KY, UNITED STATES OF AMERICA, 2 Department of Ob/gyn, 

University of Louisville, Louisville, KY, UNITED STATES OF AMERICA 

Background: Long noncoding RNAs (lncRNAs) are master regulators of 

pluripotency, differentiation, body axis patterning and promoting developmental 

transitions. Dysregulation of lncRNA expression has been shown to be associated 

with a wide range of pathologies. 

Study Design: lncRNA within exosomes of lung cancer cell line (H838) and derived 

from patients with NSCLC were analyzed. After 10,000xg centifugation, microvesicles 

were isolated by chromatography (CT). Trizol isolated total RNA, which was 

analyzed for specific lncRNAs using the LncRNA profiler qPCR array (Systems 

Biosciences). RNA and ln RNA from tumor cells and the vesicles from NSCLC 

patient (n = 8) sera were analyzed the same way. 

Results: Microvesicles’ size, 50-200nm, was consistent with exosomes (CD63 

confirmed). Exosomes contained RNA and lncRNA. Comparison of lncRNA 

between tumor cells and their released exosomes revealed selectivity on the lncRNAs 

appearing in the exosomes. Three of 90 examined lncRNAs had a 10-fold increase 

within exosomes. Representative lncRNAs were compared between the cells and their 

released exosomes. For lncRNAs exhibiting epigenetic silencing, splicing regulation, 

regulating apoptosis and translational control the CT values of lncRNA within cells 

and the lncRNA within exosomes were the same (ANRIL cells 23.80 vs. 26.44 

exosomes. MALAT-1 cells 31.84 vs. 32.85 exosomes. BACE1AS cells 34.14 vs 34.86 

exosomes). The lncRNA profiles of cancer patients were distinct from normal.An 

increase of greater than 20-fold was observed in 58 lncRNAs in cancer 

patient-derived exosomes. In contrast, a decrease of 10-fold or greater was observed 

in 20 lncRNAs in cancer patients. LncRNAs exhibiting epigenetic silencing, In 

lncRNAs exhibiting splicing regulation and lncRNAs regulating apoptosis,were 

elevated 20-40 fold in cancer patient-derived exosomes versus controls. Conclusions: 

Misexpression of lncRNAs contributes to cancer development and progression. 

Cancer patients’ exosomes contain lncRNA distinct from non-cancer controls.Some 

lncRNAs, such as MALAT-1 (metastasis-associated in lung adenocarcinoma 

transcript) were identified in serum of NSCLC patients. The stability of exosomes in 

the peripheral circulation and the unique profile of lncRNAs suggest their ideal 

utility as a diagnostic biomarker. 



178P TUMOR ENDOTHELIAL MARKERS (TEMS) AS PROGNOSTIC 

AND PREDICTIVE MARKERS IN NON-SMALL CELL LUNG 

CANCER (NSCLC) 

A. Pircher 1 , G. Untergasser 1 , I.M. Heidegger 2 , J. Kern 1 , E. Gunsilius 1 , M. Fiegl 1 , 

W. Hilbe 1 

1 Hematology and Oncology, Internal Medicine V, Medical University Innsbruck, 

Innsbruck, AUSTRIA, 2 Department of Urology, Medical University Innsbruck, 

Innsbruck, AUSTRIA 

Background: Tumor angiogenesis plays a crucial role in tumor development and 

progression. Genome analyses of endothelial cells identified genes specifically 

expressed by tumor endothelial cells. These so called tumor endothelial markers 

(TEMs) are discussed as potential new therapeutic targets or as biomarkers for 

monitoring anti-angiogenic therapies. In non-small cell lung cancer (NSCLC) the 

role of TEMs is not yet investigated. Therefore, the present study aims to define the 

expression of TEMs in NSCLC cancer cell lines and tumor samples of NSCLC 

patients. 

Patients and methods: The expression of different TEMs (Robo4, Clec14 and 

ECSCR) was evaluated by qPCR and Western blot analyses in several NSCLC cancer 

cell lines (A549, Calu1, Colo699) compared to human umbilical vein endothelial 

cells (HUVEC) and human bronchial epithelial cells (HBEpC). The expression of 

TEMs in resected tumor tissue of NSCLC patients (n = 64) was measured by 

qPCR and compared to adjacent lung tissue (n = 52). Further correlation analyses of 

patient samples with clinical course were performed using the data from the TYROL 

register. 

Results: NSCLC cancer cell lines and HBEpC do not express TEMs neither on 

mRNA or on protein level compared to HUVECs (p = 0.001). Quantitative analyses 

of Robo4, ECSCR and Clec14 mRNA expression showed a significant up-regulation 

of CLEC14 in tumor samples (p = 0.01). Evaluating paired tissue samples from 

cancerous and corresponding non-cancerous tissues (n = 31) also Robo4 showed a 

significant upregulation in cancer specimens (p = 0.04). ECSCR showed a statistical 

trend towards an overexpression in tumor tissue (p = 0.09). Immunohistochemichal 

analyses of Robo4 revealed a higher expression in tumor tissue in comparison to the 

adjacent tissue (tumor vs. adjacent tissue; n = 20). Correlation with clinical data 

showed that increased TEM expression correlated with prolonged overall survival of 

NSCLC patients. 

Conclusion: TEMs are overexpressed in NSCLC tissue specimens but not in cancer 

cells suggesting that TEMs are upregulated in stromal tissue including tumor vessels. 

Therefore, TEMs provide a potential new target structure for anti-angiogenic 

therapies. Increased TEM expression levels correlated with prolonged OS possibly 

due to vascular stabilization. 


179P INTEGRIN BETA1 MEDIATES EGFR TKI RESISTANCE 

THROUGH C-MET SIGNALING PATHWAY IN NON-SMALL 

CELL LUNG CANCER 

L. Ju 1 , C. Zhou 2 

1 Traditional Chinese Medicine, Shanghai Pulmonary Hospital, Tongji University, 

Shanghai, CHINA, 2 Oncology, Shanghai Pulmonary Hospital, Shanghai, CHINA 

Introduction: Although some patients are initially sensitive to epidermal growth 

factor receptor tyrosine kinase inhibitors (EGFR TKIs), resistance invariably 

develops. Therefore, it’s very important to study the molecular mechanism of this 

resistance. For the first time, we found that integrin β1 associates with EGFR TKIs 

resistance. We also investigated the crosstalk between integrin β1 and c-MET that is 

a recognized mechanism of EGFR TKIs resistance in non-small cell lung cancer 

(NSCLC) to explore the mechanism. 

Materials and methods: We study the the crosstalk between integrin β1 and c-MET 

using MTT, Western blot, TUNEL, xenograft model and immunohistochemical. 

Results: We found that integrin β1 and c-MET co-expressed in PC9 and PC9/AB2 

cell lines and the ligands of integrin β1 and c-MET could synergistically promote cell 

proliferation and their inhibitors could synergistically improve the sensitivity to 

gefitinib, increase apoptosis, and inhibit the phosphoralation of their downstream 

signal transduction: FAK and AKT. Ligand-dependent activation of integrin β1 could 

induce EGFR TKIs resistance and decreased gefitinib-induced apoptosis through 

activating c-MET and its downstream signals: FAK and AKT. On the other hand, in 

integrin β1 overexpressed xenograft tumor models, gefitinib couldn’t inhibit the 

tumors growth effectively and reduce phosphorylation of AKT, FAK and c-MET 

effectively. 

Conclusions: Herein, it can be concluded that there is crosstalk between integrin β1 

and c-MET and integrinβ1 mediates EGFR TKI resistance through c-MET signaling 

pathway in non-small cell lung cancer. 




180P PREDICTIVE VALUE OF LKB1 IN PATIENTS WITH RESECTED 

NON SMALL CELL LUNG CANCER 

E. Fabre 1 , N. Pécuchet 1 , P. Laurent-Puig 2 , K. Pallier 2 , F. Le Pimpec-Barthes 3 , 

M. Riquet 3 , A. Cazes 4 , H. Blons 2 

1 Medical Oncology, Hopital Européen Georges Pompidou, Paris, FRANCE, 

2 UMR-S775, Université Paris Descartes, Paris, FRANCE, 3 Thoracic Surgery, 

Hopital Européen Georges Pompidou, Paris, FRANCE, 4 Pathology, Hopital 

Européen Georges Pompidou, Paris, FRANCE 

Background: LKB1/STK11 is a serine threonine kinase involved in signal 

transduction, energy sensing and cell polarity. We tested the predictive value of 

STK11 inactivating mutations in a series of resected non-small cell lung cancer 

(NSCLC) patients (pts). 

Methods: STK11 mutations were determined in a surgical series prospectively 

collected, No pts had received prior induction chemotherapy. The entire coding 

region (exons 1-9) of STK11 including intron/exon boundaries was screened by 

direct sequencing. These tumors had previously been characterized for EGFR, TP53, 

KRAS, BRAF, PI3KCA, ERBB2 and AKT1 mutations for CDKN2A homozygous 

deletions and for CCND1, CCND3, CCNE1 amplifications. Prognostic factors were 

determined using univariate and multivariate log-rank analysis on disease-free 

survival (DFS) and cancer-specific survival (C-SS). 

Results: Clinical genotyping was performed in 69 pts including 29 females and 41 

males, histological diagnosis was adenocarcinoma in 54 cases. Tumor stage was IA 

(n =16), IB (n =25), IIA (n =6), IIB (n =8), or IIIA (n =14). Somatic mutations were 

observed: 27 (39%) TP53, 17 (24%) KRAS, 11 (16%) EGFR, 8 (11%) STK11, 1 (1%) 

PIK3CA, 1 (1%) ERBB2, and 0 (0%) BRAF. Cyclin amplifications were indentified in: 

10 (14%) CCND1, 8 (11%) CCNE1, 9 (13%) CCND3. In 9 cases (13%) CDKN2A 

were homozygously deleted. STK11 and EGFR mutations were mutually exclusive. 

CCND3 amplifications tended to be more frequent in STK11 mutated (3/8, 38%) 

relative to STK11 wild type (6/61, 10%) (p = 0.06). KRAS mutations had similar rate 

in STK11 mutated (3/8, 38%) and STK11 wild type (14/61, 23%) (p = 0.40). STK11 

mutations were more frequent in men (n= 5/8), adenocarcinoma (n = 6/8) and 

smokers (n= 7/8). In univariate analysis, STK11 was the only prognostic factor 

associated with a lower DFS (HR = 4.78 (95%CI: 0.08-0.65); p = 0.01). C-SS was lower 

in pts with: STK11 mutation, CCND3 amplification, stage II-III and no radiation 

therapy. Multivariate analysis identified STK11 mutation to be an independent 

negative prognostic biomarker of C-SSl [hazard ratio (HR) =4.36 (95%CI 1.18-14.78); 

p =0.03). 

Conclusions: STK11 mutations appear as a useful biomarker that can be regarded as 

an independent factor for predicting the recurrence of resected NSCLC. 


181P PROGNOSTIC RELEVANCE OF FIBROBLAST GROWTH 

FACTOR RECEPTOR 1 (FGFR1) GENE COPY NUMBER IN 

PURE LUNG SQUAMOUS-CELL CARCINOMA 

L. Terracciano 1 , E. Rossi 2 , L. Landi 2 , M. Roncalli 3 ,A.D’Incecco 2 , 

M. D’Arcangelo 2 , A. Destro 3 , M. Incarbone 4 , M. Andreozzi 1 , F. Cappuzzo 2 

1 Pathology, University Hospital Basel, Basel, SWITZERLAND, 2 Oncology, Istituto 

Toscano Tumori, Livorno, ITALY, 3 Pathology, Milan University-Istituto Clinico 

Humanitas Cancer center, Rozzano, ITALY, 4 Surgery, Thoracic Surgery, 

Ospedale S.Giuseppe-Multimedica, Milan, ITALY 

Background: FGFR1 belongs to a family of five different receptors often dysregulated 

in human malignancies, including lung cancer. Recent studies showed that gene 

amplification is one of the mechanisms potentially responsible for FGFR 

dysregulation. Although FGFR1 gene amplification has been reported in up to 20% 

of lung cancer patients with squamous-cell carcinoma (SCC), prognostic effect is 

unknown. Aim of the present study was to assess the prognostic role of FGFR1 gene 

copy number (GCN) in pure lung SCC. 

Methods: A total of 378 patients were included in the present study. Pure SCC was 

defined as a tumor positive for P40 and negative for TTF1 using 

immunohistochemistry. FGFR1 was evaluated by fluorescence in situ hybridization 

(FISH) in tissue microarray sections from primary lung tumors. All cases with an 

FGFR1/centromere ratio ≥ 2 were considered as amplified (FGFR1 FISH+). 

Results: Among patients included onto the study, FGFR1 FISH analysis was 

successfully performed in 304 and 32 (10.5%) were FGFR1 FISH+. FGFR1 

amplification was significantly associated with P40 positive status (p = 0.002) and 

with lack of TTF1 expression (p = 0.005). In the whole population, no difference in 

disease-free survival (DFS) and overall survival (OS) was detected between FGFR1 

FISH positive and negative patients (DFS: 17.2 versus 17.0 months, p = 0.98; OS: not 

reached in both groups, p = 0.2). In the group of patients p40 + /TTF1 negative (N = 

66), 14 (21.2%) displayed FGFR1 gene amplification. No difference in survival was 

detected between FGFR1 FISH+ and negative patients in p40+ versus p40 negative 

(OS not reached versus 46.2 months, p = 0.41 in FGFR1 FISH + /p40+ versus any 

negative), nor in TTF1 negative versus TTF1+ (OS not reached versus 41.8 months 

in FGFR1 FISH + /TTF1 negative versus other subgroups) nor in FGFR FISH + /p40 

+ /TTF1 negative versus FGFR negative/p40 + /TTF1 negative (37.3 months versus 

not reached, p = 0.77). 

Conclusions: FGFR1 is amplified in 21% of pure lung SCC with no prognostic effect. 

The high percentage of gene amplification detected further support anti-FGFR1 

strategies in individuals with pure SCC. 


182P A PROSPECTIVE, MOLECULAR EPIDEMIOLOGICAL STUDY 

OF EGFR MUTATIONS IN ASIAN PATIENTS (PTS) WITH 

ADVANCED NON-SMALL-CELL LUNG CANCER WITH 

ADENOCARCINOMA HISTOLOGY (PIONEER) – CHINA 

SUBSET ANALYSIS 

Y. Shi 1 , S. Zhang 2 , M. Wang 3 , S. Yang 4 ,N.Li 5 ,G.Wu 6 , W. Liu 7 , G. Liao 8 , 

K. Cai 9 , L. Chen 10 

1 Medical Oncology Department, Cancer Institute & Hospitall, Chinese Academy 

of Medical Sciences and Peking Union Medical College, Beijing, CHINA, 

2 Department of Medical Oncology, Beijing Chest Hospital, Capital Medical 

University, Beijing, CHINA, 3 Department of Respiratory Medicine, Peking Union 

Medical College Hospital, Beijing, CHINA, 4 Department of Medical Oncology, 

Henan Cancer Hospital, Zhengzhou, CHINA, 5 Department of Medical Oncology, 

Guangzhou Chest Hospital, Guangzhou, CHINA, 6 Cancer Centre of Union 

Hospital, Tongji Medical College, Huazhong University of Science and 

Technology, Hubei, CHINA, 7 Department of Medical Oncology, Fourth Hospital, 

Hebei Medical University, Hebei, CHINA, 8 Department of Medical Oncology, 309 

Hospital, Beijing, CHINA, 9 Department of Medical Oncology, South Hospital, 

Guangzhou, CHINA, 10 Department of Medical Oncology, 301 Hospital, Beijing, 

CHINA 

Background: The presence of EGFR mutations has been demonstrated to be 

associated with sensitivity to EGFR-TKIs by several phase III studies, but there’s 

limited information of prospective EGFR mutation data in real-life setting in Asian 

population. The epidemiological prospective study (NCT01185314; PIONEER) 

investigated EGFR mutation (M) frequency in pts from Asia with newly diagnosed 

advanced lung adenocarcinoma (ADC) and the influence of demographic and 

clinical factors on EGFR M frequency. Here we report analysis results for the subset 

of pts from China. 

Methods: Pts were aged ≥20 years, with treatment naïve stage IIIB/IV lung ADC. 

Tumor sample (biopsy, surgical specimen, cytology) EGFR M status (primary 

endpoint; positive [M + ], negative [M-], undetermined [MU]) was determined using 

the Therascreen EGFR RGQ kit. EGFR M frequency was calculated and compared 

between demographic/clinical factor subgroups. 

Results: Of 747 pts in China (50.4% of the overall study population), 46.9% were 

female, mean age was 57 years (range 17-83), and 56% were never-smokers. EGFR M 

status was evaluated in 741 patients (6 [0.8%] were MU): 372 (50.2%) were M + , 369 

(49.8%) were M-. Gender, smoking status, pack years, metastasis, (all p < 0.001) and 

disease stage (p = 0.002) were significantly associated with presence of EGFR M. EGFR 

M+ frequency was 60.6% in females, 41.0% in males, 59.6% in never smokers, and 

35.3% in regular smokers. When combine gender and smoking status on overall 

judgment, the EGFR M+ frequency was 52.7% in male non-smokers, 61.5% in female 

non-smokers, 35.8% in male regular smokers, and 27.3% in female regular smokers. 

Summary of individual mutation types 

Number of patients 

with EGFR 

mutation test 

success 

Number (%) of pts 

741 (100.0) 

Exon 18 

G719X 4 (0.5) 

Exon 19 

Deletion 182 (24.6) 

Exon 20 

T790M 3 (0.4) 

S768I 8 (1.1) 

Insertion 15 (2.0) 

Exon 21 

L858R 169 (22.8) 

L861Q 6 (0.8) 

Conclusions: The overall EGFR mutation frequency in clinically unselected ADC 

was 50.2%. Smoking status and pack years had a statistically significant association 

with presence of EGFR mutation, but even in regular smokers, the mutation 

frequency was 35.3%. 



183P EPIDERMAL GROWTH FACTOR RECEPTOR MUTATIONS IN 

ITALIAN NON-SMALL-CELL LUNG CANCER PATIENTS 

ENROLLED IN THE EGFR FASTNET PROGRAM 

N. Normanno 1 , C. Pinto 2 , G.L. Taddei 3 , G. Troncone 4 , P. Graziano 5 ,G.De 

Maglio 6 , M. Mottolese 7 , M. Di Maio 8 , C. Clemente 9 , A. Marchetti 10 

1 Dept. Biologia Cellulare e Bioterapie, Istituto Nazionale Tumori di Napoli, Napoli, 

ITALY, 2 Medical Oncology, Policlinico S.Orsola Malpighi, Bologna, ITALY, 

3 Surgical Pathology, Università degli Studi di Firenze, Firenze, ITALY, 4 Surgical 

Pathology, Università Federico II, Napoli, ITALY, 5 Surgical Pathology, Az.Osp. S. 

Camillo Forlanini, Rome, ITALY, 6 Surgical Pathology, Az. Osp. Universitaria, S. 

Maria della Misericordia, Udine, ITALY, 7 Surgical Pathology, Istituto Nazionale 

Tumori Regina Elena, Roma, ITALY, 8 Clinical Trials Unit, Istituto Nazionale Tumori 

di Napoli, Napoli, ITALY, 9 Surgical Pathology, IRCCS Policlinico S.Donato e Casa 

di Cura S. Pio X, Milano, ITALY, 10 Surgical Pathology, Università G.d’Annunzio, 

Chieti, ITALY 

Background: Assessment of epidermal growth factor receptor (EGFR) mutations is 

mandatory for appropriate selection of treatment for patients (pts) with advanced 

non-small-cell lung cancer (NSCLC). 

Methods: The EGFR FASTnet program was designed to facilitate the exchange of 

biological material, clinico-pathological data and reports between medical 

oncologists, pathologists and referral laboratories. EGFR mutational analysis was 

carried by Sanger sequencing, Real Time (RT)-PCR, Pyrosequencing, and other 

techniques. The Italian Association of Medical Oncology (AIOM) and the Italian 

Society of Pathology and Cytopathology - Italian division of International Academy 

of Pathology (SIAPeC-IAP) have full access to the anonymous EGFR FASTnet 

database. 

Results: As of December 31, 2011, 503 oncologists, 135 pathologists and 38 referral 

laboratories joined the EGFR FASTnet program. The enrolled cohort of 3819 pts 

with advanced NSCLC was significantly enriched for adenocarcinoma histology 

(3172 [83%]), female sex (1361 [36%]) and smoking history (never smoker 911 

[24%], former smoker > 15 yrs 880 [23%], light smoker 194 [5%]). Mutational 

analysis was feasible in 3567 pts (93%), and was carried by Sanger sequencing in 

2021 cases (57%), RT-PCR in 174 (5%), Pyrosequencing in 636 (18%) and other 

techniques in 736 (21%). EGFR mutations were found in 520 cases (14.6%): 334 in 

exon 19 (9.4%), 163 in exon 21 (4.6%), 7 in exon 18 (0.2%) and 16 in exon 20 

(0.4%). Proportion of mutated cases was slightly higher with RT-PCR (p = 0.049). A 

higher mutation rate was found in never smokers (32.0%), light smokers (18.7%) and 

former smokers >15 yrs (12.4%), as well as in adenocarcinoma (15.7%) and females 

(25.2%). EGFR mutations were also reported in 17/227 (7.5%) squamous carcinomas. 

However, 16/17 EGFR mutation positive patients with squamous carcinoma were 

never- or former-smokers. 

Conclusions: The pts for EGFR mutational screening are spontaneously selected by 

medical oncologists according to known predictive factors. The results of the 

mutational analysis from clinical practice in Italy are consistent with data from 

literature. Never- and former-smoker NSCLC pts with squamous carcinoma should 

be tested for EGFR mutations. 


184P CLINICAL SIGNIFICANCE OF ANGIOPOIETIN-2 SERUM 

LEVELS IN NON-SMALL CELL LUNG CANCER 

A. Coelho 1 , A.M.F. Araujo 1 , R. Catarino 1 , M. Gomes 1 , A. Marques 2 

,R. Medeiros 1 

1 Molecular Oncology Unit, Portuguese Intitute of Oncology, Porto, PORTUGAL, 

2 Faculty of Medicine, University of Porto, Porto, PORTUGAL 

Introduction: Tumor vasculature is a very promising target in NSCLC, with VEGF 

inhibitors as part of standard care in some patients. Angiopoietin-2 (Ang-2) plays 

critical roles in angiogenesis in concert with VEGF. High tumor Ang-2 expression 

has negative prognostic implications in lung cancer patients, especially when VEGF 

expression is high. The aim of this study was the evaluation of Ang-2 and VEGF 

serum levels in NSCLC and tumor stages and its comparison with healthy controls. 

Patients and methods: The study included 30 controls, 145 NSCLC patients, (48 

epidermoid, 73 adenocarcinomas, 19 undiferenciated NSCLC, 4 large cells and 1 

mixed carcinoma), divided in 13 early and 132 advanced stages). Ang-2 and VEGF 

levels were evaluated in subject samples with R&D Quantikine ELISA Kit, according 

to manufacturer’s instructions. 

Results: Ang-2 levels were significantly different in the control and case groups 

(Mann-Whitney test, p = 0.003). Mean concentration values were 2855.50 pmol/ml 

(SE 268.64) vs 4164.90 pmol/ml (SE 200.56), respectively. Regarding stage analysis, 

Ang-2 levels were also statistically different according to tumor stage (Mann-Whitney 

test, p = 0.016): mean 2824.64 pmol/ml (standard error 472.82) and 4202.57 pmol/ml 

(203.05) for early and advanced stages, respectively. VEGF levels were significantly 

different in the control and case groups (Mann-Whitney test, p = 0.001). Mean 

concentration values were 312.63 pmol/ml (standard error 59.62) vs 675.51 pmol/ml 

(standard error 55.30), respectively. Regarding stage analysis, there were no 

statistically significant differences between VEGF levels and tumor stage 

(Man-Whitney test, p = 0.197). 


Conclusions: Angiogenesis inhibitors have obvious, yet modest, antitumor activity in 

NSCLC. Ang-2 seems to be a promising target of such inhibitors and its serum levels 

may be useful to predict which patients will benefit more with this type of treatment, 

surpassing the need to obtain tumor tissue samples to assess its levels of expression. 


185P ACTIVATION OF AKT BY HYPOXIA PREDICTS POOR 

OUTCOME IN MALIGNANT PLEURAL MESOTHELIOMA (MPM) 

K.A. Gately 1 , D. Stewart 2 , S. Heavey 3 , A. Davies 3 , K.J. O’Byrne 3 

1 Clinical Medicine, St James’s Hospital, Dublin, IRELAND, 2 Thoracic Oncology, 

Glenfield Hospital, Leicester, UNITED KINGDOM, 3 Clinical Medicine, Trinity 

College Dublin/St. James’s Hospital, Dublin, IRELAND 

Introduction: The Phosphatidylinositol-3 kinase (PI3K)/Akt (PKB) pathway is 

activated in a wide range of tumour types, and plays a central role in cell survival. 

Recent evidence indicates that hypoxia induces upregulation of Akt and activation of 

the Akt/PKB pathway. Once activated, Akt phosphorylates a variety of downstream 

substrates, including FOXO3a, which decreases transcription of the pro-apoptotic 

factor Bim, facilitating cell survival. We have shown that nuclear phospho-Akt 

(pAkt) expression is associated with more advanced disease or poor prognosis in 

Non-Small Cell Lung Cancer and MPM. Carbonic Anhydrase (CA)-IX, a 

tumour-specific member of the carbonic anhydrase family, is a surrogate marker of 

hypoxia overexpressed in solid tumours. This study examines the expression of 

CA-IX and phosphorylated Akt (pAkt) in tumour samples from patients with MPM, 

correlating expression with established prognostic factors. The role of pAkt in the 

survival of MPM cell lines exposed to both normoxia and hypoxia was also 

examined with both PI3K and PI3k-mTOR inhibitors. 

Methods: Tumour sections were stained using pAkt and CA-IX specific antibodies. The 

effect of hypoxia on pAkt, Akt and Bim expression in 4 MPM cell lines in the presence 

or absence of LY294002 (phosphatidylinositol-3-kinase inhibitor) was examined by 

Western blot. The percentage of apoptotic cells was also quantified in these cells using 

FACs and High-Content Analysis (HCA). Changes in subcellular localisation of pAkt 

and FOXO3a were quantified using HCA. The cells were also transfected with siRNAs to 

PDK1or DNA-PKcs (two kinases known to catalyse the phosphorylation of Akt) and 

the effect on pAkt expression was determined by Western blot. 

Results: A positive association between CA-IX and pAkt staining implies 

intra-tumoural hypoxia may stimulate Akt phosphorylation. Multivariate analysis 

showed increased expression of nuclear pAkt was associated with poor survival. 

Hypoxia induced the activation of Akt in MPM cell lines resulting in changes in the 

subcellular localisation of pAkt and FOXO3a. A greater increase in the level of 

apoptosis was seen in cells treated with PI3K inhibitors under hypoxia. 

Conclusion: pAkt plays an anti-apoptotic role in MPM and represents a potential 

therapeutic target particularly in hypoxic tumours. 


186P ASSOCIATION OF TWO BRM PROMOTER VARIANTS WITH 

SURVIVAL OUTCOMES OF STAGE IV NON SMALL CELL LUNG 

CANCER (NSCLC) PATIENTS 

S. Cuffe 1 , A.K. Azad 2 , Y. Brhane 3 , D. Cheng 2 , Z. Chen 2 ,W.Xu 3 , F.A. Shepherd 1 , 

M. Tsao 4 , D. Reisman 5 , G. Liu 1 

1 Department of Medical Oncology, Princess Margaret Hospital, University Health 

Network, Toronto, ON, CANADA, 2 Applied Molecular Oncology, Princess 

Margaret Hospital, Ontario Cancer Institute, Toronto, ON, CANADA, 

3 Department of Biostatistics, Princess Margaret Hospital, Ontario Cancer 

Institute, Toronto, ON, CANADA, 4 Pathology Department, Princess Margaret 

Hospital, University Health Network, Toronto, ON, CANADA, 5 Division of 

Hematology/Oncology, University of Florida, Florida, FL, UNITED STATES OF 

AMERICA 

Background: BRM, an ATPase subunit of the SWI/SNF chromatin remodeling 

complex, is a putative tumor susceptibility gene that is silenced in 15% of lung 

cancers. Two BRM promoter insertion variants (BRM-741 and BRM-1321) result in 

epigenetic silencing of BRM through recruitment of histone deacetylases. The 

presence of double homozygous BRM variants is associated with loss of BRM 

expression, and double the risk of lung cancer. Recently, pharmacological reversal of 

the epigenetic changes of BRM has been shown to be a potentially viable therapeutic 

strategy. We investigated the association between BRM promoter variants and 

survival outcomes in advanced NSCLC patients. 

Methods: 313 stage IV NSCLC patients treated in Princess Margaret Hospital from 

2006-2010 were genotyped for the BRM promoter variants using TaqMan. 

Association of BRM variants and overall (OS) and progression free survival (PFS) 

were assessed using multivariate Cox proportional hazards models. 

Results: 71% were Caucasian; 71%, adenoca; median age, 63 yrs; Median OS, 1.1 yrs; 

median follow up, 1.8 yrs. The frequency of homozygosity was: BRM-741 25%; 

BRM-1321 21%; both 12%. Homozygous variants of BRM-741 were strongly 

associated with worse OS (adjusted HR [aHR] 3.5 [95% CI: 2.4-5.0; p = 1x10E-11]) 



and PFS (aHR 2.3 [95% CI: 1.6-3.1; p = 8x10E-7]), compared to the wildtypes. 

Similar findings were observed for the BRM-1321 homozygous variants (aHR for OS 

of 2.5 [95% CI: 1.7-3.5; p = 1.1x10E-6]; aHR for PFS of 1.9 [95% CI: 1.3-2.6; 

p = .0004]). Finally, the presence of double homozygous BRM-741 and BRM-1321 

variants was strongly associated with substantially worse OS (aHR 4.4 [95% CI: 

2.7-7.1, p = 1x10E-9]) and PFS (aHR 3.6 [95% CI: 2.3-5.6, p = 2x10E-8]). 

Conclusion: The same two homozygous BRM promoter variants that are associated 

with increased risk of lung cancer are also strongly associated with adverse OS and 

PFS in this cohort of stage IV NSCLC patients. Validation of the results in 

prospective clinical trials is underway and will better elucidate whether these BRM 

promoter variants are prognostic or predictive. 


187P RIBONUCLEOTIDE REDUCTASE SUBUNIT 2 (RRM2) 

PREDICTS SHORTER SURVIVAL IN RESECTED STAGE I-III 

NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS 

F. Grossi 1 , G. Barletta 1 , C. Sini 1 , E. Rijavec 1 , C. Genova 1 , M.G. Dal Bello 1 , 

G. Savarino 2 , M. Truini 3 , F. Merlo 2 , P. Pronzato 4 

1 Lung Cancer Unit, National Institute for Cancer Research, Genoa, ITALY, 

2 Epidemiology, National Institute for Cancer Research, Genoa, ITALY, 

3 Department of Pathology, IRCCS AOU San Martino-IST, Genoa, ITALY, 

4 Oncologia Medica A, IRCCS AOU San Martino - IST-Istituto Nazionale per la 

Ricerca sul Cancro, Genova, ITALY 

Background: Biomarkers can help in identifying patients (pts) with early-stage 

NSCLC with high risk of relapse and poor prognosis. The aim of this study was to 

investigate the relationship between the levels of expression of 7 biomarkers, various 

clinicopathological characteristics and their prognostic significance. 

Methods: Tumor tissue from 82 radically resected stage I-III NSCLC pts were 

consecutively collected to investigate the mRNA expression and protein levels of the 

following biomarkers using quantitative reverse transcriptase real-time PCR 

(qRT-PCR) and immunohistochemistry (IHC) with a tissue microarray technique: 

excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), 

ribonucleotide reductase subunit 1 (RRM1), RRM2, p53R2, thymidylate synthase 

(TS) and class III beta-tubulin (β-Tub-III). 

Results: On a univariate analysis, p53R2 expression was significantly higher in 

adenocarcinoma (ADK) compared to squamous cell carcinoma (SSC) samples (p = 

0.002) and in stage I compared to stage II-III (p ≤ 0.001). ERCC1 expression was 

significantly higher in females compared to males (p = 0.03), and β-Tub-III 

expression was significantly higher in ADK than in SSC (p = 0.03). Pts with lower 

RRM2 expression survived longer than pts with higher RRM2 expression (p = 0.069). 

The multivariate analysis confirmed RRM2 as an independent prognostic marker of 

shorter survival (p= 0.031). The comparison between survival curves with qRT-PCR 

and IHC showed similar results with a trend towards longer survival among ERCC1 

negative pts, BRCA1 negative pts, p53R2 positive pts and among pts with low levels 

of RRM1 and RRM2, although the difference was not statistically significant with 

both methods. qRT-PCR and IHC have shown that β-Tub-III and TS had no 

significant impact on survival. 

Conclusions: This is the first study that identifies RRM2 expression as a negative 

prognostic factor in resected stage I-III NSCLC. Moreover, we have demonstrated the 

differential expression of p53R2 and β-Tub-III in ADK compared to SSC and higher 

expression of p53R2 in pts with stage I compared to stage II-III NSCLC. 


188P TROPOMYOSIN-RELATED KINASE B IS A THERAPEUTIC 

TARGET AND PROGNOSTIC FACTOR FOR AGGRESSIVE LUNG 

CANCER INCLUDING LCNEC 

S. Odate 1 , K. Nakamura 2 , H. Onishi 1 , A. Uchiyama 3 ,M.Kato 4 , M. Tanaka 2 , 

M. Katano 1 

1 Cancer Therapy and Research, Kyushu University, Fukuoka, JAPAN, 2 Surgery 

and Oncology, Kyushu University, Fukuoka, JAPAN, 3 Surgery, Kyushu Kosei 

Nenkin Hospital, Fukuoka, JAPAN, 4 Surgery, Hamanomachi Hospital, Fukuoka, 

JAPAN 

Background: Lung cancer is one of the most common types of cancer, accounting 

for more deaths than any other types of cancer. Tropomyosin-related kinase B 

(TrkB) has previously been shown to be important in tumor progression in 

neuroblastoma, pancreatic cancer, and prostate cancer. However, little is known 

about biological significance of TrkB in human lung cancer. Here we investigate if 

TrkB may be a therapeutic target and prognostic factor for lung cancer. 

Methods: Surgically resected specimen; The expression of TrkB and its ligand BDNF 

(Brain-derived neurotrophic factor) were investigated in 104 patients with primary 

lung cancers (8 small cell carcinomas, 11 large cell neuroendocrine carcinomas, 10 

large cell carcinomas, 20 adenocarcinomas, 55 squamous cell carcinomas) by 

immunohistochemical staining. In vitro assay; Large cell neuroendocrine carcinoma 

(LCNEC) cell lines (NCI-H460 and NCI-H810) expressing TrkB were used. 

TrkB-siRNA and TrkB tyrosine kinase inhibitor (K252a) were used to inhibit TrkB. 

BDNF-siRNA was used to inhibit BDNF. Cell proliferation and invasion were 

evaluated by MTT and Transwell assays, respectively. 

Results: 1) There were significantly higher TrkB and BDNF expressions in LCNEC 

cases than any other histological types. LCNEC cases also had poorer prognosis than 

any other histological types. 2) Higher expression of TrkB positively correlated with 

disease free survival (p < 0.001) and overall survival (p < 0.05) in all histological types. 

3) BDNF upregulated the invasion of LCNEC cell lines. 4) Knockdown of TrkB or 

BDNF mRNA expression using siRNA significantly decreased the invasion of LCNEC 

cell lines. K252a also significantly decreased the invasion of LCNEC cell lines. 

Conclusions: These data suggests that BDNF/TrkB signal is important in LCNEC 

and TrkB is a potential therapeutic target and prognostic factor for aggressive lung 

cancer including LCNEC. 


189P REDUCED CYP2D6 FUNCTION POTENTIATES THE 

GEFITINIB-INDUCED RASH IN PATIENTS WITH NON-SMALL 


T. Suzumura 1 , T. Kimura 1 , S. Kudoh 1 , K. Umekawa 1 , M. Nagata 1 , Y. Kira 2 , 

T. Nakai 1 , K. Matsuura 1 , N. Yoshimura 1 , K. Hirata 1 

1 Respiratory Medicine, Osaka City University, Osaka, JAPAN, 2 Department of 

Central Laboratory, Osaka City University, Osaka, JAPAN 

Background: Rash, liver dysfunction, and diarrhea are known as adverse events of 

erlotinib and gefitinib. However, clinical trials with gefitinib have reported different 

proportion of adverse events compared to those with erlotinib. In an in vitro study, 

cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib 

and not of erlotinib. It has been hypothesized that CYP2D6 phenotypes may be 

implicated in different adverse events between in the gefitinib and erlotinib therapies. 

Methods: The frequency of each adverse event was evaluated during the period that 

the patients received EGFR-TKI therapy. CYP2D6 phenotypes were determined from 

the CYP2D6 genotype using real-time polymerase chain reaction methods, which are 

able to determine single nucleotide polymorphisms. The CYP2D6 phenotypes were 

categorized into 2 groups according to functional or reduced metabolic levels. In 

addition, we evaluated the odds ratio (OR) of adverse events with each factor, 

including CYP2D6 activities as well as treatment types. 

Results: Patients were identified through a query of patient information for subjects 

prospectively enrolled in the Medical Information System within Osaka City 

University Hospital between January 1999 and February 2012 that tracks all of the 

patients referred for CYP2D6 sequencing from our hospital. A total of 232 patients 

received gefitinib therapy, and 86 patients received erlotinib therapy. Reduced 

function of CYP2D6 was associated with an increased risk of rash of grade 2 or more 

(OR 0.44, 95% confidence interval [CI] 0.21-0.94, p = 0.03), and not of diarrhea ≥ 

grade 2 (OR 0.49, 95%CI 0.17-1.51, p = 0.20) and liver dysfunction ≥ grade 2 (OR 

1.08, 95%CI 0.52-2.34, p = 0.84) in gefitinib cohort. No associations were observed 

between any adverse events in erlotinib cohorts and CYP2D6 phenotypes (rash: OR 

1.77, 95%CI 0.54-6.41, p = 0.35; diarrhea: OR 1.08, 95%CI 0.21-7.43, p = 0.93; and 

liver dysfunction: OR 0.93, 95%CI 0.20-5.07, p = 0.93). 

Conclusions: CYP2D6 may relate to the metabolism of gefitinib and not of erlotinib. 

CYP2D6 phenotypes are one of promising factors for the development of rash in 

gefitinib therapy. 


190P INCREASE OF PLASMA ADIPONECTIN LEVELS AND 

DECREASE OF PRO-INFLAMMATORY CYTOKINES IN 

NON-SMALL CELL LUNG CANCER PATIENTS TREATED 

WITH EGFR-TKIS 

K. Umekawa 1 , T. Kimura 1 , T. Suzumura 2 , S. Kudoh 1 , T. Nakai 1 , M. Nagata 1 , 

K. Matsuura 1 , S. Mitsuoka 1 , N. Yoshimura 1 , K. Hirata 1 


Respiratory Medicine, Graduate School of Medicine, Osaka City University, 

Osaka, JAPAN 

Background: Malnutrition in non-small cell lung cancer (NSCLC) is associated with 

advanced stage of disease and is needed for careful choice of treatment. The 

epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are 

routinely used for the treatment of advanced NSCLC with EGFR active mutations, 

which are promising the excellent responses. Recently, pro-inflammatory cytokines 

have been proposed as mediators of cancer cachexia. Adipose tissue produces and 

release substances called adipokines which include tumor necrosis factor-alpha 

(TNF-α), leptin, adiponectin, and resistin. Adiponectin suppresses the secretion of 

inflammatory cytokines such as IL-8, TNF-α, and induces the secretion of 

anti-inflammatory cytokines such as IL-10. It has been hypothesized that EFGR-TKI 

therapy may affect this adipokine network. 

Methods: The prospective study which evaluated correlations between the pre and 

post-treatment point of days 30 plasma adipokines and cytokines after EGFR-TKIs 

administration and clinical outcomes in advanced NSCLC was conducted at Osaka 

City University Hospital. Plasma adipokines and cytokines were analyzed by 

Luminex 200 PONENT system (Milliplex MAP kits; Millipore). 

Results: A total of 33 patients were enrolled. We obtained plasma samples for 

analyses 33 patients on pre-treatment point, and 23 patients on days 30 point. 


Plasma adiponectin level on the pre-treatment point (40.34 ± 32.00ng/ml) was 

significantly lower than those on days 30 point (45.07 ± 26.38ng/ml, p = 0.01). On 

the pre-treatment point of plasma IL-8 (16.70 ± 16.01pg/ml), IL-10 (13.06 ± 

29.69pg/ml), insulin (656.9 ± 514.6pg/ml) levels were significantly higher than those 

on days 30 point (7.154 ± 5.674 pg/ml p = 0.02; 11.53 ± 30.92pg/ml, p = 0.04; and 

551.4 ± 520.2pg/ml, p = 0.02, respectively). The levels of leptin and resistin had no 

significant changes between pre and on days 30 points. 

Conclusions: The EGFR-TKIs treatment for NSCLC increased the plasma 

adiponectin levels and decreased the plasma insulin, IL-8 and IL-10 levels. Increase 

of adiponectin levels by EGFR-TKIs may resolve the inflammation and increase 

insulin sensitivity with reduced output of insulin. 


191P PROGNOSTIC AND PREDICTIVE IMPACT OF KI-67 INDEX IN 

NEO-ADJUVANT CHEMOTHERAPY BEFORE SURGERY IN 

NON-SMALL CELL LUNG CANCER 

J.N. Jakobsen 1 , E. Santoni-Rugiu 2 , J.B. Sorensen 1 

1 Oncology, National University Hospital, Copenhagen, DENMARK, 2 Pathology, 

National University Hospital, Copenhagen, DENMARK 

Background: Immunohistochemical assessment of the proportion of 

Ki-67-expressing cells is a method for evaluating proliferation rates in malignant 

tumors. Ki-67 index is therefore a proliferation marker and may potentially be used 

as a prognostic or predictive marker during chemotherapy. In this study we 

correlated Ki-67 index to prognosis and chemo-sensitivity in non-small cell lung 

cancer (NSCLC) patients treated with neoadjuvant chemotherapy before surgery. 

Materials and methods: Immunohistochemical assessment of Ki-67 index was 

performed on diagnostic biopsies from patients with histologically verified NSCLC 

stages T1-3N2M0 treated with neo-adjuvant chemotherapy (paclitaxel 225 mg/m2 

and carboplatin AUC 6) followed by attempt of tumor resection and radiotherapy (2 

Gy x 30Fr/ 5F/W). Ki-67 index was defined as the percentage of stained tumor cells 

in biopsies containing at least 100 tumor cells. 

Results: A total of 64 biopsies (26 biopsies from primary tumors and 38 from lymph 

node metastases) from 51 consecutive patients were suitable for analysis. No 

significant differences in Ki-67 index between primary tumor (median ki-67 index 

40%) and lymph nodes (median Ki-67 index 50%) were observed (p = 0.871). The 

5-year-survival was 30% (Ki-67 index


were analyzed by cobas KRAS Mutation Test (Roche) from DNA purified from 

diagnostic samples. 

Results: 30 patients were enrolled in the BVZ group: 24 male, 6 female; median age: 62 

years; ECOG 1/2: 22/8; 27 adenocarcinoma and 3 undifferentiated large cell carcinoma. 

From them, 7 (23.3%) patients were KRAS mutated. 16 patients were enrolled in the 

control group: 14 male, 2 female; median age 58; ECOG 1/2: 9/7; 13 adenocarcinomas 

and 3 undifferentiated large cell carcinoma. From control group, 3 (18.8%) were KRAS 

mutated. BVZ therapy showed a significant improved efficacy in KRAS wild-type 

compared to mutated patients (RR: 88.9% vs 14.3%, p = 0.045; and TTP: 9.4 months vs 

7.5 months, p = 0.033), but did not impact on overall survival (12.4 months vs 11.1 

months, p= 0.780). These differences were not observed in control group. Moreover, in 

KRAS wild-type patients, the BVZ addition to therapy showed a significant improved 

efficacy compared to control group (RR: 88.9% vs 20%; p = 0.001). 

Conclusions: KRAS wild-type status in wild-type EGFR stage IV non-squamous 

NSCLC might be associated with enhanced RR and TTP in BVZ-platin-docetaxel 

treated patients, suggesting a potential role as a predictive biomarker in this 

population. 


195P THE PREVALENCE AND CLINICAL CHARACTERISTICS OF 

ALK AND ROS1 FUSIONS IN EAST ASIAN PATIENTS WITH 


W. Cai 1 , C. Zhou 2 ,S.Ren 1 , X. Chen 1 ,X.Li 2 

1 Oncology Department, Shanghai Pulmonary Hospital, Shanghai, CHINA, 2 Lung 

Cancer Institute, Shanghai Pulmonary Hospital, Shanghai, CHINA 

Background: ALK and ROS1 fusions have been proven to be oncogenic drivers in 

some subsets of lung cancer. The prevalence of ALK and ROS1 fusions in East Asian 

patients with non-small cell lung cancer (NSCLC) remains unclear. 

Objective: To determine the prevalence and clinical characteristics of ALK and ROS1 

fusions in East Asian patients with NSCLC. 

Patients and Methods: We screened 304 biopsied or surgically resected specimens 

from patients with histologically confirmed NSCLC for EML4-ALK and ROS1 

fusions using multiplex RT-PCR and validated all positive samples by Sanger 

sequencing. The patterns of ROS1 fusions involved in this study contained 

CD74-ROS1 and SLC34A2-ROS1. 

Results: Of these 304 patients with NSCLC screened, 246 had adenocarcinoma, 21 

had adenosquamous and 35 had squamous cell lung cancer, with the male to female 

ratio of about 1:3 and median age of about 59 years. 89.8% of patients were never or 

light smokers. Patients with stage I, II, III or IV disease at diagnosis accounted for 

47.2%, 11.3%, 33.3% and 8.2%, respectively. The data of EML4-ALK fusion test were 

available on all the 304 patients, with an incidence of about 8.2%. The data of ROS1 

fusion test were available on 195 patients so far, with overall incidence of 3.0%. The 

relationship between EML4-ALK and ROS1 fusions and clinical characteristics will 

be presented at the conference. 

Conclusion: The EML4-ALK and ROS1 fusions are quite rare events, with the 

prevalence of about 8.2% and 3.0% in East Asian patients with NSCLC, respectively. 

The data of clinical characteristics will be presented at the congress. 


196P PHARMACOGENETICS OF TAMOXIFEN ADJUVANT THERAPY 

AND ITS EFFICIACY: MDR1 POLYMORPHISMS IN CYP2D6 

EXTENSIVE METABOLIZERS WITH BREAST CANCER 

S. Argal csov 1,2,4 , O. Slanarˇ 2,3 , H. Bakhouche 2 ,M.Draždˇ áková 3 , 

O. Matoušková 2 , T. Zima 3 , L. Pertuželka 1 

1 Department of Oncology, First Faculty of Medicine, Charles University and 

General Teaching Hospital, Prague, CZECH REPUBLIC, 2 Institute of 

Pharmacology, First Faculty of Medicine, Charles University and General 

Teaching Hospital, Prague, CZECH REPUBLIC, 3 Institute of Clinical Biochemistry 

and Laboratory Diagnostics, First Faculty of Medicine, Charles University and 

General Teaching Hospital, Prague, CZECH REPUBLIC, 4 Institute of 

Radiotherapy, First Faculty of Medicine, Charles University and Hospital Na 

Bulovce, Prague, CZECH REPUBLIC 

Background: The role of CYP2D6 polymorphisms in adjuvant breast cancer therapy 

has not been standardised until now. Recent pre-clinical evidence suggests that the 

active metabolite of tamoxifen, endoxifen, is a substrate for efflux pump 

P-glycoprotein (P-gp). The polymorphic MDR1 gene encoding the P-gp may thus 

represent a prognostic factor for the treatment outcome in addition to the previously 

studied pharmacogenetic factors. The aim of our study was to evaluate, if the 

polymorphisms within MDR1 gene and CYP2D6 gene alter tamoxifen adjuvant 

treatment efficacy in breast cancer. 

Methods: Totally 252 women signed informed consent and participated in the study. 

After exclusion of poor metabolizers for CYP2D6, 227 women with estrogen receptor 

positive breast cancer were followed retrospectively for median period of 79 months. 

The primary analysis was conducted on time-to-event. 

Results: The cumulative observed recurrence rate was approximately 26.5%. The 

Cox-proportional hazard regression model revealed C3435T polymorphism, age and 

clinical tumor size at the time of diagnosis as significant covariates affecting the event free 

survival. The patients carrying at least one variant allele 3435T in MDR1 gene had 

significantly longer time to event survival resulting in hazard ratio of 0.44 (95%CI 

0.21-0.92) as compared with CC3435 patients. For the G2677T/A polymorphism, a 

non-significant trend suggesting that the wt homozygous may had worse treatment 

outcome as compared with the heterozygous or homozygous subjects for the variant alleles 

was noted. The respective median event free survival times were 93, 103, and 126 months. 

Conclusions: Wild type homozygous genotype in MDR1 polymorphism C3435T 

predicts for worse treatment outcome of tamoxifen adjuvant therapy. This should be 

taken into account as a potential pharmacogenetic biomarker for the drug efficacy. 


197P BREAST CANCER PATIENTS RESISTANT TO ENDOCRINE 

THERAPY ARE IMMUNODEFICIENT AND SHOW ENHANCED 

TRANSFORMING GROWTH FACTOR - BETA AND VASCULAR 

ENDOTHELIAL GROWTH FACTOR IN PLASMA 

E. Zavadova 1 , B. Konopasek 1 , M. Vocka 1 , T. Fucikova 2 , L. Petruzelka 3 

1 Oncology, General Hospital and Charles University, Prague, CZECH REPUBLIC, 

2 Immunology, Genreral Hospital and Charles University, Prague, CZECH 

REPUBLIC, 3 Oncology, General Faculty Hospital-Charles University, Prague, 

CZECH REPUBLIC 

Although more than 2/3 of treated patients respond to endocrine therapy, most patients 

with metastatic breast cancer will develop resistance. It appears that another factor 

contributing to the resistance may be transforming factor-beta (TGF-beta). It is a highly 

immunosuppressive factor that inhibits the natural and specific immunity against tumors 

and stimulates production of vascular endothelial growth factor /VEGF. The purpose of 

the study was to monitor immune responses in patients with hormone receptor positive 

breast cancer resistant to hormone therapy, particularly the examination of cellular (CD4, 

CD8, HLA-DR) as well as humoral immunity. TGF-beta, and VEGF production was 

monitored and we analyzed the changes during hormonal treatment. 

Methods: 80 patients included in the research project were receiving routine cancer 

treatment with endocrine therapy. Basic parameters (histological type and grade, the 

degree of expression of ER and PR, HER2,and the proliferative markers) were 

established. Patients were evaluated by a cancer clinical immunologist to exclude 

immune disorders, allergic or autoimmune origin. TGF-beta, VEGF were measured 

by ELISA and anti-tumor cellular immunity (CD4, CD8,) were measured by flow 

cytometry. 

Results: In patients with resistance to endocrine therapy mainly depression in 

cellular immunity was found. Immunglobulin plasma level was decreased as well 

(mainly IgG4 subtype). Most patients have shown clinical symptoms of 

immunodeficiency (frequent infections of respiratory or urinary tract, herpetic 

infections); TGF-beta as well as VEGF plasma levels were increased. 

Conclusion: Correlation of these factors with resistance to hormonal therapy, and 

the state of anticancer immunity could help in the future with the prediction of 

resistance to hormonal therapy and contribute to the selection of targeted immune 

therapy in cancer patients. 

Dedication: This project was supported by grant IGA NT11168-3/2010. 


198P BIOMARKER (BM) RESULTS FROM GOG-0218, A PHASE 3 

TRIAL OF FRONT-LINE BEVACIZUMAB (BV) + 

CHEMOTHERAPY (CT) FOR OVARIAN CANCER (OC) 

M.J. Birrer 1 , H. Lankes 2 , R.A. Burger 3 , R. Mannel 4 , H. Homesley 5 , V. Henschel 6 , 

M. Sovak 7 , S.J. Scherer 7 , S. de Haas 8 , C. Pallaud 9 

1 Hematology/Oncology, Massachusetts General Hospital, Cancer Center, 

Boston, MA, UNITED STATES OF AMERICA, 2 Gynecologic Oncology Group, 

Statistical & Data Center, Roswell Park Cancer Institute, Buffalo, NY, UNITED 

STATES OF AMERICA, 3 Department of Surgical Oncology, Fox Chase Cancer 

Center, Philadelphia, PA, UNITED STATES OF AMERICA, 4 Department of 

Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, 

Oklahoma City, OK, UNITED STATES OF AMERICA, 5 Department of Obstetrics 

and Gynecology, Wake Forest University School of Medicine, Winston-Salem, 

NC, UNITED STATES OF AMERICA, 6 Biostatistics, F Hoffmann-La Roche Ltd, 

Basel, SWITZERLAND, 7 Pharma Development, Genentech, Inc., South 

San Francisco, CA, UNITED STATES OF AMERICA, 8 Pharma Development, 

F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 9 Pdo Department, 

F. Hoffmann-La Roche Ltd., Basel, SWITZERLAND 

Background: GOG-0218 showed significantly improved progression-free survival 

(PFS) in patients (pts) receiving BV 15 mg/kg q3w concurrently with CT and 


Table: 198P 

PFS OS 

Median, mo HR Median, mo HR 

Subgroup 

VEGF-A 

PL BV PL BV 

≤ median 12.3 18.6 0.52 43.0 48.5 0.87 

> median 11.0 17.5 0.70 33.9 41.8 0.78 

≤ Q3 12.3 18.6 0.59 45.1 48.5 0.89 

> Q3 

VEGFR-2 

9.7 13.8 0.67 28.6 37.7 0.72 

≤ median 12.0 18.0 0.68 35.1 40.6 0.90 

> median 10.4 18.2 0.53 38.4 48.5 0.69 

≤ Q3 11.0 17.3 0.63 38.2 41.8 0.87 

> Q3 12.5 22.1 0.46 38.6 − 0.59 

Q = quartile 

continued alone until progression or for up to 15 mo. GOG-0218 includes extensive 

BM evaluation to identify pts benefitting most from BV. Analysis of plasma VEGF-A 

and VEGFR-2 was prioritised based on encouraging findings in BV trials in several 

tumour types. 

Methods: Pts with newly diagnosed stage IV or macroscopic optimal stage III OC 

were randomised to 6 cycles (c) of CT with: placebo (PL) c2−22 (arm A); BV c2 

−6 → PL c7−22 (arm B); or BV c2−22 (arm C). Post-surgery pre-CT plasma 

samples were analysed using a multiplex ELISA. Baseline (BL) BM levels were used 

to dichotomise pts. Potential interactions between BM levels and PFS (1° endpoint) 

and overall survival (OS; 2° endpoint) were tested using log-rank testing and Cox 

regression approaches. 

Results: Post-surgery samples were available from 582 of 1248 pts in arms A and 

C. Median BL VEGF-A and VEGFR-2 levels were 144.3 pg/mL and 14.7 ng/mL, 

respectively. No significant interaction was seen at α = 0.05. Exploratory analyses with 

other cut-offs are hypothesis generating for potential predictive (VEGF-A and 

VEGFR-2) or prognostic (VEGF-A: OS) value. Exploratory analyses revealed no 

correlation between plasma VEGF-A and time since surgery. 

Conclusions: The potential prognostic (VEGF-A) and predictive (VEGF-A, 

VEGFR-2) value seen in breast, pancreatic and gastric cancers was not apparent in 

post-surgery samples from GOG-0218 using a median cut-off. Results with other 

cut-offs provide a rationale for further investigation of potential prognostic and 

predictive value. Findings may reflect differing biology and interplay between 

VEGF-A isoforms across tumour types. The possible impact of pre- vs post-surgery 

samples is also being investigated. 

Disclosure: R.A. Burger: RB has served on Advisory Boards for Roche/Genentech. R. 

Mannel: RM has served on Advisory Boards for Genentech. V. Henschel: VH is 

employed by and holds shares in Roche. M. Sovak: MS is an employee of Genentech. 

S.J. Scherer: SS is an employee of Genentech Inc. S. De Haas: SdH is an empoloyee 

of F Hoffmann-La Roche Ltd. C. Pallaud: CP is an employee of F Hoffmann-La 

Roche Ltd. All other authors have declared no conflicts of interest. 

199P CHANGE IN HER2 STATUS AFTER NEOADJUVANT 

CHEMOTHERAPY AND THE SURVIVAL IMPACT 

A. Yoshida 1 , N. Hayashi 1 , O. Sachiko 2 , Y. Kajiura 1 , H. Yagata 1 , S. Nakamura 3 , 

H. Yamauchi 1 

1 Breast Surgical Oncology, St. Luke’s International Hospital, Tokyo, JAPAN, 

2 Researcher, Center For Clinical Epidemiology St. Luke’s Life Science Institute, 

St. Luke’s International Hospital, Tokyp, JAPAN, 3 Department of Breast Surgical 

Oncology, Showa University School of Medicine, Tokyo, JAPAN 

Background: The incidence of change in HER2 status in primary breast cancer after 

neoadjuvant chemotherapy (NAC) and whether the change affect prognosis is not 

well known. 

Patients and methods: One hundred eighty-four patients who were treated with 

anthracycline- and/or taxane-based NAC and had non-pathologic complete 

response between 2003 and 2005 in our hospital were enrolled. Human 

epidermal growth factor receptor 2 (HER2) status was assessed in specimen by 

core needle biopsy before NAC and in residual tumor of surgical specimen. We 

determine the impact of change in HER2 status on recurrence-free survival 

(RFS). All patients had not received HER2-targeting agents during study period. 

HER2-positive was defined as 3+ by immunohistochemistry and/or amplification 

by fluorescent in situ hybridization. Association between clinicopathologic 

factors, including clinical T stage, estrogen receptor (ER), progesterone receptor 

(PR), Nuclear grade (NG), and clinical response, and change in HER2 status 

after NAC were determined. 

Result: A median follow-up term was 74.1 months (range, 6.0 to 120.9 months). 

One hundred forty-nine of the 184 patients (80.9%) had HER2-negative tumors 


and 35 patients (19.0%) had HER2-positive tumor before NAC. HER2-negative 

tumors in 5 of the 149 patients (3.3%) changed to HER2-positive tumor. 

HER2-positive tumors in 7 of the 35 patients (20%) changed to HER2-negative 

tumor. In terms of RFS, there was no difference between patients with and 

without change in HER2 status in both of the 149 patients with HER2-negative 

tumors and 35 patients with HER2-positive tumors before NAC (p = 0.56, p = 

0.96, respectively). Any clinicopathologic factors were not associated with change 

in HER2 status after NAC. 

Conclusion: We herein reported the incidence of change in HER2 status after NAC 

with the large sample size. However, change in HER2 status did not seems to affect 

prognosis due to the small events in this study. Further well-powered study in 

needed to confirm the prognostic impact of change in HER2 status and needs 

of HER2-targeting agents for these populations. 


200P NEW IMAGING AND MOLECULAR BIOMARKERS TO PREDICT 

PATHOLOGICAL RESPONSE TO BEVACIZUMAB-BASED 

TREATMENT IN NEOADJUVANT BREAST CANCER 

J. Garcia-Foncillas 1 , A. Plazaola 2 , B. Hernando 3 , R. Sanchez 4 , I. Alvarez 5 , 

A. Antón 6 , P. Martinez Del Prado 7 , A. Llombart 8 , S. Sherer 9 , J.M. Lopez-Vega 10 

1 Oncology, Hospital Universitario. Fundacion Jimenez Diaz. Universidad 

Autónoma de Madrid, Madrid, SPAIN, 2 Oncology, Onkologikoa, Donosti, SPAIN, 

3 Oncology, Hospital de Burgos, Burgos, SPAIN, 4 Oncology, Hospital San Pedro, 

Logroño, SPAIN, 5 Medical Oncology Dept., Hospital Donostia, San Sebastian, 

SPAIN, 6 Oncology, H U Miguel Servet, Zaragoza, SPAIN, 7 Medical Oncology, 

University Hospital of Basurto, Bilbao, SPAIN, 8 Medical Oncology Service, 

Hospital Arnau de Vilanova, Valencia, SPAIN, 9 Research, Roche A.G. Basel, 

Basel, SWAZILAND, 10 Servicio de Oncologia Medica, Hospital Universitario 

Marques de Valdecilla, Santander, SPAIN 

Background: Early and robust prediction of pathological response in neoadjuvant 

breast cancer may help to identify which patients may benefit from 

bevacizumab-based therapy. Different imaging and molecular approaches have been 

0evaluated in a multicenter clinical trial. 

Methods: 73 chemotherapy naïve, stage II and III breast cancer (BC) patients 

(pts) were enrolled in a phase II, single-arm, multicenter, open-label and 

prospective clinical trial. Pts received single infusion of bevacizumab (15 mg/ 

kg)(C1)3weekspriortothebeginningof neoadjuvant chemotherapy (NAC) 

consisting of 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and 

bevacizumab (15 mg/ kg) every 21 days (C2-C5), followed by surgery. Tumor 

proliferation, hypoxia and perfusion were evaluated respectively using 

18F-Fluorothymidine (FLT) and 18F-Misonidazole (FMISO) positron emission 

tomography (PET/CT) and dynamic contrast enhancement magnetic resonance 

(DCE-MR). Serial imaging studies were performed in parallel at several time 

points including baseline (BL) and 14-21 days after bevacizumab alone (C1). 

Biomarker expression was assessed by immunohistochemistry (Ki67, CD31, 

CD31/Ki67, VEGFR2, pVEGFR2 [Y951]) before and after bevacizumab 

infusion (C1). Gene expression was analyzed using Affimetrix Human Gene 

ST 1.0. 

Results: Decrease in FMISO uptake >10% yielded a ROC curve area of 0.7 (95% CI: 

0.56 - 0.85) with high specificity (94%). Decrease in the phosphorilation status of 

VEGFR2 (Y951) >70% yielded a receiver operating characteristic (ROC) curve area of 

0.681 (95% CI: 0.536 - 0.825) with 84% sensitivity and 95% specificity. The change 

in phosphorilation status of VEGFR2p remains a significant predictor biomarker of 

response in multivariate analysis (OR = 0.9, IC%95 0.96-0.99, p = 0.04) after adjusting 

for clinical-pathological characteristics. 



Conclusion: Our findings suggest that early changes on both biomarkers, FMISO 

and pVEGFR, with one cycle of bevacizumab alone predict pathological response in 

bevacizumab-based neoadjuvant therapy in breast cancer. 


201P PROGNOSTIC VALUE OF KI-67 LABELING INDEX IN 

PATIENTS WITH DUCTAL INTRAEPITHELIAL NEOPLASIA OF 

THE BREAST. POSTSURGICAL OUTCOME FOR 1171 WOMEN 

CARED FOR IN ONE SINGLE INSTITUTION OVER 10 YEARS 

M. Lazzeroni 1 , E. Botteri 2 , A. Guerrieri Gonzaga 1 , M.C. Leonardi 3 , D. Serrano 1 , 

A. De Censi 4 , N. Rotmensz 2 , C. Varricchio 1 , B. Bonanni 1 , G. Puneri 5 

1 Division of Cancer Prevention and Genetics, European Institute of Oncology, 

Milan, ITALY, 2 Division of Epidemiology and Biostatistics, European Institute of 

Oncology, Milan, ITALY, 3 Division of Radiotherapy, European Institute of 

Oncology, Milan, ITALY, 4 Medical Oncology, E.O. Ospedali Galliera, Genoa, 

ITALY, 5 Division of Pathology, European Institute of Oncology, Milan, ITALY 

The aim of this analysis was to investigate the prognostic relevance of Ki-67 labeling 

index (LI) in patients with Ductal Intraepithelial Neoplasia (DIN) of the breast. From 

January 1997 to December 2007, histopathologic and clinical data on 1,171 

consecutive patients operated for DIN in a single institution were collected through 

the institutional clinical database. The study was performed in accordance with 

REMARK criteria. The independent prognostic role of Ki-67 LI was evaluated with a 

multivariable Cox regression model. Median age was 52 years, median Ki-67 LI 15% 

(range 1-80) and median follow-up was 86 months (range 1-192). A total of 872 

(74.5%) patients underwent breast conservative surgery. Whole breast radiotherapy 

was administered to 356 patients, and 506 patients received endocrine treatment. 

Overall, 549 (46.9%) women were premenopausal at the time of diagnosis. In regard 

to histology, most DINs were solid or cribriform (75%), moderately-low differentiated 

(80%), with a low proliferating index (Ki-67 LI < 14%, 46%), and with estrogen 

receptor positive immunostaining (80%). Overall, ipsilateral recurrence of both 

invasive and in situ disease (5-year cumulative incidence) was 163 (10.7%). When 

dividing patients into three subgroups on the basis of Ki-67 LI (< 14%, 14-20% and 

>20%), the 5-year cumulative incidence of breast recurrences were 9.4%, 10.3%, and 

13.0% respectively [Hazard Ratio (HR) 14-20 vs 20 vs 40 pg/ml had improved TTP (328 D; p = 

0.01), compared to those with PlGF levels 66.3 pg/ml at D8-56 had improved PFS (p = 0.029) and OS (p = 

0.02). In RCC, 5 pts with ΔPlGF below this threshold had median PFS of 100 D 

vs 207 D in the remaining pts (p = NS). Across the P2 studies, toxicity 

thresholds were determined using PlGF levels at D8 and toxicity events resulting 

in dose reductions or interruptions. The efficacy and toxicity thresholds were 

used to identify optimal ΔPlGF levels associated with improved OS in HCC (p 

= 0.01) and RCC pts (p = 0.001). 

Conclusions: Optimal ΔPlGF plasma levels were identified and associated with 

improved outcome in HCC and RCC pts receiving linifanib. Monitoring of PlGF 

levels may allow clinicians to identify pts with increased sensitivity or toxicity risk on 

linifanib. Further evaluation in randomized linifanib studies is warranted, including 

dose adjustments based on ΔPlGF levels. 

Disclosure: E.M. Mc Keegan: Full time Abbott employee who owns stock. A. 

Chakravartty: Full time Abbott employee who owns stock. P.J. Ansell: Full time 

Abbott employee who owns stock. S. Datwyler: Full time Abbott employee who owns 

stock. M.D. McKee: Full time Abbott employee who owns stock. J.L. Ricker: Full time 

Abbott employee who owns stock. D.M. Carlson: Full time Abbott employee who 

owns stock. All other authors have declared no conflicts of interest. 


204P EVALUATION OF PTEN AND PIK3CA STATUS IN BREAST 

CANCER FOR PATIENT SELECTION 

V. Serra 1 , J. Rodon 2 , C.M. Aura 3 , A. Vivancos 4 , K. Stemke-Hale 5 , 

H. Hibshoosh 6 , Y. Wang 7 , S. Ramon Y Cajal 3 , J. Tabernero 8 , J. Baselga 9 

1 Experimental Therapeutics Laboratory, Vall d’Hebron Institute of Oncology, 

Barcelona, SPAIN, 2 Phase I Unit, Medical Oncology Service, VHIO, Barcelona, 

SPAIN, 3 Molecular Pathology Laboratory, VHIO, Barcelona, SPAIN, 4 Cancer 

Genomics Group, VHIO, Barcelona, SPAIN, 5 Systems Biology, MD Anderson 

Cancer Center, Houston, TX, UNITED STATES OF AMERICA, 6 Department of 

Pathology and Cell Biology, Columbia University, New York, NY, UNITED STATES 

OF AMERICA, 7 Assay Application & Product Development, Mip, Affymetrix, 

Santa Clara, CA, UNITED STATES OF AMERICA, 8 Medical Oncology / 

Gastrointestinal Tumors Group, Vall d’Hebron University Hospital / VHIO, 

Barcelona, SPAIN, 9 Hematology/Oncology, MGH Cancer Center, Massachusetts 

General Hospital, Boston, MA, UNITED STATES OF AMERICA 

PTEN and PIK3CA status are potential predictors of response to PI3K-pathway 

inhibitors. Therefore, we searched the most reliable platform to assess both PTEN 

expression and PIK3CA mutations in primary and metastatic breast cancer (BC). 

We cross-validated the assays between different institutions. Studies were 

performed using four different sample sets of formalin-fixed paraffin-embedded 

(FFPE) breast cancers from VHUH/VHIO and from Columbia University. PTEN 

alterations were genotyped in 14 TNBCs by Oncoscan TM platform (Affymetrix) 

and were correlated to immunohistochemistry (IHC). PTEN loss of heterozygosity 

(LOH, n = 4) with or without overlapping PTEN mutation (n = 5) was concordant 

to PTEN protein loss (H-Score < 60) by IHC in 7 samples (7/8, 88% 

concordance). PTEN protein loss by IHC was also cross-validated between two 

institutions. In a cohort of 12 TNBCs containing eight PTEN low samples, only 

two samples were discordant (2/12, 17% discordance). Paired primary versus 

metastatic tumors were identified to transit either way, in the PTEN assessment 

by IHC (2/8 paired samples, 25% transition). PIK3CA mutations by Oncoscan TM 

were concordant to MassARRAY (Sequenom) in 4 out of 5 mutated samples 

within the panel of 17 BCs. The discrepancy (1/17, 6%) was likely due to 

differences in the sensitivity of the two assays. In another cohort of 21 BC 

samples, PIK3CA mutational status was cross-validated by MassARRAY at two 

institutions (MDACC and VHIO). Using identical, customized panels we found 

that only two samples were discordant because of mutant allele frequency close to 

the sensitivity of the assay (10%). Among 14 paired primary vs metastatic breast 

cancers we detected two transitions from wild type (WT) to H1047R mutation 

and one transition from E545K to WT (3/14, 21% transition), underscoring the 

need to determine PIK3CA status in metastatic lesions. The divergence evaluating 

PTEN and PIK3CA status between institutions was due to different scoring 

methodologies and to sensitivity of the assays respectively. For patient 

pre-screening purposes, MassARRAY and IHC can be performed at each 

institution both in primary and metastatic breast cancer lesions. Oncoscan TM is a 

valid, centralized platform for evaluation of PTEN and PIK3CA genomic 

alterations in BC. 

Disclosure: Y. Wang: Yuker Wang is employee of Affymetrix Inc. All other authors 


205P SIGNIFICANCE OF C-MET AS A THERAPEUTIC TARGET 

IN TRIPLE-NEGATIVE BREAST CANCER 

S. Kashiwagi, M. Yashiro, N. Aomatsu, H. Kawajiri, T. Takashima, N. Onoda, 

T. Ishikawa, K. Hirakawa 

Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, 

JAPAN 

Background: The molecular and biological mechanisms of cancer proliferation and 

metastasis are being elucidated. Therapies targeting the biological characteristics of 

various cancers have been adopted. Hormone therapy, molecular target therapy, etc., 

are chosen depending on against estrogen receptor (ER), progesterone receptor (PR) 

and human epidermal growth factor receptor 2 (HER2) expressions in breast cancer. 

However, no effective therapy is available for ER-, PR-, and HER2-negative 

triple-negative breast cancer (TNBC) because their targets are unknown. c-met 

tyrosine kinase receptor for Hepatocyte growth factor (HGF) has attracted attention 

as a novel molecular target of cancer therapy. The c-met receptor for HGF is 

involved in the migration, invasion, and proliferation of cancer cells. The activation 

mechanisms of c-met include the overexpression, amplification, and mutation of the 

met gene, as well as ligand binding. Increased c-met protein expression, including 

coexpression with its ligand HGF, is observed in various cancers. Reportedly, the 

prognosis of breast cancer is correlated with HGF/c-met coexpression and c-met 

overexpression. c-met signaling plays an important role in the proliferation of breast 

cancer cells. However, few reports have been published regarding their correlation 

with TNBC. 

Material and methods: A total of 1,036 patients who had undergone resection of a 

primary breast cancer at our institute were enrolled. ER / PR / HER2 status and 

c-met expression were assessed by immunohistochemistry. In vitro study, TNBC cell 

lines, MDA-MB 231 and OCUB-2, and non-TNBC cell lines, MCF-7 and OCUB-1, 

were used. c-met mRNA expression was examined by RT-PCR. Then, the effects of 


HGF, c-met siRNA, and c-met inhibitors on the proliferation of breast cancer cell 

lines were examined. 

Results: The 1,036 patients included 190 TNBC patients, whose prognoses were 

poorer than those of non-TNBC patients. In the TNBC patients, the c-met 

expression-positive group showed a poorer prognosis than the control group. c-met 

was expressed in the TNBC cell lines, whose proliferation was enhanced by HGF. 

c-met kinase inhibitors and c-met siRNA inhibited the proliferation of TNBC cell 

lines. 

Conclusion: c-met expression is a potential molecular target and useful in classifying 

TNBC. 


206P PREDICTION OF DISEASE OUTCOME WITH QUANTITATIVE 

MEASUREMENT OF HER-2 RECEPTOR EXPRESSION AND 

DIMERIZATION IN PATIENTS WITH BREAST CANCER 

H. Bazin 1 , F. Andre 2 , M. Mathieu 3 , A. Ho-Pun-Cheung 4 , E. Lopez-Crapez 4 , 

G. Mathis 1 , P. Garnero 1 

1 Research, Cisbio Bioassays, Codolet, FRANCE, 2 Department of Medical 

Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 3 Department of Pathology, 

Institut Gustave Roussy, Villejuif, FRANCE, 4 Translational Research Unit, CRLC 

Val d’Aurelle Paul Lamarque, Montpellier, FRANCE 

Introduction: Expression of HER2 is commonly assessed by immunohistochemistry 

(IHC) and IHC-HER2 positive patients with breast cancer are candidate for 

anti-HER2 therapy. However IHC is not quantitative, does not allow to detect subtle 

changes in HER2 expression and cannot assess HER2 dimerization which is critical 

for its activation. The aim of this study was to quantify the expression and 

dimerization of HER2 in patients with breast cancer and to relate these 

measurements to disease outcome. 

Methods: Using a novel microtiter plate based Time Resolved Fluorescence 

(TR-FRET) assay we quantify HER2 receptor expression and dimerization on frozen 

tumor samples from 100 patients with breast cancer. Normalized fluorescence signals 

allowed a quantitative measure of the overall receptors/dimers expression. Disease 

free (DFS) and overall survival (OS) was assessed in each subject. 

Results: Among the 100 patients, 82 were IHC-HER2 negative, including 60 subjects 

who were ER+ and treated with hormonal therapy. Using Cox proportional hazard 

analyses we showed that in IHC-HER2 negative, ER+ subjects, the presence of HER2 

dimer was significantly associated with both reduced DFS (p = 0.0001) and OS 

(p = 0.00237). Quantitative measure of HER2 expression was also associated with 

DFS (p = 0.0005) and OS (p = 0.03). 

Conclusion: Quantitative measurement of expression and dimerization of HER2 by 

the novel TR-FRET assay predicts disease outcome in IHC-HER2 negative, ER+ 

breast cancer patients. These new biomarkers may be useful to identify failure 

patients to hormonal treatment who may benefit from adjuvant therapy with 

anti-HER therapy. Validation series is ongoing in 200 FFPE-samples and will be 

presented. 

Disclosure: F. Andre: research funding. M. Mathieu: research funding. All other 


207P KRAS MUTATIONAL STATUS AND OXALIPLATIN SENSITIVITY: 

THE OTHER SIDE OF THE MOON? 

A. Orlandi, M. Di Salvatore, M. Basso, C. Bagalà, A. Strippoli, A. Calegari, 

A. Astone, C. Pozzo, A. Cassano, C. Barone 

Unit of Medical Oncology, Catholic University of Sacred Heart, Rome, ITALY 

Background: Oxaliplatin is a milestone of colorectal cancer therapy, but it is still 

lacking of a validated predictive biomarker of response. In a recent retrospective 

study we found a greater efficacy of oxaliplatin in KRAS mutated patients with 

metastatic colorectal cancer. Aim of the present study is to investigate “in vitro” the 

molecular basis of this finding and the possible role of ERCC1, the main mechanism 

of oxaliplatin resistance. 

Methods: We selected four colorectal cancer cell lines, two KRAS wild type (wt) 

(HCT-8, HT-29) and two KRAS mutated (mt)(SW620, SW480). The sensitivity of 

these cell lines to oxaliplatin was evaluated by MTT-test. ERCC1 levels before and 

after exposure to oxaliplatin were determined by RT-PCR. KRAS was silenced in a 

KRAS mt cell line (SW620) in order to evaluate the effect on oxaliplatin sensitivity 

and on ERCC1 levels. ERCC1 was also silenced in all cell lines to confirm his role in 

the KRAS-mediated oxaliplatin resistance pathway. 

Results: KRAS mt cell lines were more sensitive to oxaliplatin (OR 2,68; IC 95% 

1.511-4.757 p < 0.001). KRAS mt and wt cell lines did not show significant 

differences in ERCC1 basal levels, however, after 24h exposure to oxaliplatin, only 

resistant KRAS wt cell lines showed a statistically significant upregulation of ERCC1 

compared to KRAS mt cell lines (OR 42.9; IC 95% 17.260-106.972 p < 0.0005). 

Silencing of KRAS demonstrated to reduce Oxaliplatin sensitivity and to restore the 

ability to induce ERCC1 in KRAS mt cell lines. Finally, silencing of ERCC1 increased 

Oxaliplatin citotoxicity only in those cells able to upregulate ERCC1 after exposure to 



Oxaliplatin, that is KRAS wt and KRAS mt/KRAS silenced colorectal cancer cell 

lines. 

Conclusions: KRAS mt cell lines were more sensitive to oxaliplatin probably due to 

their inability to upregulate ERCC1 after exposure to this drug. Therefore, KRAS 

mutational status could represent a predictor of response to Oxaliplatin in colorectal 

cancer patients, as a surrogate for ERCC1 modulation. 


208P EZH2 EXPRESSION IN COLORECTAL (CRC) CANCER: SINGLE 

NUCLEOTIDE POLYMORPHISM (SNP) CHARACTERIZATION 

AND CORRELATION WITH CLINICO-PATHOLOGICAL AND 

MOLECULAR PARAMETERS 

L. Fornaro 1 , F. Crea 2 , P. Faviana 3 , G. Masi 1 , C. Vivaldi 1 , V. De Gregorio 1 , 

E. Paolicchi 2 , G. Fontanini 3 , R. Danesi 2 , A. Falcone 1 

1 U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria 

Pisana, Pisa, ITALY, 2 Dept of Internal Medicine, Dept of Oncology, Transplants 

and New Technologies, Pisa, ITALY, 3 Pathology, Azienda 

Ospedaliero-Universitaria Pisana, Pisa, ITALY 

Background: EZH2 is an epigenetic factor, essential for stem cell self-renewal. EZH2 

rs3757441 SNP is associated with outcome in metastatic CRC patients treated with 

FOLFIRI + /-bevacizumab. 

Material and methods: We are investigating the correlation between EZH2 

expression and other clinico-pathological and molecular parameters in 129 primary 

CRC samples. EZH2 expression was evaluated by immunohistochemistry, KRAS 

codon 12-13 and BRAF V600E mutations were screened by pyrosequencing analysis, 

and EZH2 SNP variants were identified by real-time PCR. Studied parameters were 

correlated with the percentage of EZH2-positive cells by T test and ANOVA. 

Results: Characteristics of the specimens so far evaluated are: stage I/II/III/IV, 5/47/ 

54/23; grading 1/2/3, 0/81/48; right colon/left colon/rectum, 56/49/24; mucinous 

histology, 40; KRAS wt/mut, 74/55; BRAF wt/mut, 115/14; rs3757441 genotype CC/ 

CT/TT, 5/36/59. The percentage of EZH2-positive cells does not correlate with tumor 

stage and grading, nor with KRAS and BRAF status. There is a trend toward higher 

EZH2 expression with rs3757441-CC genotype (p = 0.1). The percentage of 

EZH2-positive cells is significantly higher in mucinous than in non-mucinous 

tumors (p = 0.022). 

Conclusions: CRC tumors with mucinous features show higher EZH2 expression, 

which may represent one of the mechanisms behind a more aggressive tumor 

behavior. EZH2 could therefore represent a putative prognostic indicator and a 

candidate therapeutic target in CRC. 


209P PREDICTIVE VALUE OF CIRCULATING ENDOTHELIAL CELL 

(CEC) LEVELS IN METASTATIC OR LOCALLY ADVANCED 

NEUROENDOCRINE DIGESTIVE TUMOR PATIENTS TREATED 

WITH CHEMOTHERAPY AND BEVACIZUMAB 

F.F. Farace 1 , C. Lombard-Bohas 2 , E. Mitry 3 , M. Ychou 4 , L. Bengrine-Lefevre 5 , 

T. Lecomte 6 , K. Joly 7 , M. Ducreux 8 , E. Baudin 9 

1 Laboratory of Translational Research, Institut Gustave Roussy, Villejuif, FRANCE, 

2 Medical Oncology, Hôpital Edouard Herriot Hospices Civils de Lyon, Lyon 

Cedex, FRANCE, 3 Oncologie Médicale, Institut Curie, Paris, FRANCE, 

4 Oncologie Médicale Digestive, Centre Val d’Aurelle, Montpellier, FRANCE, 

5 Oncologie Médicale, Hôpital Saint-Antoine, Paris, FRANCE, 

6 Hepato-gastro-enterologie, Hopital Trousseau, Tours, FRANCE, 7 Statistique, 

Laboratoires Roche, Boulogne Billancourt, FRANCE, 8 Oncologie Digestive, 

Institut de Cancérologie Gustave Roussy, Villejuif, FRANCE, 9 Oncologie, Institut 

Gustave Roussy, Villejuif, FRANCE 

Background: The efficacy/safety of bevacizumab in combination with chemotherapy 

was investigated in patients (pts) with advanced progressive digestive neuroendocrine 

tumors (DigNET) (phase II BETTER study (ML20383)). Circulating endothelial cell 

levels were explored as potential prognostic or predictive marker. 

Methods: Pts were enrolled in two arms depending on tumor primary localisation. Pts 

with duodeno-pancreatic NET were treated with 5-FU/streptozocin combined to 

bevacizumab (arm 1, n = 34). Patients with other digNET received capecitabine 

combined to bevacizumab (arm 2, n = 49). In 50 dig NET patients, CEC levels were 

monitored at several time points: -before treatment (baseline, BL), -on day 2 (d2) of 

cycle 1 (C1), -on day 22 (d22) of cycle 1 (C1) for arm 1 and day 1 (d1) of cycle 2 (C2) 

for arm 2, -at day 1 of each of the subsequent cycles and at the end of treatment. CECs 

were measured in 1ml erythocyte lysed whole blood by four color flow cytometry (FCM) 

and identified by a CD45 − CD31 + CD1467-amino-actinomycin (7AAD) − phenotype. 

Relation between CEC levels and clinico-biological characteristics, response to treatment 

and progression/death at 1 or 2 years (1 yr-, 2 yr-PFS) was examined. Non parametric 

Wilcoxon tests were used to analyze change from baseline and to evaluate the 

association beteween CEC values and efficacy parameters. 

Results: Median CEC values were low at BL (4 CEC/mL) and similar for the 2 arms. 

CEC levels significantly increased on C1d2 onlv (media value: 7CEC/mL for the 2 

pooled arms, p = 0.019). A trend towards an association between changes in CEC 

levels between BL and C1d2, and progression/death during the first two years of 

treatment was observed (p = 0.078). 

Conclusions: Increased CECs at baseline could be an indicator of shorter PFS in 

digNET treated with the combination of bevacizumab and chemotherapy. The 

mechanism of increased CECs at day 2 of treatment remains to be understood. 

Disclosure: E. Mitry: Honoraries: Roche. K. Joly: Employment: Roche. M. Ducreux: 

Consultant: Roche, Merck Serono Honoraries: Roche, Merck Serono, Amgen, Bayer, 

Fresenus, Pfizer, Sanofi Clinical research project: Pfizer, Chugai, Merck Serono. E. 

Baudin: Honoraries : Scientific committee of BETTER Trial. All other authors have 

declared no conflicts of interest. 

210P REVIEW OF THE CURRENT STATUS OF KRAS MUTATION 

TESTING IN FRANCE IN 2011: THE FLASH-KRAS STUDY 

M. Ducreux 1 , A. Lièvre 2 , P. Artru 3 , M. Guiu 4 , J. Merlin 5 , J.C. Sabourin 6 , 

J. Viguier 7 , A. Bastie 8 , A. Seronde 8 , P. Laurent-Puig 9 

1 Oncologie Digestive, Institut Gustave Roussy, Villejuif, FRANCE, 2 Service 

d’Hépato-Gastroentérologie, Hopital Ambroise Paré, Boulogne-Billancourt, 

FRANCE, 3 Service d’Hépato-Gastroentérologie et d’Oncologie Digestive, Hopital 

Privé Jean Mermoz, Lyon, FRANCE, 4 Anatomie-Pathologie, Cabinet, Perpignan, 

FRANCE, 5 Unité de Biologie des Tumeurs, Centre Alexis Vautrin, Nancy, 

FRANCE, 6 Department of Pathology, INSERM U614, Rouen University Hospital, 

Rouen, FRANCE, 7 Centre De Coordination Des Dépistages des Cancers, CHRU 

Trousseau, Tours Cedex, FRANCE, 8 Medical Affairs, Merck Serono, Lyon, 

FRANCE, 9 UMR-S775, Université Paris Descartes, Paris, FRANCE 

Background: KRAS testing is required before treatment initiation of cetuximab in 

the management of metastatic colorectal cancer (mCRC). The objective of the study 

was to examine the current situation in 2011 regarding KRAS testing in the initial 

management of mCRC. 

Methods: This observational, retrospective, national study was carried out between 

March 28th and April 8th 2011. During this period 538 patients with mCRC were 

included across 160 french hospitals. The main objective was to assess the rate of 

KRAS testing in patients who had started first line (L1) treatment for mCRC. The 

secondary objectives were to describe the time taken and techniques used for KRAS 

testing, the possible reasons this test was not requested, to describe and analyse the 

clinical characteristics of the patients and the planned L1 treatments and those finally 

received. 

Results: KRAS testing was carried out for 433 patients (81.1%) and not carried out 

for 101 patients (18.9%). The main reasons for not requesting the KRAS status were 

(several answers possible): anti-EGFR not prescribed (n = 58), candidate for surgery 

(n = 8), samples not useable (n = 5), age of the patient (n = 3), other (n = 24), data 

missing (n = 13). The genotyping results were available after a mean delay of 23.6 ± 

28.2 days. The KRAS testing was requested by an oncologist (45.5%), a 

gastroenterologist (31%), a surgeon (11.2%), a pathologist (7.2%) or a 

multidisciplinary group (5.1%) approximately 15 days (-66.5;33.6) median (min; 

max) after the diagnosis of metastases, and 15 days (-66.9;3.7) median (min; max) 

before the start of L1 treatment. Result of KRAS status had not been received before 

the L1 treatment was chosen in 56.6% of the patients. For patients with wild-type 

KRAS status whose therapeutic management was modified after the result of KRAS 

testing (n = 108), this change was a prescription of an anti-EGFR in 77.8% of the 

cases. 

Conclusion: The Flash-KRAS study is the first one to assess the current modalities of 

KRAS genotyping in France. It shows that in 2011 the KRAS test is an integral part 

of the management of patients with mCRC. Nonetheless, it shows disparities 

between regions in terms of time to obtain results, which need to be improved to be 

compatible with the therapeutic management. 

Disclosure: M. Ducreux: Merck Serono. A. Lièvre: Merck Serono. P. Artru: Merck 

Serono. M. Guiu: Merck Serono. J. Merlin: Merck Serono. J.C. Sabourin: Merck 

Serono. J. Viguier: Merck Serono. A. Seronde: Merck Serono. P. Laurent-Puig: Merck 

Serono. All other authors have declared no conflicts of interest. 

211P SOMATIC KRAS MUTATIONS AND RESISTANCE TO 

EGFR-TARGETED THERAPIES: IS KRAS READY TO INCLUDE 

AS A REFLEX TEST WITH EGFR IN NSCLC? AN EVIDENCE 

SYNTHESIS BASED APPROACH 

S. Murray 1 , F. Siannis 2 , D. Bafaloukos 3 , P. Kosmidis 4 , H. Linardou 5 

1 Oncology, GeneKor SA, Athens, GREECE, 2 Department of Mathematics, 

University of Athens, Athens, GREECE, 3 31st Department of Medical Oncology, 

Metropolitan Hospital, Athens, GREECE, 4 Data Office, Hellenic Cooperative 

Oncology Group (HECOG), Athens, GREECE, 5 Medical Oncology, Metropolitan 

Hospital, Athens, GREECE 

Background: The intrinsic nature of the constitutive KRAS mutational activation in 

predicting an absence of response to anti-EGFR tyrosine kinase inhibitors (TKIs: 

gefitinib and erlotinib) in non-small-cell lung cancer (NSCLC) has recently been 

demonstrated. We questioned the validity of the inclusion of KRAS in reflex 

stratification of NSCLC patients. 


Material and methods: We searched PubMed and MEDLINE for publications to 

31st August 2011 (last search 17/09/2011) pertaining to KRAS mutational status in 

patients with NSCLC receiving TKIs. Eligible studies reported complete (CR) and 

partial responses (PR), stratified by KRAS. Potential between-study heterogeneity was 

accommodated by use of random-effects models for bivariate meta-analysis of 

sensitivity and specificity. Positive and negative likelihood ratios (+LR and –LR) of 

KRAS and EGFR for predicting an absence (or presence) of response were calculated 

by use of pooled estimates for sensitivity and specificity. 

Results: For non-response, 26 studies (n = 1957; KRAS = 335, 17.1%) demonstrated a 

+LR = 40.65, and -LR = 0.82 (specificity = 0.99 [95% CI: 0.95-1.00]; sensitivity = 0.19 

[0.15-0.23]). For EGFR, 70 studies (n = 5346; EGFR = 1919, 35.9%) demonstrated a 

+LR = 5.6 and –LR = 0.25 (specificity = 0.86 [0.82-0.89]; sensitivity = 0.78 [0.74-0.82]) 

for response. In a three way analysis the apparent difference in the likelihood of a 

patient with an EGFR mutation responding compared to KRAS is summarized in LR 

of +422.46 [95%CI: 56.98-3132.43, p < 0.001]; and LR +32.91 fold compared to WT 

patients [18.51-55.01, p < 0.001]. The likelihood of a ‘no-detectable’ mutation (WT) 

patient responding compared to a KRAS is LR +13.24 [1.76-99.65, p = 0.012]. 

Conclusions: Although several studies examined KRAS and EGFR, insufficient data 

addresses the effect of KRAS on outcomes. The three-way stratification suggests 

significant differences in survival outcomes due to the high specificity of 

non-response to KRAS, and response to EGFR. It appears that reflex stratification 

incorporating KRAS with EGFR treatment decisions in NSCLC is ready for clinical 

implementation, prospective data on survival outcomes are still however welcome. 


212P BRAF V600E: PROGNOSTIC MARKER IN COLORECTAL 

CANCER 

S. Plestina 1 , I. Rako 2 , J. Jakic-Razumovic 3 , D. Katalinic 1 , J. Sertic 2 

1 Department of Oncology, University Hospital Center Zagreb, Zagreb, CROATIA, 

2 Department of Laboratory Diagnostics, University Hospital Center Zagreb, 

Zagreb, CROATIA, 3 Department of Pathology and Cytology, University Hospital 

Center Zagreb, Zagreb, CROATIA 

Activation of BRAF oncogene has been implicated in colorectal carcinogenesis. BRAF 

protein is a serin/threonine kinase, component of a conserved signaling pathway that 

regulates cellular responses to exstracellular signals. In human cancer, it is commonly 

activated by somatic hotspot mutation at nucleotide 1799 of the BRAF gene which 

leads to a single aminoacid substitution Val600Glu (V600E). The aim of this study 

was to compare clinical and pathological phenotype of colorectal cancers with 

incidence of BRAF gene mutation. Clinical and pathological characteristics such as 

age, sex, tumor size, histologic grade, Dukes’ stage, angioinvasion and tumor position 

were collected for each patient. Sections from 113 formalin-fixed paraffin-embedded 

(FFPE) tumor samples were evaluated for the BRAF V600E mutation using 

LightCycler PCR with allele-specific fluorescent probe melting curve analysis. 

Differences in clinical and pathological variables between the groups of patients with 

and without BRAF mutation were analyzed using Fisher exact test. Our results show 

that BRAF gene mutation was detected in 8.8% (10/113) samples. Statistical analysis 

revealed a significant association between the BRAF mutation and Dukes’ stage (p = 

0.04) where all mutations were found in tumors classified as Dukes’C (10/10). 

Incidence of mutation was higher in males, patients older than 60 years, tumors 

bigger than 5 cm, tumors with angioinvasion and poor differentiated tumors, but no 

significant association was found. All BRAF gene mutations were detected in colon 

cancers (p = 0.01). We can conclude that incidence of BRAF gene mutation was 

higher in tumors with poor prognostic markers which have been associated with 

poor tumor prognosis and progression of disease. 


213P RESULTS OF THE SECOND PILOT EXTERNAL QUALITY 

ASSURANCE SCHEME FOR SOMATIC EGFR MUTATION 

TESTING IN NON-SMALL-CELL LUNG CANCER (NSCLC) 

N. Normanno 1 , S. Patton 2 , F.H. Blackhall 3 , S. Murray 4 , K. Kerr 5 , M. Dietel 6 , 

M. Filipits 7 , S. Benlloch 8 , R.A. Stahel 9 , E. Thunnissen 10 

1 Dept. Biologia Cellulare e Bioterapie, Istituto Nazionale Tumori di Napoli, Napoli, 

ITALY, 2 Genetic Medicine, St Mary’s Hospital, Manchester, UNITED KINGDOM, 

3 Medical Oncology Department, Christie Hospital NHS Trust, Manchester, 

UNITED KINGDOM, 4 Genetics, GeneKOR, Athens, GREECE, 5 Department of 

Pathology, Aberdeen Royal Infirmary, Aberdeen, UNITED KINGDOM, 6 Surgical 

Pathology, Charité, Humboldt-Universität zu Berlin, Berlin, GERMANY, 

7 Medicine, Medical University of Vienna, Vienna, AUSTRIA, 8 Pangaea Biotech, 

USP Dexeus University Institute, Barcelona, SPAIN, 9 Oncology, University 

Hospital Zurich, Zurich, SWITZERLAND, 10 Pathology, VU University Medical 

Center, Amsterdam, NETHERLANDS 

Background: The External Quality Assurance (EQA) process aims at establishing 

performance levels and may identify systematic errors in methodology that may not 

be revealed by internal QA processes. The European Molecular Genetics Quality 

Network (EMQN), the European Society for Pathology (ESP), the European Thoracic 

Oncology Platform (ETOP) and the European Society of Medical Oncology (ESMO) 


with other leading European groups collaborated in a pilot EQA scheme for somatic 

EGFR gene mutational analysis in NSCLC. 

Material and methods: Samples generated from cell lines mimicking clinical 

fractions of neoplastic cell content were validated by 5 laboratories and then provided 

to participating laboratories. Each sample was supplied with a mock clinical case. 

Participating laboratories registered with the EMQN, performed the analysis using 

their usual method(s), and submitted their results within a 6 week timeframe. 

Anonymous results were assessed and made available to all participants. 

Results: Of a total of 117 labs from 30 countries registered, 91 labs returned results. 

Sequencing and the DxS Therascreen kit were the main methodologies used by the 

participants. The standard of genotyping was worrying, with a significant number of 

genotyping errors made. Only 42 (46.1%) participants reported the correct result for 

all 10 samples. The majority of errors were false-negative results (82.2%); however, 

15.1% of errors were due to false-positive results and 2.7% to a combination of both 

errors. There were 42 (4.8%) analytical failures of which 88.1% were distributed 

across 6 laboratories. The performance of 18 (19.8%) labs fell below the criteria for 

acceptable performance (score A, 

rs2293649, A > G) and beta-4 (rs743554, C > T, rs8669, C > G, rs871443, T > C, 

rs9367, T > C) integrins was performed by real-time PCR. Among 128 K-RAS wild 

type metastatic colorectal cancer patients treated with third-line irinotecan cetuximab 

62 (48%) were HER-3 negative and were included in the present study. At univariate 

analysis the beta-4 rs8669, rs871443 and rs9367 polymorphisms correlated with both 

median progression free survival and overall survival, whereas only the beta-4 rs8669 

genotype showed a trend for a statistically significant correlation with response 

(partial remission rate for genotype G vs. C-G/C = 20% vs. 48%, p = 0.059). At 

multivariate analysis only the same allelic variant of beta-4 (rs8669 G vs. C-G/C) 

maintained an independent role in negatively influencing median PFS (HR = 0.13, 

95%CI 0.051-0.35, p < 0.0001) and OS (HR = 0.29, 95%CI 0.10-0.81, p < 0.0001). We 

believe that beta-4 rs8669 genotyping may help identifying a sub-group of HER-3 

negative, K-RAS wild type colorectal cancer patients less likely to benefit from 

anti-EGFR treatment. Our findings could be also relevant in planning future trials 

testing treatment strategies against the integrins-activated molecular pathway. 


215P CANCER STEM CELL GENETIC PROFILE AS PREDICTOR OF 

RELAPSE IN RADICALLY RESECTED COLORECTAL CANCER 

R. Giampieri 1 , M. Scartozzi 1 , F. Piva 2 , C. Loretelli 1 , A. Mandolesi 3 , L. Faloppi 1 , 

M. Bianconi 1 , A. Bittoni 1 , I. Bearzi 3 , S. Cascinu 1 

1 Clinica di Oncologia Medica, AOU Ospedali Riuniti Ancona Università 

Politecnica delle Marche, Ancona, ITALY, 2 Department of Specialized Clinical 

Sciences and Odontostomatology, Università Politecnica delle Marche, Ancona, 

ITALY, 3 Anatomia Patologica, AOU Ospedali Riuniti Ancona Università Politecnica 

delle Marche, Ancona, ITALY 

Although disease stage is the most relevant factor influencing treatment choice in locally 

advanced radically resected colorectal cancer, it is not uncommon to observe disease 

relapse in patients with apparent low risk stage that are usually excluded from an 

adjuvant therapy. On the contrary we also know that some patients with high risk stage 

are not likely to relapse independently from medical treatment received. Preclinical data 



suggested that cancer stem cells may influence the biological behaviour of many solid 

tumours including colorectal cancer. We tested a panel of genetic markers of stemness in 

resected Dukes stage B and C colorectal cancer and their impact on prognosis. We 

performed k-means unsupervised clustering (K = 2) using the mRNA expression data of 

66 genes. The algorithm divided the patients into two groups (A and B) and most of the 

patients clustered in a manner consistent with relapse free survival, defined as the time 

between primary surgery and first radiological sign of metastatic involvement or patients 

death, whichever came first. A total of 62 patients were analysed (46, 74% stage II and 16, 

26% stage III), 36 (58%) patients relapsed during the follow-up period (range 1.63-86.5 

months). Respectively 12 (19%) and 50 (81%) patients were allocated into group A and 

B. A significantly different median relapse-free survival was observed between the 2 

groups (22.18 vs 42.85 months, p = 0.0296). Interestingly enough, even if group A had a 

worse outcome in terms of risk of relapse, an higher percentage of stage II patients could 

be found in this group (83%) when compared with the group B (52%). Among of all 

genes tested, those with the higher “weight” in determining allocation into one of the two 

groups were CD44, ALCAM, DTX2, HSPA9, CCNA2, PDX1, MYST1, COL1A1 and 

ABCG2. This analysis supports the idea that, other than (or maybe more than) stage, 

biological variables, such as expression levels of colon cancer stem cell genes, may be 

relevant in determining an increased risk of relapse in resected colorectal cancer patients. 


216P GENE EXPRESSION PROFILING IN ESTOROGEN RECEPTOR 

POSITIVE BREAST CANCER WITH CANCER STEM-LIKE 

CELLS 

Y. Tsunoda 1 , M. Sakamoto 1 , E. Fukma 1 ,T.Sawada 2 , A. Sasaki 3 , 

G. Yamamoto 3 , T. Tachikawa 3 

1 Breast Center, Kameda Medical Center, Kamogawa City, JAPAN, 2 Breast 

Surgery, Showa University School of Medicine, Tokyo, JAPAN, 3 Dental 

Pathology, Showa University School of Medicine, Tokyo, JAPAN 

Objective: Breast cancer cells with CD44 + CD24-/low gene expression signature have 

been suggested to have stem cell-like tumor-initiating properties. The purpose of this 

study is to clarify the gene expression profiling of cells with CD44 + CD24-/low gene 

expression signature in the estrogen receptor (ER) positive tumors. 

Methods: Laser-captured microdissection was used to select the isolation of cancer 

cells in 32 frozen tissues of breast cancer, and RNA extracted from these cells was 

examined by real-time RT-PCR to quantify CD44 and CD24 expressions. Human 

stem cell RT 2 Profiler PCR Array was used for gene expression analysis in the groups 

of CD44 + CD24-/low and CD44 + CD24+ gene expression signature. 

Results: Thirty-two tumors were divided into 2 groups. Group A was composed of 

the CD44 + CD24-/low type, in which the ratio of CD44/CD24 was >10.0. Group B 

was composed of the CD44 + CD24+ type, in which the ratio was >0.1 and ≦ 10.0. 

The number of tumors in group A and B were 4 and28, respectively. Regarding the 

correlation of CD44/CD24 status with tumor characteristics, the tumors of group A 

were significantly associated with axillary lymph node metastasis compared with 

those of group B (P = 0.009). There were no significant differences in tumor size, 

nuclear grade between the two groups. HER2 status in the tumors of group B was 

significantly higher than group A (P = 0.028). According to signaling pathways, the 

number of expression genes for the Notch pathway in group A was significantly 

greater than in group B (P = 0.028). Overexpressed genes for ALDH1 (P = 0.021) and 

SOX2 (P = 0.018) were noted in group A compared to group B. 

Conclusion: This study suggests that the Notch pathway may be an important 

signaling pathway in luminal subtype with CD44 + CD24-/low gene expression 

signature. In addition, either ALDH1or SOX2 may be a candidate marker for cancer 

stem cells in the ER positive breast cancer. 


217P CARBON NANOTUBE DEVICES FOR THE DETECTION OF 

CIRCULATING TUMOR CELLS 

G. Kloecker 1 , B. King 2 , B. Panchapakesan 2 

1 Department of Medical Oncology & Hematology, Brown Cancer Center 

University of Louisville, Louisville, KY, UNITED STATES OF AMERICA, 

2 Department of Mechanical Engineering, University of Louisville, Louisville, KY, 


Introduction: Combining clinical and imaging tools with the presence and level of 

circulating cancer cells (CTC) has great potential. Carbon nanotube electrical devices 

are a promising technique to detect CTCs in small samples of blood. This study tests, 

if free energy change for specific interactions is higher than for non-specific 

interactions. Cell surface receptors found on breast cancer cells are targeted by 

functionalizing the carbon nanotube electronic devices with cancer-specific 

antibodies. The study also tested, if the concentration of CTCs correlates with the 

change in the electronic properties of the nanotube device. 

Methods: Antibodies, specific for IGF1R, EPCAM, Her2, and a nonspecific antibody 

(EMD Biosciences, San Diego CA) in PBS are adsorbed on to the individual 

nanodevices. One ml drops of fresh human donor blood is mixed with 1 micro-liter 

of cancer cells (1000 cells). This mixture is applied to the device using a 

micro-pipette and the change in conductivity is measured. Negative control cell lines 

that do not overexpress IGF1R, EPCAM, or Her2, such as human Jurkat cells, 

human nontumorigenic MCF10A cells, and nontumorigenic R- mouse embryonic 

fibroblast cells with targeted disruption of the IGF1R gene are used as negative 

controls to test the device efficacy. 

Results: Functionalized nanotubes with specific antibodies elicited significant changes 

in conductivity (10 times change per 100 cells, r∧2 0.95) while non-specific interaction 

caused negligible conductivity changes. Larger conductivity drops were seen in blood 

containing cancer cells than blood alone or isolated white blood cells (change in 

resistance from 2-6 kW for 200 cells in blood, r∧2 0.95). Changes in conductance were 

linear with an increasing number of cells in the range of 10-300 cells/5 ml. (5 kW per 

100 cells, 20 kW per 200 cells and 30 kW per 300 cells, r∧20.95). 

Conclusion: The specific and proportional changes in conductivity suggest that this 

approach could be useful in sensing cancer cells in a small volume of blood. 

Monitors based on nano-technology may be of clinical utility in the detection of a 

wide variety of cancer types. This non-invasive test would give clinicians immediate 

results (similar to a glucometer), which can improve screening, response assessment 

and surveillance. 


218P CIRCULATING TUMOR CELLS AS A PROGNOSTIC MARKER 

IN ADVANCE COLORECTAL CANCER PATIENTS TREATED 

WITH CETUXIMAB-CONTAINING SALVAGE CHEMOTHERAPY 

S. Matsusaka 1 , Y. Kuboki 1 , M. Suenaga 1 , E. Shinozaki 1 , N. Mizunuma 1 , 

K. Hatake 2 

1 Gastroenterology, Cancer Institute Hospital, Tokyo, JAPAN, 2 Medical Oncology, 

Cancer Institute Hospital of JFCR, Tokyo, JAPAN 

Background: Circulating tumor cells (CTC) can be a predictive, or a prognosis 

marker in advance colorectal cancer (ACC) patients treated with chemotherapy plus 

targeted agents as front-line therapy. We assessed assessed the prognostic and 

predictive role of CTC in ACC patients treated with cetuximab (with or without 

irinotecan) who had been previously treated with a fluoropyrimidine, irinotecan, and 

oxaliplatin. 

Material and methods: Between October 2008 and March 2011, 63 patients with 

KRAS wild-type ACC were treated with cetuximab as a third-line therapy at the 

Cancer Institute Hospital, providing written informed consent for CTC collection. 

We used CellSearch system for detection and EGFR expression for CTC. Patients 

were stratified into low (less than three CTC per 7.5ml of blood) or high (three or 

more CTC per 7.5ml of blood). 

Results: A total of 63 patients were assessable for CTC analysis. Of the 63 patients with 

evaluable baseline CTC results, 19 patients (30%) had high CTC. The median number of 

CTC was one (range 0- 220, mean 7.28) at baseline. Patients with high CTCs had a 

shorter median overall survival (8.9 months) than those with low CTCs (15.3 months) 

[P < 0.005; HR 2.2 (95% CI 1.2–3.9)]. There was no significant difference in PFS between 

the two groups (PFS; HR 1.2). Of the 33 patients with positive CTC, 7 patients (21%) 

had EGFR-positive CTC, and 26 patients (79%) had EGFR-negative CTC. The 

concordance rate for EGFR between tumor and CTC was 30.5%. 

Conclusion: High CTC count at baseline is a poor prognostic factor for OS in ACC 

patients treated with cetuximab-containing chemotherapy as salvage. 


219P ASSESSMENT OF CIRCULATING FREE DNA (CFDNA) AND 

CIRCULATING MELANOMA CELLS (CMCS) AS PROGNOSTIC 

BIOMARKERS IN METASTATIC CUTANEOUS MELANOMA 

K. Aung 1 , L.T. Khoja 1 , C. Zhou 1 , M. Lancashire 1 , R. Sloane 1 , G. Brady 1 , 

G. Clack 2 , A. Hughes 2 , P. Lorigan 3 , C. Dive 1 

1 Clinical and Experimental Pharmacology, The Paterson Institute for Cancer 

Research, Manchester, UNITED KINGDOM, 2 Early Phase Oncology, 

AstraZeneca Pharmaceuticals, Macclesfield, UNITED KINGDOM, 3 Medical 

Oncology, The Christie NHS Foundation Trust, Manchester, UNITED KINGDOM 

Background: cfDNA is detectable in patients with metastatic cutaneous melanoma and 

its plasma concentration could potentially predict their clinical outcomes. We assessed 

the correlation between cfDNA concentration and patients’ overall survival and clinical 

characteristics including known poor prognostic factors in melanoma. Prognostic value 

of CMCs number and its association with cfDNA level was also explored. 

Methods: Pre-treatment blood samples from 50 patients with metastatic cutaneous 

melanoma were collected prospectively. cfDNA was extracted from 1 ml of plasma using 

QIAamp Circulating Nucleic Acids Kit (Qiagen, Hilden, Germany) and quantified by 

RNase P qPCR (ABI Life Technologies, Foster City, NJ, USA). CMC enumeration per 

7.5 ml whole blood was performed within 96 hours of sample collection using the 

CellSearch Melanoma Kit (Veridex, NJ, USA). Correlation between cfDNA 

concentration and clinical characteristics and CMC number was performed using 

χ 2 -test and Fisher’s exact test where appropriate. Survival curves were produced and 

compared by the Kaplan-Meier method and log-rank test respectively. 


Results: The median concentration of cfDNA was 6.8 ng/ml (range 0-205.8) and 

median CMC number was 0/7.5ml (range 0-16). Patients with cfDNA concentration 

of >75% percentile had significantly shorter overall survival compared to those with 

cfDNA level


223P THE ANALYTICAL VALIDATION OF PROSTATE SPECIFIC 

MRNA DETECTION IN WHOLE BLOOD BY REVERSE 

TRANSCRIPTION-POLYMERASE CHAIN REACTION (RT-PCR) 

AS A PROGNOSTIC BIOMARKER FOR PATIENTS WITH 

CASTRATION-RESISTANT PROSTATE CANCER (CRPC) 

D. Danila 1 , A. Anand 1 , G. Heller 2 ,M.Wan 1 , M. Zehnder 1 , R. Khanin 3 , 

N. Schultz 3 , M. Fleisher 4 , H. Lilja 5 , H.I. Scher 1 

1 Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, 

New York, NY, UNITED STATES OF AMERICA, 2 Department of Epidemiology 

and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 

UNITED STATES OF AMERICA, 3 Department of Computational Biology, 

Memorial Sloan Kettering Cancer Center, New York, NY, UNITED STATES 

OF AMERICA, 4 Department of Laboratory Medicine, Memorial Sloan Kettering 

Cancer Center, New York, NY, UNITED STATES OF AMERICA, 5 Urology Service, 

Memorial Sloan Kettering Cancer Center, New York, NY, UNITED STATES OF 

AMERICA 

Background: To estimate the association between molecular biomarkers and 

outcomes, robust assays are needed before qualification in prospective trials. 

Although tumor specific transcripts detected in blood by PCR have been associated 

with clinical outcome, an analytically validated PCR platform enabling detection of 

CTC-associated transcripts in clinical settings remains to be identified. Here we 

explore the efficacy of detecting a panel of prostate specific transcripts in conjunction 

with conventional markers in CRPC. 

Method: Blood was collected from 97 patients with progressive CRPC in PAXgene 

tubes (2.5 ml) for total RNA extraction using PAXgene Blood RNA Kit. Five genes 

expressed in prostate but not in nucleated blood cells were analyzed by 

primer-specific RT-PCR. We used a Fluidigm Dynamic Array platform to 

analytically validate RT-PCR assays for KLK3, KLK2, HOXB13, GHRL2 and FOXA1 

transcripts. Each PCR-reaction was run in 6 replicates, detection thresholds for each 

gene were chosen by ROC analysis of an independent set of 56 CRPC patients versus 

51 healthy volunteers, and results were reported as transcripts present or absent. 

CellSearch reported CTC number/7.5 ml of blood drawn into CellSave tube. 

Result: Prostate specific transcripts were detected in 70/97 (72%, 95% CI 62-80%) of 

patients with progressive CRPC studied with a median survival time of 17 months 

(95% CI: 13.8, 23.5). 42/45 CRPC-patients with ≥5 CTC and 28/52 CRPC patients 

with

Table: 226P 

Methods: Pts were randomized 1:1 to T-DM1 3.6 mg/kg q3w or H 6 mg/kg q3w (8 

kg/mg in cycle 1) + T 75 or 100 mg/m 2 q3w and treated until disease progression. 

HER2 expression was measured by qRT-PCR in archival tissue samples from all 

randomized pts. Efficacy outcomes included investigator-assessed PFS and ORR. The 

analysis results presented here are based on the clinical data with a median follow-up 

of ∼14 mo in each arm. 

Results: In total, 122 tumor samples from 137 randomized pts were available for 

analysis of pre-treatment HER2 by qRT-PCR, resulting in a valid result for 116 pts (6 

samples were below the limit of quantification). Efficacy outcomes by low (


229P RELATIONSHIP BETWEEN INTESTINAL FUNCTION AND 

EXPOSURE TO SORAFENIB AND SUNITINIB IN CANCER 

PATIENTS 

J. Durand 1 , B. Blanchet 2 , M. Buyse 3 , N. Neveux 4 , P. Boudou-Rouquette 1 , 

O. Mir 1 , M. Vidal 2 , L. Cynober 5 , F. Goldwasser 1 

1 Medical Oncology, Cochin Teaching Hospital, Paris, FRANCE, 

2 Pharmacology-Toxicology, Cochin Teaching Hospital, Paris, FRANCE, 

3 Pharmacy, St Antoine Teaching Hospital, Paris, FRANCE, 4 Clinical Chemistry 

Laboratory, Cochin Teaching Hospital, Paris, FRENCH GUYANA, 5 Laboratory of 

Biological Nutrition Ea 4466, Université Paris Descartes, Paris, FRANCE 

Background: Variability in exposure to sorafenib (SO) and sunitinib (SU), two oral 

tyrosine kinase inhibitors (TKI) approved for the treatment of various solid tumours, 

is large. Plasma citrulline (CIT) levels reflect the functional small bowel cell mass. 

We studied the relationship between TKI exposure and intestinal function in adult 

cancer patients (pts). 

Methods: CIT concentration and drug exposure were determined in 56 pts under SO 

(n = 38) or SU (n = 18) on day (D) 0 (baseline), then D8 and D22 after treatment 

initiation. The clinical results led to in vitro studies. In vitro concentration 

dependent-cytotoxicity of SO and SU was evaluated in Caco-2 cell lines using 

mitochondrial toxicity test (MTT) assay. Under clinically relevant concentrations of 

SO (2-10 µg/mL) or SU (0.05-0.10 µg/mL), transepithelial electrical resistance 

(TEER) and CIT levels at the basolateral side of Caco-2 cells were determined. 

Results: In SO-treated pts, mean citrullinemia on D8 was lower than at D0 (26.2 ± 

10.9 mmol/L vs 35.2 ± 13.4, p < 0.0001). Baseline citrullinemia correlated with SO 

Area Under Curve (AUC) (r = 0.59, p =0.0001). Median SO AUC on D22 was 

1.23-fold lower than SO AUC on D8 (67.0 vs 82.4 mg/L.h respectively, p = 0.033). 

Magnitude of decrease in citrullinemia between D0 and D8 correlated with 

subsequent decrease in SO AUC (r = 0.61, p < 0.001). In SU-treated pts, baseline 

citrullinemia was not correlated with drug exposure (r = -0.29, p = 0.26). Neither 

citrullinemia nor SU AUC varied over the study period (p = 0.55 and p = 0.23 

respectively). In vitro lethal concentration 50 (LC50) of SO (9.64 + 0.44 µg/mL) was 

close to therapeutic concentration unlike SU LC 50 (2.07 + 0.11 µg/mL) which was 

40-fold higher. In SO-treated Caco-2 cells, TEER and CIT levels decreased compared 

to those of control group (p < 0.0001 and p = 0.017 respectively). SU did not cause 

any change of these 2 parameters. 

Conclusions: Contrary to SU, SO caused in vitro a cytotoxic effect on Caco-2 cells at 

therapeutic concentrations. This likely explains the different kinetics of CIT 

concentrations between SO- and SU-treated pts. Correlation between SO AUC and 

citrullinemia suggests strongly that functional enterocytic mass contributes to the 

intra- and inter-individual variability in sorafenib exposure in cancer pts. 

Disclosure: O. Mir: BAYER, PFIZER, ROCHE. F. Goldwasser: BAYER, PFIZER, 

ROCHE. All other authors have declared no conflicts of interest. 

230P FEASIBILITY OF GENETIC ABERRATIONS ANALYSIS IN THE 

CIRCULATING TUMOR CELLS (CTCS) 

J. Antonello 1 , E. Rossi 2 , U. Basso 3 , A. Facchinetti 2 , V. Zagonel 3 ,J. 

F. Swennenhuis 4 , L.W. Terstappen 4 , A. Amadori 1 , R. Zamarchi 1 

1 Immunology and Molecular Oncology, IOV-IRCCS, Padova, ITALY, 2 Department 

of Surgery, Oncology and Gastroenterology, University of Padova, Padova, 

ITALY, 3 Medical Oncology, IOV-IRCCS, Padova, ITALY, 4 Medical Cell Biophysics, 

University of Twente, Twente, NETHERLANDS 

Background: In current practice cancer tissue is taken at diagnosis to assess the 

presence of treatment targets. This however is suboptimal since tumor cells evolve 

due to genomic instability. Assessment of the genotype and phenotype of the CTCs 

will provide insights into which treatments would be most beneficial for the 

individual patient. Feasibility to detect treatment targets in CTCs has been 

demonstrated (Meng, Tripathy et al. 2004; de Bono, Attard et al. 2007; Rossi, Basso 

et al. 2010; Wang, Pfister et al. 2010). In this context, the development of a 

cytogenetic assay for CTCs will be crucial for successful molecular targeted therapy 

in cancer patients. Genetic characterization of CTCs is expected to gather new 

knowledge on the mechanism of metastasis and on potential targets of novel 

therapeutic strategies. 

Patients and methods: Assay optimization for analysis of genetic aberrations of 

CTCs was performed with cells from tumor cell lines. Tumor cell lines with known 

chromosomal aberrations and mosaicism were spiked into 7.5mL whole blood 

samples, at numbers similar to those observed in-vivo in cancer patients. Tumor cells 

were enriched by CellSearch System and off-line purified and individually analyzed 

for chromosomal alterations. The procedure was next validated by using blood 

samples collected from cancer patients. 

Results/Conclusions: A robust protocol for the isolation of individual CTCs followed 

by DNA extraction and amplification after CellSearch enrichment was established. 

The number and the quality of CTCs needed to obtain an informative analysis of 

chromosomal aberrations were set up. Accrual of cancer patients for individual CTC 

isolation and molecular characterization is ongoing. Updated data including 

evaluations on prognostic value of the genetic aberrations analysis of the CTCs and 

correlation with clinical stage, tumor burden, metastatic sites and survival will be 

available and presented at the meeting. 


231P META-ANALYSIS OF HER3 EXPRESSION AND PROGNOSIS 

IN SOLID TUMORS 

A. Ocana 1 , F. Vera Badillo 2 , B. Seruga 3 , A. Pandiella 4 ,E.Amir 2 

1 Medical Oncology, Albacete University Hospital, Albacete, SPAIN, 2 Medical 

Oncology, Princess Margaret Hospital, Toronto, CANADA, 3 Sector of Medical 

Oncology, Institute of Oncology, Ljubljana, SLOVENIA, 4 Salamanca Cancer 

Research Center, CIC-CSIC, Salamanca, SPAIN 

Introduction: Aberrant activation of various ErbB receptors has been linked with 

malignant transformation. HER3 is an ErbB family member that can dimerize with 

other ErbB receptors such as HER2 and can modulate the transmission of oncogenic 

stimuli. The prognostic role of HER3 is not clear, but numerous agents against HER3 

are currently in clinical development. Here we present a meta-analysis of studies 

evaluating the prognostic impact of HER3 expression. 

Material and methods: Pubmed was searched for studies evaluating expression of 

HER3 (as measured by immunohistochemistry-IHC) and overall survival (OS) in 

solid tumors. Published data were extracted and computed into odds ratios (ORs) for 

death at 3 and 5 years. Subgroup analyses were performed to evaluate the association 

of HER3 with overall survival in different tumor types. Data were pooled using 

generic inverse variance and random-effect modeling. 

Results: Eleven studies were eligible for analysis. Median sample size was 126. 

Colorectal cancers were evaluated in three studies and gastric in two, while breast, 

melanoma, pancreas, ovary, head and neck and cervix cancers were assessed in one 

study respectively. The median percentage of cases with HER3 expression was 43%. 

HER3 expression was associated with worse OS at both 3 and 5 years (OR: 2.23; 95% 

confidence interval [CI], 1.74 to 2.86, p < 0.001 and OR: 2.25; 95% CI, 1.77 to 2.86, 

p < 0.001, respectively). Among studies with known HER2 over-expression (breast, 

gastric and ovary cancers), the magnitude of effect of HER3 on OS was significantly 

greater (3-years OS OR: 3.33, 95% CI, 2.30 to 4.83, p < 0.001 and 5-year OS OR: 

3.17, 95% CI, 2.23 to 4.49, p < 0.001). 

Conclusion: Expression of HER3 is associated with worse survival in solid tumors. 

The effect of HER3 may be greater in those tumors where HER2 is also 

over-expressed. A validated method for HER3 assessment is required, but the 

potential clinical benefit from targeting HER3 appears favorable. 


232 NESTED CASE CONTROL STUDY OF PROTEOMIC 

BIOMARKERS FOR INTERSTITIAL LUNG DISEASE IN 

JAPANESE PATIENTS WITH NON-SMALL CELL LUNG CANCER 

TREATED WITH ERLOTINIB 

N. Katakami 1 , S. Atagi 2 , H. Yoshioka 3 , M. Fukuoka 4 , A. Ogiwara 5 , M. Imai 6 , 

M. Ueda 7 , S. Matsui 8 

1 Division of Integrated Oncology, Institute of Biomedical Research & Innovation 

Hospital, Kobe, JAPAN, 2 Internal Medicine, National Hospital Organization 

Kinki-Chuo Chest Medical Center, Sakai, JAPAN, 3 Respiratory Internal Medicine, 

Kurashiki Central Hospital, Kurashiki, JAPAN, 4 Medical Oncology, Izumi 

Municipal HospitalCancer Center, Izumi City, JAPAN, 5 Research and 

Development, Medical ProteoScope Co., Ltd, Yokohama, JAPAN, 6 Primary 

Lifecycle Management, Chugai Pharmaceutical Co., Ltd, Tokyo, JAPAN, 7 Clinical 

Research Planning, Chugai Pharmaceutical Co., Ltd, Tokyo, JAPAN, 8 Data 

Science, The Institute of Statistical Mathematics, Tachikawa, JAPAN 

Background: Interstitial lung disease (ILD) is a serious adverse drug reaction 

associated with EGFR tyrosine kinase inhibitors, but its risk factors are yet to be 

elucidated. We sought to identify the proteomic biomarkers associated with ILD in 

Japanese patients with non-small cell lung cancer treated with erlotinib, and to build 

predictive models for development of ILD using the proteomic biomarkers. 

Methods: We conducted a nested case control study. The cases were subjects in 

whom ILD developed within 120 days after the administration of erlotinib following 

enrolment in the cohort, and the controls were randomly selected from patients 

without ILD who were treated with erlotinib. For the proteomics analysis, albumin 

and IgG were removed from serum samples obtained before the first administration 

of erlotinib, then the samples were digested with protease and the resultant peptide 

fragments were separated, identified and assayed by LC–MS/MS. Logistic regression 

analysis was used for the identification and examination of predictability for ILD. 

Results: A total of 645 patients were enrolled in the cohort, 15 cases and 64 controls 

were analysed. Logistic regression analysis was performed to identify the peptide 

peaks and proteins assossiated with ILD. When multiplicity was taken into account, 

we were unable to statistically verify any genuine association between individual 

markers and ILD. Investigation of the predictive power based on leave-one-out 

cross-validation showed that the area under the ROC curve was 0.73 at a maximum. 


However, additional analysis suggested that three proteins (C3, C4A/C4B and 

APOA1) have a stronger association with ILD than the other proteins tested. 

Conclusions: We were unable to conclude from the results of this study that any 

promising serum protein markers for predicting ILD had been identified. However, 

C3, C4A/C4B and APOA1 were suggested to be worth further investigation. 

Disclosure: N. Katakami: corporate-sponsored research (Chugai Pharmaceutical 

Company). S. Atagi: corporate-sponsored research (Chugai Pharmaceutical Company). 

H. Yoshioka: corporate-sponsored research (Chugai Pharmaceutical Company). M. 

Fukuoka: other substantive relationships (Chugai, Astra Zeneca). A. Ogiwara: 

corporate-sponsored research (Chugai, Astra Zeneka). M. Imai: M Imai is employee of 

Chugai Pharmaceutical Co., Ltd. M. Ueda: M Ueda is employee of Chugai 

Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest. 

233 PSF3 IS A NOVEL PROGNOSTIC BIOMARKER IN LUNG 

ADENOCARCINOMA 

D. Hokka, Y. Maniwa, S. Tane, S. Tauchi, W. Nishio, M. Yoshimura 

Divisions of Thoracic Surgery, Department of Surgery, Kobe University Graduate 

School of Medicine, Kobe, JAPAN 

Background: PSF3 is a member of the highly evolutionarily conserved tetrameric 

complex termed GINS, composed of SLD5, PSF1, PSF2, and PSF3. Previous studies 

suggested that some GINS complex members are upregulated in cancer, but PSF3 

expression in lung adenocarcinoma has not been investigated. The objective of the 

current study was to elucidate the role of PSF3 in lung adenocarcinoma by 

investigating clinical samples. 

Methods: We investigated the expression of PSF3 in cancer epithelial cells 

immunohistochemically in 125 consecutive resected cases of lung adenocarcinoma. 

Results: Increased PSF3 expression was observed in 27 (21.6%) of the 125 cases. 

PSF3 expression was found to be correlated significantly with some 

clinicopathological factors. A univariate analysis and log–rank test indicated a 

significant association between PSF3 expression and lower overall survival rate (P = 

0.0001 and P < 0.0001, respectively). A multivariate analysis also indicated a 

statistically significant association between increased PSF3 expression and lower 

overall survival rate (hazard ratio, 5.2; P = 0.0027). In a subgroup analysis of only 

stage I patients, increased PSF3 expression was also significantly associated with a 

lower overall survival rate (P = 0.0008, log–rank test). Moreover, the Ki67 index level 

was higher in the PSF3- positive group than in the negative group (P < 0.0001, 

Mann–Whitney U-test). 

Conclusion: The current results indicated that PSF3 is a novel prognostic biomarker 

in lung adenocarcinoma. 


234 MUTATIONS IN THE EPIDERMAL GROWTH FACTOR 

RECEPTOR GENE IN NON-SMALL-CELL LUNG CANCER 

PATIENTS AND EGFR SERUM LEVELS 

E.Y. Romero-Ventosa 1 , M. Rodríguez Rodríguez 1 , S. Gonzalez Costas 1 , 

A. GonzÁlez-PiÑeiro 2 , S. Blanco-Prieto 3 , M. Páez de La Cadena 3 ,I. 

Arias Santos 1 , B. Leboreiro Enriquez 1 , B. Bernardez Ferran 4 , E. Brozos 5 

1 Farmacia Hospitalaria, Complejo Hospitalario Universitario de Vigo 

(CHUVI)-Hospital Xeral-Cíes, Vigo, SPAIN, 2 Pathological Anatomy, Complejo 

Hospitalario Universitario de Vigo (CHUVI)-Hospital Xeral-Cíes, Vigo, SPAIN, 

3 Bioquímica, Genética E Inmunología, Universidad de Vigo, Vigo, SPAIN, 

4 Farmacia Hospitalaria, Complejo Hospitalario Universitario de Santiago (CHUS), 

Santiago, SPAIN, 5 Dept. of Medical Oncology, Complejo Hospitalario 

Universitario de Santiagode Compostela Sergas, Santiago de Compostela, 

SPAIN 

Background: Determine the existing mutations in the epidermal growth factor 

receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) patients and correlate 

with survival. Also pretreatment EGFR serum levels were quantified and analyzed if 

there were differences between patients with or without mutations. 

Methods: From July 09 and July 11 serum samples were collected before starting 

erlotinib. Serum levels of EGFR were quantified using an ELISA. Patients were 

examined for mutations in tissue by EGFR Mutation Test Kit cobas. SPSS was used 

to calculate overall survival (OS) and progression-free survival (PFS). Mann-Whitney 

U test was used for comparison of EGFR serum level. 

Results: 58 patients were studied but we obtained information of mutations in 34 

patients. All variants were found in exons 18, 19 and 21 of EGFR. No mutation 

was found in exon 20, only two polymorphisms. Of 32 patients analyzed, we 

detected a total of 11 mutations (34.4%). In exon 19 we found 8 mutations 

(del19) and affected 8 patients (72.7% mutations). In exon 21 we found two 

mutations (L858R and L861Q), each in 1 patient (18.2% mutations). In exon 18, 

G719X mutation was found in 1 patient (9.1% mutations). The remaining patients 

(65.6%) were wild type. Patients wild type have a median OS of 5.4 months (95% 

CI, 4.2 - 6.6) and mutated patients 12.6 months (95% CI, 4.7- 21.1); p = 0.033. In 

terms of PFS, wild type patients have a median PFS of 2.8 months (95% CI: 2.0 - 

3.6) and mutated 8.6 months (95% CI 2.0 - 15.1); p = 0.012. We determined 


serum levels of EGFR in 44 patients with a mean of 57.5 ng/mL. Of these 

patients, 21 were wild type, 7 were mutated and 16 showed an unknown 

mutational status. In wild type patients, the mean serum levels of EGFR was 57.8 

ng/mL and in the mutant was 62.3 ng/mL. 

Conclusion: Patients with EGFR gene mutation have a higher OS and PFS. No 

differences were found in EGFR serum levels prior to erlotinib treatment between 

wild type and mutated patients. 


235 CORRELATION OF C609T POLYMORPHISM OF NADPH 

QUINONE OXIDOREDUCTASE 1 AND HEMATOLOGICAL 

TOXICITIES IN LUNG CANCER PATIENTS TREATED WITH 

AMRUBICIN 

M. Nagata 1 , T. Kimura 1 , T. Suzumura 1 , S. Kudoh 1 , K. Umekawa 1 , Y. Kira 2 , 

K. Matsuura 1 , T. Nakai 1 , S. Mitsuoka 1 , K. Hirata 1 


Central Laboratory, Osaka City University, Osaka, JAPAN 

Background: Amrubicin hydrochloride (AMR) is a novel synthetic 

aminoanthracycline derivative, that is metabolically activated to amrubicinol 

(AMR-OH) by carbonyl reductase. The cytotoxic activity of AMR-OH is promising 

for small cell lung cancer and considered as a key agent. NADPH Quinone 

Oxidoreductase 1 (NQO1) is a cytosolic flavoprotein that metabolizes the quinone 

structures contained in both AMR and AMR-OH. NQO1 expression genotyped 

homozygous for minor alleles (T/T) was low compared with homozygous for major 

alleles (C/C) or heterozygous (C/T). We hypothesized that NQO1 C609T 

polymorphisms may relate to the AMR pharmacokinetics and clinical outcomes. 

Methods: The patients with lung cancer received AMR at a dose of 30 or 40mg/m 2 / 

day on day 1-3 at Osaka City University Hospital were enrolled. Plasma sampling 

was performed at the time points of 24h after the third AMR injection. The 

concentrations of AMR and AMR-OH were determined by HPLC method. NQO1 

C609T polymorphism was assayed using real-time polymerase chain reaction 

methods. 

Results: A total of 35 patients were enrolled. The C/C, C/T, and T/T were observed 

in 12 (34.3%), 16 (45.7%), and 7 (20%) patients, respectively. A dose of 30 mg/m 2 

was administered to 19 patients, and 40mg/m 2 was administered to 16 patients. The 

mean plasma concentrations of AMR-OH on day4 at a dose of 30mg/m 2 and 40mg/ 

m 2 were 11.02 ± 3.83 and 16.18 ± 6.17 ng/ml, respectively (p = 0.005). In patients 

with AMR at a dose of 40mg/m 2 , the plasma concentrations of AMR-OH on day4 

exhibited a tendency toward a relationship with NQO1 genotypes with values of C/C 

20.5 ± 5.89, C/T 15.9 ± 5.43, and T/T 11.2 ± 4.47ng/ml (p = 0.066). The C/C was 

related to decrease changes in WBC, hemoglobin, and platelet counts (p = 0.01, p = 

0.03, and p = 0.0005, respectively). No significant correlations were observed between 

NQO1 genotypes and clinical outcomes at a dose of 30mg/m 2 . 

Conclusions: NQO1 C609T polymorphism had a tendency of correlation with the 

plasma concentrations of AMR-OH, and thereby had significant correlations with 

hematologic toxicities. NQO1 genotype appears to be the candidate biomarker of 

hematological toxicities of AMR treatment at a dose of 40mg/m 2 . 


236 POLYCYSTINS 1 AND 2 AS NOVEL PROGNOSTIC MARKERS 

IN COLORECTAL CANCER 

A.N. Gargalionis 1 , G. Dalagiorgou 1 , P. Korkolopoulou 2 , C. Piperi 1 , G. Levidou 2 , 

C. Adamopoulos 1 , A. Zizi-Sermpetzoglou 3 , N. Tsavaris 4 , E.K. Basdra 1 ,A. 

G. Papavassiliou 1 

1 Department of Biological Chemistry, University of Athens, School of Medicine, 

Athens, GREECE, 2 First Department of Pathology, Laikon General Hospital, 

University of Athens, School of Medicine, Athens, GREECE, 3 Department of 

Pathology, Tzaneio General Hospital, Piraeus, GREECE, 4 Oncology Unit, 

Department of Pathophysiology, Laikon General Hospital, University of Athens, 

School of Medicine, Athens, GREECE 

Background/purpose: Polycystins 1 and 2 (PC-1 and PC-2) constitute a family of 

cellular proteins detected in a variety of epithelial cells throughout human tissues. 

They function as mechanosensors and contribute to cellular homeostasis through 

proliferation, differentiation and apoptotic processes. Nevertheless, their fundamental 

role in cell-to-cell mechanical interactions, cell–matrix communication, tissue 

morphogenesis and planar cell polarity connote their engagement in processes of 

oncogenesis, including invasion and metastasis. The aim of the study was to 

investigate the expression of PC-1 and PC-2 in colorectal cancer (CRC), identify 

possible correlations with histopathological characteristics and explore the 

underpinning signal transduction mechanisms. 

Methods: The immunohistochemical expression of PC-1 and PC-2 was evaluated in 

paraffin sections of 144 CRC patients and the results were statistically correlated with 

clinical and pathologic parameters. Molecular mechanisms were explored by Western 

blot, immunofluorescence and flow cytometry in SW480 CRC cell line expressing 

PC-1 and PC-2. 



Results: Significantly elevated cytoplasmic expression was observed for PC-1 and PC-2 

in mucinous carcinomas (p = 0.0035 and p = 0.0001, respectively). High expression 

levels of PC-2 were correlated with advanced TNM stage (p = 0.0324) and depth of 

tumour invasion (p = 0.0311). High expression levels of PC-1 (p = 0.0078) and altered 

expression levels of PC-2 in the transition zone from normal to cancerous tissue (p = 

0.0198) were associated with reduced five-year survival rate. Altered expression of PC-1 

in the transition zone was correlated with higher chance of relapse for the patients (p = 

0.0019). Experiments in SW480 cells revealed funneling of PC-1 and PC-2 function via 

mammalian target of rapamycin (mTOR) and p70S6 kinases. 

Conclusions: Our findings suggest that PC-1 and PC-2 are implicated in the 

development of an aggressive phenotype in CRC, as well as in reduced five-year 

survival rate and cancer-free survival, thus constituting potential prognostic markers. 

Their function seems to be partially mediated by key molecules of the mTOR 

signaling pathway. 


237 IMPACT OF FCGR2A AND FCGR3A POLYMORPHISMS ON THE 

CLINICAL OUTCOME OF PATIENTS WITH METASTATIC 

COLORECTAL CANCER TREATED WITH CETUXIMAB AND 

FOLFIRI AS 2ND-LINE THERAPY 

I. Yuka 1 , S. Hazama 1 , N. Okayama 2 , Y. Hinoda 2 , H. Mishima 3 , J. Sakamoto 4 , 

Y. Miyake 5 , S. Iwamoto 6 , F. Goda 7 , M. Oka 1 

1 Department of Digestive Surgery and Surgical Oncol, Yamaguchi University 

Graduate School of Medicine, Ube, JAPAN, 2 Department of Oncology and 

Laboratory Medicine, Yamaguchi of University Graduate School of Medicine, 

Ube, JAPAN, 3 Surgery, National Osaka Medical Center, Osaka, JAPAN, 4 Young 

Leaders Program, Nagoya University, Nagoya, JAPAN, 5 Department of Surgery, 

Minoh City Hospital, Minoh, JAPAN, 6 Department of Surgery, Hirakata Hospital, 

Kansai Medical University, Hirakata, JAPAN, 7 Department of Gastroenterological 

Surgery, Kagawa University, Kida, JAPAN 

Background: Cetuximab, a chimeric IgG1 anti- EGFR monoclonal antibody shows 

activity in mCRC, mainly in wild-type KRAS tumors. Recent studies demonstrate 

antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the modes of action 

for cetuximab. Fragment c gamma receptors (FcGR) play an important role in 

initiating ADCC. We investigated the association of FcGR polymorphisms with the 

outcome of KRAS-wild type mCRC pts treated with cetuximab and FOLFIRI as 2 nd 

line therapy (FLIER study). 

Patients and methods: 60 mCRC pts were enrolled onto the FLIER study, and 56 

pts were finally analyzed. Tumor tissues from 56 pts were screened, BRAF and PI3K 

mutations using direct sequencing and were screened genotype for FcGR2a (H131R) 

and FcGR3a (V158F) polymorphisms by Taqman assay. The association of each 

FcGR polymorphism with response rate (RR) and progression free survival (PFS) 

were analyzed. 

Results: The RR of 56 pts was 33.9%. No patient was response to the regimen with 

mutated BRAF and PI3K. A statistically significant difference was observed for PFS for F 

carriers to 158V/V pts (286 vs 154 days; P = 0.047, Kaplan-Meier curves). The difference 

was more significant among pts without mutation of BRAF or PI3K (301 vs 185 days; P 

= 0.016). The relationship between RR and polymorphisms was as follows, FcGR2a 

(HH: 10/35, HR: 6/15, RR: 3/6), FcGR3a (FF: 15/37, FV3/14, VV1/5). There was no 

relationship between each polymorphisms and RR (Chi-square test). 

Conclusion: In our analysis, mutations such as BRAF and PI3K were also important 

biomarkers of cetuximab. Furthermore, our date suggest that the FcGR3a 

polymorphisms may be also useful molecular markers to predict clinical outcome in 

mCRC pts treated with cetuximab. We will be able to select super-responders to 

cetuximab in combination with these mutations and FcGR3a polymorphisms. 


238 TUMOR RESPONSE AND SURVIVAL IN PATIENTS WITH 

ADVANCED GASTRIC CANCER: THE PREDICTIVE VALUE OF 

CHEMOTHERAPY-INDUCED CHANGES IN FIBRINOGEN 

X. Qu, S. Zheng, Y. Teng, J. Zhang, Y. Luo, J. Wang, L. Zhao, X. Li, Y. Chen, 

Y. Liu 

Medical Oncology, The First Hospital of China Medical University, Shenyang, 

CHINA 

Purposes: Hyperfibrinogenemia in various carcinomas has previously been 

described. But, in advanced gastric cancer, whether or not chemotherapy-induced 

changes in fibrinogen level relate to chemotherapeutic response and prognosis 

remains unclear. The purposes of this study were: 1) to analyze the correlation 

between the chemotherapy-induced changes of plasma fibrinogen level and the 

chemotherapeutic response after the first two courses of standard first-line 

chemotherapy; and 2) to evaluate the prognostic significance of the change of plasma 

fibrinogen level in patients with advanced gastric cancer. 

Methods: In this retrospective study, the data of 84 patients with advanced gastric 

cancer were collected. After a median follow-up time of 280 days 

(range,58-1992days) 65patients had died by the cutoff day.The association between 

the pre-and post-chemotherapy fibrinogen levels and patient clinic characteristics, or 

the association between the changes in fibrinogen and the response to chemotherapy, 

were analyzed using SPSS software. Furthermore, the prognostic value of the change 

of fibrinogen levels was assessed. 

Results: The median pre-chemotherapy plasma fibrinogen levels were 4.55g/L. 

Pre-chemotherapy plasma fibrinogen levels correlated significantly with the age(p = 

0.017).There is a significant link between the decrease in fibrinogen level and partial 

response (PR; p = 0.000) and stable disease (SD; p = 0.015). But there is not similar 

decrease in progressive disease (PD; p = 0.851). If the decrease is more than10%, we 

get longer overall survival (OS; p = 0.03). 

Conclusions: This study showed that the reduction in plasma fibrinogen levels 

induced by chemotherapy might be a promising biomarker for evaluating the efficacy 

of chemotherapy in advance gastric cancer. In addition, the change of plasma 

fibrinogen levels could be used as a prognostic parameter for the overall survival of 

patients with advanced gastric cancer. Relationship between the decrease fibrinogen 

level and chemotherapeutic response. 

group N pre-chemotherapy post-chemotherapy P value 

Total 84 4.55 ± 1.25 4.02 ± 1.38 0.001 

DCR 72 4.45 ± 1.27 3.90 ± 1.14 0.000 

PR 14 4.88 ± 1.29 3.37 ± 0.71 0.000 

SD 58 4.41 ± 1.25 4.03 ± 1.19 0.015 

PD 12 4.83 ± 1.18 4.72 ± 2.32 0.851 


239 IMMUNODIAGNOSTIC ASSAY FOR DETECTING URINARY 

NUCLEAR MATRIX PROTEIN 52 IN PATIENTS WITH BLADDER 

CANCER 

H.A. Abdel Latif 1 , H. El-Hadaad 2 

1 Histolooy and Cell Biology, Mansoura University, Faculty of Medicine, Mansoura, 

EGYPT, 2 Clinical Oncology, Mansoura University Hospital School of Medicine, 

Mansoura, EGYPT 

Objective: To report the rapid and simple detection of a nuclear matrix protein 

(NMP) in the urine of patients with bladder cancer using dot-enzyme-linked 

immunosorbent assay (ELISA). 

Patients and methods: Urine sample from 120 patients with bladder cancer and 60 

controls were evaluated using western blot and specific immunoglobulin G antibody 

to identify the urinary NMP marker using the developed dot-ELISA. The initial 

response and follow up of 82 patients treated by irradiation were followed using 

the assay. 

Results: The NMP marker was identified in the urine of patients with cancer 

bladder at 52 KDa (NMP-52) by Western blot. The dot-ELISA detected the 

urinary NMP-52 marker in 85% of patients with squamous cell carcinoma and 

92% with transitional cell carcinoma. The positive and negative predictive values 

(95% and 91% respectively) and efficiency (92%) of the dot-ELISA were high. 

NMP-52 tumor marker detection was correlated with the response to 

radiotherapy. 

Conclusion: Detection of the urinary NMP-52 marker using dot-ELISA would be 

helpful in rapid diagnosis and follow up patients with bladder cancer. 


240 MCM AS A USEFUL BIOMARKER FOR GRADED 

DIFFERENTIATION IN UROTHELIAL CANCER 

N. Narine 1 , D.N. Rana 1 , G. Stewart 2 , B.M. Thottakam 3 , A. Donnini 3 , A. Wilson 4 , 

B. Turner 5 , W. Burrill 6 , K. Saeb-Parsy 7 , D. Harrison 8 

1 Cytology Department, Central Manchester Hospitals NHS Foundation, 

Manchester, UNITED KINGDOM, 2 Department of Urology and Edinburgh 

Urological Cancer Group, Western General Hospital, Edinburgh, UNITED 

KINGDOM, 3 Research and Development, Cytosystems Ltd, Aberdeen, UNITED 

KINGDOM, 4 Department of Computing, Robert Gordon University, Aberdeen, 

UNITED KINGDOM, 5 Department of Urology, Homerton University Hospital NHS 

Foundation Trust, London, UNITED KINGDOM, 6 University of Bradford, Ethical 

Tissue, Bradford, UNITED KINGDOM, 7 Department of Urology, Addenbrooke’s 

Hospital, Cambridge, UNITED KINGDOM, 8 Director of Laboratory Medicine, Nhs 

Lothian, Royal Infirmary of Edinburgh, Edinburgh, UNITED KINGDOM 

Introduction: Urine cytology has been used in the diagnosis of urothelial cancer 

(UC) for high grade and in-situ lesions. Sensitivity for low grade carcinoma is 

problematic leading to both over and under diagnoses. To reduce this dilemma a 


number of biomarkers have been tried with varying results. Minichromsome 

Maintenance Proteins (MCMs) play a regulatory role in eukaryotic DNA 

replication and are expressed as normal cells progress from G0 into G1/S phase 

of the cell cycle. Over expression has been demonstrated in neoplasia in many 

sites including urothelium. The aim of the study was to evaluate use of MCM2 

in urine cytology and tissue specimens to differentiate high grade from low 

grade UC. 

Methods: epithelial cells retrieved from urine samples of 114 patients were stained 

with MCM2 using an immunocytochemical technique. MCM2 was similarly applied 

to 13 archived urothelial tumour specimens. MCM positive cell counts were 

performed on all cytology specimens and results correlated to the different grades of 

UC. Tumor specimens were evaluated for MCM2 staining intensity, distribution and 

percentage of positive cells. 

Results: 26 of 114 patients were found to have UC. In cytology specimens the 

MCM mean and median cell counts increased with grade of cancer (Table 1). 

Non cancerous urines had mean and median MCMs of 232 and 14 

respectively. In urothelial solid tissue tumour specimens, MCM2 showed 

strong nuclear staining characteristics where the percentage of positive cells 

was related to tumor grade. The lowest percentage MCM stained cells was 

noted in grade 1 tumours, the highest percentage in grade 3. Staining 

distribution was predominantly in the basal zone of the urothelium in grade 1 

tumours, basal and middle epithelial zones in grade 2, and more diffusely 

distributed in grade 3 tumours. Table 1: MCM cell count with increasing grade 

of urothelial cancer. 

Grade 

Number 

of cases Mean 

Standard 

Deviation Median 

G1 3 3207 5026 600 

G2 9 8177 15975 3000 

G3 13 14795 14167 10000 

CIS 1 40000 - 40000 

Total 26 

Conclusion: MCM2 could be a useful biomarker in differentiating low grade from 

high grade UC both in cytology and biopsy tissue specimens. 


242 GENERATION OF A SOMATIC MUTATIONS BRAF 

IN MELANOMA DATABASE (WWW. 

SOMATICMUTATIONS-BRAFMELANOMA.NET) 

H. Linardou 1 , S. Murray 2 , F. Siannis 3 , D. Bafaloukos 1 

1 1st Department of Medical Oncology, Metropolitan Hospital, Athens, GREECE, 

2 Oncology, GeneKor SA, Athens, GREECE, 3 Department of Mathematics, 

University of Athens, Athens, GREECE 

Background: Somatic mutations of BRAF are correlated with improved outcomes in 

patients with melanoma treated with the anti-BRAF tyrosine kinase inhibitor 

Vemurafenib. The frequency and spectrum of these mutations is currently not well 

classified within melanoma or amongst melanocytic lesions. A systematic 

compendium of BRAF mutations in human tumors may better clarify issues related 

to incidence and spectrum. 

Methods: Using a broad search string including “BRAF”, “RAS”, “Melanoma”, 

“Cancer” and associated synonyms we identified 3,879 abstracts from inception 

through to 23/12/2011 in MEDLINE (PubMed). Sub-searches for Melanoma or 

melanocytic lesions (naevi) identified 175 articles. Data extraction was conducted 

by two investigators. Fields included: incidence, melanoma subtype, AJCC stage, 

gender, sun exposure, site, Breslow status amongst others split by mutational 

status. 

Results: With a total of 14,019 screened patients, 5,606 were identified to harbor 

a mutation (40.0%). Cumulative data indicated that there were no significant 

differences according to gender (55.2% male, 57.8% female), ulceration (46.4% 

with, 44.6% without), stage (46.6% I, 52.7% IV), metastatic and primary 

cutaneous melanoma (39.7% vs 41.1%). Differences in incidence were seen 

between sun exposure (36.2% exposed, 44.8% non-), site [except ocular/ uveal] 

(10.5% mucosal, 44.6% other) and between benign and Spitz nevi (52.5% 

versus 5.5%). 

Conclusions: This compendium of datasets allows the investigation of several trends 

in melanoma and melanocytic lesions. Technical and intra-inter-tumor 

dis-concordance issues were highlighted. A comprehensive analysis of 

clinicopathological correlations will be presented. 



243 IMPACT OF PIK3CA MUTATIONS AND P95HER2 EXPRESSION 

ON THE OUTCOME OF HER2-POSITIVE METASTATIC BREAST 

CANCER PATIENTS TREATED WITH A TRASTUZUMAB-BASED 

THERAPY 

I. Stasi 1 , A. Fontana 2 , G. Allegrini 3 , C. Mazzanti 4 , S. Lucchesi 5 , E. Bona 2 , 

I. Ferrarini 2 , B. Salvadori 2 , A. Falcone 6 , K. Zavaglia 4 

1 Medical Oncology, Azienda Ospedaliero Universitaria S.Chiara, Pisa, ITALY, 

2 Oncologia Medica Ii, Polo Oncologico, Ospedale S. Chiara, AOUP, Pisa, ITALY, 

3 Medical Oncology Unit, Pontedera Hospital, Pontedera, ITALY, 4 University of 

Pisa and Pisa University Hospital, Section of Molecular Pathology, Division of 

Surgical, Molecular, and Ultrastructural Pathology, pisa, ITALY, 5 Oncologia 

Medica, Ospedale "F. Lotti", Pontedera, ITALY, 6 Oncologia, Trapianti E Nuove 

Tecnologie In Medicina, Polo Oncologico - Azienda Ospedaliero-Universitaria 

Pisana - Istituto Toscano Tumori, Pisa, ITALY 

Background: Currently, no biomarkers of Trastuzumab (T) clinical resistance have 

been validated. The aim of this pilot study was to evaluate the impact of PIK3CA 

mutations and p95HER2 (pHER2 truncated form) expression on the efficacy of a 

T based-therapy in a HER2-positive metastatic breast cancer (MBC) patients (pts). 

Methods: 107 HER2-positive MBC pts, treated in the last 10 years, were evaluated. 

Median age was 54 years (25-79); ECOG performance status was 0 in 56% of pts; all 

pts received several lines of treatment including T; biomarkers molecular analysis was 

performed in 70 tumor specimens. The IHC expression of p95HER2 was evaluated 

by a monoclonal antibody that specifically recognizes only the HER2 external 

domain; the HER2 integrity was defined by the presence of a homogeneous 

membrane staining (moderate or intense) in at least 30% of the cells, otherwise the 

HER2 was defined as p95HER2 positive. PIK3CA mutations in exons 9 and 20 were 

detected by automated sequencing. The molecular data were correlated to Time to 

progression (TTP) of the first line treatment including T and the Overall Survival 

(OS) by using the Kaplan-Meir method and the log-rank-test. 

Results: p95HER2 positive pts and PIK3CA mutations in exon 9 or 20 were detected 

in 42% and 22% of tumor specimens, respectively. p95HER2 positive tumors showed 

a shorter TTP and OS that did not reach statistical significance; PIK3CA mutations 

correlated with a worse TTP (median 7,6 vs 11,3 months) and OS (median 20,1 vs 

41,0 months, p= 0,046). 

Conclusions: These preliminary results suggest a possible role of PIK3CA mutational 

status in predicting the outcome of MBC pts treated with T. 


244 DETECTION OF CIRCULATING TUMOUR CELLS IN 

PERIPHERAL BLOOD OF PATIENTS WITH MALIGNANT 

PLEURAL MESOTHELIOMA 

J. Raphael 1 , C. Massard 2 ,F.Farace 3 , G. Le Teuff 4 , J. Margery 5 , F. Billiot 3 , 

B. Besse 1 , A. Hollebecque 2 , J. Soria 1 , D. Planchard 1 

1 Thoracic Group, Inserm U981, Institut Gustave Roussy, Villejuif, FRANCE, 

2 Department of Medical Oncology, Institute Gustave Roussy, Villejuif, FRANCE, 


4 Department of Statistics and Epidemiology, Institut Gustave Roussy, Villejuif, 

FRANCE, 5 Pulmonary Department, Percy Hospital, Paris, FRANCE 

Background: The independent prognostic value of Circulating Tumour Cells (CTC) 

level has been demonstrated in patients with advanced breast, prostate and colorectal 

cancers. There is currently few data on Malignant Pleural Mesothelioma (MPM) and 

CTC. We investigated whether the presence of CTC was correlated with prognosis 

factors and treatment efficacy in MPM patients. 

Methods: Patients (pts) with MPM in progression were enrolled before any new line of 

treatment in a prospective monocentric study. CTC detection was made on peripheral 

blood samples (7.5ml) using the “CellSearch” assay according to the manufacturer’s 

protocol. The correlation between the presence of CTC and known worse prognosis 

factors was assessed using the X2 test. Progression Free Survival (PFS) was defined as the 

time from diagnosis until first progression (PFS1) and as the time from CTC measure 

until progression or death (PFS2). Comparison of PFS according to CTC detection was 

performed using the log-rank test. The cut-off date of the analysis was May 2012. 

Results: Twenty-five MPM pts with a median follow-up of 4.2 months were included. 

The median age and sex ratio (M/F) were 65 years old and 2.1 respectively. Eighty-four 

percent of pts had an epithelioid MPM, 64% had a stage 4 disease, 60% had an anemia, 

a thrombocytosis or a leucocytosis at the time of inclusion. All pts except one had an 

Eastern Cooperative Oncology Group performance status (ECOG) < 2 and 64% received 

more than one line of chemotherapy. CTC were detected in 48% of pts (n = 12) with a 

median level of 1.5 (0-36). No significant correlation was observed between the presence 

of CTC and a metastatic disease, an ECOG ≥ 1, the presence of anaemia, leucocytosis, or 

thrombocytosis and the non-epithelioid type. The median PFS (1 and 2) were 17.9 (95% 

CI= [10.1-24.0]) and 2.5 (95%CI= [1.3-3.5]) months respectively. CTC detection was 

not a significant predictor of PFS 2 (p = 0.27). 

Conclusion: Detection of CTC has been done in a small cohort of MPM patients. It 

could be an important tool though we were not able to demonstrate a significant 

prognostic value or a difference in PFS between CTC levels. The "Cellsearch" assay 

might not be the best technique to use in this setting. Further analyzes are in 

progress, and updated results will be presented in September. 



east cancer, early stage 

246O DOSE-DENSE SEQUENTIAL ADJUVANT CHEMOTHERAPY 

WITH EPIRUBICIN, PACLITAXEL AND CMF VERSUS 

EPIRUBICIN, CMF AND WEEKLY DOCETAXEL OR 

PACLITAXEL FOLLOWED BY TRASTUZUMAB FOR ONE YEAR 

IN PATIENTS WITH EARLY BREAST CANCER 

G. Fountzilas, H. Gogas, N. Pavlidis, A. Eleftheraki, D. Skarlos, A. Koutras, 

E. Timotheadou, C. Papandreou, D. Pectasides, M. Dimopoulos 

Data Office, Hellenic Cooperative Oncology Group (HeCOG), Athens, GREECE 

Background: Dose-dense sequential chemotherapy including anthracyclines and 

taxanes has been well established in the adjuvant setting of high-risk operable breast 

cancer. However, the preferable taxane and optimal schedule of administration have 

not been defined, as yet. 

Patients and methods: From July 2005 until November 2008, 1,001 patients (990 

eligible) were randomized to receive 3 cycles of epirubicin 110 mg/m 2 followed by 3 

cycles of paclitaxel 200 mg/m 2 followed by 3 cycles of CMF (cyclophosphamide 840 

mg/m 2 ; methotrexate 57 mg/m 2 ; fluorouracil 840 mg/m 2 ) with G-CSF support 

(Group A; 333 patients) or to 3 cycles of epirubicin followed by 3 cycles of CMF, as 

in Group A, followed 3 weeks later by 9 weekly cycles of docetaxel 35 mg/m 2 (Group 

B; 331 patients) or 9 weekly cycles of paclitaxel 80 mg/m 2 (Group C; 328 patients). 

Radiation and hormonal therapy were given after the completion of chemotherapy. 

Trastuzumab was administered for 1 year to all HER2-positive patients post 

radiation. 

Results: At a median follow-up of 60 months, 123 patients had documented disease 

relapse (51 in Group A, 37 in Group B and 35 in Group C) and 81 deaths (30 in 

group A, 22 in group B and 29 in group C) had been observed. The 3-year 

disease-free survival (DFS) rate was 86%, 91% and 89%, with overall survival (OS) 

rates of 96%, 97% and 96%, respectively. No differences were found in DFS or OS 

between the three treatment groups (log-rank, p = 0.38 and p = 0.48, respectively). 

The most frequently reported severe adverse events were neutropenia (29% vs 27% vs 

24%, p = 0.31) and leucopenia (12% vs 13% vs 10%, p = 0.66). Febrile neutropenia 

occurred in fifty patients (6%, vs 5% vs 5%, p = 0.81). Severe mucositis was more 

frequent in Group B (3% vs 6% vs 1%, p = 0.001), while severe neuropathy was more 

frequent in Group A (4% vs 0% vs 1%, p < 0.001). 

Conclusions: No significant differences in DFS and OS between the three regimens 

were identified. Taxane regimen and schedule of administration preferentially 

influenced the type of severe toxicities. HER2-positive patients demonstrated 

comparable 3-year DFS and OS rates with those reported in other similar studies. 


247O PR THE DISCREPANCY BETWEEN HIGH PATHOLOGICAL 

COMPLETE RESPONSE (PCR) RATE AND LOW BREAST 

CONSERVING SURGERY (BCS) FOLLOWING 

NEOADJUVANT THERAPY: ANALYSIS FROM THE 

NEOALTTO TRIAL (BIG 1-06) 

C. Criscitiello1 , H.A. Azim, Jr2 , D. Agbor-Tarh3 , E. De Azambuja4 , M. Piccart5 , 

J. Baselga6 , H. Eidtmann7 , S. Di Cosimo8 , I. Bradbury3 , I.T. Rubio9 1 2 

Department of Medicine, European Institute of Oncology, Milan, ITALY, Breast 

Cancer Translational Research Laboratory, Institute Jules Bordet, Brussels, 

BELGIUM, 3 Frontier Science, Frontier Science, Kincraig, UNITED KINGDOM, 

4 5 

Breast Data Centre, Institute Jules Bordet, Brussels, BELGIUM, Institut Jules 

Bordet, Institut Jules Bordet, Brussels, BELGIUM, 6 Hematology/Oncology, MGH 

Cancer Center, Massachusetts General Hospital, Boston, MA, UNITED STATES 

OF AMERICA, 7 Klinik für Gynäkologie und Geburtshilfe, Universitäts Frauenklinik 

Kiel, Kiel, GERMANY, 8 Medical Oncology, Istituto Nazionale Tumori, Milan, ITALY, 

9 

Department of Gynecology, Hospital Universitario Vall d’Hebron, Barcelona, 

SPAIN 

Background: The NeoALTTO trial showed that paclitaxel plus lapatinib and 

trastuzumab nearly doubles the rate of pCR compared to paclitaxel combined with 

either drug alone (51.3% vs 29.5% vs 24.7%). However, this high pCR rate did not 

translate into a higher rate of BCS, which was around 40% across the 3 arms. We 

investigated different factors that may have affected the choice of surgery. 



Patients and methods: In the NeoALTTO trial, patients (pts) with HER2+ breast 

cancer were randomized to either trastuzumab, lapatinib or their combination 

concomitantly with paclitaxel prior to surgery. The 1 ry endpoint was pCR, defined as 

the absence of invasive cancer in the breast at the time of surgery. Here, we 

investigated the association between achieving pCR, and type of surgery, age, 

histology, grade, tumor size, ER status, multicentricity, response to therapy and the 

country where the treatment was given. 

Results: 429 pts were eligible for the analysis (26 have been excluded as they did 

not undergo breast surgery), of whom 160 (37%) achieved a pCR. 242 (57%) 

and 187 (43%) pts had mastectomy and BCS, respectively. Mastectomy was more 

frequent if the patient was < 50, if treated in developing country, if the tumor 

was multicentric, >5 cm, or ER-. All pts diagnosed with lobular cancer (n = 17) 

underwent mastectomy regardless of pCR. 68 pts had a radiological complete 

response, yet 36 of those (53%) were subjected to mastectomy (25 pts (70%) 

achieved a pCR). Of the 128 pts considered for BCS at screening, only 95 (74%) 

had a conservative surgery and rates were similar according to pCR status (79% 

in pCR vs. 72% in no pCR). Conversely, 30% of pts initially evaluated as 

inoperable or requiring mastectomy had a BCS. 

Conclusion: Tumor characteristics prior to neoadjuvant therapy appeared to play 

a main role in deciding the type of surgery irrespective of response. This may 

deny a large fraction of women the chance of preserving their breast. These 

results should be taken into account in addressing the criteria for BCS after 

neoadjuvant therapy. GSK distributed the study drugs and provided financial 

support to the NeoALTTO trial, but imposed no restriction to the current 

analysis. 

Disclosure: E. De Azambuja: advisory board from GSK; honoraria from Roche. 

M. Piccart: Consulting/advisory role/honoraria from SanofiAventis, Amgen, 

Bayer, Bristol Myers Squibb, Roche, Glaxo Smith Kline, Boehringer, PharMar. S. 

Di Cosimo: Speaker for GSK. All other authors have declared no conflicts of 

interest. 

248O ANALYSIS OF CORRELATION BETWEEN WEIGHT AT 

DIAGNOSIS, WEIGHT GAIN AFTER BREAST CANCER 

TREATMENT AND RECURRENCE IN WOMEN WITH EARLY 

STAGE BREAST CANCER (EBC) 

P. Fedele 1 , A. Nacci 2 , A.M. Lapolla 1 , L. Orlando 1 , P. Schiavone 1 , A. Marino 1 , 

M. Cinefra 1 , A. Ardizzone 1 , M. De Pasquale 1 , S. Cinieri 1 

1 Ospedale Perrino, Oncologia Brindisi, Brindisi, ITALY, 2 U.O.C. Oncologia, 

Ospedale A. Perrino, Brindisi, ITALY 

Background: Overweight at the time of EBC diagnosis has been linked frequently to 

poorer survival in most studies and some evidence suggests that women who gain 

weight after breast cancer diagnosis are at increased risk of cancer recurrence and 

death. Most previous studies on this topic have relied on retrospective chart reviews. 

The aim of this prospective, observational, single-center study is to determine 

whether weight at diagnosis and weight gain after EBC treatment are predictive of 

BC recurrence. 

Methods: From August 1997 to March 2012, the study included a total of 520 EBC 

patients (stage I-IIIa). We assessed weight and body mass index (BMI = kg/m 2 )at 

baseline (≤ 1 month after surgery) and 24 months after completion of treatment 

(chemotherapy ± radiotherapy). The chi square test (X 2 ) was conducted to determine 

if a significant correlation exists between BC recurrence and 3 categories of BMI at 

diagnosis (lean weight: BMI 25) and BC 

recurrence and weight changes after EBC treatment (loss of

Table: 248O 

249PD PROTEOMIC PREDICTORS OF OUTCOME AFTER ADJUVANT 

ANTI-HORMONAL THERAPY FOR HORMONE 

RECEPTOR-POSITIVE BREAST CANCER 

B. Hennessy1 , D. Faratian2 ,Z.Ju3 , A. Lluch-Hernandez4 , S. Myhre5 ,A. 

M. Gonzalez-Angulo6 , J. Overgaard7 , J. Alsner7 , A. Borresen-Dale5 , G.B. Mills8 1 2 

Medical Oncology, Beaumont Hospital, Dublin, IRELAND, Division of Pathology 

& Edinburgh Breakthrough Research Unit, University of Edinburgh, Edinburgh, 

UNITED KINGDOM, 3 Biostatistics and Applied Mathematics, MD Anderson 

Cancer Center, Houston, TX, UNITED STATES OF AMERICA, 

4 

Serv. Hematologia Y Oncologia Medica, Hospital Clinico Universitario de 

Valencia, Valencia, SPAIN, 5 Department of Genetics, Institute for Cancer 

Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, 

Norway, Oslo, NORWAY, 6 Breast Medical Oncology, MD Anderson Cancer 

Center, Houston, TX, UNITED STATES OF AMERICA, 7 Department of 

Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, DENMARK, 

8 

Systems Biology, MD Anderson Cancer Center, Houston, TX, UNITED STATES 

OF AMERICA 

Purpose: This study aimed to identify predictive proteomic biomarkers of outcome 

in women with estrogen and/or progesterone receptor-positive (ER/PR-positive) 

breast cancer after adjuvant tamoxifen, with sufficient power to alter patient 

management. 

Methods: Using reverse phase protein arrays (RPPA), 140 antibodies were applied to 

a training set of 197 ER/PR-positive breast cancers to identify predictors. An 

algorithm was developed that predicted patient outcomes using a subset of 

antibodies. Since RPPA is a useful exploratory tool but does not lend itself as a 

practical clinical tool to assay validated biomarkers, quantitative immunofluorescence 

for selected proteins was applied to 313 ER/PR-positive breast cancers (test set) for 

validation. Seventy-seven other ER/PR-positive cancers with transcriptional profiling 

data were used to compare the performance of the proteomic biomarkers and 

established genomic predictors. All patients were treated with adjuvant tamoxifen 

after loco-regional therapy. 

Results: Two different combinations (4-protein/3-protein models) of four proteins 

(CCNB1/PAI1/PR/BCL2), subdivided lymph node-negative breast cancer patients 

into low-, medium- and high-risk groups with significantly different 10-year 

recurrence-free survival. The proteomic markers predicted 10-year distant 

metastasis-free survival in lymph node-negative patients in the test set in the low-, 

medium- and high-risk groups as follows: 0.9, 0.8, 0.7 (4-protein model (p = 0.05)), 

0.91, 0.8, 0.74 (3-protein model (p = 0.004)), with 74%/64% patients in the low-risk 

groups, respectively. The proteomic models outperformed clinical variables and 

genomic predictors in multivariate analyses. 

Conclusion: This study validates proteomic biomarkers that can be assayed in a 

practical inexpensive manner using immunofluorescence to identify lymph 

node-negative ER/PR-positive patients with excellent outcomes after adjuvant 

tamoxifen. 


250PD CLINICAL SIGNIFICANCE OF MICRORNA EXPRESSION AS A 

PROGNOSTIC FACTOR IN EARLY N+ BREAST CANCER (BC) 

E. Ciruelos 1 , G.A. De Velasco 1 , A. Gamez 2 , C. Castañeda 3 , J. Sepúlveda 1 , 

I. Ghanem 1 , H. Cortes-Funes 1 , J.A. Fresno 4 

1 Medical Oncology, University Hospital 12 de Octubre, Madrid, SPAIN, 

2 Medicine, Autonoma University, Madrid, SPAIN, 3 Medical Oncology, Instituto de 

Enfermedades Neoplasicas, Lima, PERU, 4 Medical Oncology, University Hospital 

LaPaz, Madrid, SPAIN 

Background: MicroRNAs (miRNAs) are small noncoding RNA molecules that 

post-transcriptionally regulate gene expression. In the present study, we describe 

miRNA expression in early node-positive BC and identify a 8-miRNA score that 

could contribute to prognosis assessment. 

Methods: First, microarray analysis was performed using RNA samples extracted 

from primary breast cancer. The expression of miRNAs was analyzed by RT-qPCR 

using the TaqMan Arrays from Applied Biosystems. After a suitable normalization of 

the 677 miRNAs analyzed, 96 presented a good correlation between their expression 


Body Mass Index 

At diagnosis Changes after BC treatment 

30 kg/m 2 

Loss >1 kg/m 2 

Loss


252PD META-ANALYSIS OF PROSPECTIVE EUROPEAN STUDIES 

ASSESSING THE IMPACT OF USING THE 21-GENE 

RECURRENCE SCORE ASSAY ON CLINICAL DECISION 

MAKING IN WOMEN WITH ER-POSITIVE, HER2-NEGATIVE 

EARLY STAGE BREAST CANCER 

J. Albanell 1 , S. Holt 2 , J. Gligorov 3 , W. Eiermann 4 , C. Svedman 5 

1 Medical Oncology, University Hospital del Mar, Barcelona, SPAIN, 2 Surgical 

Department, Prince Philip Hospital, Llanelli, UNITED KINGDOM, 3 Medical 

Oncology Department, Tenon Hospital, Paris, FRANCE, 4 Medical, 

Interdisciplinary Oncology Center, Munich, GERMANY, 5 Medical, Genomic 

Health Inc, Redwood City, CA, UNITED STATES OF AMERICA 

Background: The Oncotype DX® Recurrence Score is a validated assay to help 

inform the appropriate treatment of estrogen receptor-positive (ER+), early stage 

breast cancer. Adjuvant treatment traditions vary significantly among different 

countries. Prospective studies assessing the impact of the Oncotype DX test on 

adjuvant treatment decisions have been performed in several European countries. 

This is a meta-analysis of these studies. 

Methods: Four prospective studies assessing the impact of using the Recurrence 

Score result on clinical decision making in patients with node negative and pN1 (mi) 

disease were identified. Node positive patients were excluded. The identified studies 

had a similar study design with consecutive patients and treatment recommendations 

before and after having the Recurrence Score results were recorded. In three of the 

studies, medical oncologists completed questionnaires regarding their confidence in 

their recommendation before and after knowing the patient’s Recurrence Score result. 

The final results of the studies in Germany, Spain and the UK have been presented 

and final data from the French study will be presented at ASCO 2012. 

Results: A total of 589 patients with node negative or pN1 (mi) ER pos HER2 

negative early breast cancer were included in the four identified studies. Overall, 45% 

(range 36-52%) of patients in these studies were recommended chemo-endocrine and 

55% endocrine treatment alone. After having the Recurrence Score result, 47% (range 

38-60%) of patients recommended chemotherapy were changed to endocrine 

treatment alone and 17% (range 11-22%) of those recommended endocrine 

treatment alone were recommended chemo-endocrine treatment. There was a 

significant improvement in physician confidence in treatment recommendations 

when using the assay. 

Conclusion: Using Oncotype DX® is associated with a significant change in 

treatment decisions and a reduction in chemotherapy use in studied European 

countries despite differences in therapeutic traditions. The consistency of the results 

from different countries underlines the tests utility. 

Disclosure: J. Albanell: Participated advisory board (Genomic Health). S. Holt: 

Participated as a speaker, and in advisory board for Genomic Health. J. Gligorov: 

Has participated as speaker for Genomic Health. W. Eiermann: Participated as 

speaker and in advisory board for Genomic Health. C. Svedman: Employee and 

stocks in Genomic Health. 

253PD SECRAB (SEQUENCING OF CHEMOTHERAPY AND 

RADIOTHERAPY IN ADJUVANT BREAST CANCER) 

COSMESIS RESULTS 

I.N. Fernando 1 , S.J. Bowden 2 , C. Brookes 2 , A.M. Brunt 3 , M. Churn 4 , 

J.H. Steven 1 , R.K. Agrawal 5 ,D.Rea 2 

1 Cancer Centre, University Hospitals Birmingham NHS Foundation Trust, 

Birmingham, UNITED KINGDOM, 2 CRCTU, School of Cancer Sciences, 

University of Birmigham, Birmingham, UNITED KINGDOM, 3 The Cancer Centre, 

University Hospital North Staffs, Stoke-on-Trent, UNITED KINGDOM, 4 Deansley 

Centre, New Cross Hospital, Wolverhampton, UNITED KINGDOM, 5 Department 

of Oncology, Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UNITED 

KINGDOM 

Background: SECRAB, a randomised trial comparing sequential (Seq) to 

synchronous (Syn) chemo-radiation using a CMF or Anthracycline-CMF regimen, 

demonstrates reduces local recurrence rates after Syn treatment for early breast 

cancer (EBC) (Fernando 2011 EJC:47 S2). Cosmesis study results are presented. 

Table: 253PD 

Cosmesis, n 

(%) 

Telangiectasia, 

n (%) 

Methods: 2296 women were randomised and cosmesis was assessed in 382. Cosmesis 

and telangiectasia were assessed as excellent, good, moderate and poor for patients 

having wide local excision (WLE) while telangiectasia alone was assessed for those 

having mastectomy. Photographs were taken for 301 patients for blinded 

independent review using a consensus method (Haviland 2008 Clin Oncol 20:497). 

Patient perception was assessed using EORTC BR23 quality of life questionnaire 

(Q 39-42). Assessments were made at baseline, 1, 2 and 5 years post surgery. 

Results: The results of clinician assessed cosmesis and telangiectasia are shown 

below. There was no statistically significant difference between the arms. Data on 

independent assessment of change in breast appearance after WLE was available for 

145 (98%) patients. Minimal, mild and marked changes were observed in 70, 29 and 

1% of patients respectively for the Syn arm and 72, 28 and 0% for the Seq arm. 

There was no difference between treatment arms (OR, mild/marked vs minimal, 1.10, 

95% CI 0.54-2.26, p = 0.8). There was no change in patient’s perception of their 

breast appearance (baseline vs. final assessment questionnaire). 

Conclusions: There was no significant difference in cosmesis or telangiectasia 

between the two arms as assessed by the clinician or by independent photographic 

review. There was no difference in patient perception of breast appearance. Contrary 

to the result of the main study, which showed a borderline significant worsening of 

telangiectasia in the Syn arm, no such difference was seen in the cosmesis study. Syn 

chemo-radiation reduces local recurrence in EBC without affecting cosmesis. 


254PD PATHOLOGICAL COMPLETE RESPONSE TO TRASTUZUMAB 

SUBCUTANEOUS FIXED-DOSE FORMULATION IN THE 

HANNAH STUDY: SUBGROUP ANALYSIS OF PATIENT 

DEMOGRAPHICS AND TUMOR CHARACTERISTICS AND 

INFLUENCE OF BODY WEIGHT (BW) AND SERUM TROUGH 

CONCENTRATION (CTROUGH) OF TRASTUZUMAB 

B. Melichar 1 , D. Stroyakovskiy 2 , J.S. Ahn 3 , M.V. Kopp 4 , V. Srimuninnimit 5 , 

G. Kunz 6 ,J.Li 7 , T. van der Horst 8 , S. Muehlbauer 8 , C. Jackisch 9 

1 Oncology, University Hospital Olomouc Palacky University, Faculty of Medicine, 

Olomouc, CZECH REPUBLIC, 2 Chemotherapy, Moscow City Oncology Hospital 

62, Moscow, RUSSIAN FEDERATION, 3 Haematology/Oncology, Samsung 

Medical Centre, Seoul, KOREA, 4 Chemotherapy, Samara Regional Clinical 

Cancer Center, Samara, RUSSIAN FEDERATION, 5 Department of Medicine, 

Siriraj Hospital, Bangkok, THAILAND, 6 Oncology, St Johannes Hospital, 

Dortmund, GERMANY, 7 Clinical Pharmacology, Genentech Inc, South 

San Francisco, CA, UNITED STATES OF AMERICA, 8 Clinical Science, 

F. Hoffmann La-Roche Ltd, Basel, SWITZERLAND, 9 Oncology, Klinikum 

Offenbach GmbH, Offenbach, GERMANY 

Background: Intravenous (IV) trastuzumab (H) is the standard of care for 

HER2-positive breast cancer. The Phase III, neoadjuvant-adjuvant HannaH study 

(Jackisch et al. EBCC 2012) demonstrated the non-inferiority of H subcutaneous 

(SC) vs. H-IV with respect to serum C trough of H and pathological complete response 

(pCR), with comparable safety profiles for the two formulations. The aim of the 

presented analyses was to determine whether pCR rates (H-SC vs. H-IV) were 

consistent across subgroups, and to investigate the relationship of pCR with BW and 

serum Ctrough of H. 

Methods: Subgroup analyses of pCR were performed in the per-protocol population 

(PPP) based on patient demographics (race, age [< 65 and ≥ 65 years]) and disease 

characteristics (breast cancer type/subtype/histological grade, hormone receptor 

status). Further analyses, including multiple logistic regression (MLR), investigated 

the relationship of pCR rate with BW and serum C trough of H. Covariates in the MLR 

model included treatment arm, serum Ctrough, BW, and all interactions between 

covariates, in order to account for the different dosing schemes (BW-based vs. fixed 

dosing). 

Results: pCR subgroup analyses showed that the numerically higher pCR rate point 

estimate in H-SC vs. H-IV was reflected in the majority of subgroups, with all 

confidence intervals for the rate difference (SC-IV) containing ‘0‘. The findings of the 

PPP analysis were supported by results obtained in the ITT population. Further 

analyses, including MLR, showed that neither BW nor serum Ctrough of H correlated 

with pCR rates in either treatment arm. 

Category Odds Ratio (OR) 

Excellent Good Moderate/Poor (95% CI) 

Excellent/good vs 

Seq Syn Seq Syn Seq Syn 

moderate/poor 

14 (23) 15 (21) 37 (60) 37 (51) 11 (18) 21 (29) 1.87, (0.82,4.27) p = 0.1 

79 (68) 99 (62) 33 (28) 54 (34) 4 (4) 7 (4) 1.28, (0.37,4.48) p = 0.7 


Conclusions: BW and serum Ctrough of H did not impact on efficacy (pCR). The 

600 mg fixed dose of H-SC is efficacious irrespective of BW. This finding supports 

H-SC as a treatment alternative to the registered IV formulation. 

Disclosure: B. Melichar: Prof. Melichar has participated in advisory board 

meetings and received honoraria from F. Hoffmann-La Roche Ltd. J. Li: Jing Li 

is an employee of F. Hoffmann La-Roche Ltd, and owns stock in Roche 

Holdings. T. van der Horst: Tina van der Horst is an employee of 

F. Hoffmann-La Roche Ltd. S. Muehlbauer: Susanne Muehlbauer is an employee 

of F. Hoffmann-La Roche Ltd and owns stock in Roche Holdings. C. Jackisch: 

Christian Jackisch has participated in advisory board meetings for 

F. Hoffmann-La Roche Ltd. All other authors have declared no conflicts of 

interest. 

255PD CORRELATION BETWEEN CIRCULATING TUMOR CELLS 

(CTCS), PET/CT RESPONSE AND PATHOLOGICAL 

COMPLETE RESPONSE (PCR) IN PRIMARY HER2-POSITIVE 

(HER2+) BREAST CANCER PATIENTS: A SUB-STUDY FROM 

THE NEOALTTO TRIAL 

H.A. Azim, Jr 1 , F. Rothe 1 , C.M. Aura 2 , M. Bavington 3 , M. Maetens 1 , G. Rouas 1 , 

E. De Azambuja 4 , C. Sotiriou 1 , S. Di Cosimo 5 , M. Ignatiadis 1 

1 Breast Cancer Translational Research Laboratory, Institute Jules Bordet, 

Brussels, BELGIUM, 2 Molecular Pathology Laboratory, VHIO, Barcelona, SPAIN, 

3 Programming, Frontier Science, Kincraig, UNITED KINGDOM, 4 Breast Data 

Centre, Institute Jules Bordet, Brussels, BELGIUM, 5 Medical Oncology, Istituto 

Nazionale Tumori, Milan, ITALY 

Background: Although CTC detection has been studied in patients receiving 

preoperative chemotherapy, fewer data exist for preoperative chemotherapy combined 

with anti-HER2 agents. Here, we report a sub-study of CTC detection within the 

NeoALTTO trial. 

Methods: NeoALTTO is a randomized phase III trial in which patients with 

primary HER2+ breast cancer were randomized to trastuzumab, lapatinib or 

their combination for 6 weeks followed by the addition of paclitaxel for 12 

weeks prior to surgery. Participation in the CTC sub-study was optional. Blood 

samples were prospectively collected at baseline, after 2 weeks of anti-HER2 

treatment alone and prior to surgery. A total of 22.5mL of blood was reduced to 

7.5mL using a modified ficoll procedure that was then processed using 

CellSearch®. Evaluation of HER2 expression in CTCs was performed using the 

CellSearch® HER2 profiling kit. CTCs with HER2 staining intensity of 2 + /3+ 

were considered as HER2+. Associations between CTC detection and primary 

tumor characteristics, pCR and PET/CT response (at week 2 & 6) were assessed 

using the chi-square test. 

Results: Out of 455 patients randomized, samples for CTC analysis were 

available for 51 (11%) patients from 16 sites, of whom 11 (21%) had ≥ 1 CTC/ 

22.5ml in at least one time point (Table 1). At baseline, week 2 and surgery, 

we detected ≥1 CTC/22.5ml in 5/46 (11%), 4/41 (10%), and 5/31 (16%) 

patients with evaluable samples respectively. HER2+ CTCs were still detectable 

after 18 weeks of preoperative treatment with anti-HER2 agents plus paclitaxel 

in 3/31 (10%) patients. No significant association was observed between CTC 

detection (either at baseline or week 2 or surgery), and clinicopathologic 

characteristics, pCR (p = 0.36) or PET/CT response at week 2 (p = 0.34) or week 

6 (p = 0.90). 

Conclusion: CTC detection does not appear to be associated with pCR in patients 

receiving preoperative anti-HER2 agents plus paclitaxel, acknowledging the lack of 

power within our study. 

Patient Treatment arm 

CTC / HER2+ CTC 

(number per 22.5mL) pCR 

Baseline Week 2 Prior to Surgery 

1 L 0 0 2 /2 NO 

2 L NA 2 /2 2 /2 NO 

3 L 1 /1 0 0 NO 

4 L NA 4 /3 NA NO 

5 T 0 1 /0 0 NO 

6 T 65 /52 0 2 /1 NO 

7 L+T 0 0 1 /0 NO 

8 L + T 1 /0 0 NA NO 

9 L + T 1 /0 0 0 YES 

10 L + T 1 /0 0 NA YES 

11 L + T 0 1 /0 1 /0 YES 

L: lapatinib; T: trastuzumab; NA: not applicable. 



256P FIVE YEARS FOLLOW UP OF PROSPECTIVE RANDOMIZED 

STUDY TO ASSESS THE EFFECT OF PROPHYLACTIC 

CRANIAL IRRADIATION IN HIGH RISK BREAST CANCER 

PATIENTS 

E.A. Elkhouly, H.M. Metwally, T.A. Hashem, K.K. Abdalaziz 

Clinical Oncology Dep., Menoufia University Hospital, Menoufia, EGYPT 

Aim: To assess the effect of Prophylactic cranial irradiation (PCI) in patients with 

high risk early breast cancer with primary end point CNS relapse where the 

secondary end point is to assess the toxicity and QOL. At 5 years the aim is to assess 

CNS relapse, Overall Survival, NCF and QOL re-evaluation. 

Methods: It is 5 years re-evaluation of 62 patients with high risk invasive breast 

cancer. After adjuvant treatment, patients were randomized into: arm I who didn’t 

receive PCI, arm II who received PCI. Patients were collected from Jan. 2005 and 

followed up till Dec. 2007 with re-evaluationone on April 2012. After a signed 

informed consent, the whole brain received 240 cGy per fraction, once daily, five 

times per week to a total dose of 2400cGy. Brain assessment by MRI studies as a 

baseline before PCI, at 6 months in the first year, and then annually for at least 

5 years, and Assessment of Neuro-cognitive Function (NCF): basically before PCI, 

6 months, 1 year after PCI using Mini-Mental State Exam (MMSE). Health related 

quality of life was assessed for all patients with the Functional Assessment of Cancer 

Therapy-Brain (FACT-Br) Questionnaire Version 4, before PCI and 3 weeks, three 

months after PCI. Patients were followed up till April 2012. 

Results: At the end of the study, there is no incidence of CNS metastasis in PCI arm 

compared to 3.2% in control arm. In PCI arm, there is no statistical difference in 

MMSE (before and after PCI, p = 0.619 ) and QOL assessment. At 5 years, in PCI 

arm, the incidence of CNS metastasis is 3.2 (only one case) while in Control arm it is 

12.9 (four cases). In PCI arm,there was no statistically significant change in NCF and 

QOL in all items of FACT-Br questionnaire except in additional concerns (p 0.05, Log rank of 5 years survival = 0.59 

Conclusion: The rationale behind PCI is to control or eradicate undetectable 

micro-metastases before they become clinically significant without inducing severe 

adverse effects .PCI associated with decreased incidence of CNS metastases with 

tolerated toxicities and did not negatively affect patient survival. This may be 

translated into therapeutic gain at least for this short follow up period which 

warrants further evaluation after a longer follow up period. 


257P EGFR AND P53 EXPRESSION IN ANDROGEN RECEPTOR 

(AR)-POSITIVE, TRIPLE NEGATIVE BREAST CANCER (TNBC) 

A. Gucalp 1 , G. Gupta 2 , S. Patil 3 , Y.H. Wen 4 , M. Akram 4 , E. Brogi 4 , S. Powell 2 , 

A. Ho 2 , C.A. Hudis 1 , T.A. Traina 1 

1 Dept of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, 

UNITED STATES OF AMERICA, 2 Radiation Oncology, Memorial Sloan-Kettering 

Cancer Center, New York, NY, UNITED STATES OF AMERICA, 3 Biostatistics and 

Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY, UNITED 

STATES OF AMERICA, 4 Dept of Pathology, Memorial Sloan-Kettering Cancer 

Center, New York, NY, UNITED STATES OF AMERICA 

Background: TNBCs are a heterogeneous group characterized by lack of ER/PR/ 

HER2 expression. Doane et al described a subgroup of TNBC associated with 

AR-dependent growth. While expression of EGFR and p53 are common in TNBC, 

their role in AR+ TNBC is less clear. We report the rates of EGFR and p53 

expression and clinicopathologic features of AR+ TNBC from a retrospective cohort 

at MSKCC. 

Methods: We identified 1,032 patients (pts) with resectable, TNBC (ER/PR < 1%; 

HER2 < 2 + /FISH < 2) who had surgery at MSKCC (1998-2006). Exclusions: 

neoadjuvant chemotherapy, prior XRT, inflammatory/metastatic BC. TMAs were 

constructed from 210 readily available primary tumors (> 1 cm) with each tumor 

represented by 3 cores. AR was tested with DAKO Clone AR441, dilution (dil) 1:500; 

ratio of DAB nuclear staining to hematoxylin signal >1 SD above mean was defined 

as AR+. EGFR and p53 were tested with Thermo-Scientific Clone EP38Y, dil 1:50 

and DAKO Clone D07, dil 1:50 respectively. Scoring: 0-1+ negative, 2-3+ positive. 

Fisher’s exact test used to evaluate correlation between AR with EGFR and p53. RFS 

and OS evaluated using Kaplan-Meier methods. Clinicopathologic variables by AR 

status were compared using Chi-square/t-tests. 

Results: 166 pts had adequate cores for AR testing. 10% were AR+ (17/166). 160 pts 

were evaluable for EGFR and 164 pts for p53. Median (med) followup: AR + =6 years 

(y), AR- = 5.6y. Adjuvant chemotherapy received: AR+ 82%, AR- 87%, P = 0.40. 

EGFR was expressed more frequently in AR- than AR+ TNBCs (111/143 (78%) vs 9/ 

17 (53%); P =0.04). p53 expression was similar in AR- and AR+ TNBC (82/147 

(56%) vs 7/17 (41%); P =0.30). Clinicopathologic variables based on AR and EGFR 

status appeared similar. 3y RFS and OS data are below. 

Conclusion: Consistent with published reports, loss of AR expression correlates with 

EGFR expression. In contrast, no association was observed with p53 and AR. These 



data are hypothesis generating regarding the mechanism of interaction of AR and 

EGFR in TNBC. 

-3 year RFS (95% CI) -3 year OS (95% CI) 

AR+ 76% (47-90) 88% (59-97) 

AR- 81% (74-87) 93% (87-96) 

AR+ EGFR+ (n = 9) 67% (39-98) 78% (36-94) 

AR+ EGFR- (n = 8) 88% (39-98) 100% 

AR- EGFR+ (n = 111) 82% (73-88) 91% (84-95) 

AR_ EGFR- (n = 32) 81% (61-92) 97% (80-100) 


258P PROGNOSTIC FACTORS IN EARLY-STAGE TRIPLE NEGATIVE 

BREAST CANCER (TNBC): THE LIMITS OF CLINICAL AND 

PATHOLOGICAL FEATURES 

N. Pécuchet 1 , M. Le Frère Belda 2 , T. Popovski 3 , S. Haouas 1 , F. Chamming’S 4 , 

F. Lécuru 5 , S. Oudard 1 , J. Medioni 1 

1 Dept. Medical Oncology, Hopital European George Pompidou, Paris, FRANCE, 

2 Dept. Pathology, Hopital European George Pompidou, Paris, FRANCE, 

3 Gynecology, Necker University Hospital, Paris, FRANCE, 4 Dept. Radiology, 

Hopital European George Pompidou, Paris, FRANCE, 5 Dept. Gynecologic 

Surgery, Hopital European George Pompidou, Paris, FRANCE 

Background: Triple negative breast cancer (TNBC) patients (pts) is an 

heterogeneous population regarding prognostic. Therefore, clinical and histological 

features were evaluated in a large monocenter cohort of patients treated for localized 

TNBC to identify good-prognostic TNBC. 

Methods: All consecutive early-stage TNBC (ER 0%, PR 0%, HER2 neg) patients treated 

at European Georges Pompidou Hospital, Paris, France, between 2000 and 2011 were 

included. Records were reviewed for demographic, clinical and pathological data. 

Prognostic factors were determined using univariate and multivariate stepwise log-rank 

analysis on disease-free survival (DFS) and overall survival (OS). 

Results: This analysis included 128 women with early-stage TNBC. Clinical and 

histological characteristics are summarized below. After a median follow-up of 37 

months 36 relapses and 19 deaths were observed. The 3-years recurrence rate was 

30% (95%CI 22-40) in the whole population. For DFS, bad prognostic factors in 

univariate analysis were: large tumor size (T3-4), node involvement (N1-3), node 

capsular effraction, lymphovascular invasion (LVI) and high grade (SBR 2-3). 

Multivariate analysis identified tumor size (T3-4) (HR 3.70, 95%CI 1.61-8.52) and 

LVI (HR 2.87, 95%CI 1.39-5.93) as independent factors. The 3-years recurrence rate 

remained high (20%, 95%CI 10-34) in patients with two good prognostic factors 

(T0-2 and no LVI). For OS, bad prognostic factors significant in univariate and 

multivariate analysis were: node capsular effraction (HR 3.57, 95%CI 1.17-10.92) and 

LVI (HR 3.43, 95%CI 1.18-9.92). 

Conclusions: In this early-stage TNBC series, LVI was a bad prognostic factor of 

relapse and death. However, the 3-years recurrence rate remained high in patients 

with good prognostic features. Therefore, new biomarkers are mandatory for a better 

stratification of this heterogeneous population. 

Clinical and histological characteristics 

N (128pts) % 

Median age (yrs) 

Histological type 

56 range 22-88 

Invasive ductal carcinoma 123 96 

Invasive lobular carcinoma 

Tumor stage 

5 4 

T0-T2 105 82 

T3-T4 

Node stage 

23 18 

N0 97 76 

N1-3 

Node capsular effraction 

31 24 

pos 14 11 

neg 111 87 

NE 

Tumor grade (SBR) 

3 2 

1 8 6 

2-3 107 84 

NE* 

Lymphovascular invasion (LVI) 

13 10 

pos 34 27 

neg 74 58 

NE** 20 16 

*Due to neoaduvant chemotherapy **Due to small biopsies. 

Disclosure: S. Haouas: Grant from Association pour la Recherche en Thérapeutiques 

Innovantes en Cancérologie (ARTIC). All other authors have declared no conflicts of 

interest. 

259P CLINICAL BEHAVIOR AND PROGNOSIS OF DIFFERENT 

IMMUNOHISTOCHEMISTRY-DETECTED SUBTYPES OF 

INVASIVE BREAST CANCER: A MONOINSTITUTIONAL SERIES 

A. Ferro 1 , C. Eccher 2 , R. Triolo 1 , A. Caldara 1 , M.C. Di Pasquale 1 , S. Moroso 1 , 

L. Russo 1 , M. Barbareschi 3 , E. Galligioni 1 

1 Medical Oncology, Santa Chiara Hospital, Trento, ITALY, 2 E-health, FBK, Trento, 

ITALY, 3 Pathology, Santa Chiara Hospital, Trento, ITALY 

Background: Invasive breast cancer (IBC) is a heterogeneous disease. Gene 

expression profiling has identified several biologically distinct subtypes of IBCs. As 

proposed by Cheang et al, immunohistochemical (IHC) markers can be used as a 

surrogate for the molecular classification of IBC. 

Purpose: To evaluate different clinical behavior, relationship with other 

clinical-pathological features and survival outcomes of patients (pts) with different 

subtypes of IBC as classified using IHC markers. 

Methods: We evaluated 3461 IBC pts treated from 1995 to 2008 classified as: luminal 

A (ER and PR + , HER2- and Ki67< 14%), luminal B (ER and/or PR + , HER2- and 

Ki67 ≥ 14%), luminal C (ER and/or PR + , HER2 + , any Ki67), HER2+ (ER and PR, 

HER2 + , any Ki67), triple negative-TN (ER and PR-, HER2-, any Ki67). Log-rank 

test and Cox regression model were performed to evaluate the impact of IHC 

subtypes on overall survival (OS), Event Free Survival (EFS) and their correlation 

with other known prognostic factors. 

Results: We identified 909 (26.4%) luminal A, 1722 (49.9%) luminal B, 325 

luminal C (9.4%), 209 (5.7%) HER2+ and 296 (8.6%) TN. Median age was 61 

years. Luminal A was more frequently associated with older age, smaller size, 

negative axilla involvement, low grade (p < 0.001). There were 644 (18,6%) events 

(local and distant relapses, contralateral and second tumors): 100 in luminal A 

(11%), 334 in luminal B (19.4%), 62 in luminal C (19%), 66 in HER2+ (31%) 

and 84 in TN (28%). Different subtypes showed preferential sites of first local or 

distant relapses: luminal A had more bone and loco-regional and less visceral 

relapses than other subtypes. Median disease free interval (DFI) was longer in 

luminal A (60.3 months) than in luminal B (39.1 m), C (27.8 m), HER2 (30.8 

m) and TN (23.3 m). At median follow up of 77 months, EFS and OS were 94.0 

and 92.1% in luminal A, 86.2 and 82.7% in luminal B, 86.2 and 86.8% in 

luminal C, 72.7 and 72.7% in HER2 + , 78.0% and 73.9% in TN (p < 0.001). 

Luminal A presented the best prognosis among other luminal subtypes. 

IHC-based subtypes prognosis (EFS and OS) was independent of nodal status, 

grading, tumor size and age. 

Conclusions: In our experience IHC-based classification appared to be useful to 

divide IBCs in different biological entities. Its application could help the tailoring of 

adjuvant therapies improving patient outcomes. 


260P PERITUMORAL VASCULAR INVASION AS PRINCIPAL 

ISTOLOGICAL PROGNOSTIC FACTOR IN TNBC 

G. Rizzo, V. Fregoni, G. Daprada, L. Pavesi, G. Gallizzi, I.T. Lorenzetti, 

R. Tancredi, E. Ferraris, A. Pagani 

Oncology Division, Fondazione Salvatore Maugeri, Pavia, ITALY 

Purpose: Triple-negative breast cancers (TNBC) is a specific histological subclass 

of breast cancer that has gained attention in recent years for its clinical and 

molecular heterogeneity with still no evidence of an optimal therapeutic strategy. 

Aim of this study is to identify clinical and pathological features of TNBC 

reviewed in our center and try to figure out prognostic factors that can drive 

therapeutic approach. 

Methods: In this retrospective study we reviewed 127 cases of TNBC (median 

Age 59) that underwent surgical treatment from 2003 to 2008 analyzing the 

outcome (in terms of Disease Free Survival) in relation to clinical and 

pathologic features. 

Results: Univariate analysis performed on the entire cohort revealed that the cha 

Staging (P

261P BREAST CANCER SUBTYPES AND OUTCOME IN ELDERLY 

BREAST CANCER PATIENTS AGED 70 YEARS AND OLDER 

R. Königsberg 1 , G. Pfeiler 2 , N. Hammerschmid 2 , T. Klement 2 , A. Brunner 3 , 

C. Dittrich 1 

1 Ludwig Boltzmann Institute for Applied Cancer Research (lbi-acr Vienna) – LB 

Cluster Translational Oncology, 3rd Medical Department – Centre for Oncology 

and Haematology, Kaiser Franz Josef-Spital, Vienna, AUSTRIA, 2 Department of 

Obstetrics and Gynaecology, Medical University of Vienna, Vienna, AUSTRIA, 

3 Department of Obstetrics and Gynaecology, Landesklinikum Thermenregion 

Moedling, Mödling, AUSTRIA 

Background: Tumor characteristics and patterns of recurrence in luminal A, luminal 

B, Her2 pos and triple negative breast cancer (bc) patients (pts) 70 years and older 

are still an area of uncertainty. In this investigation clinical pathological 

characteristics, disease recurrence and death were analysed according to the 4 bc 

subcategories and age in pts ≥70 years. 

Methods: Data of 274 elderly bc pts (≥70 years of age) diagnosed between 1998 and 

2004 were retrospectively analyzed by computer based chart information. Baseline 

tumor characteristics, patient demographics and patterns of recurrence were 

compared between luminal A, luminal B, Her2 pos and triple negative bc pts and 3 

age categories (70-75, 76 -80, ≥ 81 years). 

Results: Mean age was 76.95 years and mean time of follow-up was 52.23 months 

(range 0-144 months). Overall, recurrences were detected in 18.4% of pts. At the end 

of follow-up 69.0% of pts were alive, 15.0% and 16.1% died from bc and from other 

causes, respectively (p = 0.745). Median overall survival (OS) was 114.1 months (95% 

confidence interval 100.3 -181.7 months). 41.1%, 20.4%, 16.1% and 12.5% of patients 

had luminal A, luminal B, Her2 pos and triple negative bc, respectively. No 

significant differences were found regarding recurrences according to bc subtypes (p 

= 0.241). Triple negative bc had a significant shorter OS compared to lumianl A, 

luminal B and Her2 pos bc (72.7 months vs 124.1, 119.4 and 105.0 months, 

respectively (p < 0.001)). Overall, 21.5% of pts received no therapy. Pts aged ≥81 

years (15.8%) received significantly less (p < 0.01) chemo-/antihormonal therapy 

compared to pts ≤80 years. Pts aged 70-75 years (42.7%) had significantly (p = 

0.032) more recurrences compared to pts 76 years or older. Pts aged 70 - 75, 76 - 80 

and ≥ 81 years had median OS of 116.9, 115.4 and 73.1 months. 

Conclusions: Pts aged 70-75 years had significantly more recurrences; perhaps due 

to their lower risk of death from other causes. These data emphasize the necessity to 

foresee all bc subgroups of the elderly for adjuvant treatment irrespective of age but 

carefully considering co-morbidities, performance status and life-expectancy. 


262P OUTCOMES OF ETHNIC MINORITY GROUPS WITH 

NODE-POSITIVE, NON-METASTATIC BREAST CANCER IN A 

TERTIARY REFERRAL CENTRE IN SYDNEY 

S.H. Lim 1 , J. Descallar 2 , P. Sayaloune 3 , G. Papadatos 4 , P. De Souza 1 , 

G. Delaney 4 

1 Medical Oncology, Liverpool Hospital, Liverpool, NSW, AUSTRALIA, 2 Statistics, 

Ingham Institute for Applied Medical Research, Liverpool, NSW, AUSTRALIA, 

3 Data Management, Liverpool Hospital, Liverpool, NSW, AUSTRALIA, 4 Radiation 

Oncology, Liverpool Hospital, Liverpool, NSW, AUSTRALIA 

Background: South-Asian women in Europe are significantly younger than 

non-Asian at diagnosis, present with larger tumours, and have higher mastectomy 

rates. In Australia, there is a paucity of data on early breast cancer in ethnic minority 

groups. The aim of this study is to examine racial differences in tumour 

characteristics and outcome in early node-positive breast cancer patients at Liverpool 

and Macarthur Cancer Therapy Centres in New South Wales (NSW), Australia. 

These tertiary centres service 20% of the NSW population, with 40% from a 

non-English speaking background. 

Methods: A retrospective review of patients referred to Liverpool and Macarthur 

with node-positive non-metastatic breast cancer diagnosed before November 2006. 

Variables included tumour size, number of positive nodes, histological grade, 

hormone receptor status, age at diagnosis, country of birth and treatment. Outcome 

was disease-free survival. Women of Australian/New Zealand or European 

backgrounds were classed as Caucasian; women from Indian sub-continent, East 

Asia, South-east Asia, Middle East and Polynesia were classed as Asian. The study 

was approved by ethics. 

Results: There were 644 patients, with median follow up of 6.1 years. The proportion 

of Australian/New Zealand, European, South/East/South-east Asian, Middle-Eastern 

and Polynesian populations comprised 48%, 20%, 12%, 6% and 2% respectively. 

Women with Asian backgrounds were significantly younger at presentation (48 vs 55 

years), and more likely to undergo mastectomy (46% vs 34%) and chemotherapy 

(82% vs 68%) than non-Asians. Tumour grade, stage and receptor status were not 

statistically different between the two groups. Median age, tumour size, number of 

nodes involved, disease-free survival and overall survival, respectively, was 52.5 years, 

22mm, 2/19, 148 months and 177 months. Multivariate analysis identified risk 

factors of tumour size > 2cm (hazard ratio HR = 1.51, confidence interval CI 


1.06-2.41, p value 0.02), > 10 lymph nodes involved (HR = 2.64, CI 1.75-3.98, p-value 


Results: Of the 400 patients, 139 (34.8%) were under 35 years old and 261 (65.2%) 

were 35-39 years old with a median follow-up of 72.5 months (range,1-211months). 

Postoperative radiation therapy was associated with longer DFS (HR, 0.130; 

p = 0.007) and OS (HR, 0.017; p = 0.001) in multivariate analysis of the 400 patients. 

However, there were no significant differences in clinicopathological factors, DFS and 

OS between under 35 years and those 35-39 years of age. 

Conclusion: Our results suggested that postoperative radiation therapy improved the 

prognosis in young breast cancer patients. However, age at diagnosis was not 

associated with DFS or OS in patients under 40 years. Therefore, we recommend 

patients under 40 years to receive unified therapy. 


265P BREAST CANCER IN YOUNG WOMEN IN INDIA 

S.P. Deshmukh 1 , A.D. Mane 1 , B.P. Zade 2 , S.P. Sane 3 

1 Surgical Oncology, Ruby Hall Clinic, Pune, INDIA, 2 Radiation Oncology, Ruby 

Hall Clinic, Pune, INDIA, 3 Statistics, Ruby Hall Clinic, Pune, INDIA 

Background: The incidence of breast cancer is rising in India. It presents at a 

younger age in Indian population as compared to the western countries. Aims and 

objectives: This is a retrospective study of all breast cancer patients less than 40 years 

of age treated in single tertiary care center from June 2006 to June 2011. The aim 

was to assess the factors that may influence clinical outcome and prognosis including 

demographics, clinical characteristics and pathological findings and treatment. 

Materials and methods: Clinical data was collected from medical records. Variables 

like age, stage at presentation, surgery type, chemotherapy, radiation, tumour size, 

grade, nodal status, perinodal extension, lymphovascular emboli, ER, PR and Her2 

neu status were analyzed in relation to outcome. 

Results: Out of 613 breast cancer patients, 91 were under 40 years of age 

corresponding to an incidence of 14.8%. Median tumour size was 3 cm and lymph 

node positivity was 56.9%. Lymphovascular emboli was positive in 42 patients 

(48.8%) and perinodal extension was positive in 36 patients (41.8%). Thirty patients 

(34.8%) were ER positive, while 39 patients (45.3%) were PR positive. Her 2 neu 

receptors were positive in 20 patients (23.2%). Thirty nine patients were triple 

negative (45.3%). The median follow up period was 27 months with the DFS being 

73.2% and OS being 87.2%. In univariate analysis, factors significantly associated 

with survival were stage at presentation, presence of lymhovascular emboli, presence 

of perinodal extension and grade of the tumour. 

Conclusions: Breast cancer in India is seen in younger patients and most of these are 

triple negative breast cancers. Patients with breast cancer below 30 years of age are 

surviving more than the age group of 30 to 40 years. Survival of young breast cancer 

patients in India is comparable to western studies. 


266P TUMOR CHARACTERISTICS, TREATMENT AND OVERALL 

SURVIVAL (OS) IN BREAST CANCER PATIENTS (PTS) OVER 80 

YEARS: A COHORT FROM A SINGLE INSTITUTION 

C. Baldini 1 , A. Donnadieu 1 , A. Kramar 2 , V. Servent 1 , J. Bonneterre 3 

1 Breast Cancer, Centre Oscar Lambret, Lille, FRANCE, 2 Biostatistics, Centre 

Oscar Lambret, Lille, FRANCE, 3 Breast Cancer, Centre Oscar Lambret, 

Université Lille Nord de France, Lille, FRANCE 

The incidence rate of breast cancer in elderly women over 75 years old is 220 per 

100000 in France and is likely to increase in the future. We studied the impact of 

tumor and treatment characteristics on overall survival. 

Patients and methods: Data were collected for 208 non metastatic breast cancer pts 

over 80 years (213 tumors), treated from January 2000 to December 2009. 

Pathological data were obtained on a biopsy or on mastectomy specimens if patients 

had not received presurgical treatment. 

Statistical methods: Survival rates were estimated by Kaplan-Meier method. Tests 

were performed with the logrank test. Five year relative survival rates were estimated 

by Ederer2 method. 

Results: Median age at diagnosis was 83 years (80-95). 29% tumors were T1, 58% T2 

and 15% T3, 141 (66%) were ductular, 34 (16%) lobular and 38 (18%) had another 

histological type. SBR grade (I/II/III) was 22%/49%/29% and unspecified in 42 

(20%). 167 pts (80%) were ER + , 129 (62%) PR + ; 40 (19%) ER–PgR–, and 171 

(81%) ER + PgR+. HER2 status, known in 126 pts, was positive in 18 (14%), and 

negative in 108 (86%). Ten pts were strictly triple negative (5%)(ER = 0, PgR = 0, 

HER2 = 0). Ki 67 among 59 tumors was over 15% in 43 pts (73%). Forty-nine pts 

(23%) had conservative surgery, 80 mastectomy (38%), 72 axillary dissection (34%) 

and 30 sentinel lymph node biopsy (14%). Axillary lymph node metastasis were 

observed in 52 pts (38%). 195 pts received hormonotherapy (68 as adjuvant therapy, 

89 before surgery or alone), 72 patients radiotherapy (37%), 5 chemotherapy (3%) 

and 1 had trastuzumab (0.5%). Median overall survival was 59 months. Median 

follow up was 76 months. The only significant prognostic factors on overall survival 

were age (48 months over 83 years, 79 before), ER and PgR status. ER positive and 

negative pts had a median survival of 60 months and 32 months respectively. Five 

year relative survival rate was 63%. 

Conclusion: Even if most pts had a ER+ tumor, the rate of poor prognosis factors is 

high: 29% SBR III, 14% HER2 positive, 5% triple negative and 73% had a KI67 index 

over 15%. Despite these poor prognostic factors, survival was rather long with a 

median OS of 5 years. 


267P DISEASE-FREE SURVIVAL ACCORDING TO PATHOLOGIC 

RESPONSE AND P95-HER2 IN THE CHER-LOB 

NEOADJUVANT STUDY OF CHEMOTHERAPY PLUS 

TRASTUZUMAB, LAPATINIB OR COMBINED TRASTUZUMAB 

AND LAPATINIB IN HER2+ OPERABLE BREAST CANCER 

V. Guarneri 1 , G. Bisagni 2 , A. Bottini 3 , K. Cagossi 4 , A. Frassoldati 5 , F. Piacentini 1 , 

C. Holford 6 , J. Bruey 7 ,R.D’Amico 1 , P.F. Conte 1 

1 Dept. of Hematology/Oncology, Modena University Hospital, Modena, ITALY, 

2 Department of Oncology, Arcispedale S Maria Nuova, Reggio Emilia, ITALY, 

3 Unit, Istituti Ospitalieri di Cremona, Cremona, ITALY, 4 Medical Oncology, 

Ospedale Ramazzini, Carpi, ITALY, 5 Dept of Clinical Oncology, Azienda 

Ospedaliera di Ferrara St. Anna, Ferrara, ITALY, 6 Research & Development, 

GlaxoSmithKline, Stockley Park, Uxbridge, UNITED KINGDOM, 7 Biomarker 

Research & Development, BioTheranostics, Inc, San Diego, CA, UNITED 


Introduction: This is a randomized phase II trial of preoperative sequential 

taxanes-anthracyclines in combination with trastuzumab, lapatinib, or combined 

trastuzumab and lapatinib in HER2 positve operable breast cancer. We previously 

reported that dual HER2 blockade with trastuzumab and lapatinib significantly 

increased the pathologic complete response (pCR) rate. The aim of the present 

post-hoc analysis is the evaluation of disease free survival (DFS) according to pCR, 

p95-HER2 expression, and treatment arm. 

Methods: 121 patients were randomly assigned to weekly paclitaxel followed by 

FE75C combined with trastuzumab (arm A, n= 36), lapatinib (arm B, n= 39), or 

trastuzumab and lapatinib (arm C, n= 46). P95-HER2 expression was measured by 

IHC (bioTheranostics, Inc. San Diego, CA). Patients were classified as having a 

p95-HER2 positive tumor in case of strong immunostaining in ≥80% of cells. pCR 

was defined as disappearance of infiltrating disease in breast and axillary nodes. DFS 

was calculated from the date of surgery to the date of recurrence (local or distant) or 

death. 

Results: Overall, pCR was observed in 32% of patients. The pCR rates per treatment 

arm were 25% in arm A, 26.3% in arm B, and 46.7% in arm C (Arm C vs combined 

Arms A + B: p = 0.018). Thirty-five patients (29%) resulted p95-HER2 positive. At 

the time of the present analysis, 17 DFS events have been reported. The expression of 

p95-HER2 was not significantly correlated with the probability of relapse, overall and 

per treatment arm. The risk of relapse was significantly lower for patients achieving a 

pCR (hazard ratio 0.09, p = 0.019). The 3-yr DFS rate was 88% in arm C vs 72% in 

arms A + B. 

Conclusions: The achievement of a pCR in breast and axillary nodes is predictive of 

outcome in HER2 positive breast cancer patients treated with neoadjuvant therapy. 

This is consistent with other neoadjuvant studies. p95-HER2 appears to be neither 

predictive nor prognostic in this patient population. The combination arm resulted 

in a trend for a better DFS, probably reflecting the higher pCR rate observed. 

Sponsored by GlaxoSmithKline. 

Disclosure: C. Holford: Employer GlaxoSmithKline. J. Bruey: Employee at 

bioTheranostics, Inc. P.F. Conte: GlaxoSmithkline: research funds, speaker’s bureau, 

advisor. All other authors have declared no conflicts of interest. 

268P PROLIFERATION DETERMINED BY KI67 MARKER DEFINES 

PATHOLOGICAL COMPLETE RESPONSE IN A DOSE-DENSE 

NEOADJUVANT CHEMOTHERAPY SCHEDULE IN LOCALLY 

ADVANCED BREAST CANCER PATIENTS 

M.Y. Plata Fernandez 1 , A. Sanchez-Muñoz 2 , A. Jaén-Morago 1 , 

M. Lomas-Garrido 1 , M. Fernández 1 , C. Llacer 2 , M. Fernández 1 , N. Ribelles 2 , 

E. Alba-Conejo 2 , P. Sánchez-Rovira 1 

1 Oncología Médica, Complejo Hospitalario de Jaén, Jaén, SPAIN, 2 Oncology, 

Hospital Universitario Virgen de la Victoria, Malaga, SPAIN 

Background: The value of Ki67 proliferation biomarker during neoadjuvant 

chemotherapy (NC) is less clear than with neoadjuvant endocrine therapy. We study 

the role of proliferation according to Ki67 marker measured by 

immunohistochemistry (IHC) as a predictive factor of pathological complete 

response to NC. 

Methods: From May 2002 to June 2005, 127 pts diagnosed as stage II-III, including 

inflammatory tumors, breast cancer patients (pts) received one of the 2 NC regimens 

every 2 weeks with prophylactic growth factor support. Study A: adriamicin 40mg/ 

m2 d1 plus P 150mg/m2-G 2000 mg/m2 d2 for 6 cycles (n = 54); study B: epirubicin 


90 mg/m2-cyclophophamide 600 mg/m2 d1 for 3 cycles, followed by a second 

sequence with paclitaxel (P) 150 mg/m2- gemcitabine (G) 2500 mg/m2 d1 +/trastuzumab 

2mg/kg/wk according to status Her2 (n= 73). In study A pts did not 

receive trastuzumab regardless of Her2 status. Ki67 was centrally assessed by IHC 

(Master Diagnostica clon SP6). Tumors were considered to have high proliferation 

rates (Ki67) if ≥ 20% of cell nuclei stained positive. Median age was 48 years. Her2+ 

was observed in 31%, HR negative 34%, grade III 46% and high Ki67 47%. 

Pathological complete response (pCR) defined as absence of invasive cells in breast 

and lymph node was achieved in 35 pts (28%). Univariate and multivariate logistic 

regression models were used to study the association of each clinical-pathological 

variable with pCR. 

Results: High Ki67 was the main predictive factor of pCR to NC. In the univariate 

analysis histological grade (p = 0.001), HR (p < 0.001), Ki67 (p = 0.001) and p53 (p 

< 0.001) were statistically associated with pCR. A multivariate logistic regression 

showed than only high Ki67 (p = 0.02; OR = 5.5 CI95% 1.2- 18) and HR (p = 0.045; 

OR = 0.25 CI95% 0.05-0.97) were predictive for pCR. 

Conclusion: High proliferation determined by ki67 marker is an independent 

predictive factor for pCR in locally advanced breast cancer patients treated in two 

dose-dense NC schedules. 


269P NEOADJUVANT CHEMOTHERAPY IN OPERABLE BREAST 

CANCER: DATA FROM THE ASTER STUDY (AT FOR 3 CYCLES 

FOLLOWED BY CMF FOR 3 CYCLES) 

E. Puma1 , P. Mariani1 , S. Damian1 , M.C. Dazzani1 , E. De Benedictis1 , M. Parati2 , 

L. Sica2 , A. Tessari1 , F.G.M. De Braud1 , A. Moliterni1 1 

Medical Oncology, Istituto Nazionale dei Tumori di Milano, Milan, ITALY, 

2 

Oncologia Medica, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, 

ITALY 

Background: The ECTO-1 study demonstrated the efficacy of concurrent 

doxorubicin and paclitaxel (AT) for 4 cycles followed by cyclophosphamyde/ 

methotrexate/fluorouracil (CMF) for 4 cycles in the neoadjuvant treatment of 

operable breast cancer (Gianni L. et al. Clin Cancer Res 2005). With the purpose of 

ameliorating the tolerability of the regimen, we designed the ASTER study to reduce 

both the duration and the total dose of neo-/adjuvant treatment with AT followed by 

CMF. Herein we report on the efficacy of the neoadjuvant portion of the trial. 

Methods: A total of 70 patients with operable breast cancer were enrolled between 

September 2008 and November 2011. Median age was 51 years (range 32-73); 74% of 

patients presented with hormone receptor positive (HR +) and 26% of patients with 

hormone receptor negative (HR -); 8% of patients presented HER2 overexpression/ 

amplification; most of the patients had cT2 (96%); half presented with node 

involvement cN1 (54%). Patients were treated with neoadjuvant Adriamycin (60 mg/ 

mq) + Paclitaxel (200 mg/mq) q21 for 3 cycles followed by CMF i.v. 1, 8q28 for 3 

cycles. 

Results: The pathological complete response (pCR), defined as the absence of 

neoplastic cells in the primary tumor was obtained in 11.5% of cases; tnpCR, defined 

as the absence of neoplastic cells in the primary tumor and in nodes, was obtained in 

10% of cases. Overall, 29% of patients with triple negative breast cancer achieved a 

pCR, while only 6% of HR positive breast cancer achieved a pCR. 

Conclusions: Neoadjuvant treatment with three cycles of AT followed by three cycles 

of CMF is effective in patients with operable breast cancer. The rate of pCR matched 

perfectly with the data obtained with the original schema AT x 4 followed by CMF x 

4 in 69 patients treated with primary chemotherapy at our institute, within the 

ECTO-1 study. The ASTER study sets the base for developing a less toxic 

chemotherapy regimen sequential and non-cross resistant containing anthracycline 

and taxane for the treatment of operable breast cancer. 


270P LONG-TERM OVERALL SURVIVAL (OS) AND DISEASE-FREE 

SURVIVAL (DFS) ACCORDING TO PCR IN BREAST CANCERS 

SUBTYPES: LUMINAL A AND B, TRIPLE NEGATIVE AND 

HER2 + , TREATED BY NEAODJUVANT CHEMOTHERAPY 

(NCT) 

C. Abrial 1 , Q. Wang-Lopez 1 , M. Mouret-Reynier 2 , P. Dubray-Longeras 2 , I. van 

Praagh-Doreau 2 , X. Durando 2 , P. Gimbergues 3 , J. Nabholtz 2 , F. Penault-Llorca 4 , 

P. Chollet 2 

1 Clinical Research, Centre Jean Perrin, Clermont-Ferrand, FRANCE, 2 Oncology 

Department, Centre Jean Perrin, Clermont-Ferrand, FRANCE, 3 Surgery 

Department, Centre Jean Perrin, Clermont-Ferrand, FRANCE, 4 Dept. de 

Pathologie, Centre Jean Perrin, Clermont-Ferrand Cedex, FRANCE 

Background: In breast cancer, positive Hormone Receptors (HR) constitute a 

favourable prognostic factor whereas HER-2 overexpression is an adverse prognostic 

factor associated with a more aggressive tumor. In a retrospective database of 282 


breast cancer patients diagnosed from 1991 to 2006, we analysed the overall survival 

(OS) and the disease-free survival (DFS) of 4 phenotypes: HR-/HER-2- (triple 

negative, TN); HR + /Ki-67 < 20% (luminal A), HR + /Ki-67 > 20% or Her2+ (luminal 

B) and HER-2 overexpression (HER-2 + /HR-). 

Patients and methods: Median diameter of the invasive tumour was 40 mm 

[10-130]. 231 (82%) patients had a canalar carcinoma. 33% of the tumours were 

grade III SBR. Patients received either an anthracycline-based chemotherapy (47%), a 

taxane-based chemotherapy (21%) or a combination of both (32%). The median 

number of NCT courses was 6 [1-8] followed by a surgery for 97.6%, a radiotherapy 

for 93%, an adjuvant chemotherapy for 20% and/or an hormonotherapy for 56%. 

Only 5 patients received adjuvant herceptin for 1 year. In the different subgroups, we 

had 123 luminal A tumors (44%), 67 luminal B tumours (24%), 21 Her2+ tumours 

(7%) and 71 TN tumours (25% of patients). 

Results: According to tumour’s phenotype, the pCR (Chevallier’s classes1+2) 

was: 3.3% for luminal A, 16.6%, for luminal B, 33.3% for Her2+ HR- and 26% 

for triple negative tumours. On 2 April 2012, the median follow-up was 148 

months (range, 63- 252). We evaluated the OS and the DFS in the four 

subgroups, at 10 years. -For TN: OS and DFS were 58.5% and 56.2%. -For 

luminal A: OS and DFS were 76.1% and 64.7%. -For luminal B: OS and DFS 

were 81.7% and 72.4%. -For Her2 + HR- subgroup: OS and DFS were 64.5% and 

56.4%. pCR is an objective method improvement after NCT, but it is variable 

among subsets, and may constitute an acquired prognostic factor. However, it 

was much smaller in hormonal-positive tumors subsets and may there not be an 

endpoint per se. We observed a significant improvement of DFS and OS for 

patients who reached a pCR only in TN breast cancer. However Her2 subset 

may be too small to reach significance here. 

Conclusion: OS and DFS were better in luminal A and B subgroups. Conversely OS 

and DFS decreased for TN and Her2+ subtypes. When TN breast cancer patients 

reached a pCR, OS and DFS were significantly improved. 


271P ADDITIONAL SAFETY RESULTS OF HANNAH: A PHASE III 

RANDOMISED, OPEN-LABEL, INTERNATIONAL STUDY OF 

THE SUBCUTANEOUS FORMULATION OF TRASTUZUMAB (H) 

IN HER2-POSITIVE EARLY BREAST CANCER PATIENTS 

C. Jackisch 1 , M. Dank 2 , G. Frasci 3 , K.H. Park 4 , R.I. Lopez 5 , M. Johnston 6 , 

D. Heinzmann 7 , H. Weber 7 , G. Ismael 8 

1 Department of Obstrics and Gynecology, Klinikum Offenbach GmbH, 

Offenbach, GERMANY, 2 Semmelweis Egyetem, Radiológiai és Onkoterápiás 

Klinika, Budapest, HUNGARY, 3 Division of Medical Oncology A, National Tumor 

Institute, Naples, ITALY, 4 Department of Internal Medicine, Korea University 

Anam Hospital, Seoul, KOREA, 5 Medical Oncology Department, National 

Oncology Institute, Panama, PANAMA, 6 Genentech Inc, South San Francisco, 

CA, UNITED STATES OF AMERICA, 7 Clinical Science, F. Hoffmann-La Roche 

Ltd, Basel, SWITZERLAND, 8 Medical Oncology, Fundation Amaral 

CarvalhoHospital of Jau, Jau, BRAZIL 

Background: HannaH demonstrated non-inferiority of the fixed-dose subcutaneous 

(SC) formulation of H compared with the intravenous (IV) formulation, based on 

co-primary endpoints of pharmacokinetics (C trough) and efficacy (pCR) (Jackisch 

et al, EBCC 2012). 

Methods: Pts with HER2-positive, operable, locally advanced or inflammatory BC 

were randomised to receive 8 cycles of chemotherapy (4x docetaxel 75 mg/m 2 

followed by 4x FEC 600/75/600 mg/m 2 ) concurrently with 3-wkly H, either SC (600 

mg/5 mL) or IV (8 mg/kg to 6 mg/kg). After surgery, pts continued H-SC or IV to 

complete 1 year of treatment. Safety has been monitored until 24 mths after last dose 

of H, including cardiac monitoring. 

Results: Safety data from 298 (IV) /297 (SC) HannaH pts were analysed. At a 

median F/U of 12.3 months, 116 pts had completed adjuvant treatment and 

received a median of 17.5 (IV) and 17.0 (SC) H cycles. Pt characteristics were 

balanced at baseline. Overall, safety was comparable between arms. Most 

common AEs (>25% in either arm) were alopecia, nausea, neutropenia, 

diarrhoea, asthenia, and fatigue, with similar incidence in the two arms. 

Incidence of severe AEs (≥ grade 3) was comparable between arms (both 52%); 

the most common of which were haematologic (36.9 [IV] v 35.4% [SC]), GI (6.4 

v 5.7%) and infections (5.0 v 6.7%). Serious AEs (SAEs) were reported in 12.4% 

(IV) v 20.9% (SC) of pts. The imbalance was largely driven by increased 

reporting of SAEs in the “infections” disease category in the SC v the IV arm 

(38.7 v 35.1%). Multiple logistic regression analyses did not reveal interactions 

between route of H treatment, body weight, and exposure (AUC) for SAEs or 

grade 3–5 AEs. AEs led to the withdrawal of 2.3% (IV) and 5.7% (SC) pts, with 

a contribution from cardiac AEs (3.0% [SC] v 1.3% [(IV]). Grade 1/2 AEs were 

reasons for withdrawal in 43% (IV) v 61% (SC) of pts. Grade 1/2 cardiac AEs 

led to withdrawal in 1.0% (IV) v 2.0% (SC) of pts. Incidence of cardiac AEs was 

similar in both arms: 12.1% % (IV) v 11.4% (SC). 

Conclusions: The safety profile of H-SC was comparable to that of H-IV. 

Detailed analyses of observed imbalances in SAEs and withdrawals will be 

provided. 



Disclosure: C. Jackisch: I have participated in an advisory board for Roche. 

M. Johnston: I am currently an employee of Genentech Inc. D. Heinzmann: I 

am currently an employee of F. Hoffmann-La Roche. H. Weber: I am 

currently an employee of F. Hoffmann-La Roche. G. Ismael: I declare that my 

institute has received research funding from Roche and honoraria for 

attendance at conferences. All other authors have declared no conflicts of 

interest. 

272P SUBCUTANEOUS INJECTION OF TRASTUZUMAB – ANALYSIS 

OF ADMINISTRATION TIME AND INJECTION SITE 

REACTIONS 

X. Pivot 1 , V. Semiglazov 2 , S. Chen 3 , S.D. Moodley 4 , A. Manihkas 5 ,M. 

A. Coccia-Portugal 6 , M. Johnston 7 , T. van der Horst 8 , A. Bouhlel 8 , C. Jackisch 9 

1 Service Oncologie Medicale, C.H.U. Jean Minjoz, Besancon Cedex, FRANCE, 

2 Breast Cancer Department, N.N.Petrov Research Inst. of Oncology, 

St. Petersburg, RUSSIAN FEDERATION, 3 Division of Breast Surgery, Chang 

Gung Memorial Hospital, Taipei, TAIWAN, 4 Department of Oncology, Wits 

Oncology Donald Gordon Medical Centre, Johannesburg, SOUTH AFRICA, 

5 St Petersburg City Oncology Centre, St.Petersburg, RUSSIAN FEDERATION, 

6 Eastleigh Breast Cancer Care Centre, Pretoria, SOUTH AFRICA, 7 Genentech 

Inc, South San Francisco, CA, UNITED STATES OF AMERICA, 8 F. Hoffman-La 

Roche Ltd, Basel, SWITZERLAND, 9 Department of Obstrics and Gynecology, 

Klinikum Offenbach GmbH, Offenbach, GERMANY 

Background: Intravenous (IV) trastuzumab (H) is the standard of care for 

HER2-positive breast cancer (BC). A subcutaneous (SC) formulation of H has been 

developed. H SC formulation contains recombinant human hyaluronidase, which 

transiently hydrolyzes hyaluronan to facilitate delivery of H to the circulation. The 

HannaH study (Jackisch, et al. EBCC 2012) demonstrated the non-inferiority of H 

SC (vs. H IV) in terms of pharmacokinetics and efficacy in patients with 

HER2-positive early BC. Safety observations for the two routes of administration 

were also similar. 

Methods: H SC injection was via handheld syringe, and an injection time of about 

5 minutes was recommended by the study protocol. The actual time taken was 

measured in the safety population at each administration. Injection site reactions 

(ISRs) associated with H SC were identified using a predefined basket of preferred 

terms from the medical dictionary for drug regulatory activities. 

Results: Duration of SC injections was generally between 1–5 minutes, with an 

average duration of 3.3 minutes (Table 1) compared with 60–90 minutes taken 

for IV administration. A low incidence of ISRs were seen with SC injections 

(Table 1), with all but two cases (grade 2) being grade 1; every case was 

reversible. 

Injection duration (minutes) Number of injections n (%) Incidence of ISRs n (%) 

< 2 51 (1.1) 0 (0) 

≥ 2 to < 3 2231 (49.2) 27 (1.2) 

≥ 3 to < 4 961 (21.2) 15 (1.6) 

≥ 4 to < 5 200 (4.4) 6 (3.0) 

≥ 5 to < 6 1024 (22.6) 27 (2.6) 

≥ 6 45 (1.0) 9 (20.0) 

Missing 25 (0.5) 0 (0) 

Total 4537 (100) 84 (1.9) 

Summary of injection duration and ISRs (injection site pain) in the H SC arm 

of the HannaH study (safety population) (N = 297) Incidence of ISRs was 

highest for injection durations of >6 minutes with 6 pts reporting 9 ISRs over 

the course of their treatment. In 3 pts (6 ISRs) injection time was prolonged 

due to injection pain. The remaining three ISRs constituted transient tissue 

tenderness at injection site. 

Conclusion: In the HannaH study, injection of H SC was generally well tolerated 

with a low incidence of ISRs (grades 1 and 2). These findings support the potential 

of H SC to provide improved convenience for patients compared to the existing IV 

formulation. 

Disclosure: X. Pivot: X. Pivot has served as a consultant or advisor for Hoffmann-La 

Roche, Novartis, GlaxoSmithKline and has received honoraria from sanofi-aventis. 

S.D. Moodley: SD Moodly has served as a member of an advisory board for La 

Roche Hoffman, sanofi-aventis, Britol Meyers Squibb, Nayer Schering, and has 

received corporate-sponsored research funding from sanfoi-aventis. M. Johnston: M 

Johnston is an employee of Genentech, a member of the Roche Group. T. van der 

Horst: T Horst is an employee of F. Hoffman-La Roche Inc. A. Bouhlel: A Bouchel is 

an employee of F. Hoffmann-La Roche Inc. C. Jackisch: C. Jackisch has served on 

advisory boards for Hoffmann-La Roche Inc. All other authors have declared no 


273P IMMUNOGENICITY OF TRASTUZUMAB INTRAVENOUS AND 

SUBCUTANEOUS FORMULATIONS IN THE PHASE III HANNAH 

STUDY 

R. Hegg1 , T. Pienkowski2 , S. Chen3 , E. Staroslawska4 , S. Falcon5 , 

N. Kovalenko6 , N. Al-Sakaff7 , D. Heinzmann7 , G. Kolaitis8 , G. Ismael9 1 2 

Oncology, Hospital Pérola Byington and FMUSP, Sao Paulo, BRAZIL, MSC 

Memorial Cancer Centre, MSC Memorial Cancer Centre and Institute Maria 

Sklodowska-Curie, Warsaw, POLAND, 3 Changhua Christian Hospital, Taipei, 

TAIWAN, 4 St. John’s Cancer Center, Lublin, POLAND, 5 Hospital Nacional 

Edgardo Rebagliati Martins, Lima, PERU, 6 Stavropol Regional Clinical Oncology 

Dispensary, Stavropol, RUSSIAN FEDERATION, 7 Roche, Basel, SWITZERLAND, 

8 9 

Roche, Nutley, NJ, UNITED STATES OF AMERICA, Hospital Amaral Carvalho, 

Jau, BRAZIL 

Background: HannaH demonstrated non-inferiority of the fixed-dose subcutaneous 

(SC) formulation of trastuzumab (H) to the intravenous (IV) formulation, based on 

pharmacokinetics (Ctrough) and efficacy (pathological complete response [pCR]) 

(Jackisch et al, EBCC 2012). We report on efficacy and safety in relation to 

immunogenicity (anti-drug antibodies [ADAs]). 

Methods: Blood samples for ADA testing were drawn at baseline (BL), then day 1 of 

cycles 2, 5 (pre-surgery), 13 and 18 (post-surgery) and at months 3, 6, 12, 18 and 24 

following last H dose. Screening for ADAs to H and rHuPH20 was by bridging 

immunoassays. Positive (pos) samples were re-tested, with confirmed pos patients 

(pts) then tested for neutralizing antibodies (abs). Relationship between ADAs 

(against H and/or rHuPH20) with respect to, efficacy (pCR) and safety 

(infusion-related reactions, IRRs) was investigated. 

Results: The median follow-up (FU) (including ADA testing) was ∼12.3 months. At 

BL, 5.9% of pts (17/290) in the IV arm and 4.2% of pts (12/287) in the SC arm were 

pos for ADAs to H. Post-BL (treatment and FU), 3.4% (10/295) and 6.8% (20/295) 

pts in IV and SC, respectively were pos for ADAs to H. One pt was confirmed pos 

twice (non-consecutive time points). At BL, 7.6% of pts (22/290) in the SC arm were 

pos for ADAs to rHuPH20. Post-BL, the rate was 11.5% (34/295). Titer ranges 

post-BL were similar to those observed pre-BL. One pt was pos for ADAs to both H 

and rHuPH20. No neutralizing ADAs to H or rHuPH20 were seen. The pCR rate 

did not differ significantly between Anti-H ab (AHA)-pos (30% [IV n = 10], 55% [SC 

n = 20]) and AHA-neg (36.5% [IV n = 10], 41.6% [SC n = 20]) pts. Anti-rHuPH20 

status did not correlate with pCR rates (41.2% [pos n = 34] vs 41.7% [neg n = 254]) 

in the SC arm. In pts given H SC or H IV, occurrences of IRRs were similar in 

AHA-neg (46.3% [SC n = 255] 37.6% [IV n = 263]) and -pos (40% [SC n = 20] 25% 

[IV n = 10]) pts. The incidence of pts with an IRR was similar in both anti-rHuPH20 

status groups (SC arm only; neg 44.5% [n = 254], pos 41.2% [n = 34]). 

Conclusion: Using a highly sensitive assay, ADAs against both H (IV/SC) and 

rHuPH20 (SC only) were observed transiently and were of no relevance in terms of 

efficacy or safety. Immunogenicity monitoring in the study is ongoing. 

Disclosure: T. Pienkowski: Dr Pienkowski has carried out research sponsored by F 

Hoffmann La Roche. N. Al-Sakaff: I have an interest in relation of one or more 

organistations that could be perceived as a conflict of interest in the context of the 

subjuect of this abstract. Interest - other substantive relationship. Employee of F. 

Hoffman-La Roche Ltd. D. Heinzmann: I have an interest in relation of one or more 

organistations that could be perceived as a conflict of interest in the context of the 

subjuect of this abstract. Other substantive relationship: Employee of F Hoffman-La 

Roche and stockholder. G. Kolaitis: Dr Kolaitis is an employee and stockholder of F 

Hoffmann La Roche. G. Ismael: I have an interest that could be perceived as a 

conflict of interest in the context of the subjuect of this abstract. Corporate sponsored 

research - Roche Other substantive relationships - honoraria for conferences (Roche). 


274P A PHASE I DOSE ESCALATION AND BIOEQUIVALENCE STUDY 

OF A TRASTUZUMAB BIOSIMILAR (FTMB) IN HEALTHY MALE 

VOLUNTEERS 

L. Wisman 1 , E. De Cock 1 , J. Reijers 2 , I. De Visser 2 , M. De Kam 2 , S. van Os 1 , 

G. Voortman 1 , L. Hooftman 1 , K. Burggraaf 2 

1 Clinical Operations, Synthon BV, Nijmegen, NETHERLANDS, 2 Cardiovascular 

Research, Center for Human Drug Research, Leiden, NETHERLANDS 

FTMB is a biosimilar of trastuzumab (Herceptin®), a humanized monoclonal 

antibody targeting the human epidermal growth factor receptor 2 (HER2). 

Herceptin® is registered for treatment of HER2-positive breast cancer and metastatic 

gastric cancer. Pharmacokinetic profiles of FTMB were compared to Herceptin® in 

this combined dose escalation and bioequivalence study. In the dose escalation part 

healthy male volunteers received single doses of 0.5, 1.5, 3.0 or 6.0 mg/kg FTMB in 

consecutive cohorts to assess the safety profile. At each dose level, subjects were 

randomized to FTMB (n = 6) or placebo (n = 2), with the exception of the 6 mg/kg 

cohort, where subjects were randomized to FTMB (n = 9), Herceptin® (n = 9) or 

placebo (n = 2). Safety data were evaluated by an independent data safety monitoring 

board. To establish bioequivalence a total of 92 healthy male subjects, including 

those of the 6 mg/kg dose escalation cohort, were randomized equally to FTMB or 

Herceptin®. Blood samples were taken prior and at regular, predefined time points up 


to 9 weeks after dosing. Trastuzumab levels were determined in serum with a 

validated bridging ELISA method. The mean area under the concentration-time 

curve from time zero to infinity (AUC 0-inf), normalized to 1 mg/kg and corrected for 

content differences between FTMB (Test) and Herceptin® (Reference) was 221.4 µg.d/ 

mL for Test and 245.6 µg.d/mL for Reference. The ln-transformed Test/Reference (T/ 

R) ratio for AUC 0-inf was 89.6% (90% confidence interval (CI): 85.1-94.4%), 

demonstrating bioequivalence based on the acceptance interval of 80.0-125.0%. For 

the secondary endpoint, maximum concentration observed (Cmax), the T/R ratio was 

89.4% (90% CI: 83.4-95.9%). Interestingly, the elimination of both FTMB and 

Herceptin® was shown to be non-linear. Adverse events other than the documented 

side effects of trastuzumab (fever, influenza-like illness, and fatigue) did not occur, 

and signs of cardiotoxicity were not observed. In conclusion, in this first 

bioequivalence study with a trastuzumab biosimilar in healthy male volunteers, single 

administration of FTMB was considered well tolerated in doses up to 6 mg/kg, and 

FTMB was demonstrated to be bioequivalent to Herceptin®. 


275P EFFICACY AND SAFETY OF TRASTUZUMAB IN SMALL HER2 

POSITIVE TUMORS. A SINGLE INSTITUTION EXPERIENCE 

M.V. Sano, E. Taibi, M. Alì, M. Chiarenza, S. Clementi, M. Caruso, R.A. Aiello 

Medical Oncology, Humanitas Centro Catanese di Oncologia, Catania, ITALY 

Background: Patients affected by breast cancer with negative lymph-node are 

considered at high risk if at least one of the following factors is present: tumor size > 

2 cm, HR negative, histological and/or nuclear grade 2-3 or age < 35 years. However 

some patients with HER2 positive cancers develop a recurrence despite small tumor 

size (< 2 cm) and none of these factors. Four large trials confirmed the potential 

benefit of incorporating trastuzumab in adjuvant regimens as a standard treatment. 

The effectiveness of adjuvant trastuzumab has been demonstrated either for node 

negative pT1c patients and for diseases at a higher risk. However these trial were not 

able to provide any information regarding the outcome of patients with node 

negative tumours 0.05), respectively. 

Conclusions: Our data suggest that infra-centimetric HER2+ tumors are associated 

with a general poor outcome and Trastuzumab-based therapies are justified. Future 

evaluation of dual anti-HER2 blockade in combination with chemotherapy seems 

warranted in this setting. 


277P SERUM CONCENTRATION OF ESTRONE (E1), NOT 

ESTRADIOL (E2), IS THE INDEPENDENT PREDICTIVE 

FACTOR OF RESPONSE TO NEO-ADJUVANT EXEMESTANE 

TREATMENT IN POSTMENOPAUSAL BREAST CANCER 

PATIENTS: JFMC 34-0601 TR 

S. Saji 1 , M. Takada 2 , N. Honma 3 , N. Masuda 4 , Y. Yamamoto 5 , K. Kuroi 6 , 

H. Yamashita 7 , S. Ohno 8 , T. Ueno 9 ,M.Toi 9 

1 Target Therapy Oncology, Kyoto University Graduate School of Medicine, Kyoto, 

JAPAN, 2 Breast Surgery, Kyoto University, Kyoto, JAPAN, 3 Research Team For 

Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, JAPAN, 

4 Surgery and Breast Oncology, NHO Osaka National Hospital, Osaka, JAPAN, 

5 Breast and Endocrine Surgery, Kumamoto University, Kumamoto, JAPAN, 

6 Breast Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, JAPAN, 

7 Breast and Endocrine Surgery, Hokkaido University Hospital, Hokkaido, JAPAN, 

8 Breast Oncology, National Kyushu Cancer Center, Fukuoka, JAPAN, 9 Breast 

Surgery, Kyoto University Graduate School of Medicine, Kyoto, JAPAN 

Background: Local production of estrogen using aromatase at tumor site was thought to 

be the direct target of aromatase inhibitor (AI). However recent our works (Honma N, 

Can Sci 2011, Takada M, Breast 2012) and others (Lonning PE, Clin Can Res 2011) 

postulated that not local aromatase but whole body aromatase (possibly correlates to 

serum estrone (E1) level) would be the critical target of this drug. 

Patients and methods: Among the 116 postmenopausal patients who enrolled to the 

JFMC 34-0601 phase II clinical trial of neo-adjuvant 24 weeks (wks) treatment with 

AI, exemestane, serums from 60 patients at pre-treatment, at 4wks and at the end of 

treatment (24wks) were subjected to this study. Estradiol (E2), E1, 

dehydroepiandrosterone (DHEA) and androstenedione (A) were measured using 

LC-MS/MS analysis for precise measurement, and E1- sulfate (E1S) was by RIA. 

Results: Mean pre-treatment serum levels of E2, E1 and E1S were 2.29, 12.86 and 

198.87 pg/ml, respectively. All these estrogens decreased to under-detection level (0.5 pg/ 

assay for E1 and E2, 5 pg/assay for E1S) at 4wks of treatment, and it maintained to the 

end of the treatment in almost all patients irrespective of clinical response. Patients with 

higher concentration of pre-treatment E2 and E1 (cutoff = mean value) had more chance 

to obtain clinical objective response (p = 0.0245 and p = 0.0448, respectively). However 

in multivariate analysis, only E1 is the independent predictive factor for objective 

response (Odds 5.97, p = 0.0113), probably due to positive correlation of E2 to BMI, 

which is also predictive factor for AI response. When comparing pre-treatment level and 

those at 24wks (or at termination of treatment), patients with progressive disease showed 

significant increase of DHEA and A (p = 0.0313 for both), although patients with 

objective response maintained those at the same level. 

Conclusion: Pretreatment serum concentration of E1, not E2, is the independent 

predictive factor of clinical response to neo-adjuvant exemestane. Patients with 

disease progression showed significant increase of androgens during the treatment. 

Serum steroid concentrations using precise LC-MS/MS analysis may have the 

informative value for the AI treatment, and the increased androgens would be the 

important subject to be studied further. (UMIN trial ID; C000000345) 

Disclosure: S. Saji: S.S. has a honorarium for lecture from Pfizer. M. Toi: M.T. has a 

research grant and honorarium for lecture from Pfizer. All other authors have 


278P THE IMPACT OF PROGESTERONE RECEPTOR ON 

NODE-NEGATIVE BREAST CANCER SURVIVAL 


M. Solak 1 , F. Paksoy 2 , O. Keskin 1 , N. Kertmen 1 , M.K. Altundag 1 

1 Medical Oncology, Hacettepe University Oncology Institute, Ankara, TURKEY, 

2 Medical Oncology, Ankara Onkoloji Hastanesi, Ankara, TURKEY 

Background: The aim of this study was to evaluate tumor characteristics and survival rates 

of node-negative breast cancer patients according to progesterone receptor (PR) status. 

Methods: Of 2,218 breast cancer cases diagnosed between 1995 and 2011 in 

Hacettepe University, Institute of Oncology; 864 node-negative patients with known 

hormone receptor status were analyzed for age, tumor size, grade, lymphovascular 



invasion and HER-2/neu status. Estrogen receptor (ER), PR and HER-2 status were 

determined using immunohistochemistry. Patients were classified into four groups; 

ER + /PR + , ER + /PR-, ER-/PR+ and ER-/PR-. Pearson Chi-Square test and 

Kaplan-Meier with log-rank test were performed for statistical analysis. 

Results: 575 (66.6%) patients had ER + PR + , 64 (7.4%) had ER + PR-, 43 (5.0%) had 

ER-PR+ and 182 (21.1%) had ER-PR- tumor. The median age of patients were 48 years 

(20-83) and were similar in all groups (p = 0.18). Majority of patients with PR- tumors 

were postmenopausal at the time of diagnosis (p = 0.021). The follow-up period was 

39.5 (1-273) months. 

Conclusions: Patients in PR- groups are more likely to have large-size and HER-2 

positive breast cancer. ER- groups are associated with high grade disease. Patients 

with PR+ breast cancer have significantly longer overall survival, compared to 

patients with ER+ tumors. Our data suggest that PR status is an important 

prognostic factor for node-negative breast cancer survival. 


279P PROGESTERON RECEPTOR STATUS IN DETERMINING THE 

PROGNOSIS OF ESTROGEN RECEPTOR POSITIVE / 

HER2-NEGATIVE BREAST CARCINOMA 

U. Yalcintas Arslan, O. Bal, T. Ozatli, K. Helvaci, O. Esbah, B. Budakoglu, 

U. Uyeturk, O.U. Sonmez, I. Turker, O.B. Oksuzoglu 

Department of Medical Oncology, Ankara Dr. A.Y.Oncology Research and 

Education Hospital, Ankara, TURKEY 

Background: The aim of this retrospective study was to determine whether 

progesteron receptor (PgR) status have an influence on the prognosis of estrogen 

receptor positive (ER+)/HER2-negative breast carcinoma (BC). 

Methods: We retrospectively reviewed the medical files of 1680 operable BC patients 

(pts) diagnosed between 1996 and 2011 and 456 of whom ER,PgR and HER2 status 

known were included in this study. Patients were categorized into 2 groups; as group 

A (ER + /PgR-/HER2-negative) and group B (ER + /PgR + /HER2-negative). Twenty 

one percent (97 pts) of the pts were in group A. 

Results: Median follow up was 33.5 (0-177) months. Median age was 54 (21-90) years. 

Sixty-one percent (278) of the pts had node-positive BC. Sixty percent (276) of the pts 

were postmenopausal. Eighty percent (365) of the pts received adjuvant chemotherapy 

(ACT). Adjuvant hormonotherapy (AHT) was recommended to nearly all patients 

(mostly tamoxifen). Pts in group A had significantly higher lymph node positive disease 

as compared to group B (%70 vs 59%, p = .046). Although there was no statistically 

significant difference between two groups for the first site of recurrence (mostly bone 

and soft tissue, p = .51), the number of recurrence and mortality events in group B were 

proportionally less than group A [27.8% and 21.2% for group B and 42.7% and 32.2% 

for group A;p = .005 and p = .004, respectively). In the node-positive subgroup, an 

important difference for relative risk RR of BC recurrence between groups A and B was 

found (34/68 vs 75/207, RR 1.3, CI:1.02-1.86, p = .034). But, the mortality risk was 

similar for lymph node-positive pts in groups A and B (16/63 vs 50/201,RR 1.0, 

CI:0.62-1.66,p = 0.93). Although DFS for group B was shorter, it was not statistically 

significant (5-year DFS rate 45% vs 35% p = .24). However, 5-year overall survival (OS) 

was significantly longer for pts in group B than group A (78% vs 67%,p = .043). 

Conclusions: PgR status has a great influence on the prognosis of BC pts especially 

negative PgR may have a significant negative influence on the prognosis of 

node-positive ER + /HER2- BC pts. 


280P ADJUVANT AROMATHASE INHIBITORS (AIS) HORMONE 

THERAPY (HT): WHICH REASONS LEAD PATIENTS (PTS) TO 

DISCONTINUE TREATMENT? A MONO INSTITUTIONAL 

ANALYSIS 

L. Moscetti 1 , M.A. Fabbri 1 , I. Sperduti 2 , P. Frittelli 3 , F. Nelli 1 , A. Massari 4 , 

G. D’Auria 1 , L. Pompei 5 , E.M. Ruggeri 1 

1 Divisione di Oncologia, Ospedale Belcolle, ASL di Viterbo Oncology Unit, 

Viterbo, ITALY, 2 Biostatistics, Regina Elena Institute, Roma, ITALY, 3 Surgery, 

Breast Surgery, Ospedale Belcolle, ASL di Viterbo Oncology Unit, Viterbo, ITALY, 

4 Oncologia ed Ematologia, Anatomia Patologica, Ospedale Belcolle, ASL di 

Viterbo Oncology Unit, Viterbo, ITALY, 5 Oncologia ed Ematologia, Radioterapia, 

Ospedale Belcolle, ASL di Viterbo Oncology Unit, Viterbo, ITALY 

Background: AIs represents the standard HT for the adjuvant treatment of post 

menopausal endocrine sensitive early breast cancer. A percentage of pts interrupt 

treatment because of toxicity. In this setting the switch to other AIs or tamoxifen 

(TAM) may represent an option to allow the prosecution of HT. We reviewed the 

main reasons for interruption of the AIs in our institution from 2006 to the present. 

Methods: 236 pts with a minimum treatment time up of 6 months were considered 

eligible for analysis. Pts characteristics: median age 64 yrs (35-89), median follow up 

24 months (6-28). Prior adjuvant CT: taxanes based: 47 pts, anthracyclines based: 43 

pts. 118 pts (49%) had received letrozole (L), 101 (43%) anastrozole (A), 18 (8%) 

exemestane (E). An alternative HT (AIs or tamoxifen [T]) was offered to pts who 

wanted or needed to interrupt permanently the ongoing drug. 

Results: According to the CTC NCI, arthralgia was the main toxicity observed (G1 

19.4%, G2/3 5.5%/1.7%. Overall 24 out of 236 pts (10%) needed discontinuation of 

AIs as a result of toxicity. Grade 2 and 3 arthralgia was the main reason for 

discontinuation in 13/24 pts (54%). No differences in the incidence of arthralgia were 

noted in pts who had received taxanes or anthracyclines. Headache (n = 2), alopecia 

(n = 2), G3 itching (n = 2), diffuse skin reaction (n = 1) allergic reaction with 

hypertensive crisis (n = 1), xerostomia and xerophthalmia (n = 1), insomnia (n = 1) 

and somnolence (n = 1) were the other reasons for discontinuance. In the 

multivariate logistic regression analysis, age (65 yrs) and HT represent independent 

factors associated with the onset of arthralgia (respectively p = 0.006 and 0.008, OR 

2.65, CI95: 1.32-5.31). 17/24 pts were switched to E, 5 to T and 1 each to L and 

A. In pts who switched to another AI we observed a reduction in the severity of the 

arthralgia but not its complete resolution. A complete resolution of symptoms was 

observed for the other toxicities except for allergic reactions that recurred after 

switching from L to A. Moreover, the patient with the diffuse skin reaction, chose 

discontinuation of HT. 

Conclusions: In our analysis, 10% of pts discontinued AIs due to toxicity. Switching 

to alternative HT, and monitoring the toxicity, represent an option to offer to pts in 

order to avoid a premature and permanent interruption of an effective treatment. 


281P FOR WHICH PT1A, BN0M0 HORMONE RESPONSIVE INVASIVE 

BREAST CARCINOMAS COULD ENDOCRINE THERAPY BE 

AVOIDED? 

C. Perrin 1 , J. Edeline 1 , J. Leseur 2 , V. Lavoué 3 ,P.Tas 4 , H. Mesbah 5 , 

C. Lefeuvre-Plesse 6 , D. Gedouin 6 , F. Penault-Llorca 7 , P. Kerbrat 1 

1 Medical Oncology Department, Eugène Marquis Center, Rennes, FRANCE, 

2 Radiation Department, Eugène Marquis Center, Rennes, FRANCE, 3 Surgical 

Oncology, University Hospital, Rennes, FRANCE, 4 Pathology Department, 

Eugène Marquis Center, Rennes, FRANCE, 5 Informations and Statistics, Eugène 

Marquis Center, Rennes, FRANCE, 6 Medical Oncology, Eugène Marquis Center, 

Rennes, FRANCE, 7 Dept. de Pathologie, Centre Jean Perrin, Clermont-Ferrand 

Cedex, FRANCE 

Background: Overtreatment is a daily concern in adjuvant setting for invasive breast 

carcinoma. Although chemotherapy is the most controversial issue, endocrine 

therapies must also be discussed. 

Methods: In this monocentric retrospective study, we analysed results of patients 

treated for hormone responsive invasive pT1a,bN0M0 breast cancer, focusing on the 

population without adjuvant endocrine treatment. Women with previous history of 

invasive carcinoma were excluded. 

Results: In our institution, 382 patients with hormone responsive breast invasive 

pT1a,bN0M0 carcinoma were treated between 1997 and 2007. Local treatment 

involved either mastectomy or partial breast surgery followed by breast 

radiotherapy. After multidisciplinary discussion, among the 382 patients, 162 

patients (42 %) did not receive any adjuvant endocrine treatment. Comparatively 

to the group treated with endocrine therapy, these patients had significantly 

more grade I tumors (81.4 % versus 47.2 %, p< 0.0001) and Ki67 < 14% (89.6% 

versus 72.4%, p < 0.0001). In patients not treated with endocrine therapy, after a 

mean follow-up of 7.1 years, 5 years-disease free survival (DFS) was 93% and 5 

years-distant disease free survival was 98.7%. Remarkably, 5 years-DFS was 

particularly favourable for patients older than 50 years old (97.1% versus 82.1% 

for age < 50 years old, p = 0.0002) and for grade I carcinomas (97.3% versus 

76.7% for grade II-III, p= 0.0005). Only one metastatic recurrence occurred after 

10 years in the grade I group. 

Conclusion: This series of patients treated without adjuvant endocrine therapies 

raises the issue of avoiding anti tumor endocrine therapy in patients with hormone 

responsive pT1a,bN0M0, age> 50 years and grade I tumors. 


282P EVALUATION OF BONE MINERAL DENSITY (BMD) IN EARLY 

BREAST CANCER (EBC) PATIENTS TREATED WITH 

UP-FRONT OR SWITCH SCHEDULES OF AROMATASE 

INHIBITORS (AIS): RESULTS OF A SINGLE CENTRE 

RETROSPECTIVE STUDY 

P. Seminara 1 , A. Iannace 2 , G. Manna 2 , T. Losanno 2 , A. Emiliani 2 , E. Franzese 1 , 

L. Frati 2 

1 Internal Medicine, Sapienza University, Rome, ITALY, 2 Department of 

Experimental Medicine, Sapienza University, Rome, ITALY 

Background: Aromatase inhibitors (AIs) are the standard adjuvant treatment of 

hormone responsive early breast cancer (EBC) in postmenopausal women. AIs are 

well tolerated but are associated with specific toxicities, including effect on bone 

(accelerated bone loss, bone fracture, osteoporosis) and musculoskeletal symptoms 

(ostealgia, arthralgia, myalgia) Aim: The present observational study investigated the 

effect of BMD in postmenopausal women with EBC scheduled to receive AIs 

up-front or switch treatment after standard 2-3 years of adjuvant Tamoxifen 

(TAM-AIs). 


Patients and methods: We reviewed data for 89 patients with hormone 

receptor-positive EBC: 64 postmenopausal women received up-front AIs for 5 years; 

25 patients received TAM-AIs. BMD were assessed at baseline and during hormonal 

treatment once a year. Osteopenic patients received Calcium and vitamin D; 

osteoporotic patients received also oral biphosphonates. 

Results: No patient with a normal baseline BMD (T-score >-1) became osteoporotic 

during 5 years of follow-up. However, it was noted that more women receiving AIs 

up-front became osteopenic, as compared with TAMàAI treated women (AIs = 58% 

vs. TAM-AIs = 26%, p= 10% 86 124 

Unknown 10 25 

Results: SLN metastasis were found in 45 patientes in the OSNA group and in 49 in 

the historical group. There were no differences in rates of macrometastases (27 by 

OSNA, 41 by HE) and we found differences in micrometastasis rate (18 by OSNA 

and 8 by HE p =0.007). Axillary node dissection (ALND) was performed in 45 

patients in the OSNA group and in 49 in the historical group. All the patients 

diagnosed by OSNA had a complete ALND during the initial surgical procedure. In 

the historical cohort the ALND was performed during the initial surgical procedure 

in 41 patients, and ALND was performed in a second surgical procedure in 8 

patients. 

Conclusions: The OSNA assay can detect SLN metastasis as accurately as 

conventional pathology with increased detection of micrometastasis. The second 

surgery can be reduced with the OSNA assay. 


285P WHAT DO CLINICIANS DO WITH THE RESULTS OF THE 

SYSTEMATIC STAGING IMAGING AT THE TIME OF BREAST 

CANCER DIAGNOSIS? 

A. Turpin 1 , A. Mailliez 1 , P. Vennin 1 , J. Bonneterre 2 

1 Breast Cancer, Centre Oscar Lambret, Lille, FRANCE, 2 Breast Cancer, Centre 

Oscar Lambret, Université Lille Nord de France, Lille, FRANCE 

Introduction: Asymptomatic distant metastases are often looked for at the time of 

initial diagnosis of early breast cancer. However, there is no consensus on when to 

perform it and on the consequences on the treatment. 

Patients and methods: 125 asymptomatic women receiving systemic neoadjuvant 

(33 patients (pts)) or adjuvant treatment (92 pts) for breast cancer at the Oscar 

Lambret Center in 09/2011 were considered. The staging imaging was a PET scan: 59 

pts, a CT scan + a bone scan: 61 pts and both: 5 pts. Results for each procedure were 

considered normal, abnormal but typically benign or potentially malignant. In this 



case, another imaging technique was carried out to confirm the suspected diagnosis. 

The patient was considered metastatic if the results of two different procedures were 

concordant and eventually in case of response to chemotherapy. 1 patient had a 

biopsy (liver). 22 pts were Stage 1, 58 Stage 2, 44 Stage 3. 1 other patient had an 

excision of a recurrence on mastectomy scar. 

Bone scan + CT 

scan 

PET 

scan Both Total 

Pts 61 59 5 125 

Potentially 

malignant 

lesions 

13 8 2 23 (including 

confirmed 

malignant) 

Malignant lesions 5 2 2 9 

Benign lesions 33 15 1 49 

Confirmatory Procedures 19 19 2 40 

Results: 9 pts were considered metastatic (7%): 5 bone, 2 liver, 1 lung and 1 spleen. 

There was 1 Stage 1, 4 Stage 2, and 4 Stage 3. 3 of the 5 pts in the neoadjuvant 

setting were operated on (2 after the planned chemotherapy: 1 complete response of 

lung metastasis and 1 sternal lesion treated by boost and 1 after modified protocol 

for unique liver lesion which will be treated by Cyberknife®). The 2 others had bone 

lesions, received modified protocol and did not have surgery. For the pts in the 

adjuvant setting, 2 received the full treatment (1 continued Trastuzumab beyond the 

year planned), 1 received modified protocol of chemotherapy then radiotherapy and 

hormonotherapy and the last one received chemotherapy alone. 

Conclusion: In this population of 125 pts selected for (neo) adjuvant chemotherapy, 

40 imaging procedures were performed to check the lesions. 9 pts were considered as 

metastatic and only 5 had had a significant modification of their treatment. A 

systematic imaging staging in pts selected for adjuvant chemotherapy should not be 

recommended. 


286P PROGNOSTIC AND PREDICTIVE VALUES OF BI-RADS 

CLASSIFICATION IN BREAST CANCER PATIENTS 

Y. Kuo 1 , L. Cheng 2 , T. Chang 1 

1 Surgery, National Cheng Kung University, Tainan, TAIWAN, 2 Radiology, National 

Cheng Kung University, Tainan, TAIWAN 

Objective: The goal of this study is to determine the prognostic and predictive values 

of the Breast Imaging Reporting and Data System (BI-RADS) classification in breast 

cancer patients. 

Patients and methods: 1045 patients with breast cancer were disgnosed between 

January 1, 1999, and December 31, 2007, and 512 (48.9%) of them were classified as 

BI-RADS 5. Overall survival and disease-free survival were estimated with the 

Kaplan-Meier method and compared across the two groups (BI-RADS 5 versus 

BI-RADS 0-4) using the log-rank test. Univariate and multivariate analyses were used 

to identify the prognostic factors. 

Results: The median follow-up time was 87.8 months. Laplan-Meier analysis showed 

a significant difference between the two subgroups in five-year overall survival (p < 

0.0001) and five-year disease-free survival (p < 0.0001). On multivariate analysis, the 

BI-RADS mammographic findings, lymph node status, HER-2 status, and tumor 

grade were significant factors related to five-year overall survival and disease-free 

survival. 

Conclusion: The BI-RADS classification is a reliable prognostic and predictive factor. 

Taiwanese breast cancer patients with BI-RADS 5 mammographic finding showed a 

higher relapse rate than patients with BI-RADS 0-4 mammographic finding. 


287P STUDY OF STROMAL CD10 OVEREXPRESSION IN INVASIVE 

BRAEST CANCER AND ITS RELATIONSHIP WITH 

CLINCOPHATHOLOGIC FACTORS 

A. Taghizadeh Kermani 1 , A. Jafarian 2 , R. Ashabe Yamin 2 , M. Seilanian Toosi 1 , 

L. Pourali 3 , A. Omidi Ashrafi 2 

1 Oncology, MUMS, Mashhad, IRAN, 2 Pathology, MUMS, Mashhad, IRAN, 

3 Gynecology, MUMS, Mashhad, IRAN 

Background: Carcinoma of the breast is the most common non-skin malignancy in 

women. Invasion and metastasis are considered as the major causes of cancer-related 

morbidity and mortality. It has long been proposed that secreted proteinases, 

including the matrix metalloproteinases, play an important role in tumor progression 

and mediating extracellular matrix remodeling. More recently, it has been suggested 

that extracellular proteinases also regulate growth factors and cytokines that may 

contribute to tumor progression. CD10 is a 90-110kd cell surface zinc-dependent 

metalloprotease. Since CD10 is structurally similar to matrix metalloproteinase and 

stromelysin it may facilitates cancer cell invasion and/or metastasis. The aim of this 

study was to investigat the rate of CD10 expression in the stromal cells of invasive 

ductal carcinomas of breast immunohistochemically and clarify its corelation with 

other clinicopathological factors of the disease. 

Methods: 100 patients with histopathologic diagnosis of IDC and 50 patients with 

fibroadenoma of breast (as the control group) were selected and 150 parafin blocks 

were obtained. The stained slides by IHC method for CD10 marker were examined 

separately by two pathologists and discrepancies were reviewed in a common session 

to get the final result. 

Results: Stromal CD10 was detected in 28% of the IDC. No immunoreactivity was 

identified in the stromal cells of normal breast. Stromal CD10 expression in IDC was 

significantly correlated with tumor size (P < 0.001), histologic grade (P < 0.001), the 

presence of nodal metastases (P < 0.001) and estrogen receptor negative status (P = 

0.003). 

Conclusion: Stromal CD10 expression in IDC is closely correlated with invasion and 

metastasis and it may play an important role in the pathogenesis of IDC. 


288P PROGNOSTIC TOOLS IN EARLY BREAST CANCER: 

PREDICTING BENEFIT OF ADJUVANT CHEMOTHERAPY 

E.E. Parkes 1 , C. Davidson 1 , A. Hussain 1 , C.R. James 1 , G.G. Hanna 2 

1 Medical Oncology, Northern Ireland Cancer Centre, Belfast, UNITED 

KINGDOM, 2 Centre for Cancer Research and Cell Biology, Queens University 

Belfast, Belfast, UNITED KINGDOM 

Introduction: Adjuvant chemotherapy (CT) in early breast cancer reduces the risk of 

mortality. However, absolute reductions in mortality can be small. For patient with 

low risk disease prognostic tools such as ‘Adjuvant! Online’ (AO) and ‘Predict’ (PD) 

can be used to estimate the benefit of adjuvant chemotherapy. We compare the 

survival gains estimated using AO and PD in routine clinical practice, assessing the 

characteristics of patients in which AO and PD disagree. 

Methods: In a retrospective study using the hospital electronic database, the 

clinical and pathological details of all patients with early breast cancer referred 

for adjuvant therapy at the Northern Ireland Cancer Centre in a 3 month period 

in 2011 were collected and were entered in to AO and PD to assess percentage 

benefit (absolute reduction in mortality at 10 years) from CT. We categorised 

patients into three prognostic groups: those where risk from CT outweighs 

benefit (5%) We excluded patients with metastatic disease at 

presentation, DCIS, a second primary breast cancer or receiving neo-adjuvant 

treatment. 

Results: Of the 200 patients identified, 43 (21.5%) fell in to different prognostic 

groups depending on whether AO or PD was used to calculate benefit from CT. In 

total, AO suggested marginal or significant benefit in 69.8% of patients, compared to 

60.4% using PD. Eight patients had “major” comorbidities, which is weighted only in 

AO, and were excluded in subsequent analysis. Of those without major 

comorbidities, AO offered at least 2% benefit in 80% of cases, and PD in only 57.1%. 

The majority (91.4%) of cases were ER positive, and node negative (82.9%). This 

difference was notable in women aged 65 or less, with 83.3% with >2% benefit using 

AO, and 61.1% using PD. AO estimates of benefit were on average 3.7% higher for 

this age group. HER2 status had little impact, with similar recommendations using 

either AO or PD. 

Conclusions: This study highlights lack of concordance between two available online 

prognostic tools, notably in ER positive, node negative patients. For patients with a 

marginal benefit from CT, care must be used when making adjuvant treatment 

decisions. 


289P A STUDY OF THE IMPACT OF THE 21-GENE BREAST CANCER 

ASSAY ON THE USE OF ADJUVANT CHEMOTHERAPY IN 

WOMEN WITH BREAST CANCER IN A MEXICAN PUBLIC 

HOSPITAL 

J.E. Bargallo-Rocha 1 , F. Lara 1 , R.J. Shaw Dulin 1 , V. Perez-Sánchez 1 , 

C. Villarreal-Garza 1 , H. Maldonado-Martinez 1 , A. Mohar-Betancourt 2 , 

C. Yoshizawa 3 ,E.Burke 4 , C. Chao 4 

1 Breast Cancer Clinic, Instituto Nacional de Cancerología (INCan), Mexico City, 

MEXICO, 2 Biomedical Research, Instituto Nacional de Cancerología (INCan), 

Mexico City, MEXICO, 3 Biostatistics, Genomic Health, Inc., Redwood City, CA, 

UNITED STATES OF AMERICA, 4 Medical Affairs, Genomic Health, Inc., 

Redwood City, CA, UNITED STATES OF AMERICA 

Background: The majority of early stage breast cancer patients in Mexico are treated 

through the public health system, and >80% are treated with chemotherapy (CT). 

The 21-gene assay (Oncotype DX®) is available in Mexico but has been utilized 

primarily within the private health system. There are no data that describe the 

potential impact of the assay on adjuvant treatment decision-making for public 


sector patients. The aim of this study is to characterize how assay results impact the 

decision-making process and confidence of public sector physicians in Mexico to 

determine adjuvant therapy. This is the first decision impact study of the Oncotype 

DX assay in Latin America. 

Methods: At total of 98 consecutive patients with ER + , HER2-, stage I-IIIa, N0/ 

N1-3 breast cancer from the Instituto Nacional de Cancerologia in Mexico City, 

Mexico, were enrolled in the study. Via consensus discussion in multidisciplinary 

team meetings, physicians completed pre- and post-assay questionnaires 

regarding adjuvant treatment recommendations for each enrolled patient. The 

primary endpoint was the overall change in physician treatment 

recommendations resulting from the addition of the Recurrence Score® result in 

the decision-making process. 

Results: Pre- and post-assay results were available for 96 patients. Treatment 

decisions changed for 31/96 (32%: 95% CI 23%-43%) patients; 17/62 (27%; 95% 

CI 17%-40%) N0 and 14/34 (41%; 95% CI 25%-59%) N1-3 patients. Post-assay, 

8/50 (16%) of patients initially recommended hormonal therapy (HT) were 

recommended chemohormonal therapy (CHT) or CT, and 21/46 (46%) of 

patients initially recommended CHT/CT were recommended HT alone. The 

proportion of patients recommended CT decreased from 48% pre- to 34% 

post-assay (p = 0.024), a decrease of 14% overall, 6% in N0, and 26% in N1-3 

patients. 

Conclusions: These results suggest that use of the 21-gene assay in the Mexican 

public health system has an impact on adjuvant treatment recommendations and 

may reduce the use of chemotherapy. 

Pre-Assay 

Post-Assay 

Adjuvant Therapy HT alone CT + HT CT alone Total 

HT alone 42 (44%) 7 (7%) 1 (1%) 50 (52%) 

CT + HT 21 (22%) 23 (24%) 2 (2%) 46 (48%) 

Total 63 (66%) 30 (31%) 3 (3%) 96 

Disclosure: C. Yoshizawa: Genomic Health- Employment and Stockholder. E. Burke: 

Genomic Health- Employment and Stockholder. C. Chao: Genomic Health- 

Employment and Stockholder. All other authors have declared no conflicts of 

interest. 

290P BROWN FAT SEEN ON FDG PET/CT IS INCREASED IN 

BREAST CANCER PATIENTS COMPARED TO THEIR AGE- 

AND WEIGHT-MATCHED CONTROLS WITH OTHER CANCERS 

K.H.R. Tkaczuk 1 , Q. Cao 2 , L. Jones 1 , M. Smith 2 , S. Chumsri 1 , J. Jenkins 2 , 

V. Dilsizian 2 , W. Chen 2 

1 Medicine, University of Maryland Greenebaum Cancer Center, Baltimore, MD, 

UNITED STATES OF AMERICA, 2 Radiology, University of Maryland, Baltimore, 

MD, UNITED STATES OF AMERICA 

Purpose: We previously found increased brown fat deposits in mammary tissue of 

Rrca1 mutant breast cancer mouse models suggesting a potential role of brown fat 

environment in the early breast tumorigenesis. The goal of the current human study 

is to test the hypothesis that the prevalence of brown fat activity seen on FDG PET/ 

CT is increased in breast cancer (BC) patients. 

Methods: We conducted a retrospective study to assess the distribution and 

intensity of brown fat activity on FDG PET/CT in female BC patients compared to 

age- and weight-matched control subjects with other cancers mostly colon cancer. 

We analyzed 124 FDG PET/CT scans of BC patients done at the University of 

Maryland and 124 age- and weight-matched control subjects who had FDG PET/ 

CT scan on the same day for staging of other cancers (the majority were colon 

cancer). 

Results: The prevalence of brown fat was higher in BC (12.9% or 16/124) than 

in their age- and weight-matched control subjects (5.6% or 7/124) (p < 0.05). 

When the data was stratified by age, among those who were ≤ 50 years old, the 

prevalence of brown fat was 35.5% (11/31) in BC patients versus 9.1% (3/33) in 

the controls (p 50 years of age, 

there was no difference in brown fat prevalence between BC patients and 

controls (5.4% or 5/93 vs 4.4% or 4/91; p = NS), respectively. Brown fat was 

more commonly identified in the bilateral supraclavicular regions in BC patients 

than controls (22 vs 6, p = 0.049). There was no difference in the intensity of 

brown fat between the 2 groups (mean SUV max = 3.5 ± 1.5 in BC vs 3.4 ± 0.7 in 

controls, p = NS). 

Conclusion: The prevalence of brown fat seen on FDG PET/CT is increased in BC 

patients compared to their age- and weight-matched controls with other cancers, 

particularly in patients aged 2 cm, number of positive LN 

(≥4), high tumor grade (G3), and negativity of hormone receptor in univariate 

analyses. However, in multivariate analyses, number of positive LN ≥4 (HR = 2.47; 

95% CI, 1.07-5.74; p = 0.035), high tumor grade (HR = 2.76; 95% CI, 1.08-7.09, p = 

0.034), and over-expression of p53 (HR = 6.55; 95% CI, 2.40-17.85, p < 0.001) were 

independent poor prognostic factors for RFS. And p53 over-expression was also 

related to poor OS (HR = 3.93; 95% CI, 1.04-14.81, p = 0.044). Patients with high p53 

expression (≥10% of positive cells) tended to have tumors with large size, higher 

grade and lower hormone receptor positivity compared to those of low p53 

expression. 

Conclusions: p53 over-expression along with number of positive LN and tumor 

grade was found to be useful biomarker to predict poor outcomes in patients with 

LN-positive breast cancer receiving docetaxel-based adjuvant chemotherapy. 


292P SERUM LEVELS OF VEGF PRE- AND POST-TREATMENT 

WITH BEVACIZUMAB (BEV) FOR EARLY STAGE BREAST 

CANCER (ESBC): ICORG 08-10 

A.M. Canonici 1 , I. Parker 2 ,T.O’Shea 2 , B. Moulton 2 , G. Gullo 3 , M.J. Kennedy 4 , 

D. Tryfonopoulos 5 , N. Walsh 6 ,N.O’Donovan 6 , J.P. Crown 7 

1 NICB, Dublin City University, Dublin, IRELAND, 2 ICORG, Dublin, IRELAND, 

3 St Vincent’s University Hospital, Department of Medical Oncology, Dublin, 

IRELAND, 4 Dept Medical Oncology, St James’s Hospital, Dublin, IRELAND, 

5 Medical Oncology Unit, St Vincents University Hospital, Dublin, IRELAND, 

6 National Institute for Cellular Biotechnology, Molecular Therapeutics for Cancer 

Ireland, Dublin City University, Dublin, IRELAND, 7 Department of Medical 

Oncology, St Vincents University Hospital, Dublin, IRELAND 

Background: Angiogenesis, partly mediated by vascular endothelial growth factor 

(VEGF), promotes metastases. BEV, an anti-VEGF monoclonal antibody which has 

some efficacy in metastatic BC is being studied as an adjuvant treatment for ESBC. 

However, there are no validated biomarkers, and the effects of BEV on VEGF levels 

in pts with ESBC is unknown. We studied VEGF serum concentration in ESBC 

receiving BEV. 

Methods: 106 pts with HER-2 negative ESBC were included in this study. Patients 

received 4 cycles of docetaxel (75 mg/m2) + cyclophosphamide (600 mg/m2) with 

BEV (15 mg/kg) once every three weeks for one year. Serum samples were collected 

prior to commencement of treatment, at 6 months and 12 months. The VEGF levels 

in serum samples were determined, at each time point, using a VEGF enzyme-linked 

immunosorbent assay (ELISA). 

Results: VEGF concentration was determined in serum samples from 65 patients. 

Serum VEGF was detectable in 62 of 65 patients and the median level in untreated 

patients was 325.4 pg/ml (range 0.1 - 924.8 pg/ml). All of the 62 patients showed a 

significant decrease in VEGF concentration after 6 and 12 months of treatment 

(median 9 ± 42.1 pg/ml, p < 0.001 and 9 ± 43.9 pg/ml, p < 0.001 respectively). No 

significant change in median VEGF levels observed at 12 months compared to 6 

months (median 0 ± 60.3 pg/ml, p = 0.704). However, in 14 patients the levels of 

VEGF detected at 12 months were higher than at 6 months following treatment (p = 

0.045). 

Conclusion: Adjuvant therapy with chemotherapy and BEV is associated with a 

significant reduction in VEGF levels at 6 months. 




293P QUANTIFICATION OF TUMOR-SPECIFIC DNA IN BLOOD OF 

HEALTHY WOMEN AND BREAST CANCER PATIENTS 

S.N. Tamkovich 1 , V.A. Myleiko 1 , A.V. Starikov 2 , V.I. Permyakova 3 , V.V. Vlassov 1 , 

P.P. Laktionov 1 

1 Cellular Biology Group, Institute of Chemical Biology and Fundamental 

Medicine, Novosibirsk, RUSSIAN FEDERATION, 2 Mammology Department, 

National Novosibirsk Regional Oncologic Dispensary, Novisibirsk, RUSSIAN 

FEDERATION, 3 Hematology Department, Central Clinical Hospital, Novisibirsk, 


Despite of tumor location DNA from cancer cells was shown to got in circulating 

blood, thus DNA circulating in blood represent the valuable source of diagnostic 

material for non-invasive blood based tests for cancer. 

Material and methods: Blood from healthy female (n = 50) and breast cancer 

patients (n = 23, T1-2, N0-1, M0) were fractionated into plasma and cellular 

fractions, cell-surface-bound cirDNA (csbDNA) were eluted from cell surface with 

PBS/EDTA and trypsin solutions [1]. Total DNA was quantified with TaqMan PCR 

for LINE-1 repeats [2], methylated DNA of RARβ2 gene promoter was quantified 

with methylation-specific SYBR Green Real Time PCR [3]. 

Results: Breast cancer patients had significantly higher mean concentration of 

methylated RARβ2 gene promoter in circulating DNA (cirDNA) and csbDNA 

fractions as compared to healthy controls: 192 vs. 132 pg/ml and 619 ng/ml vs. 413 

pg/ml, respectively; P < 0.005. No correlation was found between cirDNA levels and 

stage of tumor. ROC-curve analysis demonstrated sensitivity and specificity of 

cirDNA-based breast cancer detection as 52% and 65% respectively for cut-off value 

of 0.61 for plasma tumor cirDNA and 70% and 61% respectively for cut-off value of 

0.75 when cirDNA and csbDNA were analysed simultaneously. The data obtained 

demonstrate that along with cirDNA csbDNA provides a valuable source of material 

for breast cancer diagnostics. 1. Clin. Chem., 2005. V. 51. P. 1317-1319. 2. Anal. 

Biochem., 2011. V. 408. P. 354-356. 3. Eur. J. Cancer Prev., 2011. V. 20. P. 453-455. 


294P HIGH FREQUENCY OF BRCA 1/2 MUTATIONS AMONG 

ISRAELI NON ASHKENAZI BREAST CANCER PATIENTS 

F. Elyan 1 , O. Maimon 2 , A.F. Salah 3 , M. Sagi 1 , L. Kaduri 2 , I. Lerer 1 , Y. Goldberg 1 , 

T. Hamburger 2 , D. Bercovich 4 , T. Peretz-Yablonski 5 

1 Department of Human Genetics, Hadassah-Hebrew University Medical Center, 

Jerusalem, ISRAEL, 2 Sharett Institute of Oncology, Hadassah-Hebrew University 

Medical Center, Jerusalem, ISRAEL, 3 Oncology and Radiotherapy, Hadassah 

University Hospital Hebrew University Medical Center, Jerusalem, ISRAEL, 4 Cga- 

Galil Genetic Analysis and Migal- Galilee Bio- Technology Center, CGA- Galil 

Genetic Analysis and Migal- Galilee Bio- Technology Center, Galil, ISRAEL, 

5 Sharett Institute of Oncology, Hadassah University Hospital Hebrew University 

Medical Center, Jerusalem, ISRAEL 

Background: Inherited mutations in the breast cancer susceptibility genes (BRCA1 

and BRCA2) are associated with a high risk of developing breast (BC) and ovarian 

cancers (OC) in females of different age and ethnic groups. The spectrum of 

mutations in these genes varies between populations, with some showing a high 

frequency of unique mutations. Ashkenazi Jews have a high rate of founder 

mutations in BRCA1/2, in some other Jewish communities in Israel (Jews who 

immigrated to Israel from Iraq, Iran and Yemen), other founder mutations had been 

identified. Still high proportions of Israeli BC cases with strong family history have 

none of the known mutations at the BRCA1/2 genes. 

Methods and patients: Over 3000 breast cancer patients were evaluated in the 

oncogentic clinic during 1997-2011. One hundred thirty seven of them underwent 

full sequencing of the BRCA1/2 genes due to strong family history of breast and/or 

ovarian cancer or young age at presentation. Clinical and pathological characteristics 

of these patients were evaluated. 

Result: Sixty seven percent were non Ashkenazi Jews, Mean age at BC onset was 44 

(22-77). In 20 patient (15%) BRCA 1(N = 8) or 2 (N = 12) mutations were identified. 

Three of the carriers had bilateral BC and 5 had OC as second primary .17 were of 

non Ashkenazi origin. Ninety five percent of the carriers had first degree family 

history of breast or ovarian cancer. The pathological information was available in half 

of the carriers. All had high grade (2-3) tumor, 90% of them were HER2 negative 

and 60% ER positive. Age at presentation had no effect on BRCA1/2 status. 

BRCAPRO is a predictive model to assess BRCA status and has assessed in 9 

carriers, in 6 of them, the probability was >80% and in one - 5%. 

Conclusions: A full sequence of the BRCA1/2 genes was performed in a selected 

group pf BC patient, who were negative for the common founder mutation in Israel. 

Fifteen percent were found to carry other BRCA1/2 mutations. We recommend that, 

patients with the following clinical features: Sephardic origin, first degree family 

history of BC or OC, high grade tumor, HER-2 negative, should be offered full 

BRCA1/2 testing. The role of BRCAPRO and other predictive model should be 

further evaluated. 


295P CONCOMITANT USE OF ANTIDEPRESSANT DRUGS AND 

TAMOXIFEN 

L. Binkhorst 1 , R.H.J. Mathijssen 1 , M.P.P. van Herk-Sukel 2 , M. Bannink 3 , E.A. 

C. Wiemer 1 , T. van Gelder 4 

1 Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, 

NETHERLANDS, 2 Oncology, PHARMO Institute, Utrecht, NETHERLANDS, 

3 Psychiatry, Erasmus MC, Rotterdam, NETHERLANDS, 4 Hospital Pharmacy, 

Erasmus MC, Rotterdam, NETHERLANDS 

The CYP2D6 enzyme is primarily involved in the metabolism of tamoxifen into its 

most important metabolite endoxifen. The efficacy of tamoxifen therapy may be 

influenced by genetic polymorphisms of this enzyme and CYP2D6-inhibiting 

co-medication (e.g. antidepressant drugs). It is therefore generally recommended to 

avoid potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine) in tamoxifen patients. 

In this study, we examined whether women using tamoxifen still received strong 

CYP2D6-inhibiting antidepressants concomitantly during the period 2005-2010. 

Drug dispensing data for tamoxifen and seven antidepressants associated with 

CYP2D6 inhibition (paroxetine, fluoxetine, sertraline, fluvoxamine, (es)citalopram 

and venlafaxine), were obtained from the community pharmacy database of the 

PHARMO Institute. This database contains dispensing data of > 3 million people 

in the Netherlands. Concomitant use of CYP2D6-inhibiting antidepressants in 

women using tamoxifen, as well as the use of antidepressants in the total 

population, were determined per year using PASW Statistics 17.0 (SPSS Inc., 

Chicago, IL). Prevalence of the use of the four most common antidepressants 

among tamoxifen users, expressed as the number of women receiving an 

antidepressant concurrently with tamoxifen per 1000 tamoxifen users, is shown in 

the table. Although there is a downwards trend for paroxetine, this drug is still 

one of the most frequently used antidepressants in tamoxifen patients. In addition, 

a similar trend was observed in the total population of the database. Venlafaxine 

and citalopram, associated with weak CYP2D6-inhibiting properties, are 

increasingly co-prescribed. 

2005 2006 2007 2008 2009 2010 

Paroxetine 47.1 44.3 46.6 41.7 36.9 28.8 

Fluoxetine 9.5 10.6 9.8 10.7 10.8 9.7 

Citalopram 17.0 23.5 22.4 26.2 25.2 28.5 

Venlafaxine 18.3 23.8 28.2 27.5 29.1 30.8 

Despite the strong biological rationale to avoid potent CYP2D6-inhibiting 

co-medication in tamoxifen treated patients, paroxetine is still often used along with 

tamoxifen. In clinical practice, one should be extremely alert to co-medication in 

these patients. It is advised that strong CYP2D6 inhibitors are switched to weaker 

CYP2D6-inhibiting alternatives, if possible. 


296P ITEM RESPONSE THEORY AND FACTOR ANALYSIS AS MEAN 

TO CHARACTERIZE OCCURRENCE OF RESPONSE SHIFT FOR 

LONGITUDINAL QUALITY OF LIFE STUDY IN BREAST 

CANCER PATIENTS 

A. Anota 1 , C. Bascoul-Mollevi 2 , F. Guillemin 3 , T. Conroy 4 , M. Velten 5 , D. Jolly 6 , 

M. Mercier 7 , S. Causeret 8 , T.S. Dabakuyo 9 , F. Bonnetain 9 

1 Plateform of Clinical Research "Quality of Life and Cancer", University hospital of 

Besançon, Besançon, FRANCE, 2 Biostatistic Unit, Centre Val-d’Aurelle - Paul 

Lamarque, Montpellier, FRANCE, 3 Clinical Epidemiology and Evaluation 

Department, CIC-EC, Nancy, FRANCE, 4 Oncology, Centre Alexis Vautrin, 

Vandoeuvre les Nancy Cedex, FRANCE, 5 Epidemiology and Public Health 

Laboratory, College of Medicine, Strasbourg, FRANCE, 6 Création Du Pôle 

Recherche Et Innovations, University Hospital, Reims, FRANCE, 7 Clinical 

Research Unit In Quality of Life, CHU Jean Minjoz, Besancon, FRANCE, 

8 Surgery, Centre Georges François Leclerc, Dijon, FRANCE, 9 Biostatistic and 

Epidemiological Unit(ea 4184), Centre Georges François Leclerc, Dijon, FRANCE 

Aims: Health-related quality of life (HRQoL) is a dynamic process which depends 

on the adaptation of the patient and reflected by a Response Shift (RS) effect. RS 

results in a recalibration, a reprioritization and a reconceptualization of key HRQoL 

domains. Longitudinal analyses of HRQoL have to take into account the possible 

occurrence of RS. However, there is no standard of statistical analysis to characterize 

RS. Two complementary methods are investigated to characterize RS. 

Methods: This work builds on data of a prospective multicenter study including all 

primitive breast cancer patients or suspicion. HRQoL was evaluated using the 

EORTC QLQ-C30 and QLQ-BR23 at baseline, after surgery, at 3 months and 

6 months, according to the « then-test/post-test » design: the retrospective 

assessments done after surgery and at 3 months refer to baseline HRQoL; the 

retrospective measurement done at 6 months refers to HRQoL at 3 months. The 

order then-test and post-test of HRQoL questionnaires was randomized. 

Recalibration was explored by Multiple Correspondence Analyses (MCA) and the 


Linear Logistic Model with Relaxed Assumptions (LLRA) of Item Response Theory 

(IRT). LLRA gives trend of item easiness parameters. Reprioritization and 

reconceptualization were explored by Principal Component Analyses (PCA). 

Results: Between February 2006 and February 2008, 381 patients were included, 90% 

had a confirmed breast cancer. PCA show a secondary reprioritization of the 

QLQ-C30’s dimensions. Fatigue and pain remain priority symptoms. Secondary 

symptoms are insomnia at baseline, diarrhea after surgery, nausea and vomiting at 3 

months and 6 months. A stronger and stronger link between functional scales reflects 

a reconceptualization. Main recalibration’s profiles reflected by MCA are from one 

modality to an adjacent one. A lower or upward recalibration of each dimension is 

reflected by the IRT model. Based on retrospective assessment at six months of 

HRQoL at three months, arm and breast symptoms were overestimated with trend 

parameters equal to -0.59 and -1.05 (p < 0.001). 

Conclusions: IRT models have mainly been used to validate HRQoL questionnaires. 

This work shows their interest to characterize occurrence of RS. Further analyses 

should be lead to validate their abilities to characterize all RS components. 


297P PROFESSIONAL ATTITUDES TOWARDS TREATMENT OF 

RARE HISTOLOGICAL SUBTYPES OF CARCINOMAS OF THE 

BREAST: AN INTERNATIONAL PRACTICE SURVEY (PARIS 

STUDY) 

Z. Fadoukhair 1 , D. Lefeuvre 2 , K. Hofert 3 , E. Lanoy 2 , R. Rahhali 4 , M. Mathieu 5 , 

C. Mazouni 6 , S. Delaloge 1 

1 Breast Cancer Unit, Department of Medical Oncology, Institut Gustave Roussy, 

Villejuif, FRANCE, 2 Biosatitistics, Gustave Roussy, villejuif, FRANCE, 3 Medical 

Oncology, University of liverpool, liverpool, UNITED KINGDOM, 4 Medical 

Oncology, National Institute of Oncology, Rabat, MOROCCO, 5 Department of 

Pathology, Institut Gustave Roussy, Villejuif, FRANCE, 6 Breast Cancer Unit, 

Department of Surgery, Institut Gustave Roussy, Villejuif, FRANCE 

Background: WHO classification has identified a dozen rare subtypes that account 

for less than 10% of all breast cancers (BC). They are generally not taken into 

account in international/national treatment (trt) guidelines. We evaluated 

professionals’ attitudes towards decision making regarding rare BC subtypes and 

their need for consensus guidelines. 

Methods: This international survey was conducted among 236 international BC 

experts including surgeons, pathologists, medical oncologists and radiation 

oncologists. Experts were chosen to be representative of all regions of the world. 

They were selected if part of regional, national or international BC guidelines 

committee(s), or active member of a BC-directed scientific society, or author > 50 

publications in the field of BC. They were contacted through email up to three times 

and were asked to fill an online questionnaire. 

Results: 86 experts from 32 countries responded (36%). A total of 50% were medical 

oncologists, 21% surgeons, 17% pathologists and 12% radiation oncologists. 77% of 

the experts declared they based their general BC care decisions on regional, national 

or international guidelines. Up to 76% declared individual routine trt decisions for 

BC were taken by multi-disciplinary boards in their practice. However, only 10% 

strongly considered rare BC should be treated following national or international 

guidelines without specific individualisation. Interestingly, 50-80% described 

individualising treatment for rare breast cancers according to pathological subtype of 

the tumour in their practice. Three specific clinical situations of rare BC presented 

were associated with > 50% heterogeneity in trt decision among the 86 experts. 

Answers were associated with both region of residency and medical subspecialty. 

However, more than 90% of experts answered they would welcome international 

recommendations for rare BC subtypes. 

Conclusion: Rare BC subtypes are diagnosed and managed very heterogeneously 

depending on geographical location, habits and specialist training of medical 

professionals. There is need for international consensus guidelines regarding their 

diagnosis and trt. 


298P PROFILE OF MALE BREAST CANCER: SINGLE INSTITUTION 

STUDY OF 76 PATIENTS FROM NORTHERN INDIA 

A. Gogia 1 , V. Raina 2 , S.V.S. Deo 3 , B.K. Mohanti 4 , N.K. Shukla 3 

1 Medical Oncology, All India Institute of Medical Sciences (AIIMS) Institute Rotary 

Cancer Hospital, New Delhi, INDIA, 2 Dept. of Medical Oncology, All India 

Institute of Medical Sciences (AIIMS) Institute Rotary Cancer Hospital, New Delhi, 

INDIA, 3 Surgical Oncology, AIIMS, New Delhi, INDIA, 4 Radiation Oncology, All 

India Institute of Medical Sciences (AIIMS) Institute Rotary Cancer Hospital, New 

Delhi, INDIA 

Background: Male breast cancer (MBC) is a rare disease and accounts for 1 % of all 

breast cancer. The aim of our study was to assess clinical, pathological parameters 

and outcome in MBC. 

Methods: This analysis was carried out in 76 male breast cancer patients with 

confirmed case of MBC who were registered in our breast cancer clinic between 


1996-2011 at Institute Rotary Cancer Hospital, All India Institute of Medical 

Sciences (AIIMS). Analysis was performed with descriptive statistics, the log rank test 

was used to compare outcome. 

Results: The median age was 56 years (range 28-80). The median duration of 

symptoms was 10 months (range 0.5-120). Breast lump was the commonest (93%) 

presenting symptom (right > left side). TNM Stage distribution was stage I -3 %, 

stage II- 20%, stage III- 55%, and stage IV- 22%. Positive family history was elicited 

in 8 (10.5%) patients. The median clinical tumour size was 3.9 cm. Modified Radical 

mastectomy was the commonest surgical procedure. IDC was the most common 

histology. Sixty percent of tumours were high grade and 55% had pathological node 

positive disease. ER/PR, her2neu status was available in 75% and 65% respectively. 

ER/PR and her2neu positivity was 90% and 30% respectively. Triple negative breast 

cancer (TNBC) constituted 20%. Median follow up was 36 months. Ten patients had 

relapsed of which 70% were distant, bone being the most common site followed by 

lung and liver. Five years disease free (DFS) and overall survival (OS) was 40% and 

60%. Higher nodal stage, tumour size (>5 c.m.), negative ER/PR status, positive 

her2neu status, and visceral metastasis at baseline predicted poor outcome. 

Conclusion: Our population had more advanced disease at presentation, higher 

her2neu positivity and higher triple negative status as compared to western 

population results in poorer outcome. 


299 ASSOCIATION OF ALPHA2A AND BETA2 ADRENOCEPTORS 

EXPRESSION WITH CLINICAL OUTCOME IN BREAST CANCER 

Y. Du, J. Lu 

Breast Surgery, Shanghai Cancer Center Fudan University, Shanghai, CHINA 

Previous studies have shown that alpha2-adrenoceptor antagonists can inhibit the 

growth of breast cancer cells. The action of beta2 adrenoceptors on cell proliferation 

is still controversial. In this study, we investigated the association of alpha2a and 

beta2 adrenoceptors expression with tumor-relevant biological markers and clinical 

outcome. Immunohistochemistry assay was performed on paraffin-embedded tumors 

to detect alpha2a and beta2 adrenoceptor expression in 220 operable breast tumors. 

We initially demonstrated that alpha2a expression was associated with Her-2 status 

(P = 0.048) and a marginal significance was observed between alpha2a expression and 

ER (P = 0.061). We also find that beta2 expression was not associated with any 

tumor-relevant biological markers. Kaplan-Meier models trended to show 

associations between different beta2 expression and DFS (P = 0.092). Further analysis 

was made and we found in hormone receptor positive breast cancer patients, strong 

beta2 expression correlated with better DFS than weak beta2 expression (P = 0.031). 

Multivariate analysis demonstrated that beta2 adrenoceptor (HR = 0.31, P = 0.039) 

and lymph node (HR = 2.85, P = 0.031) were independent predictors of DFS in 

hormone receptor positive breast cancer patients. In conclusion, this study showed 

that strong alpha2a expression occurred in ER positive and Her-2 negative breast 

cancers. In hormone receptor positive breast cancer patients, strong beta2 expression 

correlates with better DFS than weak beta2 expression. In hormone receptor positive 

breast cancer patients, beta2 ADR could be an independent predictors of DFS. Our 

results also suggest that the expression of beta2 adrenoceptor may be regulated by 

estrogen and progesterone or intercross may exist between the two pathways of beta2 

adrenoceptor and hormone receptor. 


300 THE PERCENTAGE OF CD44-/CD24-/LIN- CELLS IN PRIMARY 

BREAST TUMORS AND CORRELATION BETWEEN 

PROGNOSTIC FACTORS 

E. Yetimoglu1 , D. Cabuk2 , E. Karaoz3 ,S.Kaya2 , S. Temiz2 , O. Acikgoz2 , 

K. Uygun2 , Z. Canturk4 , E. Yirmibesoglu5 , G. Aksu5 1 

Internal Medicine, Kocaeli University Medical School Hospital, Kocaeli, TURKEY, 

2 

Medical Oncology, Kocaeli University Medical School Hospital, Kocaeli, 

TURKEY, 3 Kocaeli University Center for Stem Cell and Gene Therapies Research 

and Practice, Kocaeli University Medical School Hospital, Kocaeli, TURKEY, 

4 

General Surgery, Kocaeli University Medical School Hospital, Kocaeli, TURKEY, 

5 

Radiation Oncology, Kocaeli University Medical School Hospital, Kocaeli, 

TURKEY 

Introduction: Breast cancer (BC) is associated with different molecular profiles and 

histological types. Different histological types contain cells with different phenotype 

and genotype. Many hypotheses have been taken for understanding the causes of 

breast cancer’s heterogenecity. One of these is breast cancer stem cell hypothesis. The 

hypothesis was proposed that cancers contain a subpopulation of cells similar to 

epithelial stem cells. There are many methods used for identification of BC stem 

cells. One of these methods is using cell surface markers. BC stem cells are defined 

by the phenotype CD44 + /CD24-/low/Lin-. The aim of this study is to investigate 

the percentages of CD44 + /CD24-/low/Lin- cells and the correlation between stem 

cells and prognostic factors in primary BC. 

Material and method: Twenty three women who underwent surgery for BC between 

May 2010 and January 2011 were enrolled in this study. Fresh tumor tissues were 



broken up enzymatically and CD44 + /CD24-/low/Lin- cell phenotype was idendified 

by using surface marker antibodies. The percentage of this phenotype was 

determined by surface marker expression of the cells by using flowcytometry. 

Results: The mean age of the patients (pts) was 47 and 52% had early stage BC. 

CD44 + /CD24-/low/Lin- cells were present in all tumor tissues and the mean 

percentage of these cells was 1.43 ± 1.16%. The percentage of CD44 + /CD24-/low/ 

Lin- cells was higher in postmenopausal women, early stage, Her-2 negative and low 

grade tumors, but it was not statistically significant. There was inverse correlation 

between involved lymph node numbers and the percentage of CD44 + /CD24-/low/ 

Lin- cells but it was not statistically significant. There was no statistically significant 

correlation between the percentage of CD44 + /CD24-/low/Lin- cells and menopausal 

status, stage, grade, number of lymph nodes, hormone reseptors and HER-2 status. 

Conclusion: In our study CD44 + /CD24-/low/Lin- cells were present in all tumor 

tissues and the mean percentage of these cells was 1.43 ± 1.16% as shown in previous 

studies. But there was no statistically significant correlation between prognostic 

factors and the percentage of the CD44 + /CD24-/low/Lin- cells. 


301 EARLY BREAST CANCER AGRESSIVENESS DOES NOT DIFFER 

BETWEEN INSULIN-SENSITIVE AND INSULIN-RESISTANT 

POSTMENOPAUSAL NON-DIABETIC WOMEN 

H.K. van Halteren 1 , S.B. Bins 2 ,W.DeRoos 3 , A. Bosch 3 , J. Klein Gunnewiek 4 , 

E. Ruijter 5 , J. Enserink 3 

1 Department of Internal Medicine, Ziekenhuis Gelderse Vallei, Ede, 

NETHERLANDS, 2 Internal Medicine, Gelderse Vallei Hospital, Ede, 

NETHERLANDS, 3 Surgery, Gelderse Vallei Hospital, Ede, NETHERLANDS, 

4 Clinical Chemistry, Gelderse Vallei Hospital, Ede, NETHERLANDS, 5 Pathology, 

Alysis Hospital, Arnhem, NETHERLANDS 

Background: The metabolic syndrome is known to negatively influence breast cancer 

outcome. One of the syndromès components is hyperinsulinism, which can exert 

tumor-promoting effects directly or through increased hepatic IGF1-production. A 

fasting insulin concentration > 10 µIU/ml and/or a HOMA score > 2.6 are considered 

diagnostic for the metabolic syndrome. We performed a pilot study to evaluate the 

relation between insulin resistance and tumor characteristics. 

Study design: Prior to surgery we collected blood samples of 33 consecutive 

non-diabetic postmenopausal women with early breast cancer to measure fasting 

insulin and glucose concentration. Correlation analyses were performed for both 

fasting insulin and HOMA-score (insulin resistance index) and parameters tested 

were body mass index, mitotic activity index (MAI), Bloom Richardson score (BNR) 

and tumor diameter. We also compared nodal status, ER-status and Her2-status of 

insulin-resistant and insulin-sensitive breast cancer patients. 

Results: Median age was 66 (49- 86) years and median BMI was 25.8 (18.6- 45.4) kg/ 

m2. Median MAI was 7 (1-52), median tumor diameter was 12 (3- 70) mm and 9 

patients had node-positive disease ( 2 N0itc, 5 N1, 2 N2). Insulin resistance was 

found in 5 (15 %) patients. BMI showed a strong positive correlation with insulin 

concentration and HOMA score (2-sided Pearson test; P= 0.000). Insulin resistant 

and insulin sensitive patients however did not differ in terms of MAI, BNR, tumor 

diameter, nodal status, ER-status and Her2-status. 

Conclusion: In postmenopausal non-diabetic women with early breast cancer insulin 

resistance is encountered quite often. It does however not appear to alter cancer 

biology. 


302 STUDY ON SERUM HER2 EXTRACELLULAR DOMAIN 

EXPRESSION IN EARLY STAGE BREAST CANCER PATIENTS 

L. Ma 1 , H. Yang 2 ,J.Li 3 ,F.Wang 2 , X. Han 3 ,Y.Shi 1 

1 Medical Oncology, Cancer Institute/Hospital, Beijing, CHINA, 2 Pathology, 

Cancer, Beijing, CHINA, 3 Clinical Laboratory, Cancer Institute/Hospital, Beijing, 

CHINA 

Background: The measurement of the human epidermal growth factor receptor 2 

(HER2) protein in the serum of metastatic breast cancer patients has now been 

reported, but there are no consistent data to support the clinical utility of serum 

HER2 extracellular domain (ECD) for patients with early breast cancer. We aimed to 

evaluate the correlation between serum HER2 ECD levels and tumor HER2 status, 

and analyze their relationship with clinicopathological parameters in patients with 

early stage disease. 

Methods: A prospective study was conducted on 232 breast cancer patients with 

stage I-II diseases before treatment. Preoperative serum samples were measured by 

enzyme-linked immunosorbent assay (ELISA). Tissue HER2 status was analyzed by 

immunohistochemistry and fluorescence in situ hybridization assays. 

Results: The median serum HER2 ECD concentration was 6.8 ng/ml (range 1.3 - 

42.1 ng/ml). The best diagnostic cut-off value was 7.4 ng/ml (with 72.9% sensitivity 

and 85.3% specificity), which was lower than HER2 ECD cut-off value with 

metastasis breast cancer (15 ng/ml). High serum HER2 ECD levels were reported in 

89 patients (38.3%) and HER2 tissue positive expression was observed in 77 patients 

(33.2%) with a moderate concordance of 76.7%. Elevated serum HER2 ECD 

correlated with postmenopausal (p < 0.001), high tumor grade (p < 0.001), negativity 

of both estrogen (p = 0.007) and progesterone receptors (p < 0.001), high level of 

carbohydrate antigen 153 (CA153) (p = 0.039) and tissue polypeptide specific antigen 

(TPS) (p = 0.018). 

Conclusion: HER2 ECD, which is associated with poor prognosis, may provide more 

additional information compared with HER2 tissue alone. We support that it is 

necessary to decrease the cut-off value in evaluating serum HER2 ECD level for early 

stage breast cancer. 


303 CLINICAL RELEVANCE OF HORMONE RECEPTORS, KI67 AND 

HER-2 STATUS AS BIOMARKERS SURROGATE FOR BREAST 

CANCER MOLECULAR SUBTYPES: A RETROSPECTIVE 

ANALYSIS OF DISEASE FREE SURVIVAL IN PATIENTS WITH T1 

N0/N+ BREAST CANCER 

A. Emiliani 1 , A. Iannace 1 , G. Nigita 2 , T. Losanno 1 , G. Manna 1 , E. Franzese 3 , 

L. Frati 1 

1 Department Experimental Medicine, Sapienza University, Rome, ITALY, 2 Division 

of Surgery, Policlinico Casilino, Rome, ITALY, 3 Internal Medicine, Sapienza 

University, Rome, ITALY 

Background: Early breast cancer (EBC) is a heterogeneous disease with distinct 

clinical, pathological, and molecular features and different treatment responsiveness 

and outcomes. Aim of study was to evaluate outcomes according to molecular 

subtypes breast cancer classified by four biomarkers using immunohistochemistry 

(IHC). 

Patients and methods: We retrospectively reviewed 264 women with T1 N0/N+ 

breast cancer, referred to a single centre (1986 - 2009) and treated according to 

European guidelines. The relationships between classical prognostic factors, 

molecular subtypes classified by IHC and Disease free survivals (DFS) were analyzed. 

Results: Univariate survival analysis showed a significantly different DFS at 5- and 

7-ys for N0 and N+ patient populations, with a better outcome for patients with 

node-negative tumors (5ys: N0 = 95.9% vs. N + =88.8, p = 0.03; 7ys: N0 = 94.8% vs. 

N + =86.0%, p = 0.02). Nevertheless, long-term outcome (15-ys) displayed an 

inversion of the survival curves with a lower DFS rate of 65% in N0 vs. 86% in N+ 

patients (p < 0.0001). Regarding to Ki-67 tumor expression, patients with low Ki67 

values (Ki-67 < 14%) had a better 5-ys DFS compared to patients with high Ki-67 

(Ki-67 ≥ 14%). A significant difference in DFS has been observed also considering 

the tumor grading (G1 = 100%, G2 = 88%, G3 = 94.4%, p = 0.03). Based on molecular 

subtypes breast cancer classification by IHC, the 5-ys DFS rate was 98.4% for 

Luminal A (HR + , HER2-, Ki-67 < 14%), 96.3% for Luminal B HER2 negative (HR 

+ , HER2-, Ki-67 ≥ 14%), 83.3% for Luminal B HER2 positive (HR + , HER + , any 

Ki-67), 83.6% for HER2-like (HR-, HER2+) and 74.5% for Basal-like tumors (HR-, 

HER2-). 

Conclusions: At long-term follow-up, patients with T1N0 and patients with G2 EBC 

showed worst outcomes, probably because they are considered to have a low 

recurrence risk and not received adjuvant chemotherapy. Ki-67 expression is an 

important prognostic factor in hormone-receptors positive disease, allowing better 

definition of Luminal A and B molecular subtypes. Classic prognostic factors 

evaluated by IHC could be used as biomarkers surrogate for breast cancer molecular 

subtypes and might improve therapeutic decision in EBC patients. 


304 PROGNOSTIC VALUE OF CIRCULATING TUMOR CELLS IN 

EARLY BREAST CANCER PATIENTS DETECTED BY RT-PCR 

OF MAMAGLOBIN 

A.M. Hilal 1 , H.M. Elzawahrey 1 , A.A. Abd Elwahab 2 , M.N. Abdelhafez 1 , 

M.M. Moneer 3 , A.D. Darwish 1 

1 Medical Oncology, National Cancer Institute, Cairo, EGYPT, 2 Molecular Biology, 

National Cancer Institute, Cairo, EGYPT, 3 Epidemiology & Biostatistics, National 

Cancer Institute, Cairo, EGYPT 

Background: The identification of circulating tumor cells (CTC) could potentially 

become an important prognostic factor in breast cancer patient. The aim of this 

prospective study is to detect CTC in the blood of breast cancer patients and to 

correlate between detection of CTC and other prognostic factors, disease free survival 

and overall survival. 

Material and methods: The study was conducted at medical oncology department 

NCI, Cairo University during the period from August 2008 to August 2011. Forty 

two consecutive consenting female patients with non metastatic breast cancer who 

ended their adjuvant chemotherapy and radiotherapy at least 2 years were recruited. 

Detection of CTC in the blood of our patients was done by measuring the gene 

expression for mammaglobin by RT-PCR, and then the relative fold change was 

calculated relatively to normal samples. 


Results: The median CTC fold changes were 9.3, ranging from 0 to 20.8 in the whole 

studied group while zero for the control group. There was a highly statistically 

significant difference (p = 0.001) between CTC fold changes for stage IIIA compared 

to stage II tumor, and a statistical significance (p = 0.070) in favor of higher CTC 

fold changes in those with Her2-neu receptor positivity. There was no significant 

correlation between higher CTCs and other factors related to the patients or disease 

characteristics. There was also no relation between CTC fold changes and overall 

survival or disease free survival. 

Conclusion: In this small study, mammaglobin is considered a sensitive marker for 

detection of CTC in breast cancer. CTC fold changes are correlated with tumor stage 

and Her2 status. Further studies including larger number of patients and followed for 

longer period are recommended to evaluate this protocol more thoroughly. 


305 IMMUNOHISTOCHEMICAL KI67 LABELING INDEX HAS A 

SIMILAR PROLIFERATION PREDICTIVE POWER AS VARIOUS 

FIRST-GENERATION GENE SIGNATURES IN BREAST CANCER 

N. Niikura 1 , T. Iwamoto 2 , S. Masuda 3 , N. Kumaki 4 , M. Shirane 5 , K. Mori 5 , 

T. Okamura 1 , Y. Saito 1 , Y. Suzuki 1 , Y. Tokuda 1 

1 Breast and Endocrine Surgery, Tokai University School of Medicine, Kanagawa, 

JAPAN, 2 Department of Breast and Endocrine Surgery, Okayama University 

Hospital, Okayama, JAPAN, 3 Department of Pathology, Nihon University School 

of Medicine, Tokyo, JAPAN, 4 Department of Pathology, Tokai University School 

of Medicine, Kanagawa, JAPAN, 5 Product Research, Chugai Pharmaceuticals 

Co. Ltd, Kanagawa, JAPAN 

Background: Immunohistochemical assessment of Ki67 labeling index (IHC Ki67) 

has been described as a prognostic and predictive marker for breast cancer. On the 

other hand, several genetic prognostic markers have been described for breast cancer 

However, few clinical data sets provide information on correlations between genomic 

markers, mRNA Ki67, and IHC Ki67 in the same cohort of patients with survival 

data. The objective of this study is to examine the association between 

immunohistochemical Ki67 labeling index, Ki67 mRNA expression level, and 

first-generation gene signatures in a cohort of breast cancer patients. 

Patients and methods: We assessed associations between IHC Ki67 and 

first-generation gene signatures in a panel of 40 tumor samples, using an 

oligonucleotide microarray. Gene expression analyses included Ki67 alone (MKi67), 

21-gene signature, Mitosis Kinome score signature (MKS), and Genomic grade index 

(GGI). Correlation coefficients were calculated by Spearman’s rank correlation test. 

To assess the relationship between IHC Ki67 and survival outcomes, survival curves 

were calculated by the Kaplan–Meier method and compared with the log-rank test 

according to IHC Ki67. 

Results: Median age at diagnosis was 51 years. Treatments included adjuvant 

chemotherapy (32 patients) and endocrine therapy (21 patients). IHC Ki67, MKi67, 

and 3 genetic markers were highly correlated in all cases (Rho: 0.71–0.79). Estrogen 

receptor (ER)-positive cases exhibited strong correlations between IHC Ki67 and 

other signatures (Rho: 0.79–0.83). ER-negative cases displayed slightly lower 

correlations (Rho: 0.61–0.74). In ER-positive cases, the low IHC Ki67 group 

exhibited significantly longer relapse-free survival (RFS) than the high IHC Ki67 

group (p = 0.007). This difference was confirmed by multivariate analysis. 

Conclusions: Our data indicate that IHC Ki67 exhibits similar predictive power for 

proliferation in ER-positive cancers as genomic markers. Further study of IHC Ki67 

is needed to define prognostic factors and predictive factors for chemotherapy using 

central laboratory assessment. 


306 ONCOTYPE DX® - THE SíRIO-LIBANêS HOSPITAL CANCER 

CENTER EXPERIENCE 

A.A.L. Pereira 1 , A.K. Shimada 1 , F.C. Santini 1 , E.C. Nascimento 2 , K.B. Ribeiro 3 , 

R.J. Marques 1 , M.S. Mano 1 , A. Katz 4 

1 Centro de Oncologia - 2° Andar, Sirio Libanes Hospital, Sao Paulo, BRAZIL, 

2 Imunohistoquímica e Biologia Molecular, Diagnostika, Sao Paulo, BRAZIL, 

3 Instituto de Ensino e Pesquisa, Sirio Libanes Hospital, Sao Paulo, BRAZIL, 

4 Centro de Oncologia, Sirio Libanes Hospital, Sao Paulo, BRAZIL 

Background: The Oncotype Dx® recurrence score (RS) assay quantifies the risk of 

distant recurrence (rDR) and its use has increased despite the lack of prospective 

studies. 

Methods: This is a cross-sectional study of consecutive patients (PTS) from our 

Institution with histologically confirmed invasive breast cancer (IBC) who underwent 

surgery with curative intent and in whom Oncotype Dx (ODx) was performed. The 

main objectives were to compare (1) the predicted rDR by RS and Adjuvant! (2) Risk 

allocation by RS and St Gallen Criteria and (3) the agreement between histological 

grading (HG) and RS. 


Results: From October/2006 to April/2012, 105 PTS with ER positive IBC were 

evaluated. Median age: 55y. Sixty-eight (64.8%) were EC IA; axillary lymph node 

involvement was seen in 25 PTS (14 micro and 11 macrometastasis). The rDR by RS 

was low in 64 PTS (60.9%), intermediate in 34 (32.4%) and high in 7 (6.7%). 

According to Saint Gallen, 12 (12%), 68 (68%) and 20 PTS (20%) were classified as 

low, intermediate and high risk, respectively, among 100 classifiable PTS. There was 

no statistically significant agreement between risk allocation by RS and Saint Gallen 

criteria (Kappa coefficient = -0.043; p = 0.401). Ki-67 data was available for 89 PTS: 


Aim: Retrospective analysis of relapse free (RFS) and overall survival (OS) in HER2+ 

BC patients treated with adjuvant trastuzumab in years 2005-09. 

Results: Adjuvant T received 317 patients, median age 53 (min 23; max 78) years. 

Ninety five percent were invasive ductal carcinoma and 97% grade 2/3, 55% were ER 

positive. Tumor stage was T1 (29%), T2 (48%), T3 (11%), T4 (10%), unknown (2%). 

N stage was N0 (26%), N1 (50%), N2 (16%), N3 (7%), unknown (1%). All patients 

recieved adjuvant chemotherapy, 41% anthracycline-based, 48% anthracycline and 

taxane- based. The median follow-up time was 4.5 (min 0.7; max 6.9) years. There 

were 66 relapses and 28 deaths. RFS was 98.1, 92.3, 84.2 and 80.8% at 1, 2, 3, 4 years, 

resp. OS was 99.7, 96.6, 93.4 and 92.5%, at 1, 2, 3, 4 years, resp. The independent 

prognostic factor for RFS were T stage (HR 1.2 95% CI1.0-1.4) and N stage (HR1.3 

(1.1-1.5). Chemotherapy regimen was not found as a prognostic factor for RFS. 

Conclusions: This is one of the first reports of the population based results of the 

adjuvant T treatment. Our results, based on adjuvant T treatment of real-life HER2 

+ BC patients, are fully comparable to the results obtained in HERA and Joint 

American study with 4-years RFS around 80%. 


309 DELAYED CARDIAC TOXICITY IN BREAST CANCER PATIENTS 

TREATED WITH ADJUVANT OR NEOADJUVANT 

CHEMOTHERAPY (INCLUDING ANTHRACYCLINES) AND 

TRASTUZUMAB 

A. Mailliez 1 , N. Kotecki 2 , C. Kouakam 3 , C. Fournier 4 , J. Bonneterre 5 

1 Breast Department, Centre Oscar Lambret, Lille, FRANCE, 2 Breast Cancer 

Departement, Centre Oscar Lambret, Lille, FRANCE, 3 Soins Externes, Centre 

Oscar Lambret, Lille, FRANCE, 4 Biostatistics, Centre Oscar Lambret, Lille, 

FRANCE, 5 Breast Cancer Department, Centre Oscar Lambret, Université Lille 

Nord de France, Lille Cedex, FRANCE 

New treatments in the (neo) adjuvant settings for HER2 positive breast cancer have 

recently changed their prognosis due to the systematic use of Trastuzumab (T). 

Progress however has been associated with a risk of cardiac toxicity. Since the 

incidence of cardiotoxicity is low and inconsistent across the 5 major adjuvant trials, 

we undertook a study to determine the cardiotoxicity rate of adjuvant or neoadjuvant 

sequential chemotherapy (3 FEC 100-3 Docetaxel) and T in non selected breast 

cancer pts treated at the Oscar Lambret Center between 2005-2007 and who did not 

relapse. 

Patients (pts) and methods: 121 pts met the inclusion criteria and were invited for a 

cardiac evaluation. 79 accepted and had a clinical examination, an Electrocardiogram 

(ECG) and an isotopic or echocardiographic measurement of Left Ventricular 

Ejection Fraction (LVEF). We also retrospectively collected, LVEF values at 

chemotherapy initiation, at T initiation, and after 3, 6, 9 and 12 months of 

T. Cardiotoxicity was defined as a decrease in LVEF of more than 10% or a level of 

LVEF less than 55% or clinical or ECG symptoms. The 33 pts not responding to the 

convocation had similar characteristics to those analysed. 

Results: 51 pts received 1 year T, 7 pts had 6 months T and 21 pts stopped T before 

1 year because of a decrease in LVEF. Median follow up was 5.1 years (3.2 to- 6.5). 

66 pts had at least 4 evaluations and were considered evaluable. No pts experienced 

clinical or ECG symptoms. 30 pts always had a normal LVEF. 36 pts (55%) had a 

normal initial LVEF but a decrease during follow up; 20% appeared more than 6 

months after initiation. 11 pts (16%) had previously experienced a decrease in LVEF 

with anthracyclines, eight of whom also had cardiotoxicity during T. No risk factor 

of cardiac disease was observed in pts with cardiotoxicity. No correlation was found 

with age, side of the tumor, previous radiotherapy. Cardiotoxicity was more 

frequently observed in pts with ER negative tumors (74% vs 39%). At the time of the 

last evaluation, no abnormal LVEF was observed. 

Conclusion: The cardiotoxiciy rate was unexpectedly high in these non selected pts. 

Nevertheless, LVEF remained normal after a median follow up of 5.1 year. 


310 EVALUATION OF AROMATASE INHIBITOR-RELATED 

ARTHRALGIA IN EARLY BREAST CANCER PATIENTS 

N. Romero Laorden, C. Olier, X. Mielgo, S. Falagán, A. Velástegui, S. Hernando, 

J.C. Cámara, A. Hurtado, J. Garcia-Donas, C. Jara 

Medical Oncology, Hospital Universitario Fundacion Alcorcon, Alcorcon, Madrid, 

SPAIN 

Introduction: Aromatase inhibitors (AI) have demonstrated a disease-free survival 

benefit compared with tamoxifen as adjuvant therapy in the treatment of 

hormone-dependent early breast cancer in postmenopausal women. Although the AI 

are associated with fewer thromboembolic events and endometrial abnormalities than 

tamoxifen, an increase in arthralgia, skeletal, and muscle pain has been reported and 

cited as the primary reason for discontinuation of AI therapy. The aim of our study 

was to evaluate the incidence and the impact of the arthralgia syndrome in our 

population. 

Methods: Postmenopausal patients with the diagnosis of early-stage 

hormone-sensitive breast cancer receiving AI therapy at our institution were 

included prospectively between 2010-2012. We performed a specific survey to 

evaluate articular toxicity collecting presence of arthralgias, EVA scale, use of 

analgesic, start time and localization of the pain. Clinical data was collected 

from our department database. Univariate analysis was used to compare 

those with AI-related arthralgia and different demographic and clinical 

features. 

Results: A total of 83 women were included, with a mean age 63.2, BMI 28.4, 

menopause mean age 48.2. Regarding to the features of the primary tumor, 

81.9% had ductal carcinoma histology, 28.9% stage I, 54.2% stage II, 16.8% stage 

III. At the moment of the evaluation, 68.7% (57/83) were receiving treatment 

with anastrozole, 15.7% (13/83) letrozole, 15.7% (13/83) exemestane. 86.7% (72/ 

83) had joint pain, of them 68.1% (49/72) related their pain to the hormone 

therapy, 31.9% (23/72) to previous diseases or another treatments. The 

articulations more frequently affected were located in the back, knees and hands. 

Regarding to the pain intensity, mean maximum EVA was 6.03, minimum 1.06. 

Only 2 of the patients affected stopped therapy, and it was changed for another 

aromatase inhibitor. No differences were seen between the different aromatase 

inhibitors. 

Conclusions: The incidence of arthralgia associated with aromatase inhibitors 

was superior in our series compared with results previously published in 

clinical trials. Further research in this field should be developed to clarify the 

prevalence and severity of joint symptoms related to AI and to define factors 

that may be associated with an increased risk of this treatment-related adverse 

effect. 


311 ENDOMETRIAL EFFECTS OF TAMOXIFEN AND EXEMESTANE 

IN EARLY BREAST CANCER: FINAL RESULTS OF A 

RANDOMIZED PHASE III TRIAL 

O. Garrone 1 , E. Principe 2 , M. Monteverde 3 , M. Occelli 1 , G. Bertelli 4 , B. Favilla 2 , 

T. Catzeddu 1 , P. Vanella 1 , E. Miraglio 1 , M. Merlano 1 

1 Clinical Oncology, Azienda Ospedaliera St. Croce e Carle, Cuneo, ITALY, 

2 Gynecology, Azienda Ospedaliera St. Croce e Carle, Cuneo, ITALY, 3 Oncology, 

S. Croce General Hospital, Cuneo, ITALY, 4 Oncology, South West Wales Cancer 

Instiute, Swansea, UNITED KINGDOM 

Background: Tamoxifen (T) has been for a long time the treatment of choice 

in hormonal receptor positive early breast cancer patients (EBCP). It is 

known that T has partial estrogen agonistic activity on uterus determining 

an increase in gynecological symptoms. Long-term T treatment can lead to 

an increased incidence of endometrial cancer. The availability of aromatase 

inhibitors (AI) has modified the prescription options in postmenopausal 

breast cancer patients while remaining the standard of care in 

premenopausal setting. AI do not mediate their effects through the estrogen 

receptor potentially conferring tolerability advantages to women particularly 

in relation to their effects on the endometrium. So far some studies 

including all the available AI have been published which confirmed the lack 

of estrogen effects of AI on endometrium compared to T. In 2001 we 

started a phase III study comparing T and Exemestane (E) in EBCP in 

order to evaluate the differences in the endometrial changes recorded by 

transvaginal ultrasound (TVUS). 

Material and methods: Postmenopausal hormonal receptor positive EBCP were 

randomly assigned to receive T or E. A baseline TVUS was performed and repeated 

after 6 and 12 months. The primary end-point, endometrial thickness (ET) was 

evaluated with T-test. 

Results: From 2001 to 2008 220 patients were enrolled in our department. Patients’ 

characteristics were well balanced in each arm. Definitive results are summarized in 

the table: 

ET 

(median) 

Baseline 

ET (median) 

After 6 m 

p(ET 

baseline 

vs 6 

months) 

ET (median) 

After 12 m 

p (ET 

baseline 

vs 12 

months) 

E 3 (1.4-5) 3 (1.17-9.3) NS 2.8 (0.02-13.5) NS 

T 3 (0.14-5) 6.64 (1.9-19.7)

312: Table: Chemotherapy uptake within MWRH 

Decision-making tools (DMT) 

Nottingham Prognostic Index (NPI) · Excellent (≤ 2.40) · 

Good (2.41 – 3.40) · Moderate (3.41 – 5.40) · Poor (≥ 

5.41) 

Adjuvant! Online (AO) – additional 10-year survival 

benefit of chemotherapy and hormonal therapy · 

0.0 – 2.5% · 2.6 – 5.0% · 5.1 – 7.5% · ≥ 7.5% 

Oncotype Dx Recurrence Score (RS) Assay · Low (1–17) · 

Intermediate (18 – 30) · High (>31) 

312 CORRELATION BETWEEN DECISION-MAKING TOOLS AND 

CHEMOTHERAPY UPTAKE IN NODE-NEGATIVE ENDOCRINE 

RECEPTOR EARLY-STAGE BREAST CANCER IN 

MID-WESTERN IRELAND 

K.I. Quintyne 1 , B. Woulfe 1 , J.C. Coffey 2 , R.K. Gupta 1 

1 Mid-Western Cancer Centre (MWCC), Mid-Western Regional Hospital (MWRH), 

Limerick, IRELAND, 2 Department of Surgery, Mid-Western Regional Hospital 

(MWRH), Limerick, IRELAND 

Background: Good clinical judgement remains the best tool in determining a 

therapeutic plan; however this process has become easier, and more reproducible 

with the ongoing progression of decision-making adjuncts such as: Nottingham 

Prognostic Index (NPI), which incorporates pathological features; Adjuvant! Online 

(AO), which incorporates clinic-pathological features; and Oncotype Dx ® Recurrence 

Score (RS) assay, which incorporates genetic features. We herein report our 

experience with the use of these tools, and their potential impact on chemotherapy 

uptake for patients in MWRH, Limerick, Ireland. 

Methods: Study period: 01/09/2008 – 31/12/2012. Data was derived from (1) MWCC 

Oncology database (2) pathology reports (3) patient files (4) RS assay reports. Data 

was collated and entered into an Access database and exported into SPSS (v.18) for 

analysis. Results Seventy-seven (77) patients with early stage endocrine positive breast 

cancer were analysed. Median age: 55.9 years (range: 30.6 – 72.3 years). Median 

follow-up: 20.9 months. Findings are shown below in tabular form. 

Conclusions: Chemotherapy uptake from the decision-making tools was varied 

within the cohort, but it was uniformly noted that patients were more likely to 

undertake chemotherapy if they had higher indices derived from these DMT, except 

in cases where the patients declined therapy, or if physicians’ preference differed on 

clinical grounds. This highlights that none of the available DMT are perfect in 

isolation, but when used in concert, they can elucidate the best potential treatment 

pathway following consultation between patients and their healthcare providers; this 

is given by the fact that they all rely on different subsets of information to predict 

potential outcome. Further work is needed to find an algorithm that can 

appropriately incorporate these DMT any potential patient’s best interest. 


313 DOCETAXEL IN THE TREATMENT OF BREAST CANCER: A 

MULTICENTER RETROSPECTIVE STUDY FROM CHINA 

B. Xu 

Medical Department, Cancer Hospital, Chinese Academy of Medical Sciences, 

Beijing, CHINA 

Background: Docetaxel is considered as a fundamental drug in the treatment of 

breast cancer. It has been extensively incorporated into the neoadjuvant, adjuvant 

and metastatic treatment. The aim of this study was to investigate how breast cancer 

patients are treated with docetaxel in China. 

Methods: A retrospective review of chemotherapy with docetaxel performed from 

2009 to 2011 was carried out in China. Study included all patients diagnosed with 

invasive breast cancer and treated with docetaxel-containing regimens in forty-two 

cancer centers from 12 provinces in China. Regimens were compared in different 

subgroups based on stage, subtype, and lymph node (LN) status. Patterns of 

chemotherapy were also compared to published guidelines. 

Results: Among 2188 breast cancer patients treated with docetaxel, 1881 (86.0%) 

were in adjuvant or/and neoadjuvant setting (including 91 in both settings). The 

mean age was 48.7 (range, 14-82). Compared with 288 patients using docetaxel as 

single agent therapy, more patients (86.8%) used docetaxel-containing combination 

regimens. The mean cycle administered and dose for every cycle was 4.8 and 73.0 

mg/m2, respectively. Dose reduction and delay occurred in 409 (19.7%) patients 

mainly due to non-medical factors (10.9%) and hematologic toxicity (5.9%). TAC, 

TA, TC, TX, and AC-T regimens were given in 34.8%, 19.7%, 17.4%, 5.3%, and 2.2% 

of patients respectively. TAC was used more frequently in triple-negative breast 

cancer (TNBC) than other patients (43.0% vs. 32.7%, P = 0.004). In the (neo) 

adjuvant setting, TAC regimen was used more frequently in LN-positive patients 

Chemotherapy Uptake 

Offered Undertaken Not offered 

2/7 16/41 21/29 0/0 1/7 13/41 21/29 0/0 5/7 25/41 8/29 0/0 

8/21 12/33 9/13 10/ 

10 


6/21 10/33 9/13 10/10 13/21 21/33 4/13 0/10 

13/38 20/33 6/6 11/38 18/33 6/6 25/38 13/33 0/6 

than LN-negative group (44.2% vs. 30.0%, P < 0.001). Of 1682 patients in adjuvant 

setting, 729 (43.3%) were treated with triplet (TAC or AC-T). In 290 patients 

receiving neoadjuvant chemotherapy, only 94 (32.4%) used TAC and none used 

AC-T (P = 0.013). 

Conclusions: Docetaxel was widely used in the treatment of breast cancer in China, 

especially in the (neo)adjuvant setting. TAC regimen was the most frequent option, 

especially in patients with TNBC or LN-positive BC. Although AC-T was also 

recommended in adjuvant setting by most guidelines, it was less commonly used 

compared to TAC regimen in China. 


314 MOVING FROM 2D TO 3D-CRT PLANNING OF CHEST WALL 

FOR POSTMASTECTOMY BREAST CANCER PATIENTS: 

MANSOURA UNIVERSITY EXPERIENCE 

I. Awad, D. Zayed, N. Abotouk, T. Dawood 

Clinical Oncology, Mansoura University Hospital School of Medicine, Mansoura, 

EGYPT 

Background: This study evaluates the dose distribution of the wedged tangential 

beam three-dimensionally planned conformal radiotherapy (3D-CRT) compared to 

the previously used (5 years ago) two-dimensionally(2D) planned radiotherapy of the 

chest wall for postmastectomy breast cancer patients in Clinical Oncology and 

Nuclear Medicine Department - Mansoura University. 

Patients and methods: Thirty six breast cancer patients were randomized for 

planning by both the standard 3D-CRT and 2D-RT techniques for radiotherapy of 

the chest wall. Dose-volume histograms were carried out by the 3D treatment 

planning system. They were assessed for the PTV and organs at risk. The total dose 

was 50 Gy in 25 fractions. 

Results: The three–dimensionally planned conformal radiotherapy showed a 

significantly better homogeneity index of the PTV (chest wall). The ipsilateral mean lung 

dose was significantly reduced with the tangential beam 3D-CRT plans with an average 

of 24.6% (1217 cGy versus 1614 cGy). For the left sided breast cancer patients, the mean 

heart dose was also reduced by an average of 48.6% (718 cGy versus 1398 cGy). 

Conclusions: The tangential beam 3D-CRT planning demonstrated a significantly 

better homogeneity index for the PTV of the postmastectomy breast cancer patients 

with a statistically significant reduction in the mean doses of the ipsilateral lung and 

the heart for the left –sided breast cancer patients. 


315TiP SAFEHER: A STUDY OF ASSISTED- AND 

SELF-ADMINISTERED SUBCUTANEOUS TRASTUZUMAB 

(H-SC) AS ADJUVANT THERAPY IN PATIENTS WITH EARLY 

HER2-POSITIVE BREAST CANCER (EBC) 

J. Gligorov 1 , H.A. Azim 2 , B. Ataseven 3 , M. Delaurentiis 4 , K.H. Jung 5 , F. Herbst 6 , 

A. Llombart 7 , A. Manikhas 8 , S. Osborne 9 , X. Pivot 10 

1 Medical Oncology Department, Tenon Hospital, Paris, FRANCE, 2 Clinical 

Oncology Department, Cairo University, Cairo, EGYPT, 3 Department of 

Obstetrics and Gynaecology, Rot-Kreuz-Klinikum, Munich, GERMANY, 4 Breast 

Oncology Department, National Cancer Institute “Fondazione Pascale”, Napoli, 

ITALY, 5 Department of Oncology, Asan Medical Center, University of Ulsan 

College of Medicine, Seoul, KOREA, 6 Oncology, F. Hoffmann-La Roche Ltd., 

Basel, SWITZERLAND, 7 Medical Oncology Service, Hospital Arnau de Vilanova, 

Valencia, SPAIN, 8 Oncology, Oncology Hospital of St. Petersburg, 

St. Petersburg, RUSSIAN FEDERATION, 9 Statistics, F. Hoffmann-La Roche Ltd., 

Basel, SWITZERLAND, 10 Chimiothérapie – Oncologie, CHU Jean Minjoz, 

Besançon, FRANCE 

Purpose: One year of H-based therapy, consisting of 18 q3w cycles, is standard of 

care for the adjuvant treatment of HER2-positive EBC. H is administered 



intravenously (IV) over 30–90 mins. An SC formulation of H has been developed, 

which is rapidly administered (up to 5 mins), potentially improving convenience for 

patients and clinical staff, and reducing administration costs. The Phase III HannaH 

study (NCT00950300) demonstrated that the pharmacokinetics and efficacy of H-SC 

were non-inferior to that of H-IV, meeting the co-primary endpoints. The safety 

profile of H-SC was comparable and consistent with the known safety profile of 

H-IV. SafeHer is designed to further evaluate the safety and tolerability of H-SC in a 

broader patient population; to allow greater understanding of a range of safety data. 

H-SC will be administered via one of two different routes (handheld syringe [vial 

formulation] or single-use injection device [SID]; which allows self-administration). 

Supportive data on SID safety and patient satisfaction with self-administration will be 

collected. 

Methods: SafeHer is a multicentre, international, Phase III open-label trial 

(NCT01566721). The primary objective is the safety and tolerability of H-SC. 

Secondary objectives include disease-free survival, overall survival and patient 

satisfaction with SID administration. Immunogenicity of H and recombinant human 

hyaluronidase in a subset of patients using the SID at select sites is an exploratory 

objective. Planned enrolment is 2500 patients, assigned to one of two cohorts at the 

investigators’ discretion ± concurrent/sequential chemotherapy. All patients will 

receive H-SC at a fixed dose of 600mg regardless of body weight, for a total of 18 

cycles (q3w) via injection into the thigh over a period of up to 5 minutes. Patients in 

cohort A (n = 1800) will receive H-SC using handheld syringes. Patients in cohort B 

(n = 700) will receive H-SC using an SID, first via assisted administration and then 

self-administered (in select patients). Enrolment began in May 2012 and parallel 

substudies may be performed at selected centres to evaluate medical resource 

utilisation (“time and motion study”). 

Disclosure: J. Gligorov: I disclose potential conflict of interest : advisory boards and 

speaker honoraria for Roche laboratories. H.A. Azim: I serve on the advisory board 

of Roche in the middle east. B. Ataseven: I am a Roche International Steering 

Committee member for the SafeHer trial. I have received speaker honoraria from 

Roche for giveing lectures. I participated in and received a travel grant from Roche 

for SABCS 2011. M. Delaurentiis: I am a member of a Roche Advisory Board. F. 

Herbst: I am an employee of, and am a stockholder in, F. Hoffmann-La Roche. A. 

Llombart: I am a member of a Roche Advisory Board. S. Osborne: I am an employee 

of Roche. X. Pivot: I am a member of Roche and GSK Advisory Boards. All other 


316TiP DENOSUMAB VERSUS PLACEBO AS ADJUVANT 

TREATMENT FOR WOMEN WITH EARLY-STAGE BREAST 

CANCER AT HIGH RISK OF DISEASE RECURRENCE 

(D-CARE): AN IN PROGRESS, PHASE 3 CLINICAL TRIAL 

R.E. Coleman 1 , C. Barrios 2 , R. Bell 3 , D.M. Finkelstein 4 ,H.Iwata 5 , M. Martin 6 , 

A. Braun 7 ,C.Ke 8 , T. Maniar 7 , P.E. Goss 9 

1 Academic Unit of Clinical Oncology, University of Sheffield, Sheffield Cancer 

Research Centre, Sheffield, UNITED KINGDOM, 2 Department of Medicine, 

PUCRS School of Medicine, Porto Alegre, BRAZIL, 3 The Andrew Love Cancer 

Centre, Geelong Hospital:Deakin University, Geelong, AUSTRALIA, 4 Biostatistics, 

Massachusetts General Hospital, Boston, MA, UNITED STATES OF AMERICA, 

5 Aichi Cancer Center, Breast Oncology, Nagoya University School of Medicine, 

Nagoya, JAPAN, 6 Medical Oncology Service, Hospital General Universitario 

Gregorio Marañón, Madrid, SPAIN, 7 Hematology/oncology, Amgen Inc., 

Thousand Oaks, CA, UNITED STATES OF AMERICA, 8 Biostatistics, Amgen Inc., 

Thousand Oaks, CA, UNITED STATES OF AMERICA, 9 Cancer Center, 

Massachusetts General Hospital, Boston, MA, UNITED STATES OF AMERICA 

Background: Bone represents approximately 40% of all first recurrences in 

women with early-stage breast cancer and is a common site of distant 

recurrence. In preclinical studies, RANKL inhibition significantly delays skeletal 

tumour formation, reduces skeletal tumour burden, and prolongs survival of 

tumour-bearing mice. Denosumab is approved for the prevention of 

skeletal-related events (SREs) in patients with established bone metastases from 

solid tumours. 

Purpose: The D-CARE trial is designed to assess if denosumab treatment 

prolongs bone metastasis-free survival (BMFS) and disease-free survival (DFS) 

in the adjuvant breast cancer setting. The primary endpoint of this 

event-driven trial is BMFS. Secondary endpoints include DFS and overall 

survival. Additional endpoints are safety, breast density, incidence of SREs 

(following the development of bone metastasis), patient reported outcomes, and 

biomarkers. 

Methods: In this international, randomized, double-blind, and placebo 

controlled phase 3 trial, approximately 4,500 women with stage II or III breast 

cancer, at high risk for recurrence and with known hormone and HER-2 

receptor status, are eligible. High risk is defined as biopsy evidence of breast 

cancer in regional lymph nodes, tumour size > 5 cm, (T3), or locally advanced 

disease (T4). Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or 

HER-2 targeted therapy, alone or in combination, must be planned. Patients 

with a prior history of breast cancer (except DCIS or LCIS) or distant 

metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or 

any intravenous BP use, are not eligible. Patients are randomized 1:1 to receive 

denosumab 120 mg or placebo subcutaneously monthly for 6 months, then 

every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 

400 IU) and calcium (≥ 500 mg) will be administered. The trial, sponsored by 

Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, 

began enrolling patients in June 2010 and isexpectedtocompleteenrolmentin 

late 2012. 

Disclosure: R.E. Coleman: Other substantive relationships: Expert testimony - 

Novartis. R. Bell: Advisory Board Member : Amgen. M. Martin: Advisory Board 

Member amgen, roche, bayer, novartis, gsk, sanofi. A. Braun: Employee : Amgen 

Inc Stock : Amgen Inc. C. Ke: Employer : Amgen Inc. Stock ownership : Amgen Inc. 

T. Maniar: Employee :: Amgen Inc. Stock ownership :: Amgen Inc. P.E. Goss: 

Honoraria for Pfizer and Novartis. All other authors have declared no conflicts of 

interest. 


abstracts 

breast cancer, locally advanced and 

metastatic 

317O FIRST EFFICACY RESULTS FROM THE TURANDOT PHASE III 

TRIAL COMPARING TWO BEVACIZUMAB (BEV)-CONTAINING 

REGIMENS AS FIRST-LINE THERAPY FOR HER2-NEGATIVE 

METASTATIC BREAST CANCER (MBC) 

C. Zielinski, 1 , I. Lang 2 , M. Inbar 3 , Z. Kahan 4 , R. Greil 5 , S. Beslija 6 , 

S.M. Stemmer 7 , B. Kaufman 8 , Z. Zvirbule 9 , G. Steger 1 , B. Melichar 10 , 

T. Pienkowski 11 , D. Sirbu 12 , L. Petruzelka 13 , A. Eniu 14 , B. Nisenbaum 15 , 

M. Dank 16 , R. Anghel 17 , D. Messinger 18 , T. Brodowicz 1 

1 Medical University of Vienna, Vienna, AUSTRIA, 2 National Institute of Oncology, 

Budapest, HUNGARY, 3 Tel Aviv Sourasky Medical Centre, Tel Aviv, ISRAEL, 

4 University of Szeged, Szeged, HUNGARY, 5 University Hospital Salzburg, 

Salzburg, AUSTRIA, 6 Institute of Oncology, Sarajevo, BOSNIA AND 

HERZOGOVINA, 7 Rabin Medical Center, Petach Tikva, ISRAEL, 8 Sheba Medical 

Center, Tel Hashomer, ISRAEL, 9 Riga Eastern Clinical University Hospital, Riga, 

LATVIA, 10 Fakultni nemocnice Olomouc, Olomouc, CZECH REPUBLIC, 

11 Postgraduate Medical Center, Warsaw, POLAND, 12 Oncomed Oncology 

Practice, Timisoara, ROMANIA, 13 Charles University Prague, Prague, CZECH 

REPUBLIC, 14 Cancer Institute I Chiricuta, Cluj-Napoca, ROMANIA, 15 Meir 

Medical Center, Kfar Saba, ISRAEL, 16 Semmelweis University Radiology Clinic, 

Budapest, HUNGARY, 17 Institutul Oncologic Bucuresti, Bucarest, ROMANIA, 

18 IST GmbH, Mannheim, GERMANY 

Background: TURANDOT is the first prospective trial to compare BEV combined 

with either paclitaxel (PAC) or capecitabine (CAP). We report the planned interim 

analysis (IA) of efficacy. 

Methods: Patients with HER2-negative mBC who had received no prior 

chemotherapy for mBC were randomised to receive either BEV–PAC (BEV 10 mg/ 

kg d1 & 15 + PAC 90 mg/m d1, 8 & 15 q4w) or BEV–CAP (BEV 15 mg/kg d1 + CAP 

1000 mg/m bid d1–14 q3w) until disease progression or unacceptable toxicity. The 

primary objective is to demonstrate non-inferior overall survival (OS) with BEV– 

CAP vs BEV–PAC. Interim and final OS analyses were planned after 175 and 389 

deaths, respectively, in the per-protocol (PP) population to reject the null hypothesis 

of inferiority (hazard ratio [HR] ≥1.33) with 80% power and overall α = 0.025. 

Secondary endpoints include response rate (RR), progression-free survival (PFS), 

safety and quality of life. 

Results: Median follow-up was 19 months at data cut-off for this IA (1 Sep 2011). 

Baseline characteristics were generally similar in the 2 treatment arms. 

BEV-PAC 

(n = 285) 

Median age, years 59 59 

Visceral metastases, % 65 73 

Prior (neo)adjuvant taxane, % 

OS 

20 18 

a 

Events, % 33 35 

1-year OS rate, % b 

81 79 

HR (97.5% RCI c ) 

1.04 (−∞ to 1.69) 

for non-inferiority 

p = 0.0593 d 

RR 

Overall, % 44 27 

CMH test (superiority) 

PFS 

p < 0.0001 

Events, % 62 77 

Median, months 11.0 8.1 

HR (95% CI) 1.36 (1.09 to 1.68) 

Log-rank (superiority) p = 0.0052 

BEV–CAP 

(n = 279) 

RCI = repeated confidence interval 

a PP population (n = 533) 

b Kaplan–Meier estimate 

c Using O’Brien–Fleming boundaries 

d Non-inferiority not shown as p > 0.00105 (α at IA) AEs were consistent with the 

known safety profiles of BEV, PAC and CAP. The most common grade ≥3 AEs were 

neutropenia (18%), peripheral neuropathy (14%) and leucopenia (7%) with BEV– 

PAC and hand-foot syndrome (16%), hypertension (6%) and diarrhoea (5%) with 

BEV–CAP. 



Conclusion: In this planned IA, the non-inferiority criterion has not been met but 

OS results do not indicate relevant differences. Final results are expected in 2014. PFS 

and RR were better with BEV–PAC and very similar to previous data for BEV–PAC 

(E2100) and BEV–CAP (RIBBON-1). 

Disclosure: R. Greil: RG has received research support and honoraria from Roche. S. 

Beslija: SB has received research support and honoraria from Roche. D. Messinger: 

Employee of IST GmbH, CRO which is providing various services and consultancies 

for Hoffmann-La Roche and CECOG. T. Brodowicz: TB has received honoraria from 

Roche. All other authors have declared no conflicts of interest. 

318O PH IB/II STUDY OF BKM120 PLUS TRASTUZUMAB (T) IN 

PATIENTS WITH T-RESISTANT HER2+ ADVANCED BREAST 

CANCER (BC) 

B. Pistilli 1 , A. Urruticoechea 2 , S. Chan 3 , H.S. Han 4 , G. Jerusalem 5 , A. Kong 6 , 

Q. Ru 7 , S. Ruquet 8 , D.W. Sternberg 7 , C. Saura 9 

1 Dipartimento di Oncologia, Ospedale di Macerata, Macerata, ITALY, 2 Oncology, 

Catalan Institute of Oncology, Barcelona, SPAIN, 3 Oncology and Radiotherapy, 

Nottingham University Hospital, Nottingham, UNITED KINGDOM, 4 Women’s 

Oncology, Moffitt Cancer Center, Tampa, FL, UNITED STATES OF AMERICA, 

5 Medical Oncology, Centre Hospitalier Universitaire du Sart-Tilman, Liege, 

BELGIUM, 6 Oncology, Oxford University Hospitals NHS Trust, Oxford, UNITED 

KINGDOM, 7 Oncology, Novartis Oncology, Florham Park, NJ, UNITED STATES 

OF AMERICA, 8 Oncology, Novartis Oncology, Paris, FRANCE, 9 Vall D’hebron 

Hospital, Vall d’Hebron Institute of Oncology, Barcelona, SPAIN 

Background: PI3K/AKT/mTOR pathway upregulation has been implicated in T 

resistance, and thus the impact of pathway inhibition on restoration of therapeutic 

sensitivity is being investigated. The RP2D of BKM120, an oral pan-class I PI3K 

inhibitor, plus T is 100 mg/d. Here, we present Ph II results of BKM120 + T in pts 

with T-resistant advanced HER2+ BC. 

Methods: Pts with HER2+ locally adv/metastatic BC resistant to T (progression 

while on T, or within 4 wks [metastatic] or 12 mths [adjuvant] of last T dose) 

received daily BKM120 (100 mg) and the standard wkly dose of T. Ph II eligibility 

criteria: ≥1 measurable lesion, ≥1 but ≤4 prior anti-HER2 regimens (incl. 

trastuzumab [required], lapatinib, and/or T-DM1), and ≤3 lines of prior 

chemotherapy for metastatic disease. Ph IB pts treated at the RP2D who met Ph II 

eligibility criteria were included in the analysis. 

Results: As of 23 March 2012, 53 pts were included in the Ph II analysis (safety set; 

incl. 8 pts from Ph IB). 49 pts were evaluable for response (full analysis set); median 

age 52 yrs (28–75); median no. prior antineoplastic regimens 4 (1–10); 5 pts had a 

baseline CNS lesion (3 measurable target; 2 non-target). At data cut-off, 9 pts were 

still on study. Most pts discontinued treatment due to disease progression (55%); 8 

pts (16%) withdrew due to AEs. Mean duration of BKM120 exposure was 11 wks 

(0.1–41). Most common suspected study-drug related G3/4 AEs: ALT increased 

(5 pts); rash (5 pts); AST increased (4 pts); asthenia (3 pts); nausea, anxiety, skin 

photosensitivity, hyperglycemia (2 pts each). Partial responses (RECIST) were seen in 

4 pts (8%), and stable disease (SD) was noted in 20 pts (41%); the disease control 

rate (CR, PR, or SD) was 49%. Preliminary results indicate that, of the 5 pts with 

baseline brain mets (BM), 2 pts had SD in the CNS without evidence of progression 

at study withdrawal; 2 pts had overall SD (1 for 90 days and 1 for 106 days) before 

progression in the CNS; 1 pt was not evaluated in the CNS after study entry. 

Conclusion: BKM120 in combination with T has an acceptable safety profile, and 

has shown encouraging preliminary activity in heavily pretreated HER2+ metastatic 

BC pts with T resistance, including pts with BM. 

Disclosure: Q. Ru: Employee of Novartis. S. Ruquet: Employee of Novartis. D.W. 

Sternberg: Employee of Novartis. All other authors have declared no conflicts of interest. 

319O SIGNIFICANT ANTITUMOR ACTIVITY OF E-3810, A NOVEL 

FGFR AND VEGFR INHIBITOR, IN PATIENTS WITH FGFR1 

AMPLIFIED BREAST CANCER 

R. Dienstmann 1 , F. Andre 2 , J. Soria 3 , J. Tabernero 4 , F.G.M. De Braud 5 , 

R. Cereda 6 , R. Bahleda 3 , A. Hollebecque 3 , A. Delmonte 7 , M.G. Camboni 6 

1 Molecular Therapeutics Research Unit, Vall d’Hebron University Hospital, 

Barcelona, SPAIN, 2 Department of Medical Oncology, Institut Gustave Roussy, 

Villejuif Cedex, FRANCE, 3 Dept. of Medicine, Sitep, Institut Gustave Roussy, Villejuif 

Cedex, FRANCE, 4 Medical Oncology Service, Vall d’Hebron University Hospital, 

Barcelona, SPAIN, 5 Division of Oncology, Fondazione IRCCS - Istituto Nazionale dei 

Tumori, Milano, ITALY, 6 R&d Dept., EOS SpA, Milano, ITALY, 7 Clinical Pharmacology 

- New Drugs Development, Istituto Europeo di Oncologia, Milano, ITALY 

Background: Amplification of the FGFR1 gene occurs in subsets of tumors, notably 

breast cancer (BC), where the altered FGF pathway may be clinically relevant. 




Methods: E-3810 is a kinase inhibitor targeting FGFR1 and VEGFR1, 2, 3. Its safety 

and activity, at the daily oral dose of 20 or 15 mg on a continuous schedule, are 

being assessed in patients with solid tumors and FGFR1 amplification or potentially 

sensitive to antiangiogenic agents. The study is an open label non comparative 

extension of the first in man dose-escalation trial; the efficacy threshold, set for the 

FGFR1+ cohort only, requires 3/14 confirmed objective RECIST responses or 

non-progressive disease ≥ 6 cycles (one-stage Fleming design: H0 5%, H1 30%, power 

80%). 

Results: 46 patients with various tumor types (including 13 FGFR1+) were recruited. 

8 patients (4/13 and 4/33 treated respectively at 20 and 15 mg; none in the FGFR1+ 

cohort) were withdrawn for toxicity including: G3 proteinuria (5), headache and 

vomiting (2), pancreatic enzymes increase (1), recovered in all cases. Hypertension 

G2-3, proteinuria G2, GI intolerance, asthenia and weight loss led to dose reduction 

in 20 patients; frequent TSH increase required supplementation. Tolerability was 

better in the FGFR1+ cohort, in line with a limited prior exposure to antiangiogenic 

treatments. Antitumor activity is shown in the table: 

Antiangiogenic Sensitive FGF-amplified (1) 

Evaluable PR SD PD Evaluable PR SD PD 

Breast cancer 1 1 9 4 ** 3 2 

Other 23 3 *** 13 7 2 1 * 1 

Total 24 3 14 7 11 4 4 3 

(1) incl. the two BC patients with 11q amplification; * SD ≥ 24 weeks; ** 1 PET 

response (bone lesions); ***2 thyroid; 1 thymic carcinoma. 12 women with BC were 

recruited (9 HR + , 1 HER2 + /HR + , 2 TN); 8 were FGFR1 + , 2 more had 11q 

amplification (CGH). They were treated with a median of 5 prior chemotherapy 

lines; 9, 10 and 5 patients also received ≥ 1 endocrine, antiangiogenic and 

experimental therapies, respectively. There were 4 PRs sustained over 4-6 courses (3 

FGFR1 and one FGF4 amplification), with 3 responders still on treatment. 

Conclusions: E-3810 has shown significant activity in heavily pretreated BC, with 

durable responses in patients with altered FGF pathway. Further studies are planned 

in this population. 

Disclosure: R. Cereda: Currently an employee and stock holder at EOS SpA. M.G. 

Camboni: Currently an employee and stock holder at EOS SpA. All other authors 


320PD SIGNIFICANTLY SUPERIOR OUTCOME AFTER 

NEOADJUVANT CHEMOTHERAPY WITH DOCETAXEL, 

ANTHRACYCLINE AND CYCLOPHOSPHOMIDE VERSUS 

DOCETAXEL PLUS CYCLOPHOSPHOMIDE: RESULTS FROM 

THE NATT TRIAL IN TRIPLE NEGATIVE OR HER2 POSITIVE 

BREAST CANCER 

X. Chen 1 ,G.Ye 2 , C. Zhang 3 ,X.Li 4 , K. Shen 1 

1 Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong 

University School of Medicine, Shanghai, CHINA, 2 Department of Breast 

Surgery, The First People’s Hospital of Foshan, Foshan, CHINA, 3 Department of 

Breast Surgery, Guangzhou General Hospital of Guangzhou Military Area, 

Guangzhou, CHINA, 4 Department of Breast Surgery, Shanxi Provincical Cancer 

Hospital, Taiyuan, CHINA 

Objective: To evaluate the activity and safety of docetaxel plus cyclophosphomide 

(TC) compared with docetaxel, anthracycline and cyclophosphomide (TAC) in 

neoadjuvant treatment of triple negative or HER2 positive breast cancer, which may 

help us to determine the role of anthracycline in breast cancer treatment. 

Methods: Clinical stage IIB or III breast cancer patients were treated with six cycles 

of TC (docetaxle 75 mg/m2 and cyclophosphomide 600 mg/m2) or TAC (docetaxle 

75 mg/m2, anthracycline, and cyclophosphomide 500 mg/m2). Either epirubicin 

60mg/m2 or adimycin 50mg/m2 was allowed as an anthracycline regimen. The 

primary end point was pathological complete remission (pCR), defined as no 

residual invasive cancer in breast and axillary lymph node. Seconday end points 

included safety, clinical response rate, event free survival (EFS), disease free survival 

(DFS), and overall survival (OS). 

Results: 102 patients were randomized and 96 patients were available for analysis 

(TC: n = 45; TAC: n = 51). After surgery, pCR rate was 6.8% (3/45) and 17.6% (9/51) 

in TC and TAC group, respectively, P = 0.113. There was also no difference in clinical 

response rate. However, with mean follow up of 20 (3-36) months, TAC treatment, 

compared with TC, resulted in a significantly superior EFS (80.4% vs 60.0%, 

respectively; adjusted HR = 2.42 (95% CI: 1.11 to 5.30); P = 0.027), better DFS (84.3% 

vs 64.4%, respectively; adjusted HR = 2.85 (95% CI: 1.21 to 6.74); P = 0.017) and a 

trend towards less death (96.1% vs 86.7%, respectively; adjusted HR = 2.52 (95% CI: 

0.41-15.38); P = 0.315). Patients treated with TAC had relative high rates of grade 3-4 

neutropenia and leukopenia, and rates of other severe adverse events were similar 

and no patients died on treatment. 

Conclusions: pCR rate was not significantly different between TAC and TC in 

neodajuvant treatment of triple negative or HER2 positive breast cancer. Adding 

anthracycline to TC can significantly improve patients’ outcome, which deserves 

further investigation. (Sponsored by Sanofi; ClinicalTrials.gov number, 

NCT00912444.) 


321PD IMPACT OF MULTIFOCAL OR MULTICENTRIC DISEASE 

ON SURGICAL, LOCOREGIONAL, AND DISTANT SURVIVAL 

AFTER NEOADJUVANT CHEMOTHERAPY IN 3562 BREAST 


B. Ataseven 1 , J.U. Blohmer 2 , C. Denkert 3 , B. Gerber 4 , J. Heil 5 , T. Kühn 6 , 

S. Kümmel 7 , M. Rezai 8 , S. Loibl 9 , G. von Minckwitz 10 

1 Frauenklinik, Rotkreuzklinikum München, München, GERMANY, 2 Gynäkologie 

und Geburtshilfe, Sankt Gertrauden-Krankenhaus, Berlin, GERMANY, 3 Institut für 

Pathologie, Charité Universitätsmedizin Berlin, Berlin, GERMANY, 4 Frauenklinik, 

Uniklinik Rostock, Rostock, GERMANY, 5 Universitäts-brustzentrum, 

Universitäts-Frauenklinik, Heidelberg, GERMANY, 6 Brustzentrum, Frauenklinik, 

Gifhorn, GERMANY, 7 Brustzentrum, Kliniken Essen Mitte, Essen, GERMANY, 

8 Brustzentrums, Luisenkrankenhaus, Düsseldorf, GERMANY, 9 Medicine and 

Research, German Breast Group, Neu-Isenburg, GERMANY, 10 Managing 

Director, GBG Forschungs GmbH, Neu-Isenburg, GERMANY 

Purpose: To evaluate patients outcome with multifocal or multicentric breast cancer 

after neoadjuvant chemotherapy by type of surgery. 

Patients and methods: Participants of the GeparTrio and GeparQuattro trials with 

operable or locally advanced tumors received anthracycline-taxane (+/- anti-HER2-based 

neoadjuvant chemotherapy and were classified as having unifocal (one lesion detected by 

physical examination, sonography, and mammography ± MRI), multifocal (≥2 lesions in 

one breast quadrant), or multicentric (≥ 1lesionin≥2 quadrants) disease. Breast 

conservation was allowed when tumor-free margins were achieved. 

Results: Tumors of 3,562 participants were classified as unifocal (N = 2793; 78.4%), 

multifocal (N = 429; 12.0%), and multicentric (N = 340; 9.5%). Breast conservation 

was performed in 71.7%, 56.2%, and 35.1%, respectively (P < 0.0001). At surgery 

pathological complete response (pCR) rates were 18.7%, 14.1%, and 14.9%, 

respectively (P = 0.047). After median follow up of 46.3 months locoregional and 

distant-relapse-free survival were worse in patients with multicentric disease versus 

uni- or multifocal disease treated with mastectomy (P = 0.007 and 0.061, 

respectively), but not when treated by breast conservation (P = 0.634 and 0.650, 

respectively). Patients with pCR showed a low locoregional relapse rate irrespective of 

focality (P = 0.713) but a higher distant relapse rate in case of multicentric disease (P 

= 0.003). Prognostic factors for locoregional recurrence in multivariable analysis were 

tumor and nodal status at surgery, grading, hormone-receptor status, and type of 

surgery, but not focality of the tumor. Overall survival was not statistically different 

through all focality groups. 

Conclusions: Breast conservation for multifocal or multicentric breast cancer after 

neoadjuvant chemotherapy is feasible and seems not to impair outcome if tumor-free 

margins were achieved. 


322PD A TREATMENT-INTERACTION ANALYSIS BALANCING 

PATHOLOGICAL COMPLETE RESPONSES (PCR) AND 

CARDIOTOXICITY OF SINGLE-(S)/DUAL-(D) HER2 

INHIBITION AND NEOADJUVANT CHEMOTHERAPY (CT) 

BACKBONE IN OPERABLE/LOCALLY ADVANCED BREAST 

CANCER (O/LABC) PATIENTS 

E. Bria 1 , M. Bonomi 1 , J. Furlanetto 1 , S. Pilotto 1 , L. Carbognin 1 , F. Massari 1 , 

E. Lucchini 1 , D. Melisi 1 , D. Giannarelli 2 , G. Tortora 1 

1 Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona-“Borgo 

Roma”, Verona, ITALY, 2 Medical Oncology, Regina Elena National Cancer 

Institute, Roma, ITALY 

Purpose: Given the toxicity drawbacks potentially related to the combination of 

anthracylines and a D-HER2 inhibition, a treatment interaction analysis of the 

available randomized trials was accomplished. 

Methods: pCR (breast + axilla), breast conserving surgery (BCS), grade 3-4 

neutropenia/cardiotoxicity, and febrile neutropenia (FN), events were extracted from 

papers/presentation and cumulated according to a random-effect model; 95% 

confidence intervals (CI) were derived. A sensitivity analysis according to S/D HER2 

inhibition, hormonal receptors (HRs) and CT (anthracyclines-taxanes: anthra-TAX; 

TAX alone) was accomplished to test for interaction. Absolute differences (AD) with 

95% CIs, and the number of pts needed to treat/harm (NNT/NNH) for 1 to benefit 

were calculated to derive the Likelihood of being Helped or Harmed (LHH). 


Results: 8 trials (2092 pts) with 1955 pts treated with anti-HER2 therapy 

(Trastuzumab, Lapatinib and Pertuzumab), were gathered; pCR rates according to 

HER2 inhibition follow: 

CT HER2-Inhibition Rates (95% CI) Interaction (p) NNT 

Anthra-TAX S 37.0 [34.0, 40.0] 0.22 2.7 

D 44.3 [33.3, 55.2] 2.2 

TAX S 21.7 [18.1, 25.3]


325PD PHASE I/II TRIAL OF ABIRATERONE ACETATE (AA) IN 

ESTROGEN RECEPTOR (ERα) OR ANDROGEN RECEPTOR 

(AR) POSITIVE METASTATIC BREAST CANCER (MBC) 

C.H.M. Ng 1 , I. Macpherson 2 ,D.Rea 3 , J. Spicer 4 , A. Bowman 5 , A. Jones 6 , 

M. Dowsett 7 , S.R.D. Johnston 8 , N. Dobbs 9 , J.S. de Bono 10 

1 Drug Development, Royal Marsden Hospital, Surrey, UNITED KINGDOM, 

2 Cancer Trial Research, Beatson West of Scotland Cancer CentreGartnavel 

General Hospital, Glasgow, UNITED KINGDOM, 3 Medical Oncology, The 

University of Birmingham Institute for Cancer Studies, Birmingham, UNITED 

KINGDOM, 4 Research Oncology, King’s Health Partners at Guy’s Hospital, 

London, UNITED KINGDOM, 5 Medical Oncology, Edinburgh Cancer Centre, 

Edinburgh, UNITED KINGDOM, 6 Medical Oncology, University College London 

Hospital, London, UNITED KINGDOM, 7 Academic Department of Biochemistry, 

Breakthrough Research Centre, London, UNITED KINGDOM, 8 Breast Oncology, 

Royal Marsden NHS Foundation Trust & Institute of Cancer Research, London, 

UNITED KINGDOM, 9 Drug Development Office, Cancer Research UK, London, 

UNITED KINGDOM, 10 Drug Development Unit, Royal Marsden Hospital NHS 

Foundation Trust, Surrey, UNITED KINGDOM 

Background: Abiraterone irreversibly inhibits 17-hydroxylase/c-17-20 lyase (CYP17), 

reducing androgen and estrogen levels and improves overall survival from castration 

resistant prostate cancer. We hypothesized that: A) Postmenopausal ERα+ MBC 

continue to be ERα + /AR driven; and, B) Postmenopausal ERα- AR+ MBC can be 

driven by AR. 

Methods: This Phase I/II trial of AA with hydrocortisone evaluated tolerability, 

pharmacokinetic (PK)-pharmacodynamic (PD) profile and anti-tumor activity. Two 

parallel but non-randomized Phase II arms utilized a Gehan design (95% probability 

of detecting a 24wk clinical benefit rate (CBR, partial response [PR] + stable disease) 

of > 20%; 14 patients [pts] in the first stage; 11 in the second stage for each arm). 

Prior therapy with ≥ 2 lines of endocrine therapy (for ERα+ arm); ≥ 1 line of chemo 

(for AR + ERα- arm); and prior trastuzumab if HER2-positive was required. ERα and 

AR positivity was defined as immunoreactivity in ≥ 1% cells. 

Results: In the phase I study, daily dosing of AA was well tolerated with variable PK 

at all dose levels. PD studies of CYP17 blockade demonstrated suppression of 

circulating estradiol and androgen levels below the limit of assay detection with 

1000mg and 250-2000mg AA respectively; 1000mg was selected for Phase II 

evaluation. In the ERα+ arm, 6 pts (Phase I) and 25pts (Phase II) received 1000mg 

AA, of whom 4 were HER2-positive. The median age (range) was 60 (46-80), prior 

lines of hormonal and chemotherapy were 3 (2-4) and 2 (0-5) respectively. There was 

1 partial response (PR) lasting 14m in a pt who had received 4 and 5 lines of 

hormonal and chemotherapy respectively. Median progression-free survival was 

11wk. CBR at 24wk was 21%. In the AR + ERα- arm, recruitment is ongoing. 

Hypokalaemia easily managed by hydrocortisone administration, was the commonest 

drug related adverse event (AE). 

Conclusion: AA was well tolerated and merits further evaluation in MBC. Cancer 

Research UK (Drug Development Office) Sponsored and funded the trial. Johnson & 

Johnson provided AA. 

Disclosure: M. Dowsett: The Institute of Cancer Research has a commercial interest 

in Abiraterone. Mitch Dowsett is an employee of the Institute of Cancer Research, 

which has a ‘Rewards to Inventors’ scheme and is a recipient of the scheme. J.S. de 

Bono: The Institute of Cancer Research has a commercial interest in Abiraterone. 

Prof de Bono is an employee of the Institute of Cancer Research, and recipient of a 

‘Rewards to Inventors’ scheme. He is also a consultant for Johnson and Johnson. All 

other authors have declared no conflicts of interest. 

326PD PACLITAXEL-BASED VERSUS DOCETAXEL-BASED 

REGIMENS IN METASTATIC BREAST CANCER: A 

SYSTEMATIC REVIEW AND META-ANALYSIS OF 

RANDOMIZED CONTROLLED TRIALS 

W. Qi, Y. Yao, Z. Shen, F. Lin, Y. Sun, D. Min, A. He, L. Tang 

Dept. of Oncology, The Sixth People’s Hospital Shanghai Jiaotong University, 

Shanghai, CHINA 

Background: Docetaxel and paclitaxel show significant clinical activity in metastatic 

breast cancer (MBC) and have been approved for MBC by U.S. Food and Drug 

Administration, but it is still unclear whether paclitaxel-based regimen improves 

outcome over docetaxel-based regimen in patients with MBC. We therefore 

performed a meta-analysis of randomized controlled trials that compared 

paclitaxel-based with docetaxel-based regimens in MBC. 

Method: We systematically searched for randomized controlled trials that 

comparing paclitaxel-based with docetaxel-based regimens in patients with 

metastatic breast cancer in PUBMED, EMBASE and Cochrane databases. 

Abstracts presented at the conference were also searched. The primary endpoint 

was overall survival (OS). Secondary endpoints were progression free survival 

(PFS), time to progression (TTP), overall response rate (ORR), and grade 3 or 4 

toxicity. Data were extracted from the studies by two independent reviewers. The 

meta-analysis was performed by Stata version 12.0 software (Stata Corporation, 

College Station, TX, USA). 

Results: Seven eligible trials involving 1694 patients with MBC were selected. Our 

meta-analysis results showed that paclitaxel-based regimen was comparable to 

docetaxel-based regimen in terms of OS (HR: 0.87, 95%CI: 0.60-1.27, p = 0.476),PFS 

(HR:0.76,95%CI:0.58-1.00, p = 0.052), TTP(HR: 1.13, 95%CI: 0.81-1.58, p = 0.459), 

and ORR(RR:1.01, 95%CI: 0.88-1.15, p = 0.915), but less grade 3 or 4 adverse events 

including anemia(RR:0.64,95%CI:0.44-0.94,p = 0.023), neutropenia (RR:0.74,95% 

CI:0.58-0.93, p = 0.011), febrile neutropenia (RR:0.38, 95%CI:0.15-0.96, p = 0.041), 

thrombopenia (RR:0.62, 95%CI: 0.41-0.96,p = 0.033),mucositis (RR:0.082, 95% 

CI:0.025-0.27,p = 0.000),diarrhea(RR:0.194,95%CI:0.081-0.47,p = 0.000) and fatigue 

(RR:0.434,95%CI:0.20-0.96,p = 0.039) were observed in paclitaxel-based regimen. 

Conclusion: The present systematic review and meta-analysis demonstrate that both 

taxanes-based regimens show comparable efficacy for patients with MBC, and 

paclitaxel-based regimen is associated with less toxicity and better tolerability, 

especially in older patients and when used in weekly regimens. 


327PD BODY MASS INDEX AND PROGNOSIS OF WOMEN WITH 

METASTATIC BREAST CANCER 

A. Gennari 1 , D. Amadori 2 , O. Nanni 2 , A. Decensi 1 , P.F. Conte 3 , M. Puntoni 1 , 

P. Bruzzi 4 

1 EO Galliera, SC Oncologia, Genoa, ITALY, 2 Medical Oncology, IRST - Meldola, 

Meldola, ITALY, 3 Dept. of Hematology/Oncology, Ospedale Policlinico-Modena, 

Modena, ITALY, 4 Clinical Epidemiology, IST-San Martino, Genoa, ITALY 

Obesity is a well known risk factor for the development of breast cancer and an 

adverse prognostic factor in those women who have already been diagnosed with 

breast cancer. However, the effect of obesity on the prognosis of MBC women has 

not been explored so far. The aim of this study was to evaluate the influence of Body 

Mass Index (BMI) on the prognosis of MBC patients receiving first line 

chemotherapy. 

Methods: The relationship between BMI (kg/m2), and progression free (PFS) or 

overall survival (OS) was assessed in 698 MBC patients enrolled in 3 clinical trials of 

first line chemotherapy, conducted by the same collaborative group. Conventional 

WHO BMI definitions were applied: normal 18.5-24.9 kg/m2, overweight 25-30 kg/ 

m2, obese >30 kg/m2. PFS and OS were calculated by Kaplan-Meier estimation; 

multivariate Cox analysis was performed adjusting for age, menopausal status, PS 

and study. 

Results: Information on BMI at the time of study entry, was available on 489 

women. All patients received first line chemotherapy regimens including 

anthracyclines and taxanes, either in sequence or combination. Median follow up was 

18 months (range 0.4 to 88.3). Overall, 40.3% of the patients were normal, 38.2% 

were overweight and 21.5% were obese. Median age was 57 years (range 25 to 73); PS 

was 0 in 93% of the patients. A non significant trend toward improved PFS was 

found in overweight women: median PFS was 13.1 months (95% CI 11.0-15.2) in 

BMI 25-30 versus 10.8 months (8.9-12.6) in BMI < 25 and 12.2 (95% CI 10.4-14.0) 

in BMI >30, p = 0.2. Median OS was 32.0 months (95% CI 24.9-39.1) in BMI < 25 

versus 32.9 (95% CI 27.7-38.1) in BMI 25-30 and 30.7 (95% CI 24.3-37.0) in BMI 

>30, p = 0.8. By multivariate analysis, none of the considered variables was 

significantly associated with differences in PFS and/or OS. 

Conclusions: In this study BMI at baseline was not significantly associated with the 

outcome of MBC patients treated with first line chemotherapy; however, a non 

significant trend for an improved PFS was observed in overweight women as 

compared to normal weight and obese patients. These data suggest that overweight 

should not be regarded as an adverse prognostic factor patients with MBC. 


328PD PROGRESSION-FREE SURVIVAL AS A SURROGATE FOR 

OVERALL SURVIVAL IN METASTATIC BREAST CANCER 

C. Beauchemin 1 , D. Cooper 2 , M. Lapierre 1 , L. Yelle 3 , J. Lachaine 1 

1 Faculty of Pharmacy, University of Montreal, Montreal, QC, CANADA, 2 Direction 

Scientifique De L’inscription, Institut National d’Excellence en Santé et en 

Services Sociaux (INESSS), Quebec, QC, CANADA, 3 Oncology Department, 

Notre-Dame Hospital, Montreal, QC, CANADA 

Objectives: Progression-free survival (PFS) is frequently used to establish the clinical 

efficacy of anti-cancer drugs. However, the surrogacy of PFS for overall survival (OS) 

remains a matter of uncertainty in metastatic breast cancer (mBC). Therefore, the 

aim of this study was to assess the relationship between PFS and OS in mBC using a 

trial-based approach. 

Methods: A systematic literature review was conducted using the PICO method: 

Population consisted of women with mBC; Interventions and Comparators were 

standard treatments for mBC or best supportive care; Outcomes of interest were 

median PFS or TTP and median OS. A correlation analysis between median PFS and 

OS was first performed and subgroup analyses were conducted to explore possible 

reasons for heterogeneity. Then, the relationship between the treatment effect on PFS 

and OS was assessed. The treatment effect on PFS and OS was quantified by the 


absolute difference of median values. Linear regression analysis was also conducted 

to predict the effects of a new anticancer drug on OS on the basis of its effects on 

PFS. 

Results: A total of 5041 studies were identified and 144 fulfilled the eligibility 

criteria. Selected studies included 315 treatment arms, which represents 43,459 

patients with mBC. There was a significant relationship between median PFS and 

median OS across included trials (r = 0.428; p < 0.01). The correlation between 

median PFS/TTP and median OS was higher for studies evaluating chemotherapy 

alone (r = 0.575; p ≤ 0.01) or in combination (r = 0.632; p ≤ 0.01) compared with 

those evaluating hormone therapy (non-significant r). The correlation coefficient for 

the treatment effect on PFS and OS was estimated at 0.427 (p < 0.01). The linear 

regression equation was: ΔOS = -0.088 (95% CI, -1.347 to 1.172) + 1.753 (95% CI, 

1.307 to 2.198) * ΔPFS, with a proportion of variation explained (R 2 ) of 0.86. Results 

of the regression analysis predict that a difference in median PFS/TTP of 5, 10, 15, 

and 20 months would translate into a difference in median OS of 8.7, 17.4, 26.2, and 

35.0 months respectively. 

Conclusion: The present findings point toward a statistically significant correlation 

between PFS and OS in the context of mBC and support the surrogacy of PFS for OS 

in this cancer setting. 


329P PATIENT-REPORTED OUTCOMES (PROS) FROM EMILIA, A 

PHASE 3 STUDY OF TRASTUZUMAB EMTANSINE (T-DM1) VS 

CAPECITABINE AND LAPATINIB (XL) IN HER2-POSITIVE 

LOCALLY ADVANCED OR MBC 

M. Welslau, 1 , V. Diéras2 , J. Sohn3 , S. Hurvitz4 , D. Lalla5 , L. Fang6 , E. Guardino7 , 

D. Miles8 1 

Medical Office Hematology, Praxis Dr. Klausmann / Dr. Welslau, Aschaffenburg, 

GERMANY, 2 Department of Medical Oncology, Clinical Trial Unit, Institut Curie, 

Paris, FRANCE, 3 Medical Oncology, Yonsei University College of Medicine, 

Seoul, KOREA, 4 Medical Oncology, UCLA Jonsson Comprehensive Cancer 

Center and Translational Oncology Research International, Los Angeles, CA, 

UNITED STATES OF AMERICA, 5 Health Outcomes, Genentech, South San 

Francisco, CA, UNITED STATES OF AMERICA, 6 Biostatistics, Genentech, South 

San Francisco, CA, UNITED STATES OF AMERICA, 7 Breast Medical Oncology, 

Genentech, Inc., South San Francisco, CA, UNITED STATES OF AMERICA, 

8 

Medical Oncology, Mount Vernon Cancer Center, Northwood, UNITED 

KINGDOM 

Background: The antibody-drug conjugate T-DM1 combines the antitumor activities 

of trastuzumab (T) with intracellular delivery of the cytotoxic agent DM1. In the 

EMILIA study, the efficacy and safety of T-DM1 was compared to XL. Here we 

report the PRO results. 

Methods: Pts with centrally confirmed HER2-positive MBC and prior therapy with 

T and a taxane were randomized to T-DM1 or XL administered in 21-day cycles. Pts 

completed the FACT-B, a 37-item questionnaire composed of 5 subscales at baseline 

and on day 1 every 2 cycles until disease progression (PD), 6 wks after PD and every 

3 mos thereafter. A 24-item subset of FACT-B, the Trial Outcome Index (TOI) 

provides a summary of physical and functional well-being and breast cancer-specific 

symptoms. Time to FACT-B TOI worsening (ie, ≥5 point decrease in TOI), the main 

PRO analysis, was assessed by Kaplan-Meier methods and a Cox model in female pts 

with baseline and ≥1 post-baseline TOI score. An exploratory PRO end point was 

the incidence of symptoms measured by the Diarrhea Assessment Scale (DAS), in 

which pts rated diarrhea symptoms in 4 domains (frequency, urgency, discomfort, 

stool consistency) on a 4-point scale at baseline and on day 1 of each cycle until PD. 

Results: Pts treated with T-DM1 had longer PFS (9.6 vs 6.4 months; HR=0.650; 

P1 stool per day 

(57% vs 30%); loose or watery stools (70% vs 37%); somewhat to very urgent stools 

(54% vs 26%) and mild-moderate to very severe abdominal discomfort with bowel 

movements (45% vs 25%). 

Conclusions: Improvements in efficacy and safety were accompanied by, clinically 

significant benefits in health-related quality of life in pts treated with T-DM1 vs XL. 

Keywords: diarrhea, T-DM1, patient-reported outcomes, HER2-positive. 

Disclosure: V. Diéras: *Compensated consultant/advisory relationship with 

Genentech/Roche, Novartis, Sanofi, Amgen, Clovis, Pfizer, GSK *Honoraria from 

Genentech/Roche, Novartis, Sanofi, Amgen, Clovis, Pfizer, GSK J. Sohn: Research 

funding from Roche, Amgen and GSKS. Hurvitz: *Support for study-related travel 

from Roche *Research funding for institution from Roche D. Lalla: Genentech 

employee, owns Roche stockL. Fang: Genentech employee, owns Roche stockE. 

Guardino: Genentech employee, owns Roche stock All other authors have declared 

no conflicts of interest. 


330P QUALITY OF LIFE (QOL) ASSESSMENT IN WOMEN WITH 

LOCALLY ADVANCED (LA) OR METASTATIC BREAST CANCER 

(MBC): RESULTS OF A PHASE II TRIAL WITH ERIBULIN 

W.R. Simons 1 , J. Cortes 2 

1 Global Health Technology Assessment, Eisai, Inc., Woodcliff Lake, NJ, UNITED 

STATES OF AMERICA, 2 Breast Cancer Program, Vall d’Hebron University 

Hospital, Barcelona, SPAIN 

Objective: Eribulin is a nontaxane microtubule dynamics inhibitor with a 

mechanism of action different from many other tubulin targeting agents and 

indicated for monotherapy treatment of patients with LA or MBC who have 

progressed after at least an anthracycline and a taxane. While eribulin has shown 

overall survival and extended progression free periods benefits in these women, QoL 

associated with those benefits need to be determined. 

Methods: We use a Phase II clinical trial where 291 women with LA or MBC were 

required to have received prior treatment with an anthracycline, a taxane, and 

capecitabine. Eribulin was administered at 1.23 mg/m 2 (equivalent to 1.4mg/m 2 

eribulin mesilate) i.v. over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. 

EORTC-QLQ-BR32 was administered every second cycle, before drug administration 

and before patients were informed of their tumor assessment. As these data are 

repeated observations, every second cycle, across the course of treatment, generalized 

estimating equations (GEE) were applied to individual QOL scores with response, 

complete or partial tumor response as well as progressive disease as independent 

indicators. 

Results: Two-hundred eighty three women provided a total of 1068 QOL 

assessments. Their general health status was 68.88 (P < 0.0001) on a 100 point scale, 

improving by 7.90 (P = 0.0153) when responding to eribulin. Indeed, women 

responding to eribulin improved in each of the subscale domains, including 

emotional functioning (10.54; P = 0.0004), physical functioning (12.95; P = 0.0008), 

role functioning (9.37; P =0.0005), pain (7.90; P = 0.0153) and breast symptoms 

(-12.42; P = 0.0004). Hair loss was a concern, (-9.18; P = 0.0001). Conversely, 

progressive disease significantly worsens their QOL, physical functioning by (-19.18; 

P < 0.0001), role functioning (-9.36; P < 0.0001) and emotional functioning (-10.459; 

P < 0.0001). 

Conclusion: LABC or MBC significantly impacts every aspect of these women’s lives 

as measured by the EORTC-QLQ-BR32 questionnaire. While hair loss was a 

concern, eribulin provided these women with significant relief and measureable and 

meaningful improvements in overall QOL, including emotional, social, role 

functioning subscales and pain and breast symptoms. 

Disclosure: W.R. Simons: W. Robert Simons is an Eisai Inc employee. All other 


331P IMPACT OF RESPONSE SHIFT ON TIME TO QUALITY OF LIFE 

SCORES DETERIORATION IN BREAST CANCER PATIENTS: IS 

IT TIME TO MOVE FOR QOL RECIST CRITERION? 

Z. Hamidou 1 , T.S. Dabakuyo 1 , F. Guillemin 2 , T. Conroy 3 , M. Velten 4 , D. Jolly 5 , 

M. Mercier 6 , S. Causeret 7 , J. Cuisnier 7 , F. Bonnetain 1 

1 Biostatistic and Epidemiological Unit(ea 4184), Centre Georges François 

Leclerc, Dijon, FRANCE, 2 Clinical Epidemiology and Evaluation Department, 

CIC-EC, Nancy, FRANCE, 3 Oncology, Centre Alexis Vautrin, Vandoeuvre Les 

Nancy Cedex, FRANCE, 4 Epidemiology and Public Health Laboratory, College of 

Medicine, Strasbourg, FRANCE, 5 Création du Pôle Recherche et Innovations, 

University Hospital, Reims, FRANCE, 6 Cellular and Molecular Biology Laboratory 

EA 3181, University Hospital of Besançon, Besançon, FRANCE, 7 Surgery, 

Centre Georges François Leclerc, Dijon, FRANCE 

Background: Time to quality of life (QoL) score deterioration (TD) is a method of 

longitudinal QoL data analysis that has been proposed for breast cancer (BC) 

patients (Hamidou et al Oncologist 2011). As for RECIST criteria, the optimal 

definitions dealing with reference should be explored. This study aims to study the 

impact of changes in internal standards (CIS) of response-shift (RS) and the 

influence of baseline QoL expectancies on TD. 

Methods: A prospective multicenter study including all women hospitalized for a 

primary BC was conducted. The EORTC-QLQ-C30 and BR-23 questionnaires were 

used to assess the QoL at baseline, at the end of 1 st hospitalization, and 3 and 6 

months after. CIS was investigated by the then-test method. QoL expectancy was 

assessed at baseline using Likert scale. Deterioration was defined as a decrease in 

QoL scores reaching at least the mean difference identified as minimal clinically 

important difference (MCID) using Jaeschke’s transition question. Sensitivity analyses 

were done using the then-test score as reference score, and considering 5 and 10 

points as MCID. TD was estimated using Kaplan-Meier method. Cox regression 

analyses were used to identify factors influencing TD. 

Results: From February 2006 to February 2008, 381 women were included. For role 

functioning dimension, the median TD increased from 3.2 months [95% CI: 

3.1-3.36] to 4.76 months [3.3-6.2] when adjusting on CIS. For body image when 



adjusting on CIS, sentinel lymph node biopsy became significantly associated with 

longer TD (HR: 0.64[0.43-0.94]) as compared to axillary lymph node dissection, 

radiotherapy to a shorter TD (HR: 0.63[0.42-0.95] and the type of surgery had no 

effect on TD. For global health, cognitive and social functioning dimensions, patients 

expecting deterioration in their QoL had a significantly shorter TD. For fatigue and 

breast symptom scales, patients expecting no change had a significantly shorter TD, 

as compared to patients expecting an improvement. Sensitivity analyses using a 

MDCS of 5 or 10 confirmed these results. 

Conclusions: Our results suggest that it would be more accurate to take into account 

CIS component of RS as well as QoL expectancies to estimate TD of QoL scores in 

patient with BC. 


332P HEALTH STATE UTILITY DETERMINATION IN ADVANCED 

STAGE BREAST CANCER PATIENTS 

W.R. Simons 

Global Health Technology Assessment, Eisai, Inc., Woodcliff Lake, NJ, UNITED 


Background: Quality-adjusted Time Without Symptoms of disease and Toxicity 

(Q-TWiST) survival analysis where time without disease progression is rewarded 

while time without disease progression but with toxicities is penalized by applying a 

utility weight is increasingly common in health technology assessments of cancer 

treatments. AIM: We assess women’s preferences for health states specific to 

advanced stage breast cancer including a baseline diagnoses of ABC, treatment 

response, no treatment response but no disease progression, disease progression and 

hormonal therapy specific toxicities. 

Method: Using FACT-B quality of life data from a randomized clinical trial in ABC 

univariate statistics were obtained for each item for each health state without regard 

to treatment. These item scores were paired to the actual narrative in the FACT-B to 

construct health state narratives consisting of physical, social, emotional, functional 

well-being and additional concerns content domains. The order of the content 

domains was varied to prevent order bias. One hundred and nine peri- or 

post-menopausal women were recruited and interviewed by a single woman in their 

age group using visual analogue and standard gamble techniques. Univariate and 

multivariate analyses were performed to control for age, marital status, menopausal 

status and whether the interviewee has had breast cancer or any other cancer. 

Results: Of the 109 recruited 100 women completed the interview, mean age was 

55.76 years, 64% were postmenopausal, 11% had breast cancer previously and 16% 

had another type of cancer previously. Multiple regressions results for the VAS scores 

yielded values of 51.8 (p < 0.01) for baseline ABC diagnosis, 82.5 (p < 0.01) for 

treatment response, 57.5 (p < 0.01) for no response no progression and 38.4 

(p < 0.01) for disease progression. The SG results were 0.64 (p < 0.01), 0.76 

(p < 0.01), 0.67 (p < 0.01), and 0.50 (p < 0.01), respectively. Women who previously 

had breast cancer related the health states consistently higher (p < 0.05) in the VAS 

and SG analyses. The trade-off between a chance of treatment response yet the 

possibility of toxicity yielded a utility score of 0.34 (p < 0.01). 

Conclusion: These VAS and SG scores can be used to better assess women’s 

preference for treatment options in ABC. 

Disclosure: W.R. Simons: This research was conducted independent of Eisai Inc. 

333P COST EFFECTIVENESS OF ADJUVANT CYCLOPHOSPHAMIDE 

CONTAINING REGIMES TO AT IN THE TREATMENT OF 

BREAST CANCER IN GERMANY 

E. Walter 

IPF, IPF Institute for Pharmaeconomic Research, Vienna, AUSTRIA 

Objectives: 58,000 women in Germany are diagnosed with breast cancer each year. 

Anthracycline-containing regimes - in addition to other treatment options - have 

been standard adjuvant breast cancer regimens. The purpose of this analysis was to 

estimate the cost-effectiveness of AT (doxorubicin, docetaxel) compared with AC 

(doxorubicin, cyclophosphamide), CMF (cyclophosphamide, methotrexat, 

5-fluoruracil) and FEC (5-fluoruracil, epirubicin, cyclophosphamide) administered as 

adjuvant therapy to women with node-positive breast cancer in Germany. 

Methods: We developed a multi-country Cost-Utility-Model to simulate the 

long-term consequences from initiation of adjuvant chemotherapy over 10 years. 

Markov modelling techniques were used to estimate incidence of complications 

during chemotherapy (febrile neutropenia, chemotherapy induced nausea/vomiting, 

dose-reduction, dose-delay, other grade 3/4 adverse events) and long-term 

consequences like local or distant relapse, secondary acute myelogenous leukemia, 

chronic heart failure and death. Monte-Carlo-simulation accounted for uncertainty. 

Probabilities were derived from clinical and epidemiological studies; direct costs from 

published sources from the payer’s perspective. QALYs, life years and costs were 

discounted at 3% p.a. 

Results: Over a 10-year timeframe, costs and outcomes associated with AT amounts 

to 21,055.91 € and 6.3 QALYs (7 LYs). Costs associated with AC are 17,018.04 €, 

while outcomes are comparable to AT. The cost saving potential associated to AC vs. 

AT amounts to 4,037.87 € per patient. Costs and outcomes associated with CMF are 

17,790.42 € and 6.3 QALYs (6.94 LYs), leading to a cost saving potential of € 

3,265.49 with CMF vs AT. FEC associated total costs are 18,471.84 €. 

Quality-adjusted life expectancy increases to 6.5 years, which represents a QALY gain 

of 0.2 QALYs over 10 years vs. AT. The increase in life expectancy without quality 

adjustment amounts to 7.4 years and leads to 0.4 LYs gained with FEC versus AT. 

Accordingly, FEC dominates AT. 

Conclusion: Cyclophosphamide-based regimens (FEC, AC and CMF) demonstrate a 

better performance from cost-effectiveness perspective vs. AT (doxorubicin, 

docetaxel). 


334P HEALTH-RELATED QUALITY OF LIFE (QOL) IN METASTATIC 

BREAST CANCER PATIENTS TREATED WITH EVEROLIMUS 

AND EXEMESTANE VERSUS EXEMESTANE MONOTHERAPY 

H. Burris 1 , J.T. Beck 2 ,H.Rugo 3 , J. Baselga 4 , F. Lebrun 5 , T. Taran 6 , L. Bennett 7 , 

J. Ricci 8 , T. Sahmoud 9 , G.N. Hortobagyi 10 

1 Highlands Oncology Group, Highlands Oncology Group, Nashville, TN, UNITED 

STATES OF AMERICA, 2 Highlands Oncology Group, Highlands Oncology Group, 

Fayetteville, AR, UNITED STATES OF AMERICA, 3 Helen Diller Family 

Comprehensive Cancer Center, University of California, San Francisco, CA, 

UNITED STATES OF AMERICA, 4 Massachusetts General Hospital Cancer Center 

and Harvard Medical School, Massachusetts General Hospital Cancer Center 

and Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA, 

5 Jules Bordet Institute, Institute Jules Bordet, Brussels, BELGIUM, 6 Sr Global 

Clinical Leader, Novartis Pharmaceuticals Corporation, East Hanover, NJ, 

UNITED STATES OF AMERICA, 7 Biometrics, RTI Health Solutions, Research 

Triangle Park, NC, UNITED STATES OF AMERICA, 8 Wellmera Ag, Wellmera AG, 

Basel, SWITZERLAND, 9 Gbl Clin Program Head, Novartis Pharmaceuticals 

Corporation, East Hanover, NJ, UNITED STATES OF AMERICA, 10 The University 

of Texas MD Anderson Cancer Center, The University of Texas MD Anderson 

Cancer Center, Houston, TX, UNITED STATES OF AMERICA 

Background: The phase 3 BOLERO-2 study randomized 724 patients with 

hormone-receptor–positive (HR + ) advanced breast cancer and recurrence or 

progression during/after nonsteroidal aromatase inhibitor therapy to everolimus 

(EVE) plus exemestane (EXE) or EXE and placebo (PBO). Interim analysis after 12 

months’ median follow up demonstrated that EVE + EXE significantly improved 

progression-free survival (PFS) vs EXE + PBO, with a higher rate of grade 3/4 adverse 

events but no deterioration in QOL. We report here on additional post hoc analyses 

of patient-reported QOL. 

Methods: Using the EORTC QLQ-C30 questionnaire and QLQ-BR23 module, 

QOL was assessed at baseline and every 6 weeks thereafter until progression or 

discontinuation. The QLQ-C30 consists of 30 items combined into 15 

subscales, including Global Health Status (GHS). The BR23 consists of 23 items 

specific to breast cancer combined into symptom and functioning subscales, 

including breast symptom (BS) and arm symptom (AS) scales. Average 

difference in change from baseline between treatment groups was evaluated 

using linear mixed models with several adjustment covariates. Sensitivity 

analysis was conducted using pattern-mixture models to examine the effect of 

study dropout on or before week 24. Treatments were compared using 

differences of least squares mean (LSM) changes from baseline at each 

timepoint and overall. 

Results: Linear mixed models indicated no statistically significant overall difference 

between EVE + EXE and EXE + PBO for GHS (LSM difference = –2.0; 95% CI = –4.8, 

0.9), breast symptoms (LSM difference = 0.3; 95% CI = –2.8, 2.4), or arm symptoms 

(LSM difference = –0.2; 95% CI = –2.8, 2.4). Pattern-mixture models indicated that 

patients who dropped out early had worsening QOL over time in both treatment 

arms; EVE + EXE patients who did not drop out early had stable QOL, whereas EXE 

+ PBO was associated with worsening QOL over time. 

Conclusions: These additional analyses from the BOLERO-2 study confirm that 

compared with EXE alone, EVE + EXE improved PFS without adversely impacting 

QOL in patients with HR + advanced breast cancer progressing despite nonsteroidal 

aromatase inhibitors. 

Disclosure: J.T. Beck: Has received grant support from Pfizer and Novartis. H. 

Rugo: Has received grant support from Pfizer and Merck, and has received travel 

support from Novartis. J. Baselga: Is a consultant to Novartis, Roche, Merck, 

sanofi-aventis, Verastem, Bayer, Chugai, Exelixis, Onyx, and Constellation. T. 

Taran: Is an employee of Novartis with stock options. L. Bennett: Is an employee 

of RTI Health Solutions, which contracted with Novartis for data analysis 

services. J. Ricci: Is a consultant to Novartis. T. Sahmoud: Is an employee of 

Novartis with stock options. G.N. Hortobagyi: Member of the Sci Ad Board of 

Allergan; consultant to Allergan, Novartis, Genentech, and sanofi-aventis; has 

received grant support from Novartis; travel expense reimbursement from 


Novartis, Genentech, and sanofi-aventis. All other authors have declared no 


335P DYSPHONIA AS A PREVIOUSLY UNREPORTED SIDE EFFECT 

OF BEVACIZUMAB TREATMENT IN PATIENTS WITH 

METASTATIC BREAST CANCER 

S.A. Radema 1 , P. Souverein 2 , R. Meyboom 2 , F. Ahmadizar 2 , C. Onland-Moret 2 , 

A. Maitland-Vd Zee 2 

1 Internal Medicine, Gelre Ziekenhuizen, Apeldoorn, NETHERLANDS, 

2 Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology 

and Clinical Pharmacology, Utrecht University, Utrecht, NETHERLANDS 

Introduction: Bevacizumab is a humanized monoclonal antibody directed against 

vascular endothelial growth factor A and has been approved for the treatment of 

several metastatic tumours. There is considerable heterogeneity in the response to 

treatment with bevacizumab, both in effectiveness and in toxicity. Here we describe a 

previously unreported adverse drug reaction (adr) in pts with MBC treated with 

bevacizumab. 

Methods: In a teaching hospital in the Netherlands (from Sep 2009 to Jul 2011), 32 

consecutive pts with MBC treated with chemotherapy and bevacizumab were 

registered in a retrospective database. TNM stage, comorbidities, concomitant 

medication, prior treatment for the primary tumour, date of metastatic disease, prior 

treatment for metastatic disease and toxicities were recorded. The WHO global 

individual case safety report database, VigiBase, contains summaries of suspected 

spontaneous case reports summated by health care professionals and pts to national 

pharmacovigilance centres . As of May 2010, VigiBase contained >5 million case 

reports. . We searched the VigiBase extraction of Dec 2011 for dysphonia. Reporting 

odds ratios (ROR) were calculated for the occurrence of dysphonia compared with 

other adr for bevacizumab and paclitaxel. 

Results: In total, 9/32 pts (28%) reported dysphonia during treatment with 

bevacizumab and 5/9 pts underwent ENT examination. In several pts marked 

oedema of the vocal cords and/or chronic laryngitis were found. As of Dec 2011, 

6,880,361 reports were available in VigiBase, of which16,239 were related to 

dysphonia. For bevacizumab there were 51 reports for dysphonia and 46,041 reports 

for other adr. Corresponding figures for all other drugs were 22,108 reports for 

dysphonia and 25,151,628 reports for other adverse effects: ROR of 1.26 (95% CI: 

0.95-1.66). For paclitaxel there were 45 reports for dysphonia and 85,988 reports for 

other adr. Corresponding figures for all other drugs were 22,114 reports for 

dysphonia and 25,111,681 reports for other adverse effects: ROR of 0.59 (95% CI: 

0.44-0.80)meaning that the risk of angiooedema is significantly higher in 

bevacizumab users compared to paclitaxel users. 

Conclusion: Dysphonia is a previously unreported side-effect in pts with MBC 

treated with bevacizumab and paclitaxel. 

Disclosure: S.A. Radema: I am member of an advisory board for Roche. All other 


336P PATTERNS OF CLINICAL MANAGEMENT AND RESOURCE 

UTILIZATION FOR POSTMENOPAUSAL 

HORMONE-RECEPTOR–POSITIVE HER2-NEGATIVE (HR+ 

HER2–) ADVANCED BREAST CANCER (ABC) IN EUROPE 

G. Jerusalem 1 , N. Marinsek 2 , J. Ricci 3 , J. Etchberger 2 , R. Degun 2 , G. Benelli 4 , 

S. Saletan 5 , F. André 6 

1 Centre Hospitalier Universitaire du Sart Tilman, Centre Hospitalier Universitaire 

du Sart Tilman, Liège, BELGIUM, 2 Navigant Consulting, Inc, Navigant 

Consulting, Inc, London, UNITED KINGDOM, 3 Wellmera AG, Wellmera AG, 

Basel, SWITZERLAND, 4 Novartis Farma S.p.a., Saronno, ITALY, 5 Onco Ex Dir 

Clinical Res Phys, Novartis Pharmaceuticals Corporation, East Hanover, NJ, 

UNITED STATES OF AMERICA, 6 Breast Cancer Unit, Institut Gustave Roussy, 

Villejuif, FRANCE 

Objective: To understand treatment patterns and quantify resource utilization of 

HR + HER2 − aBC, with the overall aim of comparing costs and disease burden as 

patients progress from hormonal therapy (HT) to chemotherapy (CT). 

Methods: We conducted a chart audit in France, Germany, The Netherlands, 

Belgium, and Sweden of 375 living and deceased postmenopausal female patients (75 

per country) diagnosed with ER + HER2 − aBC in the past 4 years. Patients were 

required to have progressed on ≥ 1 line of prior HT either in the adjuvant or 

advanced setting and to have completed ≥ 1 line of CT treatment (minimum 2 full 

cycles) in the aBC setting. The chart audit was completed online using a 

standardized form developed with the assistance of European academic physicians, 

pharmacy directors, and hospital administrators. Participation was sought from 25 

oncologists per country, except in Germany (15 oncologists and 10 gynecologists to 

reflect local clinical practice). Data collection was compliant with European and 

country market research regulations. 

Results: Our report details the patient care pathway, CT side effects, and resource 

utilization in the inpatient and outpatient settings throughout the continuum of aBC 


care. Preliminary analyses indicate that 55% of HR + HER2 − aBC patients are first 

treated with HT and switch to CT after 1.5 lines of HT. This switch is primarily 

influenced by the extent (56%) and progression rate (36%) of metastases. The switch 

from HT to CT is associated with increased resource utilization and the associated 

costs of treating aBC. In addition to cost of drug therapies, the main drivers of cost 

are treatment for CT side effects (chiefly febrile neutropenia and diarrhea) and 

related hospitalization events. CT side effects that have the greatest impact on the 

overall disease burden of aBC include alopecia, nausea, vomiting, fatigue, and 

peripheral neuropathy. 

Conclusions: Our results highlight the increased costs and disease burden for 

postmenopausal ER + HER2 − aBC patients treated with CT versus HT. 

Disclosure: G. Jerusalem: Consultant, Novartis Pharmaceuticals Corporation. N. 

Marinsek: Consultant, Novartis Pharmaceuticals Corporation. J. Ricci: Advisor, 

consultant, Novartis Pharmaceuticals Corporation. J. Etchberger: Consultant, 

Novartis Pharmaceuticals Corporation. R. Degun: Consultant, Novartis 

Pharmaceuticals Corporation. G. Benelli: Employees of Novartis with stock/stock 

options. S. Saletan: Employee of Novartis with stock/stock options. F. André: 

Financial support from sanofi-aventis, Novartis, Roche, AstraZeneca 

337P EFFICIENCY FRONTIER ANALYSIS (EFA) OF METASTATIC 

BREAST CANCER (MBC) TREATMENTS: A UK PERSPECTIVE 

C. Burudpakdee 1 , D. Bertwistle 2 

1 Health Economics and Outcomes Research, IMS Health, Philadelphia, PA, 

UNITED STATES OF AMERICA, 2 Heor, IMS Health, London, UNITED KINGDOM 

Background: As newer therapies for mBC become available, understanding the 

efficiency of these therapies will be important for HTA recommendations and 

treatment decisions. EFA may be a useful method of assessing the efficiency of newer 

interventions. The EFA displays the outlay (cost) and gains with technologies, and 

displays the next most efficient option going forward. This study was designed to 

evaluate whether EFA could be useful in identifying the efficiency of mBC therapies 

adopted by the NHS, and to identify the efficiency frontier for newer technologies. 

Methods: A literature search was performed to identify mBC treatments that 

underwent HTA in the UK. Reports were reviewed to identify treatment efficacy and 

HTA recommendations. Costs were determined for a course of treatment. The 

incremental costs per patient were plotted on the horizontal axis and incremental 

median overall survival (ΔOS) of each treatment was plotted on the vertical axis to 

construct the EFA line. Treatments below this line are considered inefficient options. 

Treatments above this line have better OS and may redefine the efficiency frontier. 

Treatments in the upper right quadrant beyond the frontier line are in an area where 

ceiling price has not been defined. Treatments in the lower right quadrant beyond 

the frontier line are inefficient due to higher cost for lower OS. 

Results: Ten reports that evaluated efficacy in terms of median OS were included in 

the EFA. The therapies are paclitaxel albumin, gemcitabine, trastuzumab, 

bevacizumab, lapatinib, eribulin and fulvestrant. On the frontier line are paclitaxel 

albumin (ΔOS of 2.3 months at £2020), gemcitabine (ΔOS of 2.8 months at £6020), 

and trastuzumab (ΔOS of 4 months at £16939); all received positive 

recommendations. Lapatinib (ΔOS of 1.9 months at £10180), bevacizumab (ΔOS of 

1.7 months at £36560), eribulin (ΔOS of 2.5 months at £4834) and fulvestrant (ΔOS 

of 2.3 months at £2481) are all below the frontier line and received negative 

recommendations. 

Conclusion: EFA may be a useful method for assessing the efficiency of new mBC 

treatment options for clinical use. Further studies are needed to better understand 

value in terms of efficiency of treatments in other tumor types and disease areas. 


338P A CONJOINT ANALYSIS OF WILLINGNESS TO PAY TO AVOID 

METASTATIC BREAST CANCER SIDE EFFECTS 

D. Lalla 1 , M. Brammer 1 , R. Carlton 2 , T. Bramley 2 ,A.D’Souza 3 

1 Health Outcomes, Genentech/Roche, South San Francisco, CA, UNITED 

STATES OF AMERICA, 2 Global Value Strategies, Xcenda, Palm Harbor, FL, 

UNITED STATES OF AMERICA, 3 Data Analytics, Xcenda, Palm Harbor, FL, 


Background: Patients with metastatic breast cancer (MBC) are treated with a variety 

of regimens with differing side effect profiles. In addition to efficacy, side effect 

profile can be an important consideration in therapy choice. Conjoint analysis is a 

research method used to evaluate how trade-offs are made between different 

attributes. This study assessed the willingness to pay (WTP) to avoid side effects 

related to MBC treatment using conjoint analysis. The WTP thus informs clinicians 

of patients’ preferences and which side effects they are most desirous of avoiding. 

Methods: An online, self-administered survey of MBC patients in the US was 

conducted. The survey was fielded with a sample of adult female patients with a 

diagnosis of MBC. Key variables (attributes) included in the analysis and with levels 

described in lay terms were: Alopecia, Diarrhea, Fatigue, Pain, Nausea, Neuropathy, 

Neutropenia and Out of pocket costs. 15 scenarios (choice-based conjoint questions) 



Table: 340P 

Characteristics N 201 (%) Characteristics N 201 (%) 

T size Tis-T1-T2 T3-T4 T Unk 138(68,6) 40 (20) 23 (11,4) PgR Pos Neg Unk 142(70,6) 33 (16,4) 26 (13) 

Nodal Status N0 N+ Nx 54 (26,9) 120 (59,7) 27 (13,4) Adj CT Yes No Unk 105 (51,7) 94 (46,8) 3 (1,5) 

ER Pos Neg Unk 169 (84) 12 (6) 20 (10) Adj HT Yes No Unk 141 (70,1) 46 (22,9) 14 (7) 

were presented where patients selected the most preferred therapy. Each therapy was 

described with three distinct variables. The choices of variables for each therapy 

included two side effects and an out of pocket price. The survey also collected 

information on prior treatment regimens, previous side effect history, and 

demographics. 

Results: There were 298 responses. Most respondents were white (84%), married 

(57%) over 40 years of age (86%), and had private insurance (57%). MBC patients 

were willing to pay $3,894 to avoid severe diarrhea, $3,479 to avoid being 

hospitalized due to infection, $3,211 to avoid severe nausea, $2,764 to avoid severe 

tingling in hands and feet, $2,652 to avoid severe fatigue, $1,853 to avoid obvious 

hair loss and $1,458 to avoid severe pain. The most important attributes when 

selecting a therapy for MBC in terms of average utility were neutropenia, diarrhea 

and nausea. 

Conclusions: Patients most highly value the avoidance of diarrhea, neutropenia, and 

nausea with MBC treatment regimens. These are common side effects seen in many 

regimens used for treatment of MBC. This information can aid clinical decision 

making when selecting between MBC treatment options. Treatment regimens 

providing clinical efficacy while decreasing or eliminating key side effects would be 

an important choice to consider. 

Disclosure: D. Lalla: Dr. Lalla is an employee of Genentech, which funded this 

analysis. M. Brammer: Dr. Brammer is an employee of Genentech, which funded this 

analysis. R. Carlton: Dr. Carlton is an employee of Xcenda, which received funding 

from Genentech to conduct this analysis. T. Bramley: Dr. Bramley is an employee of 

Xcenda, which received funding from Genentech to conduct this analysis. A. 

D’Souza: Dr. D’Souza is an employee of Xcenda, which received funding from 

Genentech to conduct this anaysis. 

339P FULVESTRANT 500 MG AS FIRST-LINE TREATMENT IN 

HORMONE-POSITIVE (HR+) METASTATIC BREAST CANCER 

(MBC) PATIENTS (PTS): PROSPECTIVE EVALUATION OF 

ACTIVITY, SAFETY, QUALITY OF LIFE (QOL) AND TUMOUR 

MARKERS CHANGES 

R. Palumbo 1 , G. Bernardo 1 , A. Riccardi 2 , F. Sottotetti 1 , B. Tagliaferri 1 , E. Pozzi 1 , 

C.M. Teragni 1 , A. Bernardo 1 

1 Oncologia Medica 2, Fondazione S. Maugeri IRCCS, Pavia, ITALY, 2 Medical 

Oncology, University of Pavia, Pavia, ITALY 

Background: Fulvestrant 500 mg has been shown to have a biologically greater effect 

and to produce a clinical meaningful benefit over Fulvestrant 250 mg. We carried out 

a prospective phase II trial to evaluate the activity and safety of such an option as 1 st 

line treatment of HR+ MBC; an analysis of QoL, patient compliance, and prognostic 

value of tumour markers monitoring was also performed. 

Patients and methods: Pts with HR+ MBC relapsing after Tamoxifen and/or 

Aromatase Inhibitors adjuvant therapy received Fulvestrant 500 mg i.m. on day 0, 

then 500 mg on days 14-28 and every 28 days thereafter, until disease progression or 

unacceptable toxicity or patient refusal. Changes in cancer antigen 15.3 (CA 15.3) 

and carcinoembryonic antigen (CEA) were monitored monthly over treatment; QoL 

and treatment tolerability were assessed every 2 cycles. 

Results: Forty-eight consecutive pts were enrolled and treated. The overall clinical 

benefit rate was 68%, with 3 (6%) complete (CR) and 12 (25%) partial responses 

(PR), and 18 (48%) stable diseases (SD ) lasting >24 weeks. The median PFS was 11 

months, median response duration was 9 months. Toxicity was manageable, also in 

pts given long-duration therapy (>18 months). Analysis of QoL by QLQ-BR23 

showed no deterioration of the evaluated items over treatment, while the compliance 

assessment documented an improvement of tolerability of treatment compared with 

their previous adjuvant hormonotherapy. In pts achieving a CR or PR both CA 15.3 

and CEA serial levels decreased significantly over the first 4 months of treatment, 

while in long-lasting SD a statistically significant difference from baseline was 

reached within a median of 8 months. 

Conclusions: Our results confirm the known activity and tolerability of Fulvestrant 

500 mg as 1 st line therapy for HR+ MBC, with good patient compliance over 

long-term treatment and preservation of QoL. Of interest, changes in tumour 

markers resulted significantly predictive of treatment activity in responding pts, in 

contrast with previously reported data with Fulvestrant 250 mg, reflecting and 

additional difference between the two drug dosages. 


340P FULVESTRANT AFTER FAILUR OF ADJUVANT HORMONAL 

THERAPY: MULTICENTER RETROSPECTIVE OBSERVATIONAL 

STUDY 

O. Garrone 1 , C. Bighin 2 , F. Vaira 3 , M. Donadio 4 , O. Alabiso 5 , M. Carapezza 6 , 

E. Baldini 7 , M. Merlano 1 , N. Biglia 8 , P. Pronzato 9 

1 Clinical Oncology, Azienda Ospedaliera St. Croce e Carle, Cuneo, ITALY, 

2 Medical Oncology, Ist Naz Ric Cancro, Genova, ITALY, 3 Medical Oncology, 

Ospedale Felettino, LA Spezia, ITALY, 4 Oncoematology, Ospedale S. Giovanni 

Battista, Torino, ITALY, 5 Medical Oncology, AOU Maggiore della Carità, Novara, 

ITALY, 6 Medical Oncology, Ospedale degli Infermi, Biella, ITALY, 7 Medical 

Oncology, USL 2, Lucca, ITALY, 8 Gynecology, Ospedale Umberto I, Torino, 

ITALY, 9 Oncologia Medica A, IRCCS AOU San Martino - IST-Istituto Nazionale 

per la Ricerca sul Cancro, Genova, ITALY 

Background: Aromatase inhibitors (AI) are superior to TAM in the treatment of 

hormonal receptor positive metastatic breast cancer (MBC). Fulvestrant (F), an 

estrogen receptor antagonist demonstrated activity when used after failure of previous 

TAM or AI. Objective: To evaluate the position of F in the hormonal strategy 

sequence in hormonal responsive MBC related to the evolution of adjuvant 

hormonal therapy (HT). 

Material and methods: MBC patients with disease progression after adjuvant HT or 

after treatment (CT or HT) for metastatic disease, candidate to receive F at the dose 

of 250 mg/ month (registered in AIFA database) from May 1st 2006 to July 31st 

2008. The study registered the HT sequence in clinical practice. Overall 201 patients 

were collected from 13 Italian Centers. Main patients’ characteristics are summarized 

in the table. 

Results: ORR were: CR 2%; PR 7%; SD 43%; PD 41%; NE 7%. Eighty-six patients 

(43%) had visceral metastases. Median duration of F was 7 months (1-42); 8 

patients are ongoing and for 1 patient the duration was unknown. 16, 39 and 56 

patients received F as 1st, 2nd and 3rd line therapy respectively. For the remaining 

patients F was administered as more than the 4th line therapy. The possibility to 

obtain a benefit from F did not seem to correlate with the line of treatment. One 

of the 2 CR occurred in a patient with visceral disease (lung). Among the patients 

who progressed under treatment 42% had visceral disease, that was almost the 

same rate of the whole population. This data suggests that there is lack of 

correlation between the sites of disease and the probability of benefit. Toxicity was 

negligible. 

Conclusions: More than 50% of the patients benefited from F notwithstanding 73% 

of them received the treatment as third or more line of HT. This study does not 

show any correlation between the sites of the metastases and the treatment results. 


341P ADJUSTED INDIRECT COMPARISON ANALYSIS 

DEMONSTRATES SIGNIFICANT BENEFIT IN 

PROGRESSION-FREE SURVIVAL FOR FULVESTRANT 500MG 

COMPARED TO ANASTROZOLE IN ADVANCED BREAST 

CANCER 

P. Schmid 1 , P. Turner 2 , M. Howlett 3 

1 Clinical Investigation and Research Unit, Brighton and Sussex Medical School, 

Brighton, UNITED KINGDOM, 2 Payer Evidence, AstraZeneca Ltd, Luton, 

UNITED KINGDOM, 3 Medical Affairs, Astrazeneca Ltd, Luton, UNITED 

KINGDOM 

Objectives: Randomised controlled trials (RCTs) provide the highest level of 

evidence for comparing two treatments. However, with the increasing number of 

cancer drugs, direct comparison through RCTs is not feasible for all treatment 

indications and combinations. Bucher et al (1997) have developed a method for an 

adjusted indirect comparison analysis between RCTs. This method was used to 

compare the efficacy of fulvestrant 500mg and anastrozole 1mg in advanced breast 

cancer (ABC). 

Methods: A systematic literature search on RCTs of fulvestrant 500mg or anastrozole 

1mg in ABC was performed in June 2011, using CENTRAL, EMBASE and 

MEDLINE databases. Published data were used to perform a meta-analysis and an 

adjusted indirect comparison analysis (Bucher method). The primary endpoint was 

progression free survival (PFS). 


Results: Three RCTs with 1023 patients were identified comparing fulvestrant 500mg 

(F500) with fulvestrant 250mg (F250), and two RCTs with a total of 851 patients 

were identified comparing anastrozole 1mg (Ana) with fulvestrant 250mg. 

Meta-analysis demonstrated a significant benefit in PFS for F500 compared to F250 

(Hazard ratio (HR) 0.80 95% Confidence Interval (CI):0.69-0.93). There was no 

significant difference in PFS between Ana and F250 (HR 0.95, 95%CI 0.82-1.1). 

Using F250 as common comparator, the adjusted indirect comparison analysis 

demonstrated a significant benefit in PFS for F500 compared to Ana (HR 0.76, 95% 

CI 0.62-0.94). 

Conclusions: In the absence of a direct RCT comparison, this adjusted indirect 

comparison shows that fulvestrant 500mg significantly improves PFS in ABC 

compared to anastrozole 1mg. Bucher HC, Guyatt GH, Griffith LE, Walter SD 

(1997). The results of direct and indirect treatment comparisons in meta-analysis of 

randomized controlled trials. J Clin Epidemiol. 1997 Jun;50(6):683-91. 

Disclosure: P. Turner: Pauline Turner is a full-time employee of AstraZeneca and is 

a stockholder in Astra Zeneca. M. Howlett: Matthew Howlett is a full time employee 

of Astrazeneca and is a stockholder in Astrazeneca. All other authors have declared 


342P FULVESTRANT (FUL) PLUS ENZASTAURIN (ENZA) VS FUL 

PLUS PLACEBO (PBO) IN AROMATASE INHIBITOR 

(AI)-RESISTANT METASTATIC BREAST CANCER (MBC): 

A RANDOMIZED, DOUBLE-BLIND, PHASE 2 TRIAL 

R.S. De Jong 1 , G.S. Sonke 2 , N. Maass 3 , K. Mansouri 4 , L. Cirri 5 , P. Shi 6 , 

O. Hamid 6 , G. Mariani 7 

1 Department of Internal Medicine, Martini Hospital, Groningen, NETHERLANDS, 

2 Department of Medical Oncology, Netherlands Cancer Institute - Antoni van 

Leeuwenhoek, Amsterdam, NETHERLANDS, 3 Department of Gynecology and 

Obstetrics, University Hospital Aachen, Aachen, GERMANY, 4 Oncology, Lilly 

Deutschland GmbH, Bad Homburg, GERMANY, 5 Oncology, Eli Lilly and 

Company Italia SPA, Florence, ITALY, 6 Clinical Oncology, Eli Lilly and Company, 

Indianapolis, IN, UNITED STATES OF AMERICA, 7 Department of Medical 

Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, ITALY 

AIs are used as first-line treatment for postmenopausal women with 

hormone-receptor-positive MBC. Overexpression of PKC α has been linked to AI 

resistance in several studies. We examined whether Enza, a serine/threonine kinase 

inhibitor that targets PKC, could improve the effect of Ful in pts who progressed 

following first-line AI treatment for MBC. 

Postmenopausal pts with hormone-receptor-positive, HER2-negative, locally 

advanced or MBC who progressed on prior AI received a loading dose of Ful 500 mg 

IM on Day (D) 1 and 250 mg on D 15 of Cycle (C) 1 and D 1 of each cycle 

thereafter. Enza 500 mg or PBO was administered orally once daily (QD) or 250 mg 

twice daily (BID). Primary endpoint was the clinical benefit rate (CBR). Secondary 

endpoints were response rate (RR), duration of CB, progression-free survival (PFS) 

and safety. A total of 156 pts was randomly assigned to therapy; 152 received at least 

1 dose of study drug (39 BID; 55 QD; 58 PBO). Baseline disease characteristics were 

balanced across arms. There was no statistically significant difference in CBR between 

pts in Ful + Enza vs Ful + PBO. There was no statistically significant difference in 

CBRs, RRs and PFS between pts on QD and BID dosing schedules. Pts on BID 

dosing had numerically more TEAEs vs those on QD and PBO (61.5%, 43.6%, and 

46.6%, respectively) and numerically more Grade 3/4 TEAEs vs QD and PBO 

(17.9%, 9.1%, and 5.2%, respectively). Most frequent Grade 3/4 TEAEs in the BID 

arm were fatigue (n [%]) (4 [10.3%]), dyspnea (2 [5.1%]) and nausea (2 [5.1%]). 

8 pts died; 5 due to disease, 3 due to AEs: 1 drug-related hepatic dysfunction (Enza 

QD arm), 1 non-drug-related myocardial infarction and 1 non-drug-related 

respiratory failure (both in the Enza BID arm). 

CBR 

Number of responders, 

Ful + Enza 

[QD + BID] 

N=94 

Ful + PBO 

N = 58 P-value vs PBO 

0.62 

24 (44.8) 

n (%), (95% CI) 

41 (43.6) 

(33.4, 54.2) (31.7, 58.5) 

RR, % (95% CI) 5.3 (1.7, 12.0) 5.2 (1.1, 14.4) 0.64 

PFS, months (95% CI) 5.2 (3.5, 7.4) 5.5 (3.8, 7.4) 0.59 

Median duration of CB, months 9.6 9.7 0.86 

CBR = complete response + partial response + stable disease Addition of Enza to Ful 

does not improve disease outcome in pts with locally advanced or MBC after 

progression on AI. 

Disclosure: K. Mansouri: K. Mansouri is an employees of Eli Lilly and Co. L. Cirri: 

L. Cirri is an employees of Eli Lilly and Co. P. Shi: P. Shi is an employees of Eli Lilly 

and Co. O. Hamid: O. Hamid is an mployees of Eli Lilly and Co. All other authors 



343P NEW IMMUNOHISTOCHEMICAL MARKERS PREDICTIVE 

OF RESPONSE TO NEOADJUVANT CHEMOTHERAPY PLUS 

TRASTUZUMAB IN HER2-POSITIVE LOCALLY ADVANCED 

BREAST CANCER: A SINGLE CENTER EXPERIENCE 

G. Faggioni 1 , C. Ghiotto 1 , E. Orvieto 2 , S. Valpione 1 

1 Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, ITALY, 

2 Anatomia Patologica, Azienda Ospedaliera di Padova, Padova, ITALY 

We present the results of a prospective pilot study aimed to investigate the value of 

new immunohistochemichal predictive markers of response to chemotherapy in 

locally advanced HER-2 breast cancer. pTEN loss, pAKT and HER-3 overexpression 

cause PI3K activation and induce resistance to trastuzumab in vitro and in vivo, with 

poorer clinical responses in patients with advanced disease. We studied the 

espression of EGFR, HER-3, pTEN and pAKT in 31 patients with locally advanced 

HER-2 positive breast cancer who received neoadjuvant chemotherapy plus 

trastuzumab. Mean age of patients was 55.7 years (median 55, 95% CI 44,2-63,5 

years). Results of immunohistochemistral staining are reassumed in the table. 

Mean Median 25% C.I. 75% C.I. 

ER% 40,6 40,0 0,0 77,5 

PgR% 23,1 10,0 0,0 40,0 

Ki-67% 38,2 40,0 25,0 50,0 

EGFR Hscore 6,1 0,0 0,0 1,0 

HER3 (% positive cells) 50,0 50,0 32,5 70,0 

HER3 intensity 1,5 1,0 1,0 2,0 

HER3 H score 82,6 70,0 32,5 115,0 

PTEN (% positive cells) 48,9 70,0 2,5 70,0 

PTEN intensity 1,5 1,0 1,0 2,0 

AKT Hscore 56,7 20,0 0,0 70,0 

AKT IRS 2,5 2,0 0,0 3,0 

Patients were homogeneous for tumor burden at diagnosis and received 

anthraciclin-taxane and trastuzumab-based neoadjuvant treatment. 14 out of 

31patients achieved pathological complete remission. Ki-67 and HER3 H score were 

significatively higher in patients who achieved complete remission (medians were 

45.5% versus 25%, p = 0.022; 100% versus 50%, p = 0.045 respectively. We found a 

correlation between EGFR H score and HER3 Hscore (p = 0.02), and an inverse 

correlation between age and EGFR H score (p = 0.05) and between PgR and AKT 

intensity (p = 0.03). Ki-67 and HER3 H score maintained significatively different 

medians in the group of patients who experienced pathological complete response 

versus the group on incomplete responders with multivariate analysis (p < 0.01). 


344P PHARMACOKINETICS (PK) OF PERTUZUMAB (P) WITH 

TRASTUZUMAB (T) AND DOCETAXEL (D) IN HER2-POSITIVE 

FIRST-LINE METASTATIC BREAST CANCER (MBC): RESULTS 

FROM THE PHASE III TRIAL CLEOPATRA 

J. Cortes 1 , S. Swain 2 , I. Kudaba 3 , M. Hauschild 4 , T. Patel 5 , E. Grincuka 6 , 

N. Masuda 7 , V. McNally 8 , J. Visich 9 , J. Baselga 10 

1 Oncologia, Vall d’Hebron University Hospital Institut d’Oncologia, Barcelona, 

SPAIN, 2 Medstar Washington Hospital Center, Washinton Cancer Institute, 

Washington, WA, UNITED STATES OF AMERICA, 3 Oncology Center, Riga East 

University Hospital, Riga, LATVIA, 4 Spital Rheinfelden & Laufenburg, 

Gesundheitszentrum Fricktal, Rheinfelden, SWITZERLAND, 5 The Mark 

H. Zangmeister Center, Mid Ohio Oncology/Hematology, Inc., Columbus, OH, 

UNITED STATES OF AMERICA, 6 Department of Oncology, Daugavpils Regional 

Hospital, Daugavpils, LATVIA, 7 Surgery and Breast Oncology, NHO Osaka 

National Hospital, Osaka, JAPAN, 8 Products Limited, Roche, Welwyn, UNITED 

KINGDOM, 9 Genentech, Genentech, South San Francisco, CA, UNITED 

STATES OF AMERICA, 10 Hematology/oncology, MGH Cancer Center, 


Introduction: P is a humanized mAb that inhibits heterodimerization of HER2. P 

and T bind distinct HER2 epitopes, and due to their complementary mechanisms of 

action they provide a more comprehensive blockade of HER2 signaling. Based on 

preclinical efficacy models, a steady-state trough P concentration (Ctrough) of 20 ug/ 

ml was selected as target in pts. CLEOPATRA is a Phase III study comparing P + T 

+ D vs placebo (Pla) + T + D in HER2-positive 1L MBC (Baselga NEJM 2012). The 

objectives of the substudy reported here are to characterize the P PK in the presence 

of T and D, and to explore potential drug − drug interactions. 

Methods: P/Pla (840 mg loading, 420 mg maintenance) was administered on Day 1 

of each cycle; T (8 mg/kg loading, 6 mg/kg maintenance) was administered on Day 2 

of Cycle 1 and on Day 1 of each cycle onward following P; D (75 mg/m 2 , escalation 

to 100 mg/m 2 if tolerated) was administered on Day 2 of Cycle 1 following T and on 

Day 1 of each cycle onward following T. All drugs were given q3w iv. Blood samples 



for P were collected before and after infusion at Cycles 1, 3, 6, 9, 12, 15, 18, and at 

treatment discontinuation. Samples for T were collected before and after infusion at 

Cycles 1 and 3. Samples for D were collected at Cycle 1 at 8 serial time points during 

and following the infusion over a 24 h period to allow calculation of C max, CL, V ss, 

t 1/2, AUC 0–t, and AUC 0-inf. 

Results: 37 pts (17 Pla arm, 20 P arm) were available for PK evaluation. Serum P 

Ctrough exceeded the target of 20 ug/ml in >90% of pts and there was no impact of T 

and D on P PK, compared with historical data. Mean serum T Cmax and Cmin at 

Cycles 1 and 3 were similar in both arms. Ratios of geometric LS means of P + T + 

D/Pla + T + D x100 for serum T were: Cycle 1 C max 90.3; Cycle 3 C min 95.9; Cycle 3 

C max 81.0. D PK parameters were similar in both arms. Ratios of geometric LS 

means of P + T + D/Pla + T + D x100 for plasma D were: AUC 0–t 104.9, AUC 0-inf 

101.4, C max 92.5. 

Conclusion: P PK parameters were consistent with previous studies, and 

co-administration of T and D appears not to influence P PK in HER2-positive MBC. 

There was no evidence of drug − drug interactions between P and T, or between P 

and D, which have different clearance pathways. 

Disclosure: J. Cortes: I am an advisory board member for Roche, Celgene and 

Novartis. I have received research funding from Roche, Celgene, Cephalon and 

Ferrer. S. Swain: Advisory Board for Genentech/Roche for EMILIA study and 

Avastin - uncompensated. Research funding: Genentech/Roche. T. Patel: I have 

an advisory board membership for Genentech/Roche to disclose and are a 

speaker for Genentech/Roche. I have received research funding from Genentech/ 

Roche. N. Masuda: I have honoraria to disclose received from Chugai 

Pharmaceutical Co., Ltd. V. McNally: I am a Roche employee and hold Roche 

shares. J. Visich: I am an employee of Genentech. J. Baselga: Dr Baselga reports 

the following relationships with relation to the topic of this abstract: Roche, 

Sanofi Aventis, Consulting/Scientific Advisory Board. Roche, Sanofi Aventis, 

Honoraria for speaking engagements. All other authors have declared no 


345P PROGNOSTIC FACTORS INFLUENCING THE SELECTION 

OF BEVACIZUMAB COMBINED WITH CHEMOTHERAPY IN 

PATIENTS WITH HER2-NEGATIVE METASTATIC BREAST 

CANCER IN ROUTINE CLINICAL PRACTICE. 

ONCOSUR-AVALOX: OBSERVATIONAL CROSS-SECTIONAL 

STUDY 

L. Manso 1 , R. Perez-Carrion 2 , J.I. Chacon Lopez-Muniz 3 , A. García Palomo 4 , 

E. Galve Calvo 5 , R.M. Llorente 6 , J. Casinello 7 , G. Catalán 8 , C. Llorca 9 , 

C. Grávalos 10 

1 Medical Oncology, Hopital 12 de Octubre, Madrid, SPAIN, 2 Oncology, Hospital 

Universitario Quiron, Madrid, SPAIN, 3 Oncolog, Hospital Virgen de la Salud, 

Toledo, SPAIN, 4 Oncology, Hospital de León, Leon, SPAIN, 5 Oncology, Hospital 

de Basurto, Bilbao, SPAIN, 6 Oncology, Hospital Universitario Dr. Peset, Valencia, 

SPAIN, 7 Oncology, Hospital General Guadalajara, Guadalajara, SPAIN, 

8 Oncology, Hospital Son Llatzer, Palma de Mallorca, SPAIN, 9 Oncology, Hospital 

de Elda, Alicante, SPAIN, 10 Medical Oncology, Hospital Doce de Octubre, 

Madrid, SPAIN 

Background: Combining bevacizumab (BEV) with chemotherapy (CT) improves 

survival in HER2-negative metastatic breast cancer (MBC). We investigated the 

influence of age, ECOG, hormonal status, number of sites and location of metastases 

and patient decision on the selection of BEV combined with CT in MBC. 

Methods: Observational cross-sectional multicenter study in pts with HER2- negative 

MBC who have received first-line CT with BEV. 

Results: From November 2010 to November 2011, 124 pts were included: 

median age 51 (45-64) yr; ECOG: 0 = 50%; 60% pre-menopausic; 23% 

triple-negative (TN); 77% hormone receptorpositive (HR+). Metastatic disease: 

≥3 sites = 42% (TN: 32%; HR + : 45%); location: 44% bone, 35% lung, 30% liver. 

Most frequent BEV-based combinations were paclitaxel/BEV (53%) and 

docetaxel/BEV (14.5%); median no. of CT cycles: 6 (5-8). A disease-free survival 

(DFS) ≥12 months was achieved by 73%; TN: 68%; HR + : 76%. Overall 

response rate (ORR) was 58%: 51% partial response (PR), 7% complete response 

(CR); 28% stable disease (SD) and 10% disease progression. TN: ORR 44% (40% 

PR), clinical benefit 80% (36% SD); HR + : ORR 62% (54% PR), clinical benefit 

87% (25% SD). 58% presented at least one toxicity, mainly grade 1-2; 26% 

BEV-related: only 3 (2.4%) grade 3 toxicities; no grade 4. Receiving adjuvant 

hormonal therapy was associated to DFS ≥12 months (p < 0.05). ER+ tumors 

(OR: 0.215; 95% CI: 0.08-0.56; p = 0.002) and one metastatic site, vs. ≥3 sites 

(OR: 0.309; 95% CI: 0.12-0.83; p = 0.020) were independent factors associated 

with the selection of paclitaxel-BEV therapy in the overall population (TN or 

HR+). Metastases in the liver were significantly related to paclitaxel-BEV 

administration (p < 0.01). 

Conclusions: Our findings suggest that first-line CT with BEV is an active and 

tolerable treatment option for pts with TN and HR+ MBC. ER+ tumors and a single 

metastatic site were identified as independent factors for the selection of a 

paclitaxel-BEV therapy. The presence of metastases in the liver was significantly 

associated to the administration of a paclitaxel-BEV regimen. 


346P CHARACTERISTICS OF PATIENTS WITH HER2-POSITIVE 

METASTATIC (MBC) OR LOCALLY ADVANCED BREAST 

CANCER (ABC), TREATED WITH TRASTUZUMAB (T) AS 1ST 

LINE-THERAPY AND PROGRESSION-FREE FOR AT LEAST 

3 YEARS: INTERIM ANALYSIS OF THE LORHA STUDY 

O. Tredan 1 ,B.You 2 , P. Beuzeboc 3 , D. Coeffic 4 , A. Lortholary 5 , M. Fellous 6 ,T.De 

La Motte Rouge 7 , F. Andre 8 , L. Arnould 9 , J. Ferrero 10 

1 Medical Oncology, Lyon Bérard Centre, Lyon, FRANCE, 2 Medical Oncology, 

Lyon-Sud Hospital, Lyon, FRANCE, 3 Medical Oncology Unit, Curie Institute, 

Paris, FRANCE, 4 Medical Oncology, Clinique Hartmann, Neuilly-sur-Seine, 

FRANCE, 5 Medical Oncology, Catherine de Sienne Institute, Nantes, FRANCE, 

6 Medical, Roche France, Boulogne Billancourt, FRANCE, 7 Medical Oncology, 

Salpétrière Hospital, Paris, FRANCE, 8 Department of Medical Oncology, Institut 

Gustave Roussy, Villejuif Cedex, FRANCE, 9 Biology & Pathology of The Tumor, 

Centre GF LECLERC, Dijon, FRANCE, 10 Oncologie Médicale, Centre Antoine 

Lacassagne, Nice Cedex, FRANCE 

Background: For more than ten years, treatment of HER2-positive mBC patients 

(Pts) is based on T plus taxane in 1 st line therapy. So far, in numerous studies, we 

have observed few subsets of Pts (long-term responders) who have not experienced 

disease progression for several years after T-based regimen in 1 st line treatment. This 

study aims to characterise these Pts in the daily practice from a clinical and 

biological perspective. 

Material and methods: This is an ambispective French multicentre non-interventional 

study. Eligible Pts were women aged ≥18 years with HER2-positive mBC or aBC 

treated with T as 1 st line and who were progression-free for at least 3 years after 

starting T. The primary objective was to describe the clinical and tumor characteristics 

of these Pts. Progression Free Survival (PFS), Overall Survival (OS), data on treatment 

administration and safety were also collected. An exploratory biomarkers analysis is 

planned on tumor tissue samples. Here we present some preliminary results based on 

the interim analysis performed at the end of inclusions. 

Results: 159 Pts were enrolled in 2011 and 110 Pts were eligible for data analysis. 

Median age was 59 years [34-95]. Tumor characteristics were: invasive ductal 

carcinoma for 96 Pts (88%), positive hormonal receptors in 63 Pts (58%). At initial 

diagnosis, presenting stages were I-II for 52 Pts (50%). 36 Pts (33%) had a mBC de 

novo or an aBC. The main metastatic localisations were bone, liver and lung in 51 

(47%), 35 (32%) and 22 (20%) Pts respectively. Median T treatment duration was 4.1 

years [0.8 - 11.0] in 1 st line. T was associated with a taxane-based chemotherapy in 

86 Pts (78%). Median PFS was 6.4 years [4.9; - ]. Median OS was not reached. 13 

retrospective adverse events related to T (cardiac or leading to discontinuation) were 

reported. None of these was serious. 

Conclusions: In this long PFS population treated with a T-based treatment in first 

line for aBC or mBC Pts, no specific profile in terms of clinical or histological 

characteristics have been observed. Thus, the exploratory biomarkers analysis will be 

useful to identify such a profile. 

Disclosure: O. Tredan: Roche consultant. P. Beuzeboc: Roche consultant. D. Coeffic: 

Roche consultant. M. Fellous: Roche employee. L. Arnould: Roche Consultant. All 


347P THE ENCHANTTM TRIAL: AN OPEN LABEL MULTICENTER 

PHASE 2 WINDOW OF OPPORTUNITY STUDY EVALUATING 

GANETESPIB (STA-9090) MONOTHERAPY IN WOMEN WITH 

PREVIOUSLY UNTREATED METASTATIC HER2 POSITIVE OR 

TRIPLE NEGATIVE BREAST CANCER (TNBC) 

D. Cameron 1 , M.S. Mano 2 , V. Vukovic 3 , F. Teofilovici 3 , R. Bradley 3 , A. Awada 4 

1 Oncology, Edinburgh Cancer CentreWestern General Hospital, Edinburgh, 

UNITED KINGDOM, 2 Medical Oncology, ICESP, Sao Paulo, BRAZIL, 3 Oncology, 

Synta pharmaceuticals, lexington, MA, UNITED STATES OF AMERICA, 

4 Department of Medical Oncology, Institute Jules Bordet, Brussels, BELGIUM 

Background: Hsp90 is a molecular chaperone required for proper folding and 

activation of many cancer-promoting proteins. Several Hsp90 clients are 

oncoproteins known to play a key role in the pathobiology of breast cancer, including 

HER2, p95- HER2 , EGFR, ER, PI3K, AKT, and VEGFR. The inactivation of these 

oncoproteins by Hsp90 inhibition is a promising approach for breast cancer therapy. 

Ganetespib is an Hsp90 inhibitor which has shown anti-tumor activity in heavily 

pretreated patients with lung, breast, and other cancers. Ganetespib is well tolerated 

without severe liver or common ocular toxicities. In a phase 2 trial, 22 breast cancer 

patients who had received up to 3 prior lines of chemotherapy including trastuzumab 

were treated with ganetespib monotherapy. In patients with HER2+ disease, the 

objective response rate (ORR) was 15% (2/13) and the SD rate was 46% (6/13). Only 

3 patients presented with TNBC; one of those patients achieved SD with substantial 

tumor shrinkage on treatment. 

Methods: This is a single arm international open-label Phase 2 study in patients with 

HER2 amplified, or triple negative breast cancer. Patients must not have received any 

prior therapy in the metastatic setting. Prior adjuvant therapy is allowed. 

Primary endpoint: ORR. Main secondary endpoints include disease control rate, and 

progression free survival. Additionally, fresh biopsies and serum samples are 


collected from all patients for determination of predictors of response and 

mechanisms of resistance to treatment. Patients are treated with ganetespib 

150 mg/m 2 is given twice weekly of a 4-week cycle for up to 12 weeks. A total of 

70 patients are planned for accrual. At the time of submission, the study is receiving 

IRB approvals in several centers. 


348P HGFK1 INHIBITS BONE METASTASIS IN BREAST CANCER 

THROUGH THE TAK1/P38 MAPK SIGNALING PATHWAY 

Y-Z. Bu 1 , Z. Shen 2 

1 Department of Surgery, Lianshui People’s Hospital, Jiangsu Province, CHINA, 

2 Department of Oncology, Shanghai 6th People’s Hospital, Shanghai Jiao Tong 

University, Shanghai, CHINA 

Background: Breast cancer metastasis to bone represents a devastating complication 

of advanced breast cancer, frequently resulting in significant increases in morbidity 

and mortality. An understanding of the mechanisms that govern breast cancer 

metastasis at the molecular level should lead to more effective therapies. Recently, the 

kringle 1 domain of human hepatocyte growth factor (HGFK1) was identified as a 

candidate metastasis suppressor gene. 

Methods: Here, we investigated whether HGFK1 is a key regulator of breast cancer 

bone metastasis. 

Results: Of the 193 human breast carcinoma tissue samples examined, HGFK1 

expression was positive in 82 (42.4%). The positive expression of HGFK1 was 

significantly associated with a better prognostic value (P < 0.001) and inversely 

correlated with bone metastasis (P = 0.003). The efficacy of adeno-associated virus 

carrying HGFK1 (AAV-HGFK1) in osteolytic bone metastasis was then evaluated 

using an in vivo bone metastasis model. AAV-HGFK1 significantly inhibited 

osteolytic bone metastasis and prolonged the survival of mice in this model (P < 

0.01). In vitro, HGFK1 expression resulted in significant anti-invasion effects, 

enhanced the phosphorylation of TAK1, p38 MAPK and MAPKAPK2, and 

decreased the expression of receptor activator of NF-κB (RANK), which was 

abrogated by the p38 MAPK inhibitor SB203580. 

Conclusions: This study shows for the first time that HGFK1 significantly inhibits 

the metastasis of breast cancer to bone by activating the TAK1/p38 MAPK signaling 

pathway and inhibiting RANK expression. Thus, AAV-HGFK1 treatment represents 

a potential therapy for bone metastasis in breast cancer. 


349P IMPACT OF DIABETES AND HYPERGLYCEMIA ON SURVIVAL 

IN ADVANCED BREAST CANCER PATIENTS 

R.J. Shaw Dulin 1 , C. Villarreal-Garza 1 , F. Lara 1 , L. Bacon 2 , D. Rivera 2 , A.D. 

Rivera Salceda 2 , L. Urzua 2 , L. Herrera 3 , C. Aguila 2 , J.E. Bargallo-Rocha 1 

1 Breast Tumor Department, Instituto Nacional de Cancerología Mexico, Mexico 

City, MEXICO, 2 Medical Oncology, Instituto Nacional de Cancerología Mexico, 

Mexico City, MEXICO, 3 Department of Biomedical Research In Cancer, Instituto 

Nacional de Cancerologia, Mexico City, MEXICO 

Background: Clinical experience and previous studies suggest that women with 

diabetes and breast cancer have worse outcomes than their non-diabetic counterparts. 

The purpose of this study was to examine the impact of diabetes and hyperglycemia 

on cancer-specific survival of patients with metastatic or recurrent breast cancer. 

Methods: We performed a retrospective analysis of patients with advanced breast 

cancer receiving palliative chemotherapy from 2006 to 2011 at the National Cancer 

Institute in Mexico, and compared breast cancer-specific mortality in diabetic and 

non-diabetic patients, as well as in patients that presented hyperglycemia during 

palliative treatment. 

Results: A total of 265 patients receiving palliative therapy were eligible for inclusion. 

Previous diagnosis or detection of diabetes at recurrence was recorded in 40 patients 

(15%). No difference was observed between diabetic and non-diabetic patients in 

terms of OS. A statistically significant difference in OS was observed between patients 

without diabetes and diabetic patients who had hyperglycemia (p = 0.003). OS in 

diabetic patients with proper metabolic control was shown to be superior compared 

to diabetics with hyperglycemia (p = 0.01) Hyperglycemia was identified in 14% of 

non-diabetics at some point while receiving palliative treatment. For patients that 

experienced hyperglycemia during treatment or who had a mean glucose level above 

130, either in the diabetic or non-diabetic subgroups, a worse outcome was noted 

compared to normoglycemic patients, with a HR of 1.5 (p = 0.029) and HR of 2.04 

(p = 0.006) for death, respectively. 

Conclusions: Elevated glucose levels confer a poor outcome in diabetic and 

non-diabetic patients in contrast with patients with normoglycemic levels, conferring 

an elevated risk of death. According to these results, clinicians must monitor glucose 

levels during treatment for advanced breast cancer disease, and should take action in 

order to maintain normal glucose levels. 



350P ANTITUMOR ACTIVITY OF DUAL PI3K AND ER BLOCKADE 

IN ER POSITIVE BREAST CANCER MODELS 

J. Tao 1 , M. Scaltriti 1 , S. Marlow 1 , M. Elkabets 1 , N. Morse 1 , D. Sgroi 2 , J. Baselga 1 

1 Cancer Center, Massachusetts General Hospital, Charlestown, MA, UNITED 

STATES OF AMERICA, 2 Molecular Pathology Unit, Massachusetts General 

Hospital, Charlestown, MA, UNITED STATES OF AMERICA 

Background: Activation of the phosphoinositide 3-kinase (PI3K) pathway, either by 

receptor tyrosine kinase overexpression or PI3K/Akt/mTOR axis dysregulation, has 

been implicated in endocrine therapy resistance, prompting combination of PI3K 

inhibitors and antiestrogen therapy in the clinical setting such as in the recent 

BOLERO-2 study. We hypothesize that dissecting the molecular crosstalk between 

the PI3K and estrogen receptor (ER) pathways will help define the subset of patients 

most responsive to combined PI3K/antiestrogen therapy. 

Methods: ER+ cell lines MCF7, MCF7-long term estrogen deprived (LTED), 

MCF7-fulvestrant resistant clones Fslx64 and Fslx70, T47D, ZR75-1, CAMA1, 

MDA361, KPL-1, BT474, EFM19, HCC1428, UACC812, were treated with the ER 

degrader, fulvestrant, and the p110α-specific PI3K inhibitor BYL719 in vitro. Cell 

viability was measured by CellTiter-Glo and Crystal Violet. MCF7 and ER+ 

patient-derived xenografts were treated with fulvestrant, BYL719 or the combination 

in vivo. Protein expression was measured by Western blot and 

immunohistochemistry. 

Results: Fulvestrant or BYL719 treatment resulted in variable inhibition of cell 

viability in all ER+ cell lines. Combination treatment was significantly superior to 

monotherapy in MCF7, MCF7-LTED, MCF7-Fslx64 and MCF7-Fslx70. While MCF7 

clones Fslx64 and Fslx70 were resistant to >1 µM of fulvestrant, they were exquisitely 

sensitive to BYL719. Moreover, PI3K inhibition led to ER upregulation in ER+ cell 

lines, including those most sensitive to combination treatment. Total ER levels also 

increased in MCF7 xenografts treated with therapeutic doses of BYL719. 

Conclusions: Combined treatment with BYL719 and fulvestrant in vitro was superior to 

single-agent treatment in 4 of 13 ER+ cell lines. Importantly, dual PI3K/ER blockade was 

effective in cells resistant to ER deprivation and/or degradation. Induced ER levels 

following PI3K suppression may represent a feedback mechanism by which ER+ cells 

escape PI3K inhibition. We are currently studying whether this phenomenon predicts 

sensitivity to dual PI3K/ER blockade in ER+ breast cancer models. 

Disclosure: J. Baselga: J. Baselga is a consultant/advisory board member for Aragon, 

AstraZeneca, Sanofi, Bayer, Onyx, Chugai, Constellation, Exelixis, Intellikine, Merck, 

Novartis, and Roche Genentech. All other authors have declared no conflicts of interest. 

351P SAFETY OF EVEROLIMUS FOR WOMEN OVER 65 YEARS OF 

AGE WITH ADVANCED BREAST CANCER: 18-MO FOLLOW-UP 

OF BOLERO-2 

M. Gnant 1 , S. Noguchi 2 ,Y.Ito 3 , M. Piccart 4 , J. Baselga 5 , A. Panneerselvam 6 , 

T. Taran 6 , T. Sahmoud 6 , G.N. Hortobagyi 7 , K. Pritchard 8 

1 Deparment of Surgery, Medical University of Vienna, Vienna, AUSTRIA, 

2 Department of Breast and Endocrine Surgery, Osaka University, Osaka, JAPAN, 

3 Department of Medical Oncology, Cancer Institute Hospital, Japanese 

Foundation for Cancer Research, Tokyo, JAPAN, 4 Institut Jules Bordet, Institut 

Jules Bordet, Brussels, BELGIUM, 5 Massachusetts General Hospital Cancer 

Center and Harvard Medical School, Massachusetts General Hospital Cancer 

Center and Harvard Medical School, Boston, MA, UNITED STATES OF 

AMERICA, 6 Novartis Pharmaceuticals Corporation, East Hanover, NJ, UNITED 

STATES OF AMERICA, 7 The University of Texas Md Anderson Cancer Center, 

The University of Texas MD Anderson Cancer Center, Houston, TX, UNITED 

STATES OF AMERICA, 8 Medical Oncology, Sunnybrook Odette Cancer Center, 

Toronto, CANADA 

Background: Hormone-receptor–positive (HR + ) breast cancer (BC) refractory/ 

resistant to nonsteroidal aromatase inhibitor (NSAI) may be treated with the 

steroidal AI exemestane (EXE), although there is no approved treatment standard. 

The BOLERO-2 trial showed that adding everolimus (EVE) to EXE significantly 

improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, 

Abstract S3-7). As many women with advanced BC are elderly (≥ 65 years), the 

efficacy and tolerability of EVE + EXE in this population are of interest. 

Methods: BOLERO-2 is a phase 3, randomized trial comparing EVE (10 mg once 

daily) vs placebo (PBO), both plus EXE (25 mg once daily) in postmenopausal 

women with advanced HR + BC progressing or recurring after NSAIs. 

Results: Baseline disease and prior treatment characteristics were balanced between 

study arms (N = 724). At 18 months’ median follow-up, adding EVE to EXE 

significantly improved progression-free survival in patients < 65 (n = 449; 8.3 vs 2.9 

mo; HR = 0.38; 95% CI = 0.30, 0.47) and ≥ 65 years (n = 275; 6.8 vs 4.0 mo; HR = 

0.59; 95% CI = 0.43, 0.80). Overall incidence of adverse events (AEs) was marginally 

higher in patients ≥ 65 years (n = 272, safety population) compared with those < 65 

years. Grade 3/4 AEs occurred in 50% of patients ≥ 65 years compared with 42% of 

patients < 65 years. Incidences of grade 3/4 stomatitis, rash, pneumonitis, and 

hyperglycemia in EVE-treated patients ≥ 65 years and those < 65 years were similar. 

Additional analysis using an age cutoff of 70 years also showed no meaningful 

differences in the efficacy/safety profile of EVE. Grade 3/4 AEs in patients ≥ 65 years 



reported among patients receiving EVE (n = 192) but not in those receiving PBO 

included anemia (9%), hyperglycemia (7%), stomatitis (9%), dyspnea (8%), 

pneumonitis (5%), neutropenia (3%), and hypertension (2%). These AEs were also 

reported at similar frequency in EVE-treated patients < 65 years. 

Conclusions: Adding EVE to EXE was effective and well tolerated overall and, in 

elderly patients with advanced BC, grade 3/4 AEs were uncommon and manageable. 

Overall, AEs were consistent with the known safety profile of EVE. 

Disclosure: M. Gnant: Research support from GSK, Sanofi-Aventis, Novartis, and 

Roche, consultant to Merrion and Novartis, and received honoraria & travel support 

from Amgen, Pfizer, Novartis, GSK, Bayer, Sandoz, AstraZeneca, and 

GenomicHealth. S. Noguchi: S. Noguchi received grant support from AstraZeneca, 

BMS, Chugai, GSK, Novartis, Pfizer, Sanofi-Aventis, and Takeda, and honoraria 

(speaking, advisory boards, etc.) from AstraZeneca, Chugai, GSK, Novartis, Pfizer, 

Sanofi-Aventis, and Takeda. M. Piccart: Board for PharmaMar, consultant 

Sanofi-Aventis, Amgen, BMS, GSK, Boehringer, Roche, & Bayer, grant support 

Pfizer, Amgen, Bayer, Boehringer, BMS, GSK, Roche, & Sanofi-Aventis, honoraria 

Bayer, BMS, GSK, Boehringer, Roche, Amgen, & AstraZeneca. J. Baselga: J. Baselga is 

a consultant to Novartis, Roche, Merck, Sanofi-Aventis, Verastem, Bayer, Chugai, 

Exelixis, Onyx, and Constellation. A. Panneerselvam: Employee of Novartis with 

stock/stock options. T. Taran: Employee of Novartis with stock/stock options. T. 

Sahmoud: Employee of Novartis with stock/stock options. G.N. Hortobagyi: Member 

of the Scientific Advisory Board of Allergan, is a consultant to Allergan, Novartis, 

Genentech, and Sanofi-Aventis, has received grant support from Novartis, and has 

received travel expense reimbursement from Novartis, Genentech, and 

Sanofi-Aventis. K. Pritchard: Consult sanaven AZE Roche PFE NVR ABR AMG GSK 

res funding NCICCT Grp contracted AZE BMS SanAven AMG PFE NVR GSK & 

OrthoBio honoraria & Spkr B SanAven AZE PFE Roche NVR & AMG paid expert 

test SanAven AZE & GSK AdCom SanAven AZE Roche PFE NVR GSK & AMG. All 


352P MTOR EXPRESSION IN BASAL-LIKE BREAST CANCER AND 

THE ABILITY OF EVEROLIMUS TO INHIBIT THE INVASION 

CANCER CELL CAPACITY 

D.F. Martins, B. Sousa, J. Paredes, F. Schmitt 

Cancer Genetics- Breast Pathology, Institute of Molecular Pathology and 

Immunology of the University of Porto, IPATIMUP, University of Porto, Porto, 

PORTUGAL 

The introduction of high-throughput technologies in breast cancer enabled the 

recognition of groups with prognostic value, in which target-therapies can be applied. 

However, a relevant percentage of patients show no clinical benefit or incur in the 

development of acquired resistance. A possible solution could be the inhibition of 

pathways that are common in all tumor subtypes that have a proven role in 

carcinogenesis. Alterations of the serine-threonine kinase mammalian target of 

rapamycin (mTOR) signaling pathway are common in cancer and thus mTOR is being 

pursued as a therapeutic agent. Everolimus, a rapamycin analog, has already an 

established activity in the treatment of renal cell carcinoma. In this study, we proposed 

to evaluate the expression of activated mTOR in a large series of invasive carcinoma 

samples and cell lines, and its association with the four main molecular subtypes 

(Luminal A, Luminal B, HER2-overexpressing and Basal-like). We also aimed to 

evaluate the ability of Everolimus to inhibit mTOR expression and function in breast 

cancer cells. p-mTOR expression was found in 66.7% (231/348) of the invasive breast 

carcinoma cases analysed. Considering the molecular subtypes of breast carcinomas, 

p-mTOR was more frequently observed in basal-like breast carcinomas (80.6%). All 

breast cancer cell lines, representative of distinct molecular subtypes, showed 

expression of total and activated mTOR. These cells have been treated with RAD001, 

in order to assess their sensitivity to this drug, and all cell lines showed a decrease of 

p-mTOR expression after everolimus treatment. Due to the higher prevalence of 

p-mTOR in basal-like tumors, we treated three basal-like cell lines with Everolimus to 

assess the effects on cell invasion and aggregation. Cell invasion was significantly 

inhibited in response to Everolimus. The results revealed that there is a significant 

higher frequency of p-mTOR in basal-like tumors, compared with the other subtypes. 

In addition, Everolimus is able to significantly decrease mTOR expression and activity, 

inhibiting invasion capacity of basal-like breast cancer cells emphasizing the 

antitumour activity of mTOR inhibitors in breast cancer models. 


353P THE PROGNOSTIC MEANING OF PROTEIN TYROSINE 

PHOSPHATASE NON-RECEPTOR TYPE 12 (PTPN 12) 

EXPRESSION LOSS IN BREAST CANCER PATIENTS 

M.H. Kim 1 , S. Lee 1 , J.S. Koo 2 

1 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 

KOREA, 2 Department of Pathology, Yonsei University College of Medicine, Seoul, 

KOREA 

Background: Recent preclinical studies showed that protein tyrosine phosphatase 

non-receptor type 12 (PTPN 12) appears to be an important tumor suppressor in 

breast cancer. However, the clinical and prognostic significance of PTPN 12 

expression in breast cancer patients has not been elucidated yet. 

Methods: PTPN 12 expression status was assessed for 183 patients who 

underwent curative surgery for operable breast cancer between May 2000 and 

August 2003, using immunohistochemical (IHC) assay of tissue microarray. 

Clinicopathologic characteristics, and expression status of ER, PR, EGFR, HER-2 

were compared according to PTPN 12 expression status. The prognostic 

significance of PTPN 12 expression on disease-free survival (DFS) and overall 

survival (OS) was analyzed and the prognosis was also assessed in subgroups 

defined on the basis of major prognostic factors and ER, PR, HER-2, EGFR 

expression status. 

Results: Loss of PTPN 12 expression was observed in 35.5% of the patients in this 

study. No significant differences were found in the clinicopathological characteristics 

and ER, PR, HER-2, EGFR expression status between PTPN 12 loss versus PTPN 12 

intact patients. At a median follow-up of 9.9 years (range, 0.7-11.1), patients with 

PTPN 12 loss showed worse 10-year DFS than those with intact PTPN 12 expression 

(74.8% vs. 83.1%), but without statistical significance (p = 0.220). Ten-year overall 

survival of patients was not different according to PTPN 12 expression status. In the 

subgroup analysis performed in HER2 (-) and EGFR (-) patients (n = 128), the DFS 

was shorter in patients with PTPN 12 loss in univariate analysis (p = 0.057), and the 

difference was independently significant in multivariate analysis (hazard ratio, 2.97; 

95% confidence interval, 1.05-8.37; p = 0.040). In the subgroup of patients who 

received hormone therapy alone as adjuvant treatment (n = 28), all recurrences were 

occurred in patients with PTPN 12 loss (5 recurrence in 16 patients) whereas there 

was no recurrence in patients with intact PTPN 12 expression. 

Conclusion: PTPN 12 expression loss was associated to poor disease free survival in 

HER2 negative and EGFR negative breast cancer patients in this study. Our finding 

suggests that PTPN 12 may have a prognostic meaning predicting recurrence in 

HER2 negative and EGFR negative breast cancer patients, and future validation is 

warranted. 


354P GENETIC INTERACTION PROFILE MAY PREDICT 

BEVACIZUMAB (BV) EFFICACY IN METASTATIC BREAST 

CANCER (MBC) PATIENTS (PTS): AN EXPLORATORY 

RETROSPECTIVE ANALYSIS 

G. Allegrini 1 , G. Bocci 2 , A. Fontana 3 , A. Camerini 4 , A. Ferro 5 , M.E. Cazzaniga 5 , 

V. Casadei 6 , E. Bona 7 , M. Scalese 8 , A. Falcone 3 

1 Medical Oncology Unit, Pontedera Hospital, Pontedera, ITALY, 2 Universita’ di 

Pisa, Divisione Di Farmacologia e Chemioterapia - Dipartimento di Medicina 

Interna, Pisa, ITALY, 3 Oncologia Medica II, Polo Oncologico, Ospedale S. Chiara, 

AOUP, Pisa, ITALY, 4 Oncologia Medica, Ospedale Versilia, Lido di Camaiore, 

ITALY, 5 Struttura Complessa Di Oncologia Medica, Azienda ospedaliera San 

Gerardo, Monza, ITALY, 6 Oncologia Medica, AOR Marche NORD, Pesaro, ITALY, 

7 U.O. Oncologia Medica, Oncologia Universitaria Pisa, Pisa, ITALY, 8 Istituto 

Fisiologia Clinica, Centro Nazionale di Ricerca di Pisa, Pisa, ITALY 

Background: previous retrospective studies have attempted to identify a possible role 

of VEGF single nucleotide polymorphisms (SNPs) to predict BV efficacy in terms of 

OS and PFS in MBC pts with conflicting results (Schneider 2008, Grimaldi 2011, 

Lambrechts 2011). 

Methods: on the basis of these preliminary data, we decided to assess in a MBC 

population if different VEGF, VEGFR-2, IL-8, IL-6, HIF-1alfa, EPAS-1 and TSP-1 

genotypes could predict first line BV + Paclitaxel (P) response in terms both of OS 

and PFS. Analyses were performed on germline DNA obtained from blood samples. 

Fourteen polymorphisms were investigated by real-time PCR technique. Both single 

and combinations of SNPs were investigated. The multifactor dimensionality 

reduction (MDR) methodology was applied to identify a genetic interaction profile 

for PFS (http://sourgeforge.net/projects/mdr/). 

Results: 102 pts have been enrolled from 8 Oncology Units. Main pts 

characteristics are: median age 59 years (range 32-81), ECOG-PS 0/1 in 78%/22%, 

hormone receptor positive 83%, previous adjuvant chemotherapy 68%, disease free 

interval (DFI) < 12 months 27%. After a median follow up of 17.4 months 

(1.9-54.7), mPFS was 11.6 months (95% CI: 10.6-12.6) and mOS was 32.4 months 

(95% CI: 25.9-38.9). None of SNPs were individually associated with PFS. 

Conversely, a genetic interaction profile consisting of VEGFR-2 rs11133360 and 

IL-8 rs4073 was significantly associated with PFS. mPFS was 14 months (95% CI: 

11.7-16.3) and 10.9 months (95% CI: 9.3-12.4) for the favorable and unfavorable 

genetic profile, respectively (HR = 0.63, 95% CI: 0.4-0-99, p= 0.046). Furthermore, 

at the multivariate analysis hormone receptor positive (HR = 0.22, 95% CI: 

0.12-0-41, p < 0.0001), DFI >12 months (HR= 0.4, 95% CI: 0.2-0.82, p= 0.011) and 

BV maintenance (HR = 0.63, 95% CI: 0.25.0.71, p = 0.001) were significantly 

associated with a better PFS. 

Conclusions: genetic interaction between VEGFR-2 rs11133360 and IL-8 rs4073 

polymorphisms could predict BV response in terms of PFS. With a longer follow up 

correlations with OS will be investigated. Prospective study is planned. Study 

supported by the no-profit foundation F.A.R.O. 



355P FIRST REPORT OF LONG-TERM RESPONDERS TO 

FIRST-LINE BEVACIZUMAB (BEV) COMBINED WITH 

CHEMOTHERAPY IN TWO INDEPENDENT COHORTS OF 

HER2-NEG METASTATIC BREAST CANCER PATIENTS (PTS) 

WITH HORMONE RECEPTOR –POSITIVE (HR+) AND 

TRIPLE-NEGATIVE (TN) TUMORS 

M. Saghatchian 1 , C. Levy 2 , C.B. Villanueva 3 , J. Fleury 4 , V. Diéras 5 , 

A. Mercier-Blas 6 , H. Simon 7 , C. Le Maignan 8 , N. Mesnard 9 , E. Antoine 10 

1 Breast Cancer Unit, Department of Medical Oncology, Institut de Canc, Villejuif 

Cedex, FRANCE, 2 Sénologie, Centre François Baclesse, Caen, FRANCE, 

3 Service Oncologie Medicale, C.H.U. Jean Minjoz, Besancon Cedex, FRANCE, 

4 Oncologie, Pole Santé République, Clermont Ferrand, FRANCE, 5 Department of 

Medical Oncology, Clinical Trial Unit, Institut Curie, Paris, FRANCE, 6 Oncologie, 

Centre de Radiothérapie Saint-Vincent, Saint-Grégoire, FRANCE, 7 Oncologie 

Médicale, Hôpital Augustin Morvan, Brest, FRANCE, 8 Oncologie Médicale, 

Hôpital Saint-Louis, Paris, FRANCE, 9 Medical Affair, Roche SAS, Boulogne 

Billancourt, FRANCE, 10 Oncologie Médicale, Clinique Hartmann, 

Neuilly-Sur-Seine, FRANCE 

Background: First-line BEV combined with weekly paclitaxel, docetaxel or other 

chemotherapy significantly improves progression-free survival (PFS) in 

HER2-negative metastatic breast cancer (mBC), as shown in E2100, AVADO and 

RIBBON-1 trials. In the ATHENA study, 21% of pts continued BEV for ≥1 year 

with no new safety outcome and a time to progression of 19.9 months (95% CI 

18.9-21.8 months). To further understand and provide insight into the efficacy and 

safety of long-term responders to first-line BEV, we conducted a descriptive study of 

2 different cohorts of pts with mBC: HR+ and TN, treated in routine oncology 

practice with at least 1 year of first-line BEV. 

Methods: Pts who had received first-line BEV(≥1 year) associated to chemotherapy 

were retrospectively included in the 2 independent cohorts and followed up, if they 

were alive at inclusion, for 18 months. Clinico-pathological characteristics, treatment 

received, efficacy and safety data were collected. 

Results: The recruitment of the TNBC cohort was just completed (n = 80) and 

results will be presented at the meeting. In the HR+ cohort (n = 132), 28.1% of the 

pts had a disease-free interval 3 metastatic sites at 

diagnosis, and more than 1/3 of the patient had lung and/or liver involvement. In 

association to 1 st line BEV, 93,2% had received a taxane as initial 1st line 

chemotherapy, 76.2% had received maintenance endocrine therapy and 4.2% had 

received maintenance chemotherapy (capecitabine). Best response obtained in 1st 

line was a complete response or partial response for 84,6%. With a median follow-up 

of 33 months, median PFS was 27.4 months (95% CI [23.2-33.8]). Overall survival 

data were immature as 84.8% of the pts were alive at inclusion. The most common 

BEV related grade 3/4 adverse events were hypertension (7.5%), bleeding (1.9%), 

proteinuria (1.3%) and congestive heart failure (1.3%). 

Conclusion: Prolonged BEV-containing therapy in this HR+ cohort is of interest and 

suggests that some pts achieve sustained disease control with limited side effects. 

Disclosure: V. Diéras: Advisory boards and Symposium participation. H. Simon: 

Member of an advisory board: Roche Mastology Group. N. Mesnard: Roche 

employee. E. Antoine: Membership of an advisory board. All other authors have 


356P BEVACIZUMAB–CAPECITABINE (BEV–CAP) AFTER INITIAL 

1ST-LINE BEVACIZUMAB–DOCETAXEL (BEV–DOC) IN 

PATIENTS (PTS) WITH HER2-NEGATIVE METASTATIC 

BREAST CANCER (MBC): SAFETY ANALYSIS OF THE IMELDA 

TRIAL 

J. Gligorov 1 , E. Alba-Conejo 2 , J. Bines 3 , P.A. Cortes 4 , D.C. Doval 5 , Z. Jiang 6 , 

U. Freudensprung 7 , G. Mustacchi 8 

1 Oncologie Medicale, APHP, CancerEst, Tenon Hospital, Paris, FRANCE, 

2 Oncology, Hospital Universitario Virgen de la Victoria, Malaga, SPAIN, 3 Medical 

Oncology, Instituto Nacional de Cancer, Rio de Janeiro, BRAZIL, 4 Medical 

Oncology, Centro Hospitalar Lisboa Norte - Hospital Sta Maria(HSM-CHLN), 

Lisbon, PORTUGAL, 5 Medical Oncology, Rajiv Gandhi Cancer Institute and 

Table: 356P 

Pts, n (%) 

Research Centre, New Delhi, INDIA, 6 Department of Breast Cancer, Affiliated 

Hospital of Academy of Military Medical Sciences, Beijing, CHINA, 7 Global 

Medical Affairs Biometrics, F Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 

8 

Docente Di Oncologia Medica, Centro Oncologico ASS1 Triestina, Università di 

Trieste, Trieste, ITALY 

Background: Combining BEV with 1st-line chemotherapy (CT) significantly 

improved progression-free survival (PFS) and response rate (RR) vs CT alone in 3 

randomised phase III trials (E2100, AVADO, RIBBON-1). In AVADO, DOC 100 mg/ 

m 2 was given for a median of 5.5 months (maximum 9 cycles), after which BEV 15 

mg/kg was continued as a single agent. IMELDA was designed in the context of 

BEV–DOC approval to determine whether efficacy is improved by adding CAP to 

BEV maintenance therapy after discontinuing DOC. 

Methods: Eligible pts had HER2-negative measurable mBC, ECOG PS 0/1, had 

received no prior CT for mBC and were eligible for taxane-based CT. After initial 

1st-line therapy with 3–6 cycles of BEV–DOC, pts free of progressive disease (PD) 

were randomised to BEV alone or BEV–CAP (BEV 15 mg/kg q3w; CAP 1000 mg/m 2 

bid d1–14 q3w) until PD. The primary endpoint is PFS; secondary endpoints include 

safety, RR and overall survival. 

Results: Between June 2009 and March 2011 (when enrolment to the study was 

terminated prematurely after withdrawal of BEV–DOC regulatory approval), 284 pts 

began BEV–DOC. Median age was 52 y (range 24–80), 17% were aged ≥65 y, 53% 

had ECOG PS 0 and 30% had triple-negative mBC. Maintenance therapy was 

administered in 183 pts (64%). Key safety results are below. 

Conclusions: Most grade ≥3 AEs during BEV–DOC were typical DOC-related AEs. 

Apart from hypertension and proteinuria, BEV AEs occurred predominantly in early 

cycles, suggesting that long-term BEV is well tolerated. Efficacy results are expected 

in 2013. 

Disclosure: J. Gligorov: JG has sat on Advisory Boards and received speaker 

honoraria from Roche. J. Bines: JB has served on Advisory Boards for Roche. P.A. 

Cortes: PC has served on Advisory Boards for Roche, BMS and Sanofi-Aventis. U. 

Freudensprung: UF works as a Contractor for F Hoffmann-La Roche Ltd. G. 

Mustacchi: GM has acted as a Consultant for Roche, Agendia, Celgene, Novartis, 

Merck, Glaxo, Eisai. All other authors have declared no conflicts of interest. 

357P NON PEGYLATED LIPOSOMAL DOXORUBICIN BEYOND THE 

FIRST LINE TREATMENT OF METASTATIC BREAST CANCER 

PATIENTS: A RETROSPECTIVE ANALYSIS 

S. Bernhard 1 , L. Mansi 1 , V. Nerich 2 , C.B. Villanueva 1 , E. Dobi 1 , H. Almotlak 1 , 

F. Bazan 1 , L. Chaigneau 1 , L. Cals 1 , X. Pivot 1 

1 Department of Medical Oncology, University Hospital J. Minjoz, Besancon, 

FRANCE, 2 Pharmacy Department, University Hospital J. Minjoz, Besancon, 

FRANCE 

Background: The aim of this retrospective study was to access the benefit of a 

non-pegylated liposomal doxorubicin (NPLD) treatment beyond the first line therapy 

in patients with metastatic breast cancer (MBC) after previous exposure to an 

anthracycline containing regimen. 

Patients and methods: A pharmacy prospectively collected database in the 

Franche-Comte region, was used to identify a cohort of patients with MBC treated by 

NPLD regimen between 2003 and 2010.In total, 140 patients were included in the 

analysis. Progression-free survival (PFS) was chosen as the primary efficacy endpoint. 

Cox proportional hazard models were fitted to identify factors that could influence 

both PFS and overall survival (OS) lenght. Survival data were computed according to 

Kaplan Meier method. 

Results: Primary tumours characteristics were oestrogen receptor-positive, 

progesterone receptor positive and HER2 positive in 77%, 63% and 20% respectively. 

Median PFS length was 4 months [95% CI: 2-5] and 33% of patients experienced a 

PFS longer than 6 months. Overall response (OR) was observed in 27 patients 

(19.3%, 95%CI [10.2-28.4]). Median OS after NPLD was 13 months [95% CI: 10-14]. 

In multivariate analysis, prognostic factors significantly related to longer OS from 

NPLD first exposure were age younger than 50 years old (HR = 0.57 [0.35-0.93], p = 

0.02) and HER2 positive tumour (HR = 0.53 [0.30-0.95], p = 0.03). 17 patients 

Initial 

BEV–DOC phase (N = 284) 

Maintenance 

BEV ± CAP phase (N = 183) 

Discontinued therapy 99 (35) 134 (73) 

PD AE Other/unknown 41 (14) 31 (11) 27 (10) 101 (55) 15 (8) 18 (10) 

Grade ≥3 AEs, n (%) 138 (49) 63 (34) 

Neutropenia Febrile neutropenia Diarrhoea Mucosal inflammation 44 (15) 30 (11) 3 (1) 9 (3) 6 (2) 6 (2) 2 (1) 0 2 (1) 2 (1) 1 (1) 25 (14) 

Grade ≥3 BEV AEs of 

special interest 

Asthenia Hand-foot syndrome 

AE = adverse event; TE = thromboembolic event 

Hypertension Proteinuria Bleeding Arterial TE Venous TE 

Wound-healing complication GI perforation 


5 (2) 1 (


(12.1%) discontinued NPLD treatment due to toxicity. In those, 9 (6.4%) patients 

experienced cardiac toxicity (grade 2 or 3) . There were 2 (1.4%) deaths related to 

cardiac toxicity. 

Conclusion: Re-challenge by an anthracycline-containing regimen should been 

considered in patients with MBC taking into account this encouraging ORR and the 

length of PFS and response duration. However cardiac safety of patients must be 

carefully investigated during the treatment taking into account the number of 

treatment cessation due to cardiac damage. Of interest the subset of patients with 

HER2 positive tumour seemed to highly benefit from the NLPD. This finding 

emphasizes the sensitivity to anthracycline in this subset of HER2 positive tumours 

and oncologist should not forgot anthracycline containing regimen as a possible 

option in MBC after failure to numerous lines including chemotherapy and HER2 

targeted agents. 


358P PHARMACOKINETICS OF ERIBULIN MESILATE IN 

COMBINATION WITH CAPECITABINE IN PATIENTS WITH 

ADVANCED/METASTATIC CANCER: RESULTS FROM A PHASE 

IB DOSE-ESCALATION STUDY 

C.J. Twelves 1 , M. Nasim 2 , A. Anthoney 1 ,N.Cresti 3 , C. Savulsky 4 , C. Johnston 4 , 

L. Reyderman 5 , J. Wanders 4 , R. Plummer 3 , T.R.J. Evans 2 

1 Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine and St 

James’s Institute of Oncology, Leeds, UNITED KINGDOM, 2 Medical Oncology, 

Beatson West of Scotland Cancer Centre, Glasgow, UNITED KINGDOM, 

3 Medical Oncology, Northern Institute for Cancer Research, University of 

Newcastle upon Tyne, Newcastle, UNITED KINGDOM, 4 Medical Oncology, Eisai 

Ltd, Hatfield, UNITED KINGDOM, 5 Medical Oncology, Eisai Inc., Woodcliff Lake, 

NJ, UNITED STATES OF AMERICA 

Background: Eribulin is a microtubule dynamics inhibitor EMA approved for certain 

patients (pts) with locally advanced (LA)/metastatic breast cancer (MBC) who have 

received ≥2 prior chemotherapeutic regimens for advanced disease. Prior therapy 

should have included an anthracycline and taxane. This Phase Ib, open-label 

dose-escalation study assessed maximum tolerated dose (MTD), safety and 

pharmacokinetics (PK) of eribulin in combination with capecitabine in pts with 

advanced/metastatic cancer. 

Methods: Pts received eribulin mesilate (2–5-min IV) by Schedule 1 (1.2, 1.6 or 2.0 

mg/m 2 on Day [D] 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m 2 on D1 and D8) in 

combination with twice-daily oral capecitabine 1000 mg/m 2 on D1–14 every 21 days. 

To assess PK and drug-drug interaction of eribulin, capecitabine and capecitabine 

metabolites in Cycle 1 and 2, samples were taken on D1 (pre-, 0, 0.25, 0.5, 1–4, 6 

and 8 h post-dose), any time on D2–3 and D4–6, and D8 (Schedule 1: pre-, 0.5, 1–4 

and 6 h post-capecitabine; Schedule 2: pre-dose). PK was examined by 

non-compartmental analysis, and cardiac repolarization by 12-lead ECGs at 

screening, D1 (pre- and 4 h post-dose), D2–3, D8 and D15. Correlation of eribulin 

and capecitabine plasma concentrations with change from baseline (Δ) QTc was 

explored. 

Results: Schedule 1 (n = 19) and Schedule 2 (n = 15) MTDs were 1.6 and 1.4 mg/ 

m 2 eribulin mesilate, respectively. Dose-limiting toxicities (all n = 1) were: Grade 

(G) 4 neutropenia, G3 febrile neutropenia, G3 fatigue, G3 lethargy (Schedule 1); 

G4 neutropenic sepsis, G3 neutropenia (Schedule 2). There were no unexpected 

toxicities. Eribulin PK was independent of schedule and had dose-related increases 

in exposure. No accumulation occurred upon multiple dosing; at each dose, 

eribulin PK was comparable in Cycles 1 and 2. Exposure to capecitabine and 

metabolites was variable and independent of schedule. Co-administration had no 

effect on ΔQTc. 

Conclusions: No drug-drug interaction of eribulin and capecitabine was observed. 

From these results, the combination appears to be tolerated without effect on 

cardiac repolarization. A Phase II LA/MBC study evaluating Schedule 2 MTD is 

ongoing. 

Disclosure: C.J. Twelves: The author declares the following conflicts of interest: 

consultant/advisory role (Eisai) and honoraria/speakers bureau (Eisai). C. 

Savulsky: The author declares the following conflicts of interest: employee (Eisai 

Ltd). C. Johnston: The author declares the following conflicts of interest: 

employee (Eisai Ltd). L. Reyderman: The author declares the following conflicts 

of interest: employee (Eisai Inc.). J. Wanders: The author declares the following 

conflicts of interest: employee at the time of study (Eisai Ltd). R. Plummer: 

The author declares the following conflicts of interest: research funding (Eisai 

Ltd). T.R..J. Evans: The author declares the following conflicts of interest: 

research funding (Eisai Ltd). All other authors have declared no conflicts of 

interest. 

359P ACTIVITY AND SAFETY OF A COMBINATION OF EPIRUBICIN, 

DOCETAXEL AND CISPLATIN AS NEOADJUVANT TREATMENT 

FOR LOCALLY ADVANCED BREAST CANCER (LABC): A 

PRELIMINARY REPORT 

N. Avci 1 , O. Kanat 1 , S. Gokgoz 2 , S. Tolunay 3 , U. Topal 4 , E. Cubukcu 1 , F. Olmez 1 

1 Medical Oncology, Uludag University Faculty of Medicine, Bursa, TURKEY, 

2 Surgery, Uludag University Faculty of Medicine, Bursa, TURKEY, 3 Pathology, 

Uludag University Faculty of Medicine, Bursa, TURKEY, 4 Radiology, Uludag 

University Faculty of Medicine, Bursa, TURKEY 

Aim and background: Efficacy of cisplatin-containing triplet chemotherapy regimens 

for neoadjuvant therapy of LABC has not been investigated extensively. The aim of 

this study was to evaluate activity and safety of a combination of epirubicin, 

docetaxel and cisplatin (ETC) in the neoadjuvant setting. 

Patients and methods: Forty-two patients with LABC (T2-T4, N0-N2, M0) were 

enrolled the study from March 2010 to April 2011. These patients received epirubicin 

(60 mg/m2 intravenously [I.V.] day 1), docetaxel (60 mg/m2 I.V. day 1) and cisplatin 

(60 mg/m2 I.V. day 1) every 21 days for at least 4 cycles, plus a final 2 additional 

cycles. Upon completion of therapy, the primary tumor was resected when not 

contraindicated. The primary endpoint was the pathological complete response 

(pCR) rate; seconday endpoints included response rate and toxicity. 

Results: Median patients age was 48 years (range, 23-73 years). Median tumor size 

was 3.2 cm. Thirty-seven patients (88%) received 6 cycles of ETC. The overall clinical 

response rate was 78.6%. Twenty of 42 patients (47.6%) achieved a complete 

pathological response (CPR). All tumors became operable after neoadjuvant 

chemotherapy. The most common side effect was myelotoxicity. WHO grade 4 

neutropenia developed in 30 (73%) patients. No recurrence was observed in any 

patient after a mean follow-up of 17 months (13-21 months). 

Conclusion: Although our study group was small and the follow-up period relatively 

short-term, the considerably high rates of CPR in this preliminary series suggest that 

ETC regimen may be a promising option in neoadjuvant treatment of LABC. > 


360P SEQUENTIAL DOCETAXEL AS ADJUVANT CHEMOTHERAPY 

FOR NODE-POSITIVE OR/AND T3 OR T4 BREAST CANCER: 

CLINICAL OUTCOME (MANSOURA UNIVERSITY) 

H. Sakr 1 , R.H. Hamed 1 , A.H. Anter 1 , T. Yossef 2 

1 Clinical Oncology and Nuclear Medicine, Mansoura University, Egypt, 

Mansoura, EGYPT, 2 General Surgery, Faculty of Medicine, Mansoura University, 


Purpose: This trial compared six cycles of fluorouracil, epirubicin, and 

cyclophosphamide (FEC) with a sequential regimen of three cycles of FEC followed 

by three cycles of docetaxel (FEC-D) as adjuvant treatment for women with 

node-positive or/and T3 or T4 breast cancer. 

Patients and methods: Between January 2006 and January 2010, 657 patients with 

operable breast cancer were randomly assigned to either FEC every 21 days for six 

cycles, or three cycles of FEC followed by three cycles of docetaxel, both given every 

21 days. Radiotherapy was mandatory for all patients who had undergone breast 

conserving surgery. Radiation to the chest wall, supraclavicular area, was 

recommended following mastectomy. Hormone-receptor–positive patients received 

tamoxifen for 5 years after chemotherapy. The primary end point was 5-year 

disease-free survival (DFS). 

Results: Median follow-up was 61 months. Five-year DFS rates were 74% with FEC 

and 78% with FEC-D (P= .013). Multivariate analysis adjusted for prognostic factors 

showed a 17% reduction in the relative risk of relapse with FEC-D. Five-year overall 

survival rates were 85% with FEC and 89.4% with FEC-D, demonstrating a 27% 

reduction in the relative risk of death (P= .014). The incidence of grade 3 to 4 

neutropenia, the need for hematopoietic growth factor and incidence of nausea 

/vomiting were higher with FEC. Docetaxel was associated with more febrile 

neutropenia, stomatitis, edema, and nail disorders. Though rare overall, there were 

fewer cardiac events after FEC-D, attributable mainly to the lower anthracycline 

cumulative dose. 

Conclusion: Sequential adjuvant chemotherapy with FEC followed by docetaxel 

significantly improves disease free and overall survival in node-positive or/and T3 or 

T4 breast cancer patients and. Although the magnitude of the benefit observed with 

FEC-D, differences in the toxicity profiles of FEC and FEC-D may influence the 

choice of treatment for patients 



361P A RETROSPECTIVE ANALYSIS OF PLATINUM-BASED 

NEOADJUVANT CHEMOTHERAPY FOR LOCAL ADVANCED 

TRIPLE NEGATIVE BREAST CANCER 

F. Fei, Y. Du, X. Gu, C. Chen, J. Wu, Z. Shao 

Breast Surgery, Shanghai Cancer Center Fudan University, Shanghai, CHINA 

Purpose: We retrospectively analyzed platinum-based neoadjuvant chemotherapy for 

LATNBC to compare survival outcomes between patients with PCR and with 

non-PCR. Furthermore, the disease free survival of LATNBC patients with PCR 

continuously receiving primary regimen as adjuvant setting had comparative 

advantage concerning that of “PCR” patients switching to other regimens as adjuvant 

setting as well as those without any chemotherapy after sugery. 

Patients and methods: 124 women with stage II or III TNBCs experienced 

platinum-based regimens as neoadjuvant chemotherapy from Nov 1, 2007 to Dec 31, 

2011. All patients were divided into the two groups, who were with and without PCR 

in the pathological reports after surgery. According to the adjuvant settings for 

LATNBC patients with PCR, the three arms were determined as continuous primary 

regimen (the same as neoadjuvant) arm, no more chemotherapy arm and switching 

arm. Disease free survival was computed using the Kaplan-Meier product limit 

method. 

Result: We presented a retrospective chart review of 124 LATNBC patients who 

underwent platinum-based neoadjuvant chemotherapy in our hospital. Fifty (40.32%) 

of those patients receiving neoadjuvant chemotherapy had PCR when they 

underwent surgery. After controlling for covariates associated with survival, patients 

undergoing neoadjuvant chemotherapy with residual tumor had significantly worse 

survival than patients with PCR (HR = 0.37,P < 0.05). Of 50 patients with PCR 

confirmed by surgery, the disease free survival of 24 cases switching to other 

regimens in the adjuvant setting was significantly better than that of 24 cases 

continuously receving primary regimens in the adjuvant setting (HR= 0.51, P = 

0.025)and that of 2 cases with no more chemotherapy(HR= 0.58, P = 0.017) 

Conclusion: Patients with PCR had statistically significantly better clinical survival 

than those with non-PCR after platinum-based neoadjuvant settings.So far, if 

LATNBC patients with PCR after platinum-based neoadjuvant chemotherapy, they 

might have better clinical survival if they receive switching regimens than to receive 

primary regimens and to continue with no additional chemotherapy after surgery. A 

randomized prospective study needs to be carried out to strengthen the results 

because of statistical bias. 


362P MIGHT EARLY METABOLIC RESPONSE BY 18F-FDG-PET/CT 

BE USEFUL TO SELECT PATIENTS (PTS) WITH BREAST 

CANCER (BC) WHO WILL NOT OPTIMALLY RESPOND TO 

PREOPERATIVE CHEMOTHERAPY (PCT)? 

G. Zucchini1 , S. Quercia1 , C. Zamagni1 , D. Santini2 , M. Taffurelli3 , S. Fanti4 ,A. 

A. Martoni1 1 

Medical Oncology Unit, S. Orsola-Malpighi University Hospital, Bologna, ITALY, 

2 3 

Pathology Unit, S. Orsola-Malpighi University Hospital, Bologna, ITALY, Breast 

Surgery Unit, S. Orsola-Malpighi University Hospital, Bologna, ITALY, 

4 

Department of Nuclear Medicine, S. Orsola-Malpighi University Hospital, 

Bologna, ITALY 

Purpose: To evaluate 18F-2-fluoro-2-deoxy-D-glucose positron emission 

tomography/computed tomography (18F-FDG PET/CT) changes between 

baseline and after 2 cycles of PCT in pts with early/locally advanced (E/LA) BC, 

with the aim to verify whether early metabolic assessment of response during 

PCT may have a role in clinical practice to enable early changes in the 

therapeutic strategy. 

Patients and methods: Sixty pts with newly diagnosed E/LA BC received 6-8 cycles 

of anthracycline and taxane-based PCT. Fifty-eight pts underwent surgery, which 

consisted in breast conserving surgery or radical mastectomy; axillary node dissection 

was performed in all cases. Optimal pathologic response (pR) to PCT was defined as 

absence of cancer cells in breast and ipsilateral axillary lymph nodes. All other 

conditions were defined as nonresponders (pNR). Maximum standardized uptake 

value (SUV max) with 18F-FDG PET/CT was measured for each pathologic lesion at 

baseline and after 2 cycles of PCT. SUV max percentage changes (Δ-SUV) were 

compared with pR rate according to immunohistochemical (IHC) BC characteristics. 

Δ-SUV >50% defined a metabolic response (MetR). 

Results: Thirteen (22%) of 60 pts achieved pR. According to IHC, pR rates where 

16% in ERpositive/HER2negative (ER + /HER2-) pts, 29% and 27% in 

HER2-positive (HER2+) and triple negative (TN) pts respectively. Sensitivity of 

metR to identify pR was 100% in all three subgroups, but the specificity was low: 

38% in ER + /HER2- pts (38%) was the highest value. In this subgroup of pts PET 

had a low positive predictive value (24%), while the negative predictive value was 

100%, showing, compared to HER2+ and TN pts, the highest ability to correctly 

predict pNR (32%). At a median follow-up of 36.6 months, recurrence rate was 

higher in metabolic non-responders, particularly in the ER + /HER2- subgroup, in 

which Kaplan-Meier analysis of disease-free survival confirmed a significant 

difference (p = 0.0490). 

Conclusions: PET assay after 2 cycles of PCT correctly predicted pNR in 32% of ER 

+ /HER2- pts, identifying a subgroup of BC pts with worse prognosis who might 

benefit from an early change of the therapeutic strategy. 


363P BREAST CANCER RECURRENCES AT THE CHEST WALL 

(BCRCW) WHEN STANDARD TREATMENTS (TX) HAVE FAILED: 

LYSO-THERMOSENSITIVE LIPOSOMAL DOXORUBICIN (LTLD) 

+ MILD LOCAL HYPERTHERMIA (MLH) 

H.S. Rugo 1 , S.C. Formenti 2 , R.J. Myerson 3 , C.J. Diederich 4 , B.M. O’Connor 5 , 

A.J. Matzkowitz 6 , F. Muggia 7 

1 Department of Medicine, University of California, San Francisco, CA, UNITED 

STATES OF AMERICA, 2 Radiation Oncology, NYU Langone Medical Center, NY, 

UNITED STATES OF AMERICA, 3 Radiation Oncology, Washington University 

School of Medicine in St. Louis, MO, UNITED STATES OF AMERICA, 4 Radiation 

Oncology, University of California, San Francisco, CA, UNITED STATES OF 

AMERICA, 5 Radiation Oncology, Commonwealth Atrius Cancer Center, MA, 

UNITED STATES OF AMERICA, 6 Radiation Oncology, Florida Cancer Specialists, 

New Port Richey, FL, UNITED STATES OF AMERICA, 7 Cancer Institute, NYU 

Langone Medical Center, New York, NY, UNITED STATES OF AMERICA 

Background: BCRCW has a poor prognosis, with disfigurement, pain, and 

restriction of movement. Study treatment consisted of LTLD that releases high 

concentrations of doxorubicin (Dox) in areas treated with mild hyperthermia at > 

39.5°C. MLH kills tumor cells, selectively increases liposomal permeability in tumor 

microvasculature, releases Dox from LTLD, and promotes Dox tumor uptake. 

Methods: We conducted a phase I study of LTLD + MLH in patients (pts) with 

BCRCW tumors < 3 cm deep who had failed all standard Tx including surgery, 

radiation, and chemotherapy (CTx). Pts received up to 6 LTLD/MLH Txs every 21 

days. Dosing cohorts started at 40 mg/m 2 and stopped escalation at 50 mg/m 2 . LTLD 

was infused IV over 30 minutes (min); then MLH was given by microwave or 

ultrasound. The thermal dose goal was 40°C-42°C for 60 min. Pharmacokinetic 

samples for total plasma Dox and doxorubicinol (Doxol) were taken at 0.5, 5, 10 and 

24 hours after starting infusion. 

Results: Eleven pts with a median of 4 prior CTx (range 2 – 12) were enrolled; 10 

had recurred after prior anthracycline (AC). All pts received > 2 cycles. The within 

subject variability in Dox and Doxol exposure was small with mean Cycle 2 vs Cycle 

1 ratios ranging from 0.99 to 1.06. 

Cmax/dose (ng/ml)/(mg/m 2 Dox 

) 

Doxol 

AUClast/dose ((ng*hr/ml)/(mg/m 2 ) Dox 

Doxol 


Cycle 1 

499.82 

0.46 

1,338.18 

7.96 

Cycle 2 

512.00 

0.45 

1,381.82 

8.04 

Two types of grade 3/4 toxicity were seen in > 5% of 42 cycles given: reversible 

neutropenia in 17 (40.5%) and reversible leukopenia in 9 (21.4%). One case (each) of 

mucositis (grade 1), chest wall thermal burn, and chest wall cellulitis (both grade 4) 

occurred, and no cases of cardiomyopathy or hand-foot toxicity were seen. The rate 

of clinically significant (> 6 point) QoL improvement on the FACT-B after 2 cycles 

was 54.5% (95% CI: 25.1% - 83.9%), including 1 lasting > 3 months. The local 

objective response rate was 45.5% (95% CI: 16.1% - 74.9%), with 1 complete and 4 

partial local responses. 

Conclusion: LTLD + MLH is safe and active in BCRCW pts with prior radiation and 

AC exposure. A phase II study is underway. 


364P IMMUNOHISTOCHEMICAL PREDICTORS OF THE CLINICAL 

AND PATHOLOGICAL RESPONSE TO NEOADJUVANT 

CHEMOTHERAPY IN LOCALLY ADVANCED BREAST CANCER 

M. Rodionova 1 , D. Ryabchikov 1 , S. Portnoy 2 , I. Vorotnikov 1 , N. Chkhikvadze 1 

1 Breast Cancer Department, N.N. Blokhin Russian Cancer Research Center, 

Moscow, RUSSIAN FEDERATION, 2 Department of Female Reproductive System 

Carcinomas, N.N.Blohkin Cancer Research Center, Moscow, RUSSIAN 

FEDERATION 

Purpose: To determine predictive immunohistochemical characteristics of the tumor 

correlated with the response to neoadjuvant chemotherapy in patients with locally 

advanced breast cancer. 

Material and methods: A prospective study of 87 breast cancer patients 

(Т2-4N0-M0) treated in N.N.Blokhin Russian Cancer Research Center 1997 - 2009. 

Tumor samples were taken prior to neoadjuvant chemotherapy (cor-biosy). 

Pathological criteria assessed were: histological variant, tumor grade, HR and Her-2/ 

neu status, Ki67 expression and glycoprotein Pgp-170 status. After 4-6 cycles of 

chemotherapy all the patients underwent radical surgery. We quantified the response 



clinically and pathologically (Lavnikova’s system of therapeutic pathomorphism 

evaluation). 

Results: The experimental results showed the following response rates: complete 

response – 11 (12.6%), partial response – 54 (62.1%), stable disease – 21 (24.1%) 

patients. One patient had progression of the disease. Stable disease correlated 

significantly with positive Pgp-170 status (41.7% vs. 17.7%, р = 0.04), whilst negative 

Pgp-170 – with objective response (82.4% vs. 54.2%, р = 0.02). Pathomorphism was 

achieved as follows: lack of pathomorphism - 10(11.5%), first-degree pathomorphism 

17(19.5%), second-degree – 28(32.2%), third-degree – 18(20.7%), fourth-degree – 14 

(16.1%). Rare histological variants had more often third-degree pathomorphism than 

ductal carcinoma (р = 0.02); G1 had more often fourth-degree pathomorphism than 

G2 (p = 0.002); high-degree pathomorphism was more frequently observed in 

patients with N2 status than with N0 (p = 0.006) and N1 (p = 0.009). Her-2/neu + 

tumors showed lower degree of pathomorphism that those with HR status (23.7% vs. 

45.6%, р = 0.03). Pgp 170+ tumors had significantly more often no (p = 0.004) or 

first-degree pathomorphism (p = 0.004), and as a result – lower rate of high degree 

pathomorphism than in Pgp-170 negative tumors (12.5% and 47.1%, respectively). 

Conclusions: Some pathological and immunohistochemical characteristics of the 

tumor can be assessed preoperatively and predict the likelihood of the clinical and 

pathological response to neoadjuvant chemotherapy. 


365P IS POSTMASTECTOMY RADIOTHERAPY FOR PATIENTS 

DIAGNOSED WITH BREAST CANCER WHO HAVE RECEIVED 

NEOADJUVANT THERAPY REALLY NECESSARY? 

R.M. Rodríguez 1 , M.T. Cano Osuna 1 , G. Pulido 2 , I. Porras 1 , P. Sánchez 1 , 

A. Moreno 1 , J. Jiménez 1 , M.J. Ortiz-Morales 1 , E. Aranda Aguilar 3 ,J.De 

La Haba 3 

1 Medical Oncology, Universitay Hospital Reina Sofia, Córdoba, SPAIN, 2 Medical 

Oncology, University Reina Sofia Hospital, Cordoba, SPAIN, 3 Oncology 

Deparment, IMIBIC-Hospital Reina Sofía, Córdoba, SPAIN 

Introduction: The role of adjuvant radiotherapy (RTA) after mastectomy in patients 

who have received neoadjuvant treatment is controversial and it has not been shown 

benefit in ramdomized clinical trials (ref ASCO-Guide lines). On the other hand, the 

low rates of local and distant recurrences after complete pathological response (RPc) 

question the value of local control disease. 

Objective: To analyze the rate and profile of recurrence in breast cancer patients who 

have received neoadjuvant chemotherapy, mastectomy with and without radiotherapy. 

Patients and methods: From the Department of Medical Oncology, University 

Hospital Reina Sofia we have identified 171 patients between 1997 and 2010 who 

have received neoadjuvant treatment. 36 patients have not received radiotherapy 

treatment after mastectomy. We present clinical and biological features of patients 

and their evolution. 

Results: The mean age is 53 years, 100% are stage II and III (55.6% and 44.4%), 

infiltrating ductal histology (88.9%) and poorly differentiated tumors (44.4%). 

Regarding to hormonal status, 58.3% are hormone receptor positive and Her-2 33.3% 

and 21% are triple negative. The rate of pathological complete response (T and N) is 

22.2%. at T of 41.7%. With a follow-up mean of 19.92 months (SD: 13.9), we have 

found one recurrence of the disease localized in liver. At this moment we do not 

have any local recurrence. 

Conclusions: Based on our experience and the lack of data supporting radiotherapy 

in these patients, we believe that radiotherapy should be assessed on individual basis, 

pending randomized studies provide direct benefit. 


366P THE IMPACT OF ADDITIONAL PROGNOSTIC INFORMATION 

OBTAINED FROM KI-67 CHANGES AFTER NEOADJUVANT 

CHEMOTHERAPY VARIES IN SUBTYPE OF BREAST CANCER 

N. Matsubara, H. Mukai, Y. Naito, M. Nezu, K. Itoh 

Oncology and Hematology, National Cancer Center Hospital East, Kashiwa, 

JAPAN 

Introduction: A reduction in the Ki-67 index after neoadjuvant chemotherapy has 

been reported to be associated with a favorable prognosis. The present study 

investigates whether a reduction in Ki-67 may be a predictive surrogate marker of 

favorable prognosis in each subtype of breast cancer. 

Methods: A total of 385 patients who received neoadjuvant anthracycline followed 

by taxane chemotherapy and subsequent surgery for invasive breast cancer were 

analyzed retrospectively. By immunohistochemistry (IHC), patients were divided into 

4 subtypes (Luminal A, Luminal B, Triple negative and HER2). Ki-67 was examined 

by IHC in pre-treatment core needle samples and post-treatment surgical excisional 

specimens. The relapse-free survival (RFS) rate was compared among each subtype. 

Results: The median follow-up period was 56 months. The rate of pathological 

complete response was higher for HER2 (34.8%) and Triple negative (24.3%) 

subtypes than for Luminal B (8.3%) and Luminal A (3.8%) subtypes (p < 0.0001). A 

reduction in Ki-67 was observed in 58.5%, 83.4%, 70.2% and 74.2% of patients in the 

Luminal A, Luminal B, Triple negative and HER2 subtypes, respectively. The 

differences in RFS between patients whose Ki-67 was reduced and those not reduced 

were statistically significant for Luminal B (81.4% vs. 50.0%, p = 0.003), Triple 

negative (74.8% vs. 43.5%, p = 0.003) and HER2 (82.7% vs. 59.0%, p = 0.008). 

However, for Luminal A, the difference in RFS was not observed depend on the 

changes of Ki-67 (78.8% vs. 75.3%, p = 0.78). 

Conclusions: The reduction in Ki-67 after neoadjuvant chemotherapy is a predictive 

surrogate marker of a favorable RFS. However, this conclusion could not be applied 

to Luminal A subtype. 


367P ELECTROCHEMOTHERAPY FOR CHEST WALL RECURRENCE 

FROM BREAST CANCER IN OLDER WOMEN: ANALYSIS 

OF 55 PATIENTS 

L.G. Campana 1 , S. Galuppo 2 , S. Valpione 3 , C. Falci 4 , L. Corti 2 , A. Brunello 5 , 

G. Zavagno 6 , C. Ghiotto 4 , C.R. Rossi 1 

1 Sarcoma and Melanoma Unit, Veneto Region Oncology Research Institute 

(IOV-IRCCS), Padova, ITALY, 2 Radiotherapy Unit, Veneto Region Oncology 

Research Institute (IOV-IRCCS), Padova, ITALY, 3 Medical Oncology School, 

University of Padova, Padova, ITALY, 4 Medical Oncology-ii, Veneto Region 

Oncology Research Institute (IOV-IRCCS), Padova, ITALY, 5 Medical Oncology 

Unit-I, Veneto Region Oncology Research Institute (IOV-IRCCS), Padova, ITALY, 

6 Dept. of Surgery and Gastroenterological Sciences, University of Padova, 

Surgery Branch, Padova, ITALY 

Background: The incidence of chest wall recurrence (CWR) after mastectomy for 

breast cancer (BC) ranges from 5 to 40%. It is a common finding that a number of 

patients are not suitable for radical resection or full-dose radiotherapy. When 

resistance to systemic therapies occurs, electrochemotherapy (ECT), an 

electroporation-based local drug delivery system, could represent a valuable treatment 

option for older women. 

Methods: We analyzed a prospectively maintained database of 55 BC patients (median 

70 years, range 38-88) with irresectable CWR who experienced disease progression 

after at least 2 lines of systemic therapies. Tumor response, response duration and 

toxicity profile were analyzed according to patients’ age (70 years). 

Results: The patients received a median of 2 ECT courses (range, 1-5). Younger 

(n = 27) and elderly (n = 28) patients were comparable for clinico-pathological 

features, except for the number of CW metastases (median 15 vs 8, respectively, P 

= .040). Two-month objective response was: complete 22 patients (40.0%), partial 26 

(47.3%), no change 7 (12.7%). The complete response rate was significantly higher in 

the elderly group (57.7 vs 28%, P = .02). Pain and local toxicity scores were similar, 

but worsened with the increasing number of ECT applications. Median follow-up 

was 32 months (range, 6–53), 3-year local control rate was 70%. Thirty-three patients 

(60%) developed new lesions (NL) in non-electroporated areas (median, 6.6 months). 

Less than 10 metastases (P < .001), the narrower area of tumor spread on the CW (P 

= .022), endocrine- instead of chemotherapy (P = .025) and complete response after 

ECT (P = .019) were associated to longer NL-free survival. Older women showed a 

trend to a lower local tumor control compared to younger patients (2-year local 

progression-free survival, 83 versus 88%, P = .120). On the contrary, elderly patients 

reported a better 2-year NL-free survival (45 versus 22%, P = .095). 

Conclusions: Older patients with CWR present fewer skin metastases and are more 

likely to achieve complete response after ECT. The satisfactory CW control without 

severe toxicity makes elderly women with refractory CWR suitable candidates for 

ECT application. 


368P IS SURGERY OF THE PRIMARY TUMOR CONVENIENT 

IN METASTATIC BREAST CANCER? 

F. Petrelli1 , M. Cabiddu2 , K.F. Borgonovo2 , M. Ghilardi2 , F. Maspero2 , 

M. Cremonesi2 , S. Barni2 1 

UO Oncologia, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, ITALY, 

2 

Medical Oncology Division, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, 

ITALY 

Introduction: Stage IV breast cancer is treated primarily with systemic therapies. 

Excision of the primary breast cancer tumor in presence of synchronous distant 

metastases is a controversial argument, and a standard recommendation is not 

proposed by current guidelines. We performed a meta-analysis with the aim of pooling 

the existing survival data of surgery of the breast primary tumor in stage IV disease. 

Materials and methods: We searched PubMed for publications including female, 

with histologically confirmed stage IV breast cancer at presentation and an intact 

primary tumor. Primary outcome was overall survival (OS) in patients treated with 

resection of primary breast cancer in presence of synchronous distant metastases. 

Secondary endpoints were PFS or TTP (and local and/or distant PFS or TTP, 

whichever reported). Hazard ratios (HRs) for survival when reported after 

multivariate analysis (with 95% confidence intervals) were obtained from 


publications and aggregated in a meta-analysis. A meta-regression weighted for 

extent of disease, ER/HER2 status, age, visceral or bone disease, rate of radiotherapy, 

and systemic therapies offered was also performed. 

Results: 15 articles were included in this meta-analysis (all retrospective case series), 

for a total of 15.378 patients. Surgery of the primary breast cancer appeared to be an 

independent factor for an improved survival in the multivariate analyses from the 

individual studies, with an HR of 0.69 (p < 0.00001). According to meta-regression, the 

survival benefit was independent of age, extent, site of metastatic disease and HER2 

status, but was directly proportional to rate of patients exposed to systemic therapies 

and radiotherapy and inversely correlated to ER+ status of the population included. 

Conclusions: Our pooled-analysis, reveals that surgery of an intact primary tumor, 

although associated with distant metastases, reduces the risk of death by 30%. This 

results are particular significant if local surgery is associated with systemic therapy 

and radiotherapy into a multimodality strategy. The surgical excision of a primary 

breast cancer in patients with stage IV disease – if feasible - should be discussed with 

and proposed to patients. 


369P BEING THERE FOR WOMEN WITH METASTATIC BREAST 

CANCER. A PAN-EUROPEAN PATIENT SURVEY 

C.J. Twelves 1 , J. Stebbing 2 

1 Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine and St 

James’s Institute of Oncology, Leeds, UNITED KINGDOM, 2 Oncology, Imperial 

College & Imperial College Healthcare NHS Trust, London, UNITED KINGDOM 

Background: This two-part European patient survey was designed to help identify 

needs of women with metastatic breast cancer (MBC), through understanding their 

experiences of diagnosis, treatment and care. 

Material and methods: The survey, initiated in March 2011, was conducted using a 

two-stage methodology. The first stage collected views on standards of MBC care and 

unmet needs of patients from 47 MBC-related patient groups in 8 European 

countries. This information was used to develop the second stage patient survey. The 

patient survey was designed to capture personal experiences of MBC diagnosis, 

treatment, information provision and to determine insights into the ‘trade-off’ 

between extending overall survival and side effects associated with MBC treatment. 

This online survey was open to women with locally advanced or MBC or their carers. 

All data were collected using anonymised local language questionnaires with 

responders recruited through local patient groups. 

Results: A total of 230 responses were received from 17 identified European 

countries (94% of whom had locally advanced or MBC, and 6% of whom were adult 

carers). Although the overall experience of care was generally good to excellent 

(77%), there were still gaps in terms of treatment choice and information provision. 

Specifically, findings indicate that 32% of patients perceived treatment choice to be 

lacking. Overall, results showed that 67% of women with locally advanced or MBC 

believed life-extending treatment to be important so that they could spend more time 

with their family and friends; the same proportion judged their treatment worthwhile 

if it prolonged survival, irrespective of potential side effects. Additionally, 68% of 

responders would have liked more information about future medical treatments and 

research, with 57% wishing to receive this information from their oncologist. 

Conclusions: These new survey findings highlight the unmet needs of women with 

MBC in Europe with respect to treatment choice and provision of information. 

Prolonging survival is a priority for most women, even if associated with toxicity. 

Disclosure: C.J. Twelves: The Being There survey was supported by an educational 

grant from Eisai Europe Limited. J. Stebbing: The Being There survey was supported 

by an educational grant from Eisai Europe Limited. 

370P CNS METASTASES, SUBTYPES AND SURVIVAL IN BREAST 

CANCER: A POPULATION BASED STUDY IN EASTERN 

SWITZERLAND 

D. König 1 , B. Thürlimann 2 , F. Otto 3 , L. Plasswilm 4 , M. Hoefliger 5 ,I. 

K. Senn-Schönenberger 6 , U. Müller 7 , C. Öhlschlegel 8 , H. Senn 3 , S.M. Ess 1 

1 Krebsliga Ostschweiz, Cancer Registry St. Gallen-Appenzell, St. Gallen, 

SWITZERLAND, 2 Breast Center St. Gallen, Kantonsspital St. Gallen, St. Gallen, 

SWITZERLAND, 3 Zetup, Tumor-und Brustzentrum ZeTuP AG, St. Gallen, 

SWITZERLAND, 4 Department of Radiation Therapy, Kantonsspital St. Gallen, 

St. Gallen, SWITZERLAND, 5 Oncology Practice, Altstätten, SWITZERLAND, 

6 Oncology Practice, St. Gallen, SWITZERLAND, 7 Oncology Practice, Sargans, 

SWITZERLAND, 8 Institute of Pathology, Kantonsspital St. Gallen, St. Gallen, 

SWITZERLAND 

Purpose: To examine tumor characteristics and outcomes associated with central 

nervous system (CNS) metastases in patients with metastatic breast cancer (MBC). 

Methods: Patients listed in the regional cancer registry of St. Gallen-Appenzell 

with MBC between 2003-2009 were included. Estrogen- (ER), progesterone 

receptor (PR) and HER2 status were collected from pathology reports. Biologic 

subtypes were approximated using standard immunohistochemical markers. 

Survival status was assessed in January 2012. Multivariate logistic regression 

models were used to identify factors associated with the risk of developing CNS 

metastases and with survival >12 months (mt) after the diagnosis of CNS 

involvement. 

Results: Overall, CNS metastases were observed in 170 (22%) of 773 patients 

with MBC included in the study. In the multivariate model, factors associated 

with CNS metastases were age


372P INCIDENCE OF BONE METASTASES AND SURVIVAL AFTER A 

DIAGNOSIS OF BONE METASTASES (BM) IN BREAST 


L. Holmberg 1 , M. Harries 2 , O. Agbaje 1 , H. Garmo 3 , S. Kabilan 3 , A. Taylor 4 , 

A. Purushotham 5 

1 Division of Cancer Studies, Cancer Epidemiology Unit, Research Oncology, 

Kings College London School of Medicine, Guys Hospital, London, UNITED 

KINGDOM, 2 Department of Medical Oncology, Guys and St Thomas’s Hospitals 

NHS Foundation Trust, Guys Hospital, London, UNITED KINGDOM, 3 Division of 

Cancer Studies, Cancer Epidemiology Unit, Research Oncology, King’s College 

London School of Medicine, Guys Hospital, London, UNITED KINGDOM, 

4 Centre for Observational Research (Oncology), Amgen Ltd., Uxbridge, UNITED 

KINGDOM, 5 Division of Cancer Studies, Research Oncology, Kings College 

London School of Medicine, Guys Hospital, London, UNITED KINGDOM 

Objectives: To measure crude and cumulative incidence of BM and cumulative 

survival after diagnosis of BM. BM were grouped by (i) BM only (ii) BM followed by 

visceral metastases (iii) visceral metastases followed by BM. 

Methods: Kaplan-Meier and Cox regression database analysis of women with breast 

cancer diagnosed 1975-2006 and treated at Guys Hospital London, whose details 

were prospectively updated regularly till end 2010. 

Results: Of 7064 women, 1589 (22%) developed BM by end follow-up (mean 8.4 

years); 2254 (32%) were diagnosed with breast cancer < 50 years, and 4810 (68%) 

≥50 years; 735 (14.4%) were classified as grade I, 2303 (45.3%) grade II and 2049 

(40.3%) grade III; 1530 (27.8%) were estrogen receptor (ER) –ve and 3982 (72.2%) 

ER +ve. Of all BM, 535 (33.7%) patients were in group i; 871 (54.8%) in group ii and 

183 (11.5%) in group iii. Incidence of all BM within 0-3 years from breast cancer 

diagnosis was highest in 1980 (64/1000 person years) and lowest in 2006 (11/1000 

person years), with the decline most pronounced in 1985-1990. Cumulative incidence 

of BM after 5 years follow up was highest in 1976-1982 (0.25 [95% CI 0.23-0.27]), 

falling to 0.22 (0.20-0.24) in 1983-1989, 0.18 (0.10-0.14) in 1990-1997 and 0.095 

(0.08-0.12) in 1998-2006.Risk of BM was significantly influenced by: calendar period 

of breast cancer diagnosis, HR was 0.77 (0.68-0.86) 1983-1989, 0.46 (0.40-0.54) 

1990-1997 and 0.33 (0.28-0.40) 1998-2006, all vs 1975-1982; tumour grade, HR 1.23 

(1.08 - 1.40) grade 3 vs 1-2; nodal status, HR 1.88 (1.60-2.21) 1-3 nodes vs 0 nodes 

and 3.95 (3.36-4.64) 4+ nodes vs 0 nodes; and tumour size, HR 2.00 (1.75-2.29) 2-5 

cm vs

Thus the primary aim to target BCSCs to control metastasis and relapse of disease 

was somewhat obtained. We further plan to correlate ratio of selected markers 

present in patients in pre- and post-chemotherapeutic condition with time to 

recurrence, mortality, morbidity and progression-free survival. 


376 GENETIC POLYMORPHISM IN AURORA-A AS A RISK FACTOR 

IN EGYPTIAN WOMEN WITH BREAST CANCER 

M.M. Saber 1 , S.Y. Akel 2 , G.T. Ali 2 , N.H. Ibrahim 2 

1 Dept. Medical Oncology, National Cancer Institute, Cairo, EGYPT, 2 Clinical 

Pathology Department, National Cancer Institute, Cairo, EGYPT 

Introduction: Although many risk factors have been identified, the cause of any 

individual breast cancer (BC) is most often unknowable. Aurora A, the gene, 

encoding serine/threonine kinase, has been shown to be over expressed in many 

tumors, noticeably in BC. The aim is to study the single nucleotide polymorphism in 

Aurora-A, and compare the frequency distributions of different genotypes between 

patients with BC and those with fibroadenoma to define its tumorigenic contribution 

to BC development. 

Patients and methods: This study was conducted on 60 pathologically confirmed BC 

patients, 20 patients with fibroadenoma and 40 frequency matched controls. There 

were no age, stage or histology restrictions.Serum CA-15-3&estradiol were measured. 

DNA was isolated from peripheral blood lymphocytes for genotyping of Aurora A at 

the T91A (Phe31Ile) site and were analyzed by PCR–RFLP assay. 

Results: This study showed that women carrying the Ile/Ile genotype had an increased 

risk of developing BC (P = 0.04). Logistic regression analysis showed that subjects 

having IIe/IIe genotype had a 9.3fold increased risk of developing BC compared with 

those with the Phe/Phe genotype (OR 9.3;95% CI 1.12-77.69). The heterozygous Phe/ 

IIe genotype was not significantly associated with the risk of cancer, suggesting a 

possible recessive effect of the polymorphism. No significant association was observed 

between the polymorphism and the risk of fibroadenoma. Patients with negative ER 

&PR were more likely to carry the IIe/IIe genotype compared with positive ER &PR 

positive patients (34.8% vs 5.4%). Serum estradiol showed significant increase in the 

BC category (p= 0.016), while, no significant difference was observed between the 

benign and the control categories (p = 0.41). The presence of +ve family history (FH) 

of BC and history of sex hormone intake showed significant increase in BC category 

when compared to control group and benign group. In BC group, patients with +ve 

FH had 7.5 times the chance of carrying IIe/IIe genotype compared to patients with – 

ve FH (OR7.5; 95% CI 1.53-36.71, P0.01). 

Conclusion: This study provides the evidence that the Aurora-A Ile/Ile genotype is 

associated with an increased risk for the occurrence but not progression of BC. 


377 CLINICAL, MOLECULAR PROFILES AND RESPONSE TO 

NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH LOCALLY 

ADVANCED BREAST CANCER: AN INDIAN EXPERIENCE 

D. Arya, B. Parikh, P.M. Shah, S.N. Shukla, K.M. Patel, A.S. Anand, S.S. Talati, 

S.A. Shah, A.A. Patel, B.B. Parekh 

Medical Oncology, Action Cancer Hospital, Delhi, INDIA 2 Dept. of Medical and 

Pediatric Hemato Oncology, Gujarat Cancer and Research Institute Civil Hospital 

Campus, M.P. Shah Cancer Hospital, Ahmedabad, INDIA 

Background: Breast cancer is now the most common cancer in many parts of India 

and Locally advanced breast cancer (LABC) accounts for nearly one thirds of cases. 

Advanced stages at presentation are attributed to late diagnosis and biologically 

aggressive disease in Indian women. 

Materials and methods: Patients diagnosed with inoperable LABC at the Gujarat 

Cancer and Research Institute, Ahmedabad, India were included in the study. 

Baseline evaluation included clinical assessment, testing for Estrogen Receptor(ER), 

Progesterone Receptor (PgR), Her2Neu and serum Vascular Endothelial Growth 

Factor (S. VEGF). First line NACT was FAC or FEC. Patients were assessed clinically 

and radiologically at the end of 3 cycles for response evaluation (mammography or 

ultrasonography of breast). S. VEGF levels were repeated at the end of 3 cycles of 

NACT or before surgery. All resectable patients underwent a Modified Radical 

Mastectomy. Unresectable patients were offered taxanes based chemotherapy or 

supportive care. 

Results: Fifty seven patients with LABC were included. Fifty Four patients (95%) 

received NACT. Mean age at diagnosis was 49 years. ER was positive in 51%, PgR 

in 35% and Her2Neu in 47%. Mean baseline S. VEGF was 463.4pg/ml. Baseline 

S. VEGF was higher in patients who were hormone receptor or Her2Neu positive. 

The overall clinical response rate [complete response (cCR) + partial response 

(cPR)] to the initial anthracycline based chemotherapy was 63%, cCR was 0%. 

Resectability rate after 1st line NACT was 77%. Pathological CR (pCR) rate was 

4%. There was no significant reduction in S. VEGF levels after NACT, irrespective 

of clinical or pathological responses. Nearly 17% of patients were lost to follow up 

at various stages of treatment including three patients who refused any kind of 

treatment. 

Conclusions: This study analyzes clinical and molecular profile of patients with 

LABC in India which differs from that seen in developed nations. High treatment 

drop-out rates may reflect treatment related toxicities, socio-cultural and logistical 

issues in a big developing country. Responses to anthracycline based NACT are 

comparable to the results reported from similar centers. 


378 RESPONSE TO NEOADJUVANT THERAPY AND DISEASE FREE 

SURVIVAL AND OVERALL SURVIVAL IN PATIENTS WITH 

TRIPLE-NEGATIVE BREAST CANCER (TNBC): SINGLE CENTER 

EXPERIENCE 

T. Pascual 1 , E. Ciruelos 1 , L. Manso 1 , I. Ghanem 1 , R.A. Manneh 1 , C. Mendiola 1 , 

D. Lora 2 , H. Cortes-Funes 1 

1 Medical Oncology, Hopital 12 de Octubre, Madrid, SPAIN, 2 Clinical Investigation 

Unit, Imas12, University Hospital 12 de Octubre, Madrid, SPAIN 

Background: Triple negative breast cancer (TNBC) is a distinct subtype of BC wich 

is characterized by the absence of expression of estrogen receptor (ER), progesterone 

receptor (PR) or HER2/neu. TNBC is a very heterogeneous disease, that accounts for 

15 to 20% of breast cancers. Despite initial chemosensitivity, patients with TNBC 

had a poorer outcome in terms of disease-free and overall survival, compared to 

non-triple-negative breast cancers. Neoadjuvant chemotherapy is commonly used for 

the initial treatment for TNBC, allowing for a higher rate of breast-conserving 

surgery and giving clues about the individual responsiveness of a particular cancer to 


Methods: We retrospectively reviewed 66 TNBC patients treated with neoadjuvant 

chemotherapy diagnosed at our institution between 2001-2011. They were divided 

into three subgroups: complete pathological response after neoadjuvant 

chemotherapy (group A), residual tumor smaller than 1 centimeter wide (group B), 

and residual tumor bigger than 1 centimeter wide or involving lymph nodes. 

Results: (One patient died before surgery and another patient refused it. Twenty 

(31%) of the other 64 patients achieved a complete pathological response. Mean DFS 

was 2,15 years; recurrent disease was higher for C (20,64%) vs B (3pts, 23%) vs A (2 

pts, 10%) (p = 0,0003). Most common recurrent sites were local (18) and bone (9). 

Mean OS was 4,5 years (95% IC 3,6 – 5,4); 3 (15%) pts died in A, 3 (23%) in B vs 16 

(51%) in C (p = 0,03). 

Conclusions: The pathologic complete response rate seen in our series is consistent 

with the one reported in other studies involving neoadjuvant chemotherapy for 

TNBC. The pathologic response after a neoadjuvant therapy correlates with 

disease-free and overall survival rates. 


379 ULTRASOUND ESTIMATION OF THE BLOOD FLOW IN BREAST 

CARCINOMAS AS A PREDICTIVE FACTOR OF EFFICIENCY 

OF NEOADJUVANT POLYCHEMOTHERAPY (NPCT) 

J. Zaivelieva 1 , I. Schepotin 1 , O. Zotov 1 , L. Kireeva 2 , T. Kondratova 2 

1 Oncology Department, National Medical University O.O. Bogomolets, Oncology 

Department, Kyiv, UKRAINE, 2 Department of Diagnostic, Kyiv City Consultative 

and Diagnostic Centre, Kyiv, UKRAINE 

Objective: Using ultrasound (US) techniques to determine the role of the intensity of 

the blood flow (BF) of breast tumors as a criterion of efficiency ACnPCT. 

Methods: 30 patients aged 50-62 years with verified BC, who were candidates for 3 

courses of AC-nPCT, were carried out color-coded US in the triplex mode scanning 

and power doppler. 

Luminal A Luminal B HER2(+) Triple-negative 

T2N0M0 3 1 - 2 

T2N1M0 3 2 2 2 

T3N0M0 3 4 1 3 

T3N1M0 1 1 - 2 

Average systolic blood flow 

velocity, ACBFL (cm/sec) 

14,2 ± 2,6 15,9 ± 3,9 14,6 ± 2,5 16,2 ± 2,8 

Measurements were made of resistance index (IR), pulsating index (IP). 


Results: ACBFV is increased and corresponds to the malignancy process, while 

higher rates were in patients with the triple-negative breast cancer (16,2 ± 2,8 cm/sec) 

and luminal B type (15,9 ± 3,9 cm/sec). While luminal A type had ACBFL 14,2 ± 2,6 

cm/sec and HER2(+) had 14,6 ± 2,5 cm/sec. IR in all subgroups was 0,73 ± 0,12, that 

matches the sharply increased values, and shows an increase peripheral resistance in 

vessels. IP was 12,35 ± 1,75, that reflects the amplified elastic and flexible properties 

of the newly formed blood vessels. Effect of AC-nPCT was higher in patients with 

the luminal B type (CR – 5, PR – 3). In patients with triple-negative BC effect of 

nPCT was worse, despite the high rate of BF in the tumor (PR – 1, stabilization – 6, 



progression – 2). In patients with low rate of BF in the tumor (luminal A, HER2(+) 

type) effect was the worst (PR – 2, stabilization – 7, progression – 4 patients in both 

groups). The correlation coefficient was statistically significant for BF as increased 

ACBFV, IR, IP, and the frequency of CR + PR to nPCT of luminal B type. 

Conclusions: There is a correlation between the velocity of BF and degree of 

destruction of tumor by cytostatics. While the rate of BF depended on the molecular 

type of the tumor and did not depend on the size of the primary tumor. 


380 IMPACT OF BODY MASS INDEX (BMI) ON DISEASE FREE 

SURVIVAL AND LIKELIHOOD OF PATHOLOGIC COMPLETE 

RESPONSE IN PATIENTS WITH LOCALLY ADVANCED BREAST 

CANCER TREATED WITH NEOADJUVANT CHEMOTHERAPY 

A. Armengol-Alonso 1 , A. Arance 1 , M. Campayo 1 , X. González-Farré 1 , 

A. García-Herrera 2 , P.L. Fernández 2 , X. Caparros 3 , I. Alonso 3 , B. Farrus 4 , 

M. Muñoz 1 

1 Oncologia Medica, Hospital Clinic y Provincial de Barcelona, Barcelona, SPAIN, 

2 Pathology, Hospital Clinic y Pronvincial Barcelona, Barcelona, SPAIN, 

3 Gynecology and Obstetrics Department, Hospital Clinic Barcelona, Barcelona, 

SPAIN, 4 Department of Radiation Oncology, Hospital Clinic Barcelona, 


Background: The BMI is a clinical parameter that although not perfect is often used 

to measure adiposity. In breast cancer there are multiple studies indicating that 

overweight/obesity (O/O) is related with lower survival and increased risk of relapse. 

It has been also reported less likely to achieve a pathological complete response 

(pCR) after neoadjuvant chemotherapy (NAC) in O/O patients. 

Methods: We retrospectively reviewed the records of 108 patients diagnosed with 

invasive locally advanced breast cancer (ILABC) who had been treated with NAC 

(anthracycline + taxane ± trastuzumab). The aim of our study was to review the 

impact of BMI on the pCR and the possibility of recurrence. pCR was defined as the 

criterion of strict pCR breast+nodes. 

Results: From 2004 to 2011, 108 patients received NAC. Based on their weight and 

height at baseline we divided into two groups; group 1: underweight/normal (BMI 

383 WHY DO WOMEN WITH BREAST CANCER IN SARAWAK, 

MALAYSIA PRESENT LATE? 

B.C. Devi 

Radiotherapy, Oncology & Palliative Care, Sarawak General Hospital, Sarawak, 

MALAYSIA 

Introduction: Breast cancer (BC) is the most common cancer in Sarawak. We 

explore the reasons of late stage presentation in this study. 

Methods: Based on a 175 questions questionnaire, information on barriers to late 

presentation were collected as a prospective study on 626 cases (2009 to 2011). 

Descriptive statistics and statistical tests were performed using the SPSS ver 17.0. 

Results: The stage at diagnosis differed significantly with 71% of the Chinese being 

diagnosed at early stage compared to only 50% in Malay and 45% in Natives (p < 

0.0004). The delay between first symptom and first medical consultation (DELAY 1) 

was more than one month in 57% of the patients and it differed significantly among 

ethnic groups (50% for Chinese, 64% for Malay and 65% for Natives, p < 0.002). The 

highest delay were: women aged 50 years (53%, p < 0.037); from 

rural area (65%) vs urban areas (55%, p < 0.04).The main variables affecting this 

delay were knowledge about BC (p < 0.004), lack of interest in one’s health ( p < 

0.0005) and choice of first professional consulted (doctor/nurse vs traditional healer, 

p < 0.03). The delay between first medical consultation and effective diagnosis 

(DELAY 2) for > 1 month was 14% of the patients and it differed significantly among 

ethnic groups (14% for Chinese, 23% for Malay and 13% for Natives, p < 0.0008). 

The main reasons: the number of doctors consulted before diagnosis (less the better, 

p < 0.0003); Malays (66.4%) and natives (64.4%) consulted more than two doctors 

when compared to Chinese (42.6%, p < 0.0001) and were less likely to follow the 

recommendations given by the doctors (p < 0.06). The impact of teaching Breast 

self-examination (BSE) on DELAY 1 and 2: Seventy-eight percent of patients were 

taught BSE and by 80% of government nurses. The age group (30-40 years) had been 

taught BSE more than other age groups. For DELAY 1, 72% were not taught BSE, 

p < 0.0001. There was no difference for those with DELAY 2. However for both 

DELAY 1 and 2, 42% were not taught BSE, p < 0.0001. 

Conclusions: More than 50% of the patients had DELAY 1 and 14% for DELAY 

2. Learning BSE had an impact on DELAY 1 but not for DELAY2. Those in age 

groups (>40 to 60 years) had less BSE taught and this finding is crucial for public 

health education as most BC occur after 45 years. 


384 THE ROLE OF ANTIESTROGENS IN BREAST CANSER CELLS’ 

INVASIVENESS 

D.V. Lymperatou 

Department of Medicine, Division of Oncology, University Hospital of Patras, 

Patras, GREECE 

Aim: The current study investigates the effect of two selective antagonists of the 

estrogen receptor (ER), fulvestrant (FL) and tamoxifen (Tam), on the invasive ability 

of breast cancer cells. ER blockage using anti-estrogens is associated with a small 

induction of invasiveness. Moreover, matrix metalloproteinases (MMPs) contribute 

to this procedure by cleaving components of the extracellular matrix, forming a path 

for the migrating cells. In addition, the focal adhesion kinase (FAK) plays a central 

role in invasiveness. 

Methods: We used two ER+ breast cancer cell lines, MCF7 and T47D. Cells were 

stimulated by estradiol (E2) and then treated with FL, Tam and the metabolites 

endoxifen (End) and 4OH-tamoxifen (4OHT). The invasiveness was evaluated using 

the matrigel assay and MMPs expression with gelatin zymography assay. Using 

immunofluoresence, we study the expression and localization of phospho FAK and 

its correlation with F-actin. 

Results: We found that E2 exerts a protective role in invasiveness. On the contrary, 

the anti-estrogens, as well as their metabolites reversed the effect of E2, a finding that 

was more obvious with Tam. The effect of the agents on MMPs expression was more 

pronounced at 48 h, when Tam and 4OHT were found to reduce the levels of both 

MMP-2 and MMP-9 compared to FL. Following E2 exposure, the maximum 

autophosphorylation of FAK (Y397) was observed at 10 min. At the same time point 

we assessed the effect of our agents, regarding the spatial organization of actin fibers. 

The concurrent administration of E2 with FL, Tam or End was associated with 

rearrangement of cytoskeleton, a finding that was not observed in untreated cells, as 

well as after the use of 4OHT and E2 or E2 alone. 

Conclusions: Our results indicate that the metabolite 4OHT is superior to the 

pro-drug Tam as well as the pure anti-estrogen FL with respect to invasiveness, 

MMPs induction and actin rearrangement. Regarding the comparison of Tam with 

FL, the effect on MMPs and rearrangement was similar. However, FL was found to 

be slightly superior to Tam concerning invasiveness. 



385 CANCER STEM CELL-LIKE CELLS: A THERAPEUTIC MODEL IN 

BREAST CANCER PATIENTS, WHERE ANY OTHER 

RECOMMENDED THERAPY HAS FAILED 

I. Papasotiriou 1 , M. Chatziioannou 2 , M. Toloudi 2 , E. Ioannou 2 , R. Hammon 3 , 

U. Jacob 4 , N. Hembry 5 , A. Kopic 4 

1 Research & Development-Clinical, Research Genetic Cancer Centre Ltd, Filotas, 

GREECE, 2 Research & Development, Research Genetic Cancer Centre Ltd, 

Filotas, GREECE, 3 Clinical, ATMC, Texas, TX, UNITED STATES OF AMERICA, 

4 Clinical, Privatklinik AMC, Dornstetten-Hallawangen, GERMANY, 5 Clinical, Litfield 

Medical House, Bristol, UNITED KINGDOM 

Introduction: Nowadays, the difficulty to treat metastatic breast cancers is high. 

Many clinical therapeutic lines have failed and there is no suggested therapeutic 

approach (in literature) concerning this type of tumors. The last decades, 

circulating tumor cells (CTCs) are the state – of – the –art in cancer therapy. In 

the present study, CTCs were isolated and identified. CSCs (cancer stem cells) 

were isolated from the above population of CTCs and their gene pattern was 

compared with those from the primary tumor as well as with those from the 

metastatic tumor. This study attempts to find a correlation between the CTCs and 

the metastatic regions in comparison with the primary tumor as well as to find 

out if all the CSCs have the same hallmarks in the selected breast cancer stem 

cell populations. 

Materials and methods: In order the protocol to be performed, CTCs from 

patient’s blood samples were isolated and then cultured in appropriate conditions. 

CSCs were identified and isolated from the population of CTCs. mRNA was 

extracted and was used for Microarray hybridization assays. The same procedure 

was repeated for primary tumor as well for metastatic tumor samples. The 

expression pattern of primary tumor cells was compared with those in the 

metastatic tumor. Finally, the therapeutic approach which was based on the above 

findings, was designed. 

Results: The results showed that the gene expression pattern of metastatic sites is 

similar to that of metastatic sites and less to that of the primary site. Then, the 

patients followed a therapeutic approach based on the data of the clinical results 

which were evaluated within a six- month period showing that the patients showed 

an objective response rate. 

Conclusion: The results showed that the entity that determines the clinical outcome 

in breast cancer, is the sub-population of CTCs, the circulating CSCs. Moreover, 

there are various types of CSCs in one patient, and not only one, as they have 

different growth mechanisms in primary and secondary tumors. 


386 BREAST CANCER PATIENTS WITH HER2NEU 

OVEREXPRESSION: RELATIONSHIP AMONG 

CLINICOPATHOLOGICAL CHARACTERISTICS AND LOCAL/ 

DISTANT RECURRENCES AND SURVIVAL 

C. Bellido-Ribes 1 , S. Gonzalez 2 , A. Garcia 3 , V. Obadia 2 , R. Bastus 4 , 

J. Fernández 4 , A. Aguilar 4 , L. Cirera 4 

1 Medical Oncology, Mutua Terrassa University Hospital, Terrassa, SPAIN, 

2 Medical Oncology, Hospital Mutua Terrassa, Terrassa, SPAIN, 3 Breast Unit, 

Departament of Gynecology, Hospital Mutua Terrassa, Terrassa, SPAIN, 

4 Hospital Mutua Terrassa, Terrassa, SPAIN 

Objectives: The aim of this study was to correlate the overexpression of HER2 with 

clinical pathologic characteristics and its influence on local/distant recurrence and 

survival. 

Methods: From 1998 to 2010, prospective data of 146 patients with invasive breast 

cancer with HER-2 overexpression was studied. The sample was divided into three 

groups: Negative hormonal receptors (NHR); Luminal B1 (Estrogen receptor +/-, 

Progesterone receptor +), Luminal B2 (Estrogen receptor +, Progesterone receptor -). 

Histological type (HT), size tumor (T), differentiation grade (DG), and nodal status 

were determined. Correlation with local and distant recurrence, and 5-year overall 

survival was done. 

Results: NHR: 33.5%, luminal B1: 47.5%; Luminal B2: 19% Clinical pathologic 

characteristics: 

Age (%) Size(%) HT (%) 

70 T1 T2 T3 T4 Ductal Lobular 

NHR 23 51 26 39 37 4 10 98 2 

Luminal B1 33 51 16 51 39 9 1 99 1 

Luminal B2 22 64 14 53 43 30 4 96 4 



DG (%) Nodal Status 

G1 G2 G3 Negative Positive 

NHR 0 21 79 59 41 

Luminal B1 11 37 52 48 52 

Luminal B 0 28 73 57 43 

Local and distant recurrence and overall survival at 5 years follow-up: 

Local Recurrence 

(%) 

Metastasis Recurrence 

(%) 

NHR 6 20 81.5 

Luminal B1 2 8 88.5 

Luminal B2 4 15 86.5 

Overall Survival 

(%) 

Conclusions: Patients with NHR and patients with PR- had more aggressive 

differentiation grade, less axillary infiltration and increased risk of distant metastasis. 

At 5-year follow-up, overall survival was better in the PR+ group. 


387 CRANIAL MAGNETIC RESONANCE IMAGING (MRI) IN THE 

STAGING OF HER2-POSITIVE BREAST CANCER PATIENTS 

M.A. Kaplan 1 , A. Inal 1 , M. Kucukoner 1 , Z. Urakci 1 , F. Ekici 1 , U. Firat 2 , 

A. Isikdogan 1 

1 Medical Oncology, Dicle University, Diyarbakir, TURKEY, 2 Pathology, 

Dicle University, Diyarbakir, TURKEY 

Purpose: The aim of the current study was to evaluate whether early detection of brain 

metastases could improve survival outcomes in HER2-positive breast cancer patients. 

Patients and methods: HER2-positive breast cancer patients without neurological 

symptoms within 12 months from current stage of diagnosis were included in the 

study. The factors affecting the development of brain metastasis in the entire group 

and the metastatic patients were investigated, respectively. Survival durations after 

first metastasis and brain metastasis were compared between the asymptomatic and 

symptomatic patients 

Results: Eleven of the 96 patients (11.5%) had occult brain metastasis. Of whom 9 

patients were in the metastatic group, only 2 patients were in the non-metastatic 

group, (22% vs 3.6%, respectively, p = 0.008). Although median survival durations 

from first metastasis (27.4 vs 20.2 months, respectively, p = 0.858) and brain 

metastasis (5.2 vs 4.4 months, respectively, p = 0.710) similar, cerebral death was 

numerically different (22% vs 46%, p = 0.271) in the asymptomatic and symptomatic 

patients. 

Conclusion: Present study suggests that routine cranial imaging do not bring any 

benefit to the non-metastatic HER2-positive breast cancer patients. Furthermore, 

although early detection of brain metastasis provides reduction in cerebral deaths, it 

does not prolong survival in metastatic patients. 


388 DIAGNOSIS OF BREAST CANCER METASTASES WITH PET/TC 

IN PATIENTS WITH ELEVATION OF TUMOR MARKERS: FINAL 

DATA 

A. Mafodda 1 , A. Prestifilippo 2 , R. Maisano 1 , D. Giuffrida 2 , D. Aricò 3 , D. Azzarello 1 , 

M. Mare 2 , M. Nardi 1 

1 Oncologia Medica, A.O. B.M.M., Reggio Calabria, ITALY, 2 Oncologia Medica, 

Istituto Oncologico del Mediterraneo, Viagrande, ITALY, 3 Medicina Nucleare, 

Centro Catanese di Oncologia, Catania, ITALY 

Background: Breast cancer is one of the most common cancers worldwide. PET / 

CT is more accurate than traditional methods for the detection of distant metastases 

or local recurrence and enables for early assessment of treatment response in patients 

after surgery for breast cancer undergoing primary chemotherapy. PET/CT is not 

considered a conventional examination during follow-up of patients with breast 

cancer, but recent data indicate its usefulness both in cases of asymptomatic increase 

of tumor markers that uncertain conventional imaging results. This study investigates 

the potential role of PET / CT to detect clinically occult metastases in patients with 

suspected recurrence of breast cancer during follow-up. 

Methods: The authors studied 67 patients in breast cancer follow-up after primary 

surgery and chemotherapy and/or external radiotherapy. All patients were in 

remission without any other clinical or instrumental signs of relapses, except for the 

progressive elevation of CA 15.3 and/or CEA, tested during the follow-up. In 47 

patients conventional imaging provided uncertain results and increase of CA 15.3 

that was not correlated to any evidence of metastatic disease. The final diagnosis was 

obtained by histopathology (n.13) or by combined follow-up (n.54), including 

imaging at least 6 months later. 

Results: Disease relapse was proven in 55 out of 67 patients and successfully PET/CT has 

identified clinically occult disease with an excellent sensitivity. In 21 cases the anatomical 

distribution of metastasis sites was in the bone, 16 in the lymphonode, 11 in the lung and 

7 in the liver. We found 2 false-negative, 4 false-positive and 6 true-negative. 

Conclusions: PET/TC may be more sensitive than the serum tumor markers in 

detecting relapse of breast cancer. This study demonstrated the clinical utility of 

tumor marker-guided PET in the follow-up of breast cancer patients. 


389 SURGICAL RESECTION OF LOCALLY ADVANCED PRIMARY 

TUMOR IN PATIENTS WITH DISTANT METASTATIC BREAST 

CANCER AT DIAGNOSIS: RESULTS OF A RETROSPECTIVE 

COMPARATIVE STUDY 

S. Arifi 1 , F.Z. Hijri 1 , Z. Benbrahim 2 , Y. Akasbi 1 , S. Elfakir 3 , N. Mellas 1 , 

A. Melhouf 4 , A. Banani 4 , O. El Mesbahi 1 

1 Medical Oncology, Hassan II University Hospital, Fez, MOROCCO, 2 Medical 

Oncology, University Hospital of Hassan II, Fez, MOROCCO, 3 Epidemiology, 

Hassan II University Hospital, Fez, MOROCCO, 4 Gynecology, Hassan II 

University Hospital, Fez, MOROCCO 

Background: Women with metastatic breast cancer (MBC) with intact locally 

advanced primary tumors (LAT) present aggressive local symptoms that may warrant 

palliative surgery to the breast. However, it is unclear if such surgery otherwise 

improves clinical outcome. The aim of this study is to demonstrate if surgery of the 

breast may avoid uncontrolled chest wall disease and may improve survival. 

Methods: We reviewed the records of all MBC patients presented with intact LAT, 

treated at our institution between 2007 and 2011.We compared two groups of 

patients: surgical group versus nonsurgical group. Clinical outcome was assessed in 

the two groups. Prognostic factors affecting loco regional relapse, were evaluated. 

Results: 75 patients were identified. The mean patient age was 49 ± 12.15 years. 52% 

were pre menopausal women. 87.1 % of tumors were hormone receptors positive. 

Her2 was assessed in 59 cases and was positive in 33.9%. Inflammatory breast cancer 

presented 16 %. Clinical lymph node involvement was noted in 58.7% cases. 69.6% 

had visceral metastasis and 5.3 % had brain metastasis. 89.3% have good Performans 

Status ≤ 1. All women received systemic therapy. First-line therapy consisted of 

anthracycline-based regimen (95.6%) and Taxane (39.7%). Among patients with 

HER2 positive 36.4% received Trastuzumab. Only 14% of patients with bone 

metastasis received bisphosphonate. 49.3% underwent mastectomy while 50.7% had 

intact LAT. The two groups were well balanced regarding demographics, clinicals, 

and tumors, characteristics. Among women who underwent mastectomy 48.5% had 

axillary lymph node dissection, and excision margins were positive in 25% cases. 

Loco regional radiotherapy (LRRT) was given to 8 women. pCR occurred in 7 

patients among those who were operated. Local recurrence (LR) occurred in 9 

patients (28.1%). Median time to local relapse was 3 months (2-19). LR was related 

to excision margin (p = 0.0001) and LRRT (p = 0.04). Median PFS was 10 months in 

nonsurgical group patients versus 16.5 months in surgical group. 

Conclusions: MBC patients with locally advanced breast cancer who underwent 

mastectomy had improvement in local symptoms when the excision margin was in 

sano. However, the impact of this surgery in survival is not clear. 


390 CISPLATIN, CYCLOPHOSPHAMIDE, METHOTREXATE, AND 

5-FLUOROURACIL (PCMF) AS FIRST LINE THERAPY OF 

METASTATIC TRIPLE NEGATIVE BREAST CANCER (MTNBC) 

IN PATIENTS PREVIOUSLY TREATED WITH ADJUVANT 

ANTHRACYCLINES AND TAXANES: RETROSPECTIVE 

ANALYSIS 

D.A. Donat 

Internal Oncology, Institute of Oncology Vojvodina, Sremska Kamenica, SERBIA 

Background: The purpose of this study was to evaluate the efficacy and toxicity of 

applied PCMF chemotherapy every four weeks (q4w) in the treatment of MTNBC 

patients (pts) previously treated with adjuvant anthracyclines and taxanes. 

Methods: We administered cisplatin 30 mg/m2 on day 1 to 3 with regular hydration, 

cyclophosphamide 400 mg/m 2 on day 1 to 5, 5-fluorouracil 500mg/m 2 on day 2 and 

4, and methotrexate 30mg/m 2 on day 1, 3, and 5.The evaluation was performed after 

4 cycles. We included 76 pts (median age 58 years, range: 32-71 years). PS medium 

was 1 (0-2); 21 pts (27.6%) were premenopausal and 55 (62.4%) postmenopausal. 

Adjuvant anthracyclines (AC or FAC x 4) and taxanes (paclitaxel/w x 12, or 

docetaxel/3w x 4) therapy was applied in all patients. DFS 12 months in 29 pts (38.2%). Adjuvant radiotherapy was 

applied in 48 pts (63.2%). Visceral metastases were observed in 51 pts (67.1%), bone 

metastases in 34 (44.7%), and soft tissue metastases in 11 pts (14.5%). Only one 

organ was affected in 15 pts (19.7%), in 41 (53.9%) two organs, and in 5 pts (6.6%) 

three or more. 


Results: We evaluated 76 pts with MTNBC after 4 cycles of PCMF chemotherapy. 

CR was found in 3 pts (3.9%), PR in 16 pts (21.0%), SD in 11 pts (14.5%), and PD 

in 39 pts (51.3%); with ORR in 19 pts (24.9%) and TCR in 30 pts (39.5%). 

Hematological toxicity: grade 3 and 4 anemia was found in 4 pts (5.3%) and 

leukopenia in 9 pts (11.8%). Non-hematological toxicity: renal grade 3 awas observed 

in 2 pts (2.6%). Not a single therapy was interrupted due to toxicity, but therapy 

prolongation was present in 15% of applied cycles. 

Conclusions: The application of PCMF chemotherapy q4w in the treatment of 

patients previously treated with anthracyclines and taxanes as adjuvant treatment 

appeared to be effective with ORR in 24.9% and TCR in 39.5% and can be 

administered with good tolerance.It is today our standard treatment in this pts 

population. 


391 TRASTUZUMAB-BASED CHEMOTHERAPY (CT) FOR 

HER2-POSITIVE METASTATIC BREAST CANCER (MBC): WHICH 

OPTIMAL PARTNER BEYOND THE FIRST LINE? A 

SINGLE-CENTRE RETROSPECTIVE STUDY 

R. Palumbo 1 , A. Bernardo 1 , A. Riccardi 2 , F. Sottotetti 1 , M. Azzarà 2 , 

B. Tagliaferri 1 , E. Pozzi 1 , C.M. Teragni 1 , G. Bernardo 1 

1 Oncologia Medica 2, Fondazione S. Maugeri IRCCS, Pavia, ITALY, 2 Medical 

Oncology, University of Pavia, Pavia, ITALY 

Background: The activity of trastuzumab-based chemotherapy (CT) in HER2+ MBC 

is well established, but the question of the optimal CT partner remains a relevant 

issue. We performed a retrospective comparison of the clinical outcomes associated 

with different trastuzumab-CT regimens. 

Patients and methods: Patients (pts) for this analysis were selected from a 

monoinstitutional database of HER2+ MBC pts receiving trastuzumab-based CT for 

the metastatic disease (February 2005-December 2008). Treatment activity and safety 

were assessed by the WHO criteria, time to progression (TTP) and overall survival 

(OS) were calculated by the Kaplan Meier method. 

Results: A total of 147 pts with measurable disease were evaluated: 57 received 

trastuzumab with weekly vinorelbine (T/VNR), 48 weekly or 3–weekly trastuzumab 

plus docetaxel (T/Doc), 42 a triple combination of 3-weekly trastuzumab plus oral 

vinorelbine and capecitabine (T/osVNR/Cape) as 1 st line therapy. Objective RR was 

76% in the T/VNR group, 68% in the T/Doc regimen, and 72% in the T/osVNR/ 

Cape combination. There was no significant difference in median TTP according to 

treatment type (14, 11 and 12 months, respectively, p = 0.62); median OS was 36 

months, 32 and 34 months, respectively (p = 0.48). More treatment-related grade 3-4 

toxicities were recorded in the T/Doc population. Following progression, pts received 

trastuzumab-based subsequent lines of treatment; according to our Institution police, 

shifting to a different CT partner: all had a 2 nd line, 86 a 3 rd line, 41 a 4 th line, 7 a 

5 th line. In univariate analysis no visceral involvement, T/Doc 1 st line CT, low 

primary tumor grading were correlated with better PFS and OS; in multivariate 

analysis the number of trastuzumab-based regimens was the only factor with 

statistically significant impact on OS (p = 0.02). 

Conclusions: These results confirm the high activity of the tested regimens as 1 st 

line therapy of HER2+ MBC, without significant differences in clinical outcomes, 

also suggesting the benefit of multiple lines of trastuzumab-based CT in a 

significant subset of pts, since each subsequent line may contribute to a longer 

OS. 


392 PHASE II STUDY OF SINGLE AGENT ORAL VINORELBINE (OV) 

AS FIRST-LINE CHEMOTHERAPY (CT) IN PATIENTS (PTS) WITH 

HER-2 NEGATIVE METASTATIC BREAST CANCER (MBC): A 

SINGLE CENTER EXPERIENCE 

M. Mansour 1 , C. Mourad 2 

1 Oncology, Erfan Hospital, Jeddah, SAUDI ARABIA, 2 Medical Affairs, Pierre 

Fabre Medicament, Beirut, LEBANON 

Background: Quality of life and pts’ preferences play an important role in treatment 

decision-making in the metastatic setting. Previous studies indicated that Oral CT is 

convenient and a preferred option by many pts. We hereby report the efficacy and 

safety of OV as first-line CT for MBC. 

Patients and methods: 31 pts were enrolled between January 2007 and December 

2010. All pts had measurable disease, a majority (84%) relapsing after anthracyclines 

(ANT) and/or taxanes (TXN) adjuvant treatment, WHO PS ≤ 2, adequate bone 

marrow, hepatic and renal functions and no adjuvant CT within the last 6 months. 

Pts were treated every 3 weeks with OV 60 mg/m 2 D1 and D8 for the 1 st cycle and 

thereafter 80 mg/m 2 D1 and D8 every 3 weeks in the absence of G4 neutropenia 

and/or febrile neutropenia. Treatment was administered until disease progression or 

unexpected adverse event or pt refusal to continue. Primary endpoint (EP) was 

Objective Response Rate (ORR); secondary EPs were TTP, OS and safety. Follow-up 

results until April 2012 are reported. 

Results: Median age was 42 years (range, 33 -75); median WHO PS 1 (range, 0-2). 

Previous adjuvant therapy: ANT-based alone: 29%, TXN-based alone: 19%, ANT plus 

TXN: 36%, other: 16%. Median disease-free interval from end of previous CT was 7 

months. 26 pts (84%) had 2 or more metastatic sites, liver (61%), bone (58%), lung 

(58%) being the most frequent sites. A median of 6 cycles were administered (range, 

2-20). ORR was achieved in 9 pts (29%), including 1 complete and 8 partial responses. 

12 pts (39%) had stable disease, resulting in a clinical benefit rate (CBR) of 68%. In pts 

pretreated by ANT, ORR was 35% and CBR was 70%. Median TTP was 3.7 months 

[95% CI: 2.2-5.2]. Median survival was 16 months [95% CI: 11.4-20.6]. 3 pts (10%) 

developed G 3-4 neutropenia. No events of febrile neutropenia, cardiac, renal toxicities 

or alopecia were recorded. G 3 thrombocytopenia was reported in 2 pts (6%). 5 pts 

(16%) developed G 3 nausea-vomiting. 

Conclusions: Results show a good efficacy and tolerance profile of OV as first line CT 

for HER-2 negative MBC pts. Similar activity was observed in the sub-group of pts 

pretreated by ANT. 


393 VINORELBINE WITH OR WITHOUT TRASTUZUMAB 

IN METASTATIC BREAST CANCER 


A. Stravodimou, K. Zaman, I.A. Voutsadakis 

Centre Pluridisciplinaire d’Oncologie, Centre Hospitalier Universitaire Vaudois - 

CHUV, Lausanne, SWITZERLAND 

Background: Vinorelbine is one of the most widely used drugs in metastatic breast 

cancer. We report a single center experience with vinorelbine with or without 

trastuzumab in patients with metastatic breast cancer. 

Patients and methods: All patients with metastatic breast cancer receiving 

vinorelbine with or without trastuzumab during a six years period were 

retrospectively reviewed. Demographic data and data on response, time to 

progression (TTP) and survival were collected. Patients received vinorelbine IV 

25-30 mg/m2or PO 60-80 mg/m2 in days 1 and 8 of a 21 days cycle. In patients who 

received concomitant trastuzumab a standard dosing schedule with 8 mg/kg loading 

dose followed by 6 mg/kg in subsequent administrations every three weeks was used. 

Results: Eighty seven women were included. The median age was 63 years (range 32 

to 85). Sixty two patients received vinorelbine alone and 25 patients received 

vinorelbine with trastuzumab. In 67 patients this was the first line treatment for 

metastatic disease and in 20 patients it was 2nd or later line of treatment. Seventy 

patients were evaluable for response while the remaining seventeen patients were not 

evaluable due to early progression (n = 6) or early termination of treatment for 

adversary effects (n = 11). The response rate of evaluable patients was 37.1% [1.4% 

Complete Response (CR) and 35.7% Partial Response (PR)]. Eighteen additional 

patients (25.7%) had Stable Disease (SD) for three or more months resulting in a 

Disease Control Rate of 62.8%. Twenty four of 54 (44.4%) patients receiving first line 

treatment had a response while in the second and subsequent lines setting two of 16 

(12.5%) patients responded (x2 = 9.66, p = 0.001). A response was obtained in 63.6% 

of patients receiving concomitant trastuzumab and in 25% of patients receiving 

vinorelbine alone (x2 = 13.63, p = 0.0002). The median TTP was six months (range 

1-45). Sixty six patients of the cohort have died and the median overall survival was 

11.5 months (range 1-83). Adverse effects necessitating interruption of treatment 

were observed in 18.5% of patients. 

Conclusion: This retrospective study of vinorelbine in metastatic breast cancer 

confirms a high disease control rate. Response rate is higher in first line treatment 

compared to subsequent lines and with the combination with trastuzumab. 


394 A RETROSPECTIVE STUDY OF CISPLATIN/VINORELBINE 

VERSUS CAPECITABINE/VINORELBINE AS SECOND-LINE OR 

THIRD-LINE TREATMENT IN ADVANCED BREAST CANCER 

Y. Liu 1 , S. Shi 1 ,X.Qu 1 , J. Shi 2 , L. Zhang 2 ,L.Xu 2 , Y. Teng 2 

1 Medical Oncology, The First Hospital of China Medical University, Shenyang, 

CHINA, 2 Department of Oncology, The First Affiliated Hospital of China Medical 

University, Shenyang, CHINA 

Purpose: To compare the efficacy and safety of cisplatin or capecitabine, both with 

vinorelbine, as second-line or third-line treatment in advanced breast cancer 

previously treated with anthracyclines and/or taxanes. 

Methods: From June 2004 to November 2011, 62 advanced breast cancer patients 

were eligible. Patients (38) enrolled in group NP received VIN 25mg/m 2 on day 1 

and 8 combined with Cisplatin 75mg/m 2 on day 1 of a 21-day cycle. Patients (24) 

enrolled in group NX received VIN 25mg/m 2 on day 1 and 8 of a 21-day cycle 

combined with CAP 1000mg/m 2 twice daily for 14 consecutive days followed by 7 

days of rest. Tumor assessment was performed every 2 cycles according to RESIST 

criteria. Toxicity was assessed according to National Cancer Institute Common 

Toxicity Criteria (version 3.0). 

Results: The overall response rate (ORR) in group NP was 47.4%, all were partial 

responses (PRs). In group NX, ORR was 33.3% (P = 0.275), with 4.2% CRs and 



29.2% PRs. Median time to progression (TTP) was 6.1 months (range, 3.2-9.0 

months) in group NP and 6.3 months (range, 4.1-8.5 months) in group NX(P = 

0.783). COX regression showed no statistically significant difference (P = 0.782, OR = 

0.920). Median overall survival (OS) was 28.8 months (range, 21.6-36.0 months) in 

group NP and 15.1 months (9.6-20.6 months) in group NX(P = 0.027, OR = 0.495). 

COX regression showed a statistically significant difference(P = 0.045). Neutropenia 

was the most frequent hematologic toxicity, with 57.9% grade 3/4 neutropenia 

observed in group NP and 38.1% in group NX(P = 0.145). 13.2% grade 3/4 vomiting 

was seen in group NP and no grade 3/4 vomiting in group NX. No grade 3/4 

nephrotoxicity or hand-foot syndrome was noted in both groups. 

Conclusion: Better OS was seen in group NP than in group NX. Treatment-related 

toxicity in both groups was manageable. 


395 DOCETAXEL (D), GEMCITABINE (G) AND BEVACIZUMAB (BEV) 

AS SALVAGE CHEMOTHERAPY (CT) FOR HER-2 NEGATIVE 

METASTATIC BREAST CANCER (MBC) 

E. Kontopodis 1 , C. Christophylakis 1 , N. Kentepozidis 1 , I. Boukovinas 1 , 

S. Giassas 1 , E. Saloustros 1 , A. Kalykaki 1 , V. Bozionelou 2 , V. Georgoulias 1 , 

D. Mavroudis 1 

1 Medical Oncology, Hellenic Oncology Research Group (HORG), Athens, 

GREECE, 2 Medical Oncology, University General Hospital of Heraklion, Athens, 

GREECE 

Introduction: The combination of D and G is a valid salvage CT regimen for the 

treatment of mBC. When combined with CT, Bev has increased the response rate and 

progression-free survival (PFS) in both first and second line treatment of mBC. In this 

multicenter study, we evaluated the combination of D, G, and Bev, administered 

biweekly, as second or further line CT in patients (pts) with HER-2 negative mBC. 

Methods: Women with HER-2 negative mBC, who had received at least one prior 

line of CT, were treated with D 50 mg/m2, G 1500 mg/m2 and Bev 10 mg/Kg, in 

cycles every two weeks. Bev was continued until disease progression. This was a 

study with Simon’s optimal two step statistical design. 

Results: Forty-eight pts have been enrolled. Median age was 61 years, performance 

status was 0-1 in 95.8% and 2 in 4.2% of pts, 83.3% had hormone receptor positive 

disease, and 47.9% had received one prior line of CT. All pts were evaluable for 

toxicity and 43 for response. Objective response rate was 44.2% (95% confidence 

interval [CI], 29.3-59%), median PFS was 6.8 months (95% CI, 4.5-9.1 months), and 

median overall survival 20.1 months (95% CI, 9.9-30.3 months). Grade 3-4 

hematologic toxicity consisted of neutropenia (39.6%) and febrile neutropenia 

(4.2%). Most common grade 2-3 non-hematologic adverse events included nausea 

(10.4%), diarrhea (10.5%), neurotoxicity (12.5%), fatigue (31.3%), allergic reactions 

(6.3%), hemorrhage (4.2%), and hypertension (4.2%). No grade 4 non-hematologic 

toxicities or toxic deaths were recorded. 

Conclusion: The combination of D, G and Bev has promising activity and a 

manageable toxicity profile as salvage CT for HER-2 negative mBC. Updated results 

will be presented at the congress. 


396 EFFICACY OF TRASTUZUMAB CONTAINING RETREATMENT 

AFTER PROGRESSION ON LAPATINIB THERAPY IN JAPANESE 

PATIENTS WITH HER2-POSITIVE METASTATIC BREAST 

CANCER 

M. Hattori 1 ,H.Iwata 1 , T. Fujita 1 , M. Sawaki 1 , N. Kondo 1 , A. Horio 1 , K. Muro 2 

1 Breast Oncology, Aichi Cancer Center, Nagoya, JAPAN, 2 Clinical Oncology, 

Aichi Cancer Center Hospital, Nagoya, JAPAN 

Background: Lapatinib has been approved for HER2 positive metastatic breast cancer 

patients with refractory to trastuzumab (T) therapy in Japan. Currently, it has been 

proposed that lapatinib can resensitize trastuzumab–mediated antibody-dependent 

cellular cytotoxicity (ADCC). Recent clinical data suggest the efficacy of T containing 

retreatment after progression on lapatinib therapy in patients with HER2-positive 

metastatic breast cancer. Here, we present a retrospective review of data from 25 

patients who received T containing retreatment after progression on lapatinib therapy. 

Methods: We reviewed the data of 50 patients with HER2-positive metastatic breast 

cancer who received lapatinib therapy in our institution from August 2004 through 

March 2012. Of these, 25 patients received T containing retreatment after 

progression on lapatinib therapy. We retrospectively assessed the clinical benefit of 

this treatment regimen in these patients. 

Results: Luminal-HER2 and HER2-enriched subtypes were identified in 13 (52%) 

and 12 (48%) of these cases, respectively. The median duration of lapatinib therapy 

was 5.9 months (range, 1.8-20.2 months). The median number of preceding 

regimens was 3 (range, 2-8) in metastatic setting. Seven patients (31.8%) responded 

to T containing retreatment; all 7 patients achieved PR and none achieved CR. There 

were no significant differences in subtype, number of preceding regimens and brain 

metastases; however, responders achieved higher clinical response from lapatinib 

therapy than non-responders (response rate of 84% versus 13%, respectively). The 

median time to progression of T containing retreatment was 3.0 months (95% CI, 

2.4-3.5 months). Among seven responders to T containing retreatment, one patient 

responded to refractory T containing regimen. All patients tolerated T containing 

retreatment with no occurrence of Grade 3/4 toxicities. 

Conclusion: T containing retreatment could be a favorable treatment regimen which 

can achieve clinical response in patients with HER2-positive metastatic breast cancer 

who experienced progression on prior trastuzumab and following lapatinib therapy. 


397 LOW DOSES OF GEMCITABINE (G) WITH CISPLATIN (C) 

IN TREATMENT OF METASTATIC BREAST CANCER (MBC) 

PROGRESSING AFTER ANTHRACYCLINES, TAXANES, 

CAPECITABINE AND OTHER ANTINEOPLASTIC AGENTS 

T.Y. Semiglazova 1 , M.L. Gershanovich 1 , D.H. Latipova 1 , L.V. Filatova 1 ,V. 

A. Chubenko 1 , V.F. Semiglazov 2 , V.V. Semiglazov 3 , P.V. Krivorotko 2 ,D. 

E. Matsko 4 , V.V. Klimenko 3 

1 Department of Chemotherapy, N.N.Petrov Research Inst. of Oncology, 

St. Petersburg, RUSSIAN FEDERATION, 2 Breast Cancer Department, N.N. 

Petrov Research Inst. of Oncology, St. Petersburg, RUSSIAN FEDERATION, 

3 Department of Oncology, Pavlov Medical University, St. Petersburg, RUSSIAN 

FEDERATION, 4 Department of Pathology, N.N.Petrov Research Inst. of 

Oncology, St. Petersburg, RUSSIAN FEDERATION 

Background: The highest synergism of G was registered with C, as G suppresses DNA 

reparation after its damage from C, which leads to apoptosis of tumor cell. The study of 

optimal doses of G and C combination continues for intensive pretreated MBC. 

Purpose: Evaluate efficiency and tolerability of the low doses of G and C in 131 

patients with MBC progressing after anthracyclines, taxanes, capecitabine and other 

antineoplastic agents. 

Methods: G 600-750 mg/m 2 and C 30 mg/m 2 were administered on days 1 and 8 

every 3 weeks in the 2 nd line for 28 patients, in the 3 rd for 54 patients and in the 4 th 

for 49 patients. Groups were comparable in age, performance status (PS), ER/PgR 

and HER2 expressions, localization and number of metastatic sites prior to 

treatment. 

Results: Total amount of cycles: 549, median 4.2 per patient (range: 2-12). The 

overall response (OR) of all patients was 27%, clinical benefit (OR + stable disease) – 

71.7%, with median time to progression (TTP) 4.8 months (95% CI 3.9-5.7 months) 

and median overall survival (OS) 14.6 months (95% CI 12.1-17.1 months). The OR 

in the 2 nd line was observed in 39.3%, in the 3 rd – 27.8% and in the 4 th – 18.4% (р < 

0.05), clinical benefit – in 85.7, 59.3 and 77.6% (р > 0.05) respectively. Pain intensity 

reduction and improvement of PS were noted in patients in spite of the lines. Linear 

discriminant and regression analyses showed that OR, TTP and OS didn’t depend on 

the ER/PgR and HER2 expressions, but ECOG 2-3, pain syndrome, metastases in the 

lymph nodes and liver were the factors of poor prognosis. The treatment-related 

adverse events were neutropenia, anemia, thrombocytopenia, alopecia, nausea, 

vomiting, peripheral neuropathy and fatigue. Toxicities with grade 3-4 intensity were 

neutropenia (31.6% of patients), vomiting (0.8%), anemia (2.3%), thrombocytopenia 

(3.1%). No febrile neutropenia and deaths related to the study treatment occurred. 

Conclusions: The low doses of G with C are effective and tolerable in treatment of 

MBC progressing after antracycline, taxanes, capecitabine, other antineoplastic agents not 

only in the 2 nd and 3 rd ,butalsointhe4 th lines and are suitable for outpatient therapy. 


398 LONG TERM USE OF CAPECITABINE IN PATIENTS WITH 

LOCALLY RECURRENT OR METASTATIC BREAST CANCER 

D.H. Josephs 1 , R. Mir 2 , T. Siow 1 , L.E. Dumas 1 , V. Michalarea 1 , E. Sawyer 2 ,J. 

L. Mansi 1 

1 Medical Oncology Offices, 4th Floor Bermondsey Wing, Guys Hospital, Guys 

and St Thomas’s NHS Trust, London, UNITED KINGDOM, 2 Clinical Oncology, 

Guy’s and St Thomas’ NHS Trust, London, UNITED KINGDOM 

Background: Capecitabine monotherapy is considered standard treatment in 

anthracycline- and taxane-pretreated locally recurrent or metastatic breast cancer and 

has proven efficacy in this setting. Here we report the findings of a retrospective 

study to evaluate the impact of continuing capecitabine treatment beyond the 

standard 6 cycles until disease progression, on efficacy and outcomes in patients with 

locally recurrent or metastatic breast cancer. In addition we sought to consolidate the 

information known about capecitabine dose modification and efficacy outcomes in 

this patient population. 

Patients and methods: Clinical databases in two institutions were used to identify all 

patients with locally advanced or metastatic breast cancer treated with capecitabine 

over the period July 2006 – July 2011. Baseline characteristics, progression-free (PFS) 

and overall survival (OS) were recorded. 

Results: In total, 150 patients met the inclusion criteria. Of these patients 67 (45%) 

received less than 6 cycles, 17 (11%) received 6 cycles only and 66 (44%) received 


more than 6 cycles of capecitabine. 65 (43%) patients commenced treatment at a 

dose less than 1250mg/m2 twice daily and 60 patients (40%) received a dose 

reduction during treatment. Median overall survival was longer in those patients who 

received more than 6 cycles of capecitabine treatment (20.9 months) compared to 

those who stopped at 6 cycles by clinical decision (16.3 months) although this did 

not reach significance (P = 0.088). PFS and OS were similar among patients who 

received lower vs. full-dose capecitabine (PFS P = 0.32, OS P = 0.71). 

Conclusions: In this retrospective analysis, patients receiving more than 6 cycles of 

treatment had a better OS than those who stopped at 6 cycles (by clinical decision). 

Continuing capecitabine monotherapy beyond the standard 6 cycles if well tolerated, 

should be considered in patients with locally recurrent or metastatic breast cancer as 

this may prolong PFS. In addition, these data support the practice of dose-reducing 

capecitabine, including the possibility of starting at a lower dose (


Table: 404 

Patient Sex Age Primary tumor Histology Previous treatment Survival (months) 

A F 41 breast IDC, HR- CT, S, RT, sT 1,6 + 

B F 44 breast IDC, HR+ CT, RT, HT, S, sT 23,7 

C F 31 breast IDC, HR+ S, RT, HT, sT 2,4 

D M 58 stomach ADC CT, S 1 

lymph-nodes (greater than 8). Discrete variables significantly associated with MC 

were: high tumor grade (p = 0,001), presence of vascular invasion (p = 0,038), greater 

tumor staging (pT3, pT4 p < 0,001) and axillar staging (pN3 p = 0,002), hormonal 

receptor negativity (p < 0,001) and Her-2 overexpression (p = 0,001). Multivariate 

analysis showed that only the presence of other distant metastases (p < 0,005) was 

significantly associated with high risk of develop MC with an odds ratio of 9.8. 

Conclusions: We identified breast cancer patients at high risk to develop MC. These 

patients may benefit from an early diagnosis of MC to obtain better results with 

current treatments and to improve quality of life. 


403 QUALITY OF LIFE AND SYMPTOMS IN BREAST CANCER 

PATIENTS UNDERGOING CONVENTIONAL CHEMOTHERAPY 

T.P. Nikitina 1 , K.A. Kurbatova 2 , I.V. Rykov 3 , N.A. Polyakova 4 , L.V. Kindyanova 5 , 

A.M. Yermachenkova 5 , D.A. Fedorenko 6 , T.I. Ionova 7 

1 Oncology and Hematology Department, Multinational Center for Quality of Life 

Research, St-Petersburg, RUSSIAN FEDERATION, 2 Dpartment of Biostatistics, 

1Multinational Center for Quality of Life Research, St-Petersburg, RUSSIAN 

FEDERATION, 3 Department of Oncology, The L.G. Sokolov Memorial Hospital 

№122, St-Petersburg, RUSSIAN FEDERATION, 4 Department of Chemotherapy, 

Regional Oncological Center, Ivanovo, RUSSIAN FEDERATION, 5 Department of 

Chemotherapy, Regional Clinical Oncological Center, Khabarovsk, RUSSIAN 

FEDERATION, 6 Hematology and Cellular Therapy, National Pirogov Medical 

Surgical Center, Moscow, RUSSIAN FEDERATION, 7 Department of Oncology/ 

hematology, Multinational Center for Quality of Life, St. Petersburg, RUSSIAN 

FEDERATION 

Quality of life (QoL) and symptom assessment are of increasing importance to 

evaluate treatment outcomes in breast cancer patients. We aimed to study feasibility 

of using standardized QoL and symptom assessment tools to determine benefits and 

risks of conventional chemotherapy (CT) in breast cancer patients. One hundred and 

seven breast cancer patients (Stages I-IV) were included in the study (58% patients 

with metastatic breast cancer). Mean age/SD – 53/10 y.o. All the patients underwent 

taxane based CT with the previous treatment including CT (89%), surgery (69%), 

radiotherapy (39%), hormone therapy (24%) or biotherapy (9%). QoL was assessed 

using generic QoL questionnaires, the SF-36 and the EQ-5D; symptoms – by using 

Comprehensive Symptom Profile in Patients with Breast Cancer (CSP-Br). The 

CSP-Br is a self-reported tool which allows to assess the severity of 57 symptoms 

specific for breast cancer patients. Distribution of patients according to the grades of 

QoL impairment was analyzed using the SF-36. For comparison of means at different 

time-points Wilcoxon’s matched pairs test was used. The patients reported the 

usefulness of PROs tools to facilitate patient-physician communication. The following 

distribution of patients receiving taxane based CT according to the grades of QoL 

impairment was observed: 23% of patients had no QoL impairment; 15% patients - 

mild QoL impairment, 33% - moderate or severe QoL impairment, and 19% - critical 

QoL impairment. Health index measured by the EQ-5D decreased during the CT 

cycle and improved by the next CT cycle. The most prevalent and disturbing 

symptoms were the following: hair loss (>90%), fatigue, feeling of constant tiredness 

(>80%) and psychological symptoms (>70%). Definite deterioration of symptom 

profile and severity was observed in a week after CT cycle completion: the severity of 

21 out of 47 symptoms increased significantly (p < 0.05). The usefulness of 

patient-reported outcome measures to distinguish patients in terms of QoL 

impairment as well as in terms of severity and number of symptoms experienced was 

demonstrated. The SF-36, EQ-5D and CSP-Br are robust and feasible tools to 

measure benefits and risks of breast cancer treatment from patient perspective. 


404 INTRATHECAL TRASTUZUMAB IN THE TREATMENT OF 

LEPTOMENINGEAL METASTASES FROM HER2-POSITIVE 

CANCER 

D. Machado 1 , M. Oliveira 2 , S. Esteves 3 , T. Marques 1 , A. Clara 1 , M. Brito 1 , 

J. Freire 1 , J. Bravo Marques 4 , A. Moreira 1 

1 Medical Oncology, Portuguese Institute of Oncology, Lisbon, PORTUGAL, 

2 Breast Cancer Group, Vall d’Hebron Institut d’Oncologia, Barcelona, SPAIN, 

3 Clinical Investigation Unit, Portuguese Institute of Oncology, Lisbon, PORTUGAL, 

4 Neuro-oncology, Portuguese Oncology Insitute, Lisbon, PORTUGAL 

Introduction: Up to 8% of all cancer patients develop leptomeningeal metastases 

(LM). Median overall survival after diagnosis is approximately 1 month. 

Trastuzumab, a monoclonal antibody against the HER2 receptor, is used in the 

treatment of HER2 positive cancer patients. It is still not clear if systemic 

trastuzumab can penetrate the intact blood brain barrier, because of its high 

molecular weight. Given intrathecally, trastuzumab could achieve higher 

concentrations in the cerebrospinal fluid (CSF). 

Purpose: Determine safety, response and overall survival of patients treated with 

intrathecal (IT) trastuzumab, in a single centre population. 

Patients and methods: Clinical data of patients treated with IT trastuzumab have 

been reviewed. Survival was defined as time since beginning of IT trastuzumab until 

death or last follow-up. 

Results: A total of 4 patients have been treated with IT trastuzumab (Table 1). 

Table 1. Patient characteristics, previous treatment and survival.. All HER2 positive, 

IDC invasive ductal carcinoma, ADC adenocarcinoma, S surgery, RT radiotherapy, 

HT hormonal treatment, sT systemic trastuzumab. LM were confirmed by lumbar 

puncture in patients B, C and D. In patient A LM were diagnosed by MRI (CSF 

cytology persistently negative). Patients A, B, and C received weekly IT 

trastuzumab 25 mg. Patient D received weekly IT (trastuzumab 25 mg + 

methotrexate 12 mg). Toxicity related to IT trastuzumab was not observed. The 

CSF cytology remained positive in patient D and became negative after 1 and 3 

weeks for patient C and B, respectively. Patient A was still receiving treatment at 

last follow-up. 

Conclusions: In our group of patients, IT trastuzumab was well tolerated and had 

encouraging results. Ours is a small and somewhat heterogeneous population and we 

can not extrapolate on the efficacy of trastuzumab in this setting, but a study with a 

larger number of patients is warranted and may help identify patients appropriate for 

this therapy. 


405TiP A PHASE II STUDY OF ALBUMIN-BOUND PACLITAXEL 

COMBINED WITH EPIRUBICIN AND CYCLOPHOSPHAMIDE 

AS NEO-ADJUVANT THERAPY IN BREAST CANCER WOMEN 

J. Zhang, S. Zhang, L. Liu, B.X. Zhang 

The Third Surgical Department of Breast Cancer, Tianjin Cancer Hospital, Tianjin, 

CHINA 

Purpose: To observe whether the efficacy and safety of Albumin-Bound Paclitaxel 

has advantage over Cremophor-Formulated Paclitaxel as neo-adjuvant therapy in 

breast cancer 

Patients and methods: Twenty-six breast cancer patients were enrolled into 

Albumin-Bound Paclitaxel group. Albumin-Bound Paclitaxel 260mg/m 2 , 

Epirubicin 60 mg/m 2 , Cyclophosphamide 500mg/m 2 was administrated as 

neo-adjuvant therapy. Twenty-six patients who were treated with 

Cremophor-Formulated Paclitaxel 175mg/m 2 , Epirubicin 60 mg/m 2 , 

Cyclophosphamide 500mg/m 2 as the control group. The objective observation 

include the pathologic complete response rates, clinical response rates, safety and 

toxicity. The PI3K, pAKT, mTOR, BAD protein were examined before and after 

chemotherapy in two groups. 

Results: 34.6% patients (9/26) in Albumin-Bound Paclitaxel group achieved a 

clinical complete response, this rate was 11.5% higher than control group which 

rate was 23.1%(6/26). 15.4% patients (4/26) in Albumin-Bound Paclitaxel group 

achieved a pathologic complete response, this rate was 11.6% higher than control 

group which rate was 3.8%(1/26). None patients (0/26) in Albumin-Bound 

Paclitaxel group occurs neutropenia but 15.4% patients (4/26) in control group 

occurs neutropenia during chemotherapy. All patients have normal left 

ventricular ejection fraction range (LVEF > 50%) before and after therapy. The 

positive rate of PI3K, mTOR, pAKT expression decreased 45.6%,42.5%,41.1% 

respectively in Albumin-Bound Paclitaxel group after chemotherapy and the 

control group decreased 13.2%,14.1%,10.1%. The positive rate of BAD expression 

increased 21.6% in Albumin-Bound Paclitaxel group after chemotherapy and the 

control group only increased 6.2%. 

Conclusion: Albumin-Bound Paclitaxel has advantage in clinical response rate 

over Cremophor-Formulated Paclitaxel in breast cancer. Albumin-Bound 

Paclitaxel has no more additional adverse events than Cremophor-Formulated 

Paclitaxel. Albumin-Bound Paclitaxel has lower incidence of neutropenia than 

Cremophor-Formulated Paclitaxel. Albumin-Bound Paclitaxel decrease the 

expression of PI3K, pAKT, mTOR protein and increase the expression of BAD 

protein more significantly than Cremophor-Formulated Paclitaxel after 

chemotherapy 



406TiP PHASE II TRIAL OF PRIMARY SYSTEMIC THERAPY (PST) 

WITH DOCETAXEL (D) FOLLOWED BY HIGH-DOSE 

EPIRUBICIN IN COMBINATION WITH CYCLOPHOSPHAMIDE 

(EC) PLUS CONCURRENT TRASTUZUMAB (T) FOR STAGE 

II-III HER-2 POSITIVE BREAST CANCER PATIENTS (PTS) 

P. Vici 1 , L. Pizzuti 1 , M. Mottolese 2 , D. Sergi 1 , A. Di Benedetto 2 , C. Botti 3 , 

L. Perracchio 4 , E. Pescarmona 4 , A. Carpino 5 , L. Di Lauro 1 

1 Division of Medical Oncology B, Regina Elena National Cancer Institute, Rome, 

ITALY, 2 Molecular Medicine Department, Regina Elena National Cancer Institute, 

Rome, ITALY, 3 A Surgery Division, Regina Elena National Cancer Institute, Rome, 

ITALY, 4 Pathology Department, Regina Elena National Cancer Institute, Rome, 

ITALY, 5 Cardiology Division, Regina Elena National Cancer Institute, Rome, ITALY 

Background: PST with taxanes, anthracycline-containing regimens and T showed a 

high percentage of pathologic complete response (pCR); T administered concurrently 

with chemotherapy is more effective, but the combination with anthracyclines may be at 

risk of cardiotoxicity. The present study evaluates efficacy and toxicity of T administered 

concurrently with a sequential regimen of D followed by EC in neoadjuvant setting. 

Materials and methods: This phase II single stage trial is enrolling pts with cT2-T4, 

N0-2, M0, Her-2 positive (IHC 3+ or 2+ amplified) breast cancer. A core biopsy is 

required prior treatment start to evaluate hormonal receptors, Ki67, topoisomerase II, 

Her-2, with re-evaluation of these parameters, whenever possible, at definite surgery. 

LVEF is evaluated before and during treatment. Blood samples are collected at 

baseline for evaluation of 9 genetic polymorphisms related to higher risk of 

developing cardiac toxicity. We are quantitatively evaluating gene copy number by 

multiple ligand probe amplification (MLPA), PTEN, p-Akt, p-MAPK, and PIK3CA 

mutations. Pts receive 4 cycles of D (100mg/m2) plus T (loading dose 8mg/kg 

followed by 6mg/kg), followed by 4 cycles of EC (120/600mg/m2) plus T, every 3 

weeks. Definite surgery is planned at the end of PST, and standard radiotherapy and 

hormonal adjuvant treatment in case of positive hormonal receptors are given; 

adjuvant T is given for 6 months. The primary objective of the trial is pCR (absence 

of invasive tumor cells in the breast and axilla); secondary objectives are cardiac 

safety, toxicity, disease-free survival. The planned sample size is 42 pts. 

Results: To date, 29 pts have been enrolled; median age is 45 years, pre/ 

postmenopausal 22/7, ER and/or PgR positive in 16 pts. 27 pts are evaluable for 

pathological response: we observed 20 pCR (74%, 95%C.I, 57.5-90.6). Grade 3-4 

neutropenia was the most frequent toxicity, encountered in 75% of the pts, other 

toxicities were mild to moderate. No clinical cardiotoxicity was observed. 

Conclusions: At preliminary analysis, PST with sequential administration of D 

followed by EC, given concurrently with T, appears to be very active and safe in stage 

II-III breast cancer pts. 


407TiP TREATMENT OF PATIENTS WITH HORMONE RECEPTOR 

(HR)-POSITIVE AND HER2-POSITIVE LOCALLY ADVANCED 

OR METASTATIC BC WITH A COMBINATION OF 

PERTUZUMAB AND TRASTUZUMAB PLUS AN AROMATASE 

INHIBITOR (AI): AN OPEN-LABEL RANDOMISED PHASE II 

STUDY (PERTAIN) 

G. Arpino 1 , C. Poole 2 , J. Ferrero 3 , J.R. De La Haba 4 , L. Mitchell 5 , C. Pelizon 5 ,M. 

F. Rimawi 6 

1 Università Degli Studi Di Napoli Federico II, Dipartimento di Endocrinologia ed 

Oncologia Molecolare e Clinica, Naples, ITALY, 2 Arden Cancer Research Centre, 

University Hospitals Coventry and Warwickshire, Coventry, UNITED KINGDOM, 

3 Departement d’Oncologie Medicale, Centre Antoine Lacassagne, Nice, 

FRANCE, 4 Medical Oncology Department, Reina Sofía Hospital, Córdoba, 

SPAIN, 5 F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 6 Lester & Sue Smith 

Breast Center, Baylor College of Medicine, Houston, TX, UNITED STATES OF 

AMERICA 

Background: Development of resistance to endocrine therapy in patients (pts) with 

breast cancer (BC) is a major clinical concern. Preclinical studies suggest that 

blockade of HR with HER2 inhibition may be key to overcoming resistance and 

improving clinical outcomes. The combination of pertuzumab (P) and trastuzumab 

(H) with docetaxel significantly improves outcomes by a comprehensive blockade of 

HER2 signalling. However, initial results suggest that this benefit may be less 

apparent in HR-positive pts. PERTAIN is the first study to assess whether a fuller 

blockade of HER signalling with P and H in conjunction with an AI may resensitise 

HER2-positive tumours to endocrine therapy and provide an effective first-line 

treatment option in pts with HR-positive and HER2-positive advanced BC. 

Methods: PERTAIN is a multicentre, open-label, Phase II trial for postmenopausal 

women with HER2-positive and HR-positive locally advanced/metastatic BC to assess 

the efficacy of P plus H with an AI as first-line therapy. Pts will be randomised 1:1 to 

Arm 1 (P: 840 mg initial dose, 420 mg q3w iv; H: 8 mg/kg initial dose, 6 mg/kg q3w iv; 

AI [anastrozole 1 mg or letrozole 2.5 mg qd po]) or Arm 2 (H + AI at same dose as Arm 

1). Induction chemotherapy (CT) (docetaxel or paclitaxel) may be given to pts for up to 

18 weeks at the investigator’s discretion. Administration of study medications will 

continue until disease progression or unacceptable toxicity. Pts must not have been 

treated with anti-HER2 agents, except H and/or lapatinib in the (neo)adjuvant setting, 


and must have no CNS involvement or clinically significant cardiovascular disease. The 

primary endpoint is progression free survival (PFS); secondary endpoints include overall 

survival, overall response rate, clinical benefit rate, duration of response, time to 

response, safety and tolerability, and QoL. The study opened in April 2012 and will 

recruit 250 pts. The main analysis for the primary endpoint (after 165 PFS events) will 

include a treatment group variable and be stratified by whether pts were chosen to 

receive induction CT (Yes/No) and time since adjuvant hormone therapy (


P is distinct from that bound by trastuzumab (H) and their complementary 

mechanisms of action lead to a more comprehensive HER2 blockade when 

combined. Data from the phase III trial CLEOPATRA showed significantly improved 

PFS in pts with HER2-positive 1L MBC given P + H + docetaxel (D). As H was not 

widely available in the (neo)adjuvant setting prior to CLEOPATRA recruitment, a 

relatively low proportion of pts in CLEOPATRA had previously received H. PERUSE 

will assess the safety and tolerability of P + H + one of a choice of taxanes (T) as 1L 

therapy for pts with HER2-positive metastatic or locally advanced BC. Efficacy 

endpoints will also be recorded in PERUSE, in a pt population likely to have 

experienced wider exposure to prior H therapy. 

Methods: PERUSE is a phase IIIb, multicenter, open-label, single-arm study in pts 

with HER2-positive BC who have not been treated with systemic non-hormonal 

anticancer therapy for MBC. The planned sample size is 1500. Pts will receive, P: 

840mg initial dose, 420mg q3w IV; H: 8mg/kg initial dose, 6mg/kg q3w IV, T: D, 

paclitaxel or nab-paclitaxel according to local guidelines. A planned protocol 

amendment will allow HR-positive pts to receive endocrine therapy in conjunction 

with P + H following completion of T in line with clinical practice. Treatment will be 

administered until disease progression or unacceptable toxicity. At baseline, pts must 

have an LVEF of ≥50%, ECOG PS of 0, 1 or 2 and must not have received prior 

anti-HER2 agents for MBC. Prior H and/or lapatinib in the (neo)adjuvant setting is 

allowed, provided there was no disease progression on-treatment. A disease-free 

interval of ≥6 months is required. The primary endpoint is safety and tolerability. 

Secondary endpoints include PFS, OS, ORR, CBR, duration of response, time to 

response and QoL. The final analysis will be carried out when pts have been followed 

up for ≥12 months. Interim analyses are planned after enrollment of ∼350, 700 and 

1000 pts. Regular interim safety assessments by a DSMB will take place. 

Disclosure: D. Miles: I have an interest in relation with one organisation that could 

be perceived as a possible conflict of interest in the context of the subject of this 

abstract. I have served on Advisory Board Meetings for Roche/Genentech. F. Puglisi: 

I have an interest in relation with one organisation that could be perceived as a 

possible conflict of interest in the context of the subject of this abstract. I participate 

in Advisory Board Meetings for Roche. A. Schneeweiss: I have an interest in relation 

with one organisation that could be perceived as a possible conflict of interest in the 

context of the subject of this abstract. I serve on Roche Advisory Boards and am in 

volved with corporate-sponsored research with Roche. L. Mitchell: I am currently an 

employee of F. Hoffmann-La Roche. A. Dünne: I have an interest in relation with 

one organisation that could be perceived as a possible conflict of interest in the 

context of the subject of this abstract. I am an employee of hoffmann-La Roche. 

T. Bachelot: I have an interest in relation with one organisation that could be 

perceived as a possible conflict of interest in the context of the subject of this 

abstract. I am involved with Roche sponsoredresearch and Roche advisory Board 

Meetings. All other authors have declared no conflicts of interest. 


abstracts 

CNS tumors 

410O CONDITIONAL PROBABILITY OF SURVIVAL IN PATIENTS 

WITH GLIOBLASTOMA MULTIFORME IN THE 

TEMOZOLOMIDE TREATMENT ERA 

M. McNamara 1 , Z. Lwin 2 , H. Jiang 3 , C. Chung 4 , B. Millar 4 , N. Laperriere 4 , 

W. Mason 1 

1 Medical Oncology, Princess Margaret Hospital, Toronto, CANADA, 2 Medical 

Oncology, Mater Adult Hospital, Brisbane, QLD, AUSTRALIA, 3 Biostatistics, 

Princess Margaret Hospital, Toronto, ON, CANADA, 4 Radiation Oncology, 

Princess Margaret Hospital, Toronto, ON, CANADA 

Introduction: Glioblastoma multiforme (GBM) is the most aggressive of gliomas. 

With standard treatment consisting of surgery followed by radiotherapy (RT) with 

concurrent and adjuvant temozolomide (TMZ), median survival is approximately 

14.6 mo. These estimates are not as informative to patients (pts) who have survived 

for some time after diagnosis. Aim: To retrospectively review outcomes and report 

conditional probability estimates in the TMZ treatment era of pts who presented to a 

multidisciplinary team at the tertiary referral center PrincessMargaretHospital, 

Toronto, with a diagnosis of GBM. 

Methods: 892 pts were followed from 01/04 – 08/10. Complete demographics, 

performance status (PS), GBM localization, extent of surgery, percent receiving RT 

+/− TMZ, overall survival (OS) and conditional probability were analyzed. 

Results: The cohort includes 548 (61%) males with median age 62 (5-93). Baseline 

PS was 0-1 in 600 (67%), 2-3 in 251 (28%) pts. 205 (23%) had frontal lobe tumors. 

Extent of surgery; 26% biopsy, 68% partial/subtotal resection, 6% unknown. 516 

(58%) received concurrent RT/TMZ +/− adjuvant TMZ. Survival was similar for 

those with frontal lobe tumors vs other locations (10.2 vs 9.7 mo, Logrank test p = 

0.28). OS for biopsy pts was 4.5 mo (3.5 – 6.2), and partial/subtotal resection pts; 

11.6 mo (10.3 – 12.5) (p < 0.001). OS for pts receiving standard RT/TMZ +/− TMZ 

was 14.2 mo (13.3 – 15.1). Age and PS were significant prognostic factors for OS 

(p < 0.001). The OS and conditional probability of survival for entire cohort of 

892 pts is detailed in Table. 43 (5%) are still alive, 727 (81%) deceased, status 

unknown in 122 (14%). 

Time Overall Survival (%) 95% CI 

Conditional 

Probability 

of Survival (%) 95% CI 

1 Year 43.1 39.8 – 46.4 41.4 35.9 – 47.0 

2 Year 17.9 15.2 – 20.7 57.4 47.5 – 67.4 

3 Year 10.3 8.0 – 12.8 80.6 68.4 – 92.8 

4 Year 8.3 6.1 – 10.9 85.6 71.1 – 100 

5 Year 7.1 5.0 – 9.7 81.5 60.9 – 100 

Conclusion: The conditional probability of surviving an additional yr after survival 

to 2 yrs post diagnosis exceeds the 1 yr survival rate, indicating that the future 

prognosis of a pt who has survived for 2 yrs may be as good as those recently 

diagnosed. Conditional probabilities of survival in this general disease population in 

the era of TMZ therapy may provide more accurate life expectancy predictions for 

survivors of GBM. 


411O A PILOT STUDY CORRELATING IDH-1/2 GENE STATUS WITH 

2-HYDROXYGLUTARATE (2HG) CONCENTRATION IN PLASMA 

AND URINE FROM PATIENTS (PTS) WITH GLIOMA 

G. Lombardi 1 , G. Corona 2 , P. Farina 1 , F. Zustovich 1 , R. Bertorelle 3 , P. Fiduccia 1 , 

A. Della Puppa 4 , M.P. Gardiman 5 , A. Salvalaggio 1 , G. Toffoli 2 , V. Zagonel 1 

1 Medical Oncology 1, Venetian Oncology Institute – IRCCS, Padua, ITALY, 

2 Molecular Oncology and Translational Medicine, Experimental and Clinical 

Pharmacology Unit, Aviano, ITALY, 3 Molecular Immunology and Oncology, 

Venetian Oncology Institute – IRCCS, Padua, ITALY, 4 Neurosurgery Department, 

Azienda Ospedaliera di Padova, Padua, ITALY, 5 Pathology Department, Azienda 

Ospedaliera di Padova, Padua, ITALY 

Background: IDH-1/2 mutations are a prognostic markers in gliomas. These 

mutations results in the production of 2HG. We investigated whether 2HG produced 



by IDH-1/2 mutant gliomas accumulates in patient’s plasma and urine and whether 

this accumulation can be used to assess IDH-1/2 mutation status. 

Methods: we prospectively studied PTS with intracranial gliomas and measurable 

disease on brain-MRI. All PTS had a partial surgical resection or a recurrent disease. 

The resected tissues were analyzed for IDH-1/2 mutational status; subsequently, in 

absence of chemotherapy and after 3 weeks from a prior surgery, a plasma and an 

overnight-urine samples collection were taken from consecutive PTS. 2HG 

concentrations were determinate by liquid chromatography tandem mass 

spectrometry. The statistical significance of the difference in the level of 2HG 

between the PTS with IDH-1/2 mutated and control group were evaluated by non 

parametric Mann- Whitney test. 

Results: we analyzed 13 PTS with IDH-1 mutated and 13 PTS with IDH-1/2 

wild-type; 2 PTS with low-grade glioma and 24 PTS with high-grade glioma; 10 

females and 16 males. In all PTS we analyzed the mean 2HG concentration in 

plasma (P_2HG) and urine samples normalized by creatinine concentration 

(U_2HG). The results are shown in Table 1. We found significant differences in 

mean U_2HG, and in mean P_2HG/U_2HG in patients with or without IDH 

mutated. No statistically significant associations of tumor volume and U_2HG, of 

tumor volume and P_2HG were found in all PTS and in PTS with IDH1 mutated. 

Conclusions: U_2HG and P_2HG/U_2HG might be used as markers to differentiate 

between gliomas with and without IDH mutated. No associations were found 

between tumor volume and U_2HG and P_2HG, indicating that 2HG might not be 

utilized as marker to monitor tumor growth. However, a larger number of samples 

need to be analyzed to draw final conclusions. 

IDH wt IDH mutated p 

U_2HG* 7.49 ± 3.87 5.00 ± 3.08 0.03 

P_2HG (ng/mL) 86.42 ± 38.74 112.74 ± 73.19 0.26 

P_2HG/U_2HG* 13.96 ± 7.54 23.83 ± 9.00 0.006 

*Concentration of 2HG (µg/mL) normalized by creatinine concentration (mg/mL) 


412O TYROSINE KINASE INHIBITORS WITHOUT RADIATION 

THERAPY FOR BRAIN METASTASES FROM EGFR-MUTANT 

ADENOCARCINOMA OF LUNG 

T. Iuchi 1 , M. Shingyoji 2 , T. Sakaida 1 , S. Yokoi 3 , M. Itakura 2 , K. Kawasaki 1 , 

Y. Hasegawa 1 , H. Kageyama 3 , T. Iizasa 2 

1 Neurological Surgery, Chiba Cancer Center, Chiba, JAPAN, 2 Thoracic Disease, 

Chiba Cancer Center, Chiba, JAPAN, 3 Cancer Diagnosis, Chiba Cancer Center 

Research Institute, Chiba, JAPAN 

Backgrounds: Whole-brain radiation therapy (WBRT) and/or stereotactic 

radiosurgery (SRS) are standard treatments for brain metastases (BMs). However, 

patients (pts) treated by radiation therapy (RT) have a risk of decline in learning and 

memory functions. The aim of this study is to clarify the efficacy and safety of 

chemotherapy without RT for BMs. 

Materials and methods: BMs from lung adenocarcinomas (Ads) with 

EGFR-mutation were enrolled. As tyrosine kinase inhibitors (TKIs), gefitinib was 

used at first, and erlotinib was administrated at tumor progression. Erlotinib was also 

selected for pts in whom intracranial lesions appeared after gefitinib. The response to 

TKIs was evaluated on MRI. WBRT or SRS was performed only at tumor 

progression after TKIs. The primary endpoint was overall survival, and the secondary 

endpoints were maximum response to TKIs, progression-free survival and time to 

RT after diagnosis of BMs. 

Results: In this study, 37 pts were enrolled. The types of EGFR-mutations were as 

follows: Ex19 deletion (Ex19del) in 20, Ex21L858R in 14, and other types of 

mutations in 3 cases. The maximum response was PD in one, SD in 3, PR in 22 and 

CR in 9 pts (response rate: 83.8%). The progression-free and overall survival times 

were 8.9 and 28.3 months. The median time to RT (WBRT in 14 and SRS in 3 cases) 

from diagnosis of BMs was 14.3 months. During the follow-up period, 9 deaths were 

observed but none of them were owing to the intracranial lesions. Among these 9 

pts, no RT was required in 2. Pneumonitis was observed in one case after gefitinib, 

but no other severe adverse event was observed. When we divided the pts owing to 

the types of mutations (Ex19del vs. others), response to TKI was superior in Ex19 

deleted cases (p = 0.031), and the progression-free survival time was significantly 

longer in cases with Ex19del (14.5 months) in compared with those with other types 

of mutations (8.0 months, p = 0.002). In Ex19 deleted cases, TKIs could delay RT for 

18.3 months. 




Conclusions: TKIs showed favorable effect on control of EGFR-mutant BMs, and it 

delayed RT for more than one year. Ex19del was the significant predictor of response 

to TKIs in BMs. TKIs without RT was safe and acceptable treatment for BMs from 

EGFR-mutant lung Ads. 


413PD HYPOFRACTIONATED RADIOTHERAPY FOR PEDIATRIC 

DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): A 

PROSPECTIVE CONTROLLED RANDOMIZED TRIAL 

S.A. Ahmed 1 , E. Eldebaway 2 , N. Elkhateeb 2 , M.S. Zaghloul 2 

1 Radiotherapy Department, Children’s Cancer Hospital Egypt, Cairo, EGYPT, 

2 Radiotherapy Department, Children’s Cancer Hospital, Cairo, EGYPT 

Background: Pediatric Diffuse intrinsic pediatric glioma (DIPG) remained dismal 

regardless of the new therapeutic and technical attempts. 

Purpose: To investigate the efficacy and toxicity of hypofractionated radiotherapy in 

pediatric DIPG compared to conventional radiotherapy and to determine the 

prognostic factors for its overall (OS) and progression-free survival (PFS). Patients 

and methods: Sixty four children, below the age of 18 years, who presented to 

Children’s Cancer Hospital, Egypt (CCHE) during the period July 2007 and July 

2011 were randomized into 2 groups. The hypofractionated group received 39 Gy in 

13 fractions in 21/2 weeks and the conventional arm receiving 55.8 Gy in 31 

fractions in 6 weeks using conformal radiotherapy technique. The two arms were not 

different in age, gender, performance status and tumor volume. 

Results: Thirty two children were randomized in each arm. The median OS for 

the whole group was 9.5 ± 1.0 months: 7.4 ± 1.0 months for the hypofractionated 

arm and 9.9 ± 1.0 months for the conventional arm. The whole group has median 

PFS of 7.3 ± 0.8 months; 7.0 ± 1.4 months for the hypofractionated and 7.7 ± 1.1 

for the conventional arm. On the other hand, the 1-year and 2-year OS were 41.4 

± 9.2% and 28.4 ± 8,8% in the hypofractionated arm and 36.2 ± 8.7% and 32.3 ± 

7.8% in the conventional arm. None of these differences was statistically 

significant. Furthermore, none of the tested factors (age, gender, performance 

status, tumor volume, radiation volume or tumor extension) proved to have 

statistically significant influence on OS or PFS. All patients showed marked degree 

of improvement in symptoms and signs with earlier response in the 

hypofractionated arm. The immediate and delayed side effects were not different 

between the 2 arms. 

Conclusions: Hypofractionated radiotherapy had similar overall, progression-free 

survival and delayed effect (in the long survivors) to conventional fractionation. It 

offers less burden on the patients, their families and the treating machines and 

departments. 


414PD IS BRAIN-ONLY METASTATIC BREAST CANCER A DISTINCT 

ENTITY? 

A.S. Berghoff 1 , Z. Bago-Horvath 2 , G.G. Steger 3 , C. Zielinski 3 , R. Bartsch 3 , 

M. Preusser 3 

1 Institute of Neurology, Medical University of Vienna, Vienna, AUSTRIA, 2 Institute 

of Pathology, Medical University of Vienna, Vienna, AUSTRIA, 3 Department of 

Medicine I, Clinical Division of Medical Oncology, Medical University of Vienna, 

Vienna, AUSTRIA 

Background: Up to 40% of metastatic breast cancer patients (pts) are diagnosed with 

brain metastases (BM) during their course of diseases. Some case reports and small 

patient series have indicated that breast cancer pts with the brain as only metastatic 

site (“brain-only”) may have a more favourable prognosis than BM pts with more 

widespread metastatic disease. 

Methods: We identified all breast cancer pts with BM treated at our institution 

between 1990 and 2011. For each patient, full information on follow up and 

administered therapies was mandatory for inclusion. Estrogen-receptor (ER), 

progesterone-receptor and HER2 status were determined according to standard 

protocols. We performed statistical analyses including computation of survival 

probabilities. 

Results: Overall, 223 female pts (26.0% luminal subtype; 47.5% HER2 subtype; 

26.5% triple negative subtype) with BM of metastatic breast cancer were included in 

this study. In 60/223 pts (26.9%) the brain was the first metastatic site. Brain as first 

metastatic site was significantly less common in the HER2-positive subtype than in 

luminal and triple negative subtypes (p = 0.005). 38/223 (17%) of BM pts did not 

develop extracranial metastases (ECM) during their disease course and were classified 

as “brain-only” cases. Brain-only metastatic behaviour was not associated with breast 

cancer subtype or number of BM. The median OS of the brain-only pts was 11 

months (range 0-69) and was significantly longer than in pts with BM and ECM 

(5 months, range 0 to 104) (p = 0.007). High KPS (p = 0.02), single BM (p < 0.001) 

and ER expression (p = 0.014) were associated with favourable OS in the brain-only 

cohort. 7/38 (18.4%) brain-only pts had long-time survival of more than 3 years after 

diagnosis of BM. 

Conclusions: Among breast cancer pts with BM, brain-only metastatic behaviour is 

not associated with breast cancer subtype, but with favourable survival prognosis. 

Exploitation of all multimodal treatment options is warranted in breast cancer pts 

with brain-only metastatic disease, as long-term survival is not uncommon in this 

patient population. 


415PD THE CAREGIVERS PERSPECTIVE ON THE END-OF-LIFE 

PHASE OF GLIOBLASTOMA PATIENTS 

B. Flechl 1 , M. Ackerl 1 , C. Sax 1 , S. Oberndorfer 2 , B. Calabek 3 , E. Sizoo 4 , 

J. Reijneveld 4 , R. Crevenna 5 , M. Preusser 1 , C. Marosi 1 

1 Internal Medicine, Medical University of Vienna, Vienna, AUSTRIA, 2 Neurology, 

Landesklinikum St. Pölten, St. Pölten, AUSTRIA, 3 Neurology, Kaiser Franz Josef 

Hospital, Vienna, AUSTRIA, 4 Neurology, VU University Medical Centre, 

Amsterdam, NETHERLANDS, 5 Physical Medicine and Rehabilitation, Medical 

University of Vienna, Vienna, AUSTRIA 

Objective: Glioblastoma multiforme (GBM) still harbours an inevitably fatal 

prognosis. The specially course of this disease poses unique challenges in care 

provision to the relatives. We lack data about the caregiverś perspective on the 

end-of-life (EOL) phase of GBM patients to improve counseling and support. 

Methods: In this retrospective study we included 52 caregivers of deceased GBM 

patients treated in two hospitals in Vienna, Austria. We used a specially developed 

questionnaire by the Medical University of Amsterdam to explore and document the 

last three months of living of GBM patients. 

Results: Most of the included caregivers were the partners of the patients (88%) and 

two thirds were female. The most common symptom in GBM patients was fatigue 

(87%), followed by reduced consciousness (81%) and aphasia (77%). 22% of the 

patients were bedbound during their last three months increasing to 80% in the last 

week of life. 30% of the caregivers told that they felt incompletely informed for their 

task and about the illness of their loved one. They stated the quality of life (QOL) of 

the patients with 2.2 and their own with 2.8 on a scale of 1 to 7 whereas 7 displays 

the best possible answer. The majority of the patients (46%) died in hospitals and 

38% at home, which was the most often expressed wish for place of death (45%) by 

patients. Regarding the caregiverś symptoms, sadness (90%), fear (69%), burnout 

(60%), less interest in others (54%) and irritation (42%) were the leading ones and 

did not differ significantly in-between the places of death. 

Conclusion: The caregivers reported that their quality of life (QOL) was only slightly 

better than the QOL they attributed to the patients. About two thirds of the 

caregivers felt overstrained and stress thereby the urgent need for support and 

dedicated educational programs. 


416PD RE-SURGERY FOR RECURRENT GLIOBLASTOMA: 

OUTCOME ANALISYS AND CORRELTION WITH 

MGMT STATUS 

A. Brandes 1 , E. Franceschi 1 , R. Poggi 1 , R. Degli Esposti 1 , M. Di Battista 1 , 

L. Lombardo 1 , F. Girardi 1 , D. Palleschi 1 , S. Bartolini 1 , M. Ermani 2 

1 Medical Oncology, Bellaria-Maggiore Hospital, Azienda USL, Bologna, ITALY, 

2 Department of Neurosciences, Statistic and Informatic Unit, Azienda 

Ospedale-Università, Padova, ITALY 

Introduction: treatment options for glioblastoma at recurrence are various despite 

the limited efficacy. Surgical resection have been used both for confirmation of 

recurrent disease as well as for debulking in order to provide relief of symptoms. 

Therefore, the role surgical resection for recurrent glioblastoma, has not been 

completely clarified. 

Methods: A retrospective analysis was made for glioblastoma patients followed 

between 01/2005 and 06/2010. Eligibility criteria for the study were: age ≥18 years; 

PS:0-2; chemotherapy at disease progression after RT/TMZ, availability of data 

regarding second progression. 

Results: 232 patients with recurrent glioblastoma (mean age: 52 years, range: 18-77 

years, MGMT methylated/unmethylated: 62 [37.6%] / 103 [62.4%]) were evaluated. 

At progression after RT/TMZ, 102 patients (44%) were treated with re-surgery 

followed by chemotherapy, and 130 patients (56%) with chemotherapy alone. Overall 

survival from first surgery was 22.4 moths (95% CI: 20–24.7), being 25.8 months 

(95%CI:20.6–31) in patients who received second surgery at recurrence, and 18.6 

months (95%CI:17–20.1–p = 0.003) in patients treated without surgery. However, in 

multivariate analysis no significant effect of re-surgery was found (p = 0.11) being 

age (p = 0.001), MGMT methylation (p = 0.002) and PFS6 (p = 0.0001) the only 

significant prognostic factors. Moreover, median time between first and second 

surgery was 13.1 months, being significantly longer in patients with MGMT 

methylated than in patients MGMT unmethylated (19.3 vs 13 months, p = 0.001). 

Median survival time calculated from first recurrence was 8.6 months (95% 

CI:7.4–9.8), and 9.6 months (95%CI:7.5–11.6) and 7.5 months (95%CI:5.7–9.3) in 

patients that received second surgery or not, respectively (p = 0.3). 


Conclusions: Our data suggested that second surgery may have a limited impact in 

the clinical course of recurrent glioblastoma patients. MGMT methylation status, as 

well other clinical factors (i.e. age) remain the major prognostic determinants of the 

outcome. 


417PD A PHASE 2 TRIAL OF THE MULTITARGETED KINASE 

INHIBITOR LENVATINIB (E7080) IN PATIENTS (PTS) WITH 

RECURRENT GLIOBLASTOMA (GBM) AND DISEASE 

PROGRESSION FOLLOWING PRIOR BEVACIZUMAB 

TREATMENT 

D.A. Reardon 1 ,E.Pan 2 ,J.Fan 3 , J. Mink 3 , D.P. Barboriak 4 , J.J. Vredenburgh 5 , 

A. Desjardins 5 , K. Peters 5 , J.P. O’Brien 3 , P.Y. Wen 1 

1 Neuro-oncology Department, Dana-Farber Cancer Insitute, Boston, MA, 

UNITED STATES OF AMERICA, 2 Neuro-oncology, Moffitt Cancer Center, Tampa, 

FL, UNITED STATES OF AMERICA, 3 PCU, Eisai Inc., Woodcliff Lake, NJ, 

UNITED STATES OF AMERICA, 4 Radiology, Duke University Medical Center, 

Durham, NC, UNITED STATES OF AMERICA, 5 Medicine, The Preston Robert 

Tisch Brain Tumor Center at Duke, Durham, NC, UNITED STATES OF AMERICA 

Background: There is no effective therapy for recurrent GBM pts following 

progression on the vascular endothelial growth factor (VEGF)-targeting agent 

bevacizumab (BV), with historical series reporting progression-free survival at 6 

months (PFS-6) of only 2%. Several mechanisms of tumor adaptation following 

anti-VEGF therapy have been proposed, including upregulation of alternative 

angiogenic cytokines. We therefore performed a single-arm phase 2 study to evaluate 

lenvatinib (L), an oral tyrosine kinase inhibitor targeting FGFR1-4, PDGFRβ, 

VEGFR1-3, RET, and KIT, in pts with recurrent GBM progressing on BV. 

Methods: 32 pts with recurrent GBM (≤2 prior progressions) and progression on 

BV received L 24 mg once daily in 28-day cycles until PD or unacceptable toxicity. 

Dynamic contrast-enhanced MRI was performed before and after 1 day of L on a 

subset of pts (n = 16). Response was assessed using Response Assessment in 

Neuro-Oncology criteria. Primary endpoint was PFS-6. This cohort has completed 

enrollment; 1 pt is still ongoing. 

Results: Median age was 52 y, 56% were male, and 19% had a KPS


420PD SYSTEMIC TEMSIROLIMUS ADMINISTRATION REDUCES 

TUMOR GROWTH IN AN ORTHOTOPIC MOUSE 

MENINGIOMA MODEL 

C. Mawrin, D. Pachow, E. Kirches 

Neuropathology, University of Magdeburg, Magdeburg, GERMANY 

Meningiomas represent the most frequent intracranial tumors. While most cases 

correspond to WHO grade I, about 5% belong to the aggressive atypical subtype, and 

1% are anaplastic meningiomas with poor clinical outcome. However, even the 

treatment of benign subtypes might be challenging in recurrent tumors and if 

complete resection is impossible. So far, no chemotherapy regime has been proven to 

be effective; radiotherapy is used to treat aggressive meningiomas. We have 

previously established that human meningiomas have activated mTORC-1 signalling, 

and that meningioma cells are responsive to mTORC-1 inhibitors. In the present 

study, we used an orthotopic mouse meningioma model established in our lab to 

monitore the effect of systemic temsirolimus treatment on meningioma cells grown 

in the subarachnoidal space. Following orthotopic injection of malignant IOMM-Lee 

meningioma cells, mice (n = 8) were treated daily with 20mg/kg temsirolimus 

intraperitoneally for nine days, beginning at day 3. Control animals (n = 8) were 

treated with diluent only. Tumor growth was monitored by magnetic resonance 

imaging (MRI). We observed that at day 9, mice treated with temsirolimus had a 

significantly (p < 0.01) reduced tumor volume in MRI measurements compared to 

controls. Western blot analysis of tumor tissue removed from the skull showed 

reduced phosphorylation of mTOR and p70S6K in treated mice, indicating successful 

orthotopic inihibition of mTORC-1 activity by intraperitoneal treatment. Thus, our 

study demonstrates the successful systemic inhibition of malignant meningioma cell 

growth by targeting the mTORC-1 pathway. These data might serve as a basis for 

starting a clinical trial using temsirolimus in patients with recurrent or aggressive 

meningiomas. 

Disclosure: C. Mawrin: Work was supported in part by Pfizer Inc. and the Deutsche 

Krebshilfe. D. Pachow: work was supported in part by Pfizer Inc. and the Deutsche 

Krebshilfe. E. Kirches: work was supported in part by Pfizer Inc. and the Deutsche 

Krebshilfe 

421P OUTCOME AND MOLECULAR CHARACTERISTICS OF YOUNG 

ADULT PATIENTS WITH NEWLY DIAGNOSED PRIMARY 

GLIOBLASTOMA: A STUDY OF THE SOCIETY OF AUSTRIAN 

NEUROONCOLOGY (SANO) 

C. Marosi 1 , A. Leibetseder 2 , M. Ackerl 3 , B. Flechl 3 , C. Sax 3 , A. Wöhrer 4 , 

M. Preusser 5 , K. Dieckmann 6 , J. Pichler 7 , S. Spiegl Kreinecker 7 

1 Department of Oncology, Medical University of Vienna, Vienna, AUSTRIA, 

2 Oncology, Medizinische Universität Wien, Wien, AUSTRIA, 3 Internal Medicine, 

Medical University of Vienna, Vienna, AUSTRIA, 4 Institute for Neurology, Medical 

University of Vienna, Vienna, AUSTRIA, 5 Department of Medicine I, Medical 

University of Vienna, Wien, AUSTRIA, 6 Radiotherapy, Medical University Vienna, 

Vienna, AUSTRIA, 7 Neurooncology, Wagner Jauregg Spital, Linz, AUSTRIA 

Background: Young age is well-known as favorable prognostic factor for patients 

with glioblastoma multiforme (GBM). We reviewed the outcome and molecular 

tumor characteristics of “young” adult patients with newly diagnosed GBM treated in 

two Austrian Neurooncology centers. 

Patients and methods: Data of patients with histologically proven GBM diagnosed 

between age 18 and 40 were retrospectively analysed. All cases presented as newly 

diagnosed GBM without previous history of neurological disease. All were treated 

with standard first line therapy. IDH1-R132H mutation status was analyzed by 

immunohistochemistry. Moreover, tumour samples were tested for MGMT 

promoter methylation using methylation-specific polymerase chain reaction 

(MS-PCR). The primary endpoint was overall survival (OS) and time to tumour 

progression (TTP). 

Results: We included 70 patients (36 men and 34 women; 47 from Vienna, 23 from 

Linz) with a median age of 33 (range 18 to 40 years) in our study. IDH1-R132H 

mutations were detected in 22/56 (39.3%) cases and MGMT promoter methylation in 

33/54 (61.1%) cases with available tissue samples. IDH1 mutation was highly 

significantly associated with MGMT promoter methylation (p < 0.0001, Chi-square 

test). In patients with wild type IDH median TTP was 12.6 months and median OS 

43.0 months, versus 22.2 months (TTP) and 50.6 months (OS) observed in patients 

with mutated IDH. Neither IDH1 nor MGMT status showed a statistically significant 

association with TTP or OS in our cohort. Of note, the social and economical situation 

of the young GBM patients was alarming, as only a minority of patients (17%) 

succeeded in staying employed after receiving the diagnosis. 

Conclusions: We found a high frequency of IDH1 mutations and MGMT promoter 

methylation among young adult patients with primary GBM that may contribute to 

the generally favourable outcome associated with young age in glioblastoma patients. 

The social and economic coverage of glioma patients remains an unsolved 

socio-ethical problem. 


423P THE IMPACT OF VALPROIC ACID IN OVERALL SURVIVAL 

OF PATIENTS WITH GLIOBLASTOMA MULTIFORME 

S.R. Meireles 1 , M.L. Salgado 1 , D. Almeida 1 , L. Castro 2 , P. Linhares 3 , L. Osório 4 , 

A.S.A. Costa 1 , C. Caeiro 1 , M. Damasceno 1 

1 Medical Oncology Department, Hospital São João, Porto, PORTUGAL, 

2 Histopathology Department, Hospital São João, Porto, PORTUGAL, 

3 Neurosurgery Department, Hospital São João, Porto, PORTUGAL, 

4 Radiotherapy Department, Hospital São João, Porto, PORTUGAL 

Background: Seizures occur in up to 50% of patients with glioblastoma multiforme 

(GBM). Retrospective analysis of the pivotal European Organization for Research and 

Treatment of Cancer/National Cancer Institute of Canada clinical trial showed that 

the use of the antiepileptic (AED) valproic acid (VPA) may improve survival among 

patients with newly diagnosed glioblastoma receiving temozolamide compared to 

other AED or no treatment. We aimed to analyse the impact of VPA in overall 

survival (OS) of GBM patients submitted to Stupp’s protocol. 

Material and methods: Retrospective study of GBM patients who completed 

concomitant phase of Stupp’s protocol from March 2004 until December 2011. 

Patients needing two AED to seizure control were excluded. 

Results: One hundred thirty two patients were included. Median age at diagnosis was 

61 years-old [24;79] and 68,2% were male. Seizures were present at diagnosis in 

16,7% of cases. 55,3% were AED-free, 35,6% received VPA and 9,1% took another 

AED. Median OS was 15 months (95%CI: 13,3-16,7) and 2-year OS was 31,8%. 

Patients submitted to VPA had better median OS versus other AED or no treatment 

at all, although the difference was not statistically meaningful (16 vs 15 vs 14 months, 

p = 0.74). In univariate and multivariate analysis, ECOG PS ≥ 1 (HR: 1.58, 95% CI 

1.01-2.47, p = 0.04), corticosteroid use (HR: 1.83, 95% CI 1.05-3.18, p = 0.03) and < 6 

cycles of temozolamide in maintenance phase (HR: 3.15, 95% CI 2.05-4.85, 

p < 0.001) were the only independent factors with negative impact on OS. 

VPA treatment was not significantly correlated with OS (HR: 0.96, 95% 

CI 0.47-1.96, p = 0.90). 

Conclusion: Opposite to the literature data, VPA didn’t show any survival advantage 

in GBM patients. ECOG PS ≥1, corticosteroid use and < 6 cycles of temozolamide in 

maintenance phase were correlated with worst prognosis. Future studies are needed 

to confirm and understand which mechanisms justify any potencial survival benefit 

of VPA. 


424P CAN TIME FROM LAST CHEMOTHERAPY TO RECURRENCE 

BE A PREDICTOR OF CHEMOSENSITIVITY IN RCURRENT 

GLOBLASTOMA? 

E. Franceschi 1 , R. Agati 2 , R. Poggi 3 , P. Dall’Occa 1 , M. Bartolotti 1 , M. Di Battista 1 , 

G. Marucci 4 , F. Girardi 3 , M. Ermani 5 , A. Brandes 3 

1 Department of Medical Oncology, Bellaria and Maggiore Hospitals, Azienda 

USL Bologna, Bologna, ITALY, 2 Neuroradiology Department, Bellaria-Maggiore 

Hospital, Azienda USL, Bologna, ITALY, 3 Medical Oncology, Bellaria-Maggiore 

Hospital, Azienda USL, Bologna, ITALY, 4 Section of Pathology M. Malpighi, 

Department of Haematology and Oncological Sciences L. and A. Seragnoli, 

Bellaria Hospital, University of Bologna, Bologna, ITALY, 5 Department of 

Neurosciences, Statistic and Informatic Unit, Azienda Ospedale-Università, 

Padova, ITALY 

Purpose: Since temozolomide in combination with radiotherapy (RT/TMZ) became 

a new standard for newly diagnosed glioblastoma, the scenario at recurrence became 

less defined. Moreover, the role of prognostic and predictive factors for the second 

treatment has not been clarified. 

Methods: A retrospective analysis was made for glioblastoma patients followed 

between 01/2005 and 06/2010. Eligibility criteria for the study were: age ≥18 years; 

PS:0-2; chemotherapy at disease progression after RT/TMZ, availability of data 

regarding second progression. 

Results: 232 patients with recurrent glioblastoma (mean age: 52 years, range: 

18-77years, MGMT methylated/unmethylated: 62 [37.6%] / 103 [62.4%]) were 

evaluated. At progression after RT/TMZ, 102 patients (44%) were treated with 

surgery followed by chemotherapy, and 130 patients (56%) with chemotherapy alone. 

Chemotherapy consisted in TMZ rechallenge 5/28 in 80 patients (34%), nitrosoureas 

in 120 patients (52%), experimental treatments in 32 patients (14%). PFS-6 

calculated from 1st to 2nd PD was 22% (95%CI:16.3-26.9%). Time from the last 

adjuvant TMZ treatment to recurrence (TTR) was shorter in patients treated with 

nitrosoureas (2.6 months) than in patients treated with TMZ (9.8 months, p < 

0.00001). Univariate analysis showed that longer TTR (p = 0.007) and type of 

chemotherapy (TMZ vs nitrosoureas p = 0.033) were both significantly correlated 

with PFS. Only TTR showed an effect on PFS (p = 0.07) in multivariate analysis. 

Median OS from recurrence was 8.6 months (95%CI:7.4-9.8), and 11.3 months (95% 

CI:9.5-13), 7.4 months (95%CI:6.3-8.5), and 7.1 months (95%CI:4.6-9.8), with TMZ, 

nitrosoureas, or other treatments, respectively. TTR and type of chemotherapy at 

recurrence were significantly correlated with OS (p = 0.026 and p = 0.016) in 

univariate but not in multivariate analysis. 


Conclusions: As in other cancer types (i.e. ovarian cancer), TTR seems to be 

promising as a predictive factor for PFS obtained with treatments for recurrence and 

could be useful in patients’ stratification. TMZ rechallenge seems more useful than 

nitrosoureas if TTR is longer. 


425P CLINICAL IMPACT OF [11C]-METHIONINE POSITRON 

EMISSION TOMOGRAPHY ON THE TREATMENT OF PRIMARY 

AND RECURRENT GLIOMAS 

M. Santoni 1 , R. Berardi 2 , A. Bittoni 2 , A. Paccapelo 3 , C. Nanni 4 , S. Fanti 4 , 

L. Burattini 2 , S. Cascinu 2 

1 Clinica Di Oncologia Medica, AO Ospedali Riuniti, Università Politecnica delle 

Marche, Ancona, ITALY, 2 Clinica di Oncologia Medica, AOU Ospedali Riuniti 

Ancona Università Politecnica delle Marche, Ancona, ITALY, 3 Medical Oncology, 

Ospedali Riuniti Torrette, Ancona, ITALY, 4 Department of Nuclear Medicine, 

University of Bologna, Bologna, ITALY 

Purpose: To assess whether 11C-methionine positron emission tomography 

( 11 C-MET PET) has a clinical significance in the management of glioma patients. 

Patients and methods: Fifty-three patients with histologically proven primary gliomas 

(16 grade II, 15 grade III, and 22 grade IV) were investigated repeatedly with 11C-MET 

PET. A total of 249 PET scans were performed, with a median of 4 scans for each 

patient. Functional imaging with PET was compared with concurrent MRI or CT. 

Results: We registered high sensibility and specificity in the management of glioma 

patients. The mean 11C-MET uptake index results significantly correlated with histological 

grade. The overall survival (OS) of GBM patients who underwent 11C-MET PET serial 

controls and parallel CT or MRI scans resulted to be 29.24 months, significantly higher 

compared to OS of GBM who underwent CT or MRI alone during follow up. 

Conclusion: 11C-MET PET allowed the detection of malignant progression in low 

grade glioma patients and the assessment of post-surgery status in both low and 

anaplastic gliomas with high sensibility and specificity. Thus, 11C-MET PET 

expresses its maximum potential in earlier disclosing recurrence during the 

long-term follow-up of GBM patients, with a relevant impact on therapeutic course 

and survival of these patients. 


426P COMPARISON OF MICRORNA EXPRESSION LEVELS 

BETWEEN INITIAL AND RECURRENT GLIOBLASTOMA 

SPECIMENS 

A. Ilhan-Mutlu 1 , A. Wöhrer 2 , A.S. Berghoff 3 , G. Widhalm 4 , C. Marosi 1 , 

L. Wagner 5 , M. Preusser 1 

1 Department of Oncology, Medical University of Vienna, Vienna, AUSTRIA, 

2 Institute for Neurology, Medical University of Vienna, Vienna, AUSTRIA, 3 Institute 

of Neurology, Medical University of Vienna, Vienna, AUSTRIA, 4 Department of 

Neurosurgery, Medical University of Vienna, Vienna, AUSTRIA, 5 Department of 

Nephrology, Medical University of Vienna, Vienna, AUSTRIA 

Background: Glioblastoma is the most frequent primary brain tumour in adults. 

Recent therapeutic advances increased patient’s survival rates, but tumour recurrence 

inevitably occurs and is associated with dismal prognosis. The pathobiological 

mechanisms involved in glioblastoma recurrence are still mostly unclear. MicroRNAs 

are a recently identified class of small non protein encoding RNAs and tumour‐ 

specific microRNA signatures have been proposed as novel indicators for tumour 

proliferation, aggressiveness, differentiation and metastases development for many 

cancer types. However, there are only few data on the involvement of microRNAs in 

therapy resistance and recurrence of glioblastoma. 

Methods: We selected the following 7 microRNAs with potential relevance for 

glioblastoma pathobiology by means of a comprehensive literature search: 

microRNA196b, microRNA21, microRNA10b, microRNA181b, microRNA181c, 

microRNA221, microRNA222 and microRNA195. We further selected 17 primary 

glioblastoma patients, of whom formalin fixed and paraffin embedded tissue (FFPE) 

tumor tissue samples of the initial operation and a re-operation for tumor recurrence 

were available. Patients had received first line treatment consisting of postoperative 

combined radiochemotherapy with temozolomide (n = 15) or fotemustine and 

dacarbazine (n = 2). We analysed the expression of the 7 microRNAs in all 34 tumor 

tissue samples by RT-qPCR. Expression levels were correlated with each other and 

with clinical parameters. 

Results: All microRNAs except microRNA196b showed detectable levels of expressions. 

Comparison of microRNA levels between first and second resections revealed no 

significant change. Cox regression analyses showed no significant association of 

microRNA expression levels in the tumor tissue with progression free survival times. 

Conclusion: Expression levels of microRNA21, microRNA10b, microRNA181b, 

microRNA181c, microRNA221, microRNA222 and microRNA195 do not to differ 

significantly between initial and recurrent tumors and seem not to influence time to 

recurrence in primary glioblastoma. 


427P ABLATIVE RADIOTHERAPY OF BRAIN METASTASES AND 

POSTOPERATIVE RADIOTHERAPY WITH OR WITHOUT 

“PROPHYLACTIC” CRANIAL IRRADIATION USING RAPIDARC 

AND SIMULTANEOUS INTEGRATED BOOST (SIB) 

P.A. Gut 1 , K.F. Kothbauer 2 , R. Seiler 1 , R. Greiner 1 

1 Radioonkologie, Luzerner Kantonsspital, Luzern, SWITZERLAND, 

2 Neurochirurgie, Luzerner Kantonsspital, Luzern, SWITZERLAND 


Objective: Patients with solitary or few brain metastases and good performance 

status should be treated with a local radical intention. It remains unclear, whether 

additional whole brain radiotherapy WBRT is necessary. We report about our 

alternative radiotherapy procedure with fractionated radical dose to metastases and 

"mild" dose to the remaining brain. 

Materials and methods: From 1/2010 until 12/2011 we treated 84 metastases in 46 

patients with radical intent. 25 patients had a solitary lesion and 12 were irradiated 

after resection. Using RapidArc technique with simultaneous integrated boost (SIB) 

most metastases were treated to 15 × 4 Gy = 60 Gy (PTV1) and the whole brain 

received - if indicated- a "prophylactic" dose of 15 × 1.8 Gy = 27 Gy (PTV2) . 13 

Patients received local treatment for their metastases without WBRT. Following 

resection of the metastasis the tumour bed was irradiated to 15 x 3.2 Gy = 48 Gy, 

residual/unresected macroscopic tumour to 15 x 4 Gy = 60 Gy. A 3-5 mm margin 

was used from GTV to PTV, with no additional margin for CTV. The minimum 

dose of PTV1 was 95% of the prescribed dose, wheras the median dose for PTV2 

was 27 Gy. 

Results: This treatment regime was tolerated very well without major toxicity and in 

general better than conventional WBRT (10 × 3 Gy). Median follow-up time after 

treatment was 7 months. 18 (39%) patients died and the median survival time is 12 

months. Local tumour control after treatment with15x4 Gy has been 100%, whereas 

one metastasis relapsed after resection and postoperative RT (15 × 3.2 Gy). 10 

patients (21%) were presented with new distant brain metastases. 

Conclusions: Ablative treatment of brain metastases can be performed efficiently 

with RapidArc and combined with prophylactic cranial irradiation using SIB. Local 

tumor control is nearly 100% and the toxicity is very low. 


428P PHASE 1 STUDY OF VELIPARIB WITH CONCURRENT WHOLE 

BRAIN RADIATION THERAPY (WBRT) IN PATIENTS (PTS) 

WITH BRAIN METASTASES (METS) 

M.P. Mehta 1 , W.J. Curran 2 , D. Wang 3 , F. Wang 4 , L. Kleinberg 5 , A. Brade 6 , 

J. Qian 7 , T. Leahy, 8 , B. Desai 9 , V.L. Giranda 9 

1 Radiation Oncology, Northwestern University Feinberg School of Medicine, 

Chicago, IL, UNITED STATES OF AMERICA, 2 Department of Radiation 

Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, UNITED 

STATES OF AMERICA, 3 Department of Oncology/hematology, Henry Ford 

Hospital, Detroit, MI, UNITED STATES OF AMERICA, 4 Dept. of Radiation 

Oncology, Kansas University Medical Center, Kansas City, KS, UNITED STATES 

OF AMERICA, 5 Department of Radiation Oncology and Molecular Radiation 

Sciences, Johns Hopkins University, Baltimore, MD, UNITED STATES OF 

AMERICA, 6 Dept. of Radiation Oncology, Princess Margaret Hospital, University 

of Toronto, Toronto, ON, CANADA, 7 Global Statistics and Data Management, 

Abbott, Abbott Park, IL, UNITED STATES OF AMERICA, 8 Clinical Program 

Management-oncology, Abbott, Abbott Park, IL, UNITED STATES OF AMERICA, 

9 Global Pharmaceutical Research and Development, Abbott, Abbott Park, IL, 


Background: Veliparib, an oral PARP-1 and -2 inhibitor, potentiates the antitumor 

activity of DNA damaging agents including radiation therapy in vivo, and is shown 

to cross the blood-brain barrier. Updated data on safety and antitumor activity from 

an ongoing phase 1, dose-escalation study of veliparib with concurrent WBRT in pts 

with brain mets are presented here. 

Methods: Pts with brain mets (including leptomeningeal) from primary non-CNS 

metastatic solid tumors (except germ cell cancer), adequate organ function, and 

Karnofsky performanace status (KPS) ≥70 were treated with WBRT (37.5 Gy in 15 

fractions or 30 Gy in 10 fractions daily) and veliparib BID in escalating doses of 10– 

300 mg; the final WBRT fraction was followed by 1 extra day of veliparib. Safety and 

exploratory efficacy were assessed. Safety was evaluated in pts who received at least 1 

dose of veliparib. Best brain tumor response (complete or partial per RECIST) rates 

were calculated for all pts who had at least 1 measureable lesion at baseline. Median 

survival time was estimated using Kaplan-Meier methodology for all dosed pts. 

Results: To date, 66 pts (M/F, 23/43; median age 58 y) have been treated. Baseline 

KPS was 70, 80, 90, and 100 in 7.6, 31.8, 37.9, and 22.7% pts, respectively; primary 

tumor types were breast (n = 21), NSCLC (n = 23), melanoma (n = 10), colorectal 

(n = 3), renal (n = 1), and others (n = 8); 74.2% pts had multiple lesions, and 16.7% 

had prior brain stereotactic radiosurgery. Treatment-emergent dose-limiting toxicities 

were grade 3 hypokalemia and hyponatremia in 1 pt each at the 150 mg dose. Grade 

3/4 treatment-emergent adverse events (≥4%) were fatigue (6.1%), dehydration 

(6.1%), anemia (4.5%), thrombocytopenia (4.5%), hyperglycemia (4.5%), and 



hyponatremia (4.5%). Best tumor response rate and median survival time were 36.8% 

and 6.6 months (m) for NSCLC, and 50% and 8.3 m for breast cancer. 

Conclusion: Addition of veliparib up to 200 mg BID was well tolerated with 

concurrent standard WBRT and dose escalation is ongoing. These encouraging safety 

and preliminary efficacy data suggest that veliparib requires further evaluation as a 

radiosensitizer with WBRT in pts with NSCLC and brain mets in a randomized trial. 

Disclosure: M.P. Mehta: Consultant: Abbott, BMS, Elekta, Merck, Novartis, Novocure, 

Tomotherapy, Vertex; Stock Options: Accuray, Pharmacyclics; DSMB: Apogenix; 

Protocol Data Review: Adnexus; Board of Directors: Pharmacyclics. W.J. Curran: Dr. 

Curran had served on the advisory board of Lilly, BMS, and Plexxikon. There are no 

conflicts. D. Wang: As a clinical investigator, and the principle investigator at Henry 

Ford Health System, I have conducted this clinical trial that is financially supported by 

Abbott Oncology. I have no other conflict of interest to be disclosed, otherwise. L. 

Kleinberg: I have received research funding from Abbott. J. Qian: Full-time Abbott 

employee and stockholder. T. Leahy: Full-time Abbott employee and stockholder. B. 

Desai: Full-time Abbott employee and stockholder. V.L. Giranda: Full-time Abbott 

employee and stockholder. All other authors have declared no conflicts of interest. 

429P NEUROLOGICAL (NEU) AND CYTOLOGICAL (CYT) RESPONSE 

(R) AS EARLY PREDICTORS OF TIME-TO-PROGRESSION 

(TTP) AND OVERALL SURVIVAL (OS) IN PATIENTS (PTS) WITH 

LEPTOMENINGEAL CARCINOMATOSIS (LMC) TREATED WITH 

INTRATHECAL (I.T) LIPOSOMAL CYTARABINE (LYC) 

J.P. Fusco, E. Castanon Alvarez, L. Zubiri, P. Martín, O.E. Carranza Rua, 

J. Espinos Jimenez, J. Rodriguez, M. Santisteban, J.M. Aramendia, 

I. Gil-BazoDepartment of Oncology, Clínica Universidad de Navarra, Pamplona, 

SPAIN 

Background: The palliative treatment of LMC involves i.t chemotherapy or supportive 

care. Lcy is a slow-releasing cytarabine formulation approved for leptomeningeal 

involvement of hematological malignancies. In pts with LMC from solid tumors 

interesting Neu and Cyt R rates after i.t Lcy have been observed. However, the potential 

use of those responses as early predictors of TTP and OS has never been explored. Here 

we show how both Neu and Cyt R can precociously predict a longer TTP and OS. 

Patients and methods: Twenty-seven pts with LMC consecutively treated at our 

institution with i.t Lcy under compassionate use (17/27 female), were studied. All pts 

received i.t Lcy (50 mg) every 2 weeks (w) during induction and every 4 w during 

maintenance. Neu and Cyt responses were assessed before every Lcy cycle. 

Results: The predominant primary tumor origin was breast (15/27), followed by 

gastrointestinal (3), lung (3), brain (2), and 4 other organs. A complete Neu R 

(resolution of all Neu symptoms) was seen in 3/27 pts; partial R (improvement of 

>50% of Neu symptoms for >2 w) in 6/27 pts; stable disease (no change in Neu 

symptoms) in 8/27 pts and progressive disease (progression or appearance of new 

Neu symptoms) in 10/27 pts. The Cyt assessment was available in 9/27 pts with a 

Cyt complete R confirmed in 7/9 pts. The median time to Neu and Cyt R was 15 

days (d) and 14 d, respectively. The overall median TTP was 22 d and the median 

OS was 41 d. In a subgroup analysis regarding the type of R achieved with the 

treatment, the median TTP and OS for pts showing a combined Neu and Cyt R were 

significantly longer compared to those in pts showing both, Neu and Cyt progression 

as shown in table 1. The most frequently reported adverse event was grade 2 

headache with no grade 4 toxicities. 

Conclusions: For the first time, Neu and Cyt R are shown to be early predictors of 

TTP and OS in pts receiving i.t Lcy for LMC. This result could help to early select 

patients most likely to benefit from i.t Lcy and to consider discontinuation when very 

poor prognosis is estimated. 

Neu R Cyt R TTP (d) OS (d) p 

Yes Yes 122 141 0.001 

Yes No 14 32 0.001 

No Yes 42 72 0.001 

No No 3 3 0.001 


430P DEMOGRAPHIC DATA AND TREATMENT OUTCOME IN 

RETINOBLASTOMA: RETROSPECTIVE REVIEW FROM 

TERTIARY CENTRE IN INDIA 

F.A. Ansari 1 , P. Shukla 2 , V. Roshan 1 , B. Mohanti 1 

1 Radiotherapy, aiims, Delhi, INDIA, 2 Radiation Oncology, All India Institute of 

Medical Sciences (AIIMS) Institute Rotary Cancer Hospital, New Delhi, INDIA 

Purpose: To characterize the patient population and analyse treatment outcome in 

patients with retinoblastoma. 

Method and material: A retrospective study of 180 patients with retinoblastoma 

affecting a total of 297 eyes. Demographic data, tumor features and outcome were 

assessed. 

Results: The mean age of diagnosis was 32 months (range 2-204 months) for 

unilateral eyes and 26 months ( range 2-132months) for bilateral eyes. The male 

to female ratio was 1.4:1. The most common symptoms was leukokoria (74%), 

followed by proptosis of eye (11.5%), strabismus (8%) and poor vision (6.5%). 

Out of 297 eyes 39 were Group I-II, 17 were Group III, 198 were group IV-V 

and 43 had missing information. The mean basal diameter was 14mm (range 

2–37mm). The mean interval between initial diagnosis and treatment was 

7months ( range 1-36 months). Familial history was seen in eight patients (4.4%). 

Out of 180 patients 64 patients received radiation. 144 patients underwent 

enucleation. No children underwent bilateral enucleation. All patients were treated 

with 6–12 cycles of chemotherapy vincristine, etoposide and carboplatin. 

Chemotherapy offer satisfactory local control for Group I-III, with treatment 

failure necessitating additional radiation and or enucleation in only 14% of 

patients. The radiation doses were either 39Gy in 13 fraction, three fraction per 

week or 40Gy in 20 fraction, five fraction per week. The mean duration of follow 

up was 28 months (0-64months). The overall local control or freedom from 

relapse was 55%. Local control in patients receiving radiation after enucleation 

was 84%. Distant metastases were seen in 13 patients (preauricular node (5), 

vertebrae (3), humerus (1), suprasellar (1), scalp (1), CSF(1), and meningeal 

dissemination (1)). No case of second malignant neoplasm has been reported. 

Conclusion: Lack of awareness leads to delay in diagnosis and treatment. 

Multimodality treatment is required for management of retinoblastoma. 

Chemoreduction offer satisfactory control retinoblastoma in group I-III, with 

preservation of vision. There is significant improvement in local control with 

radiation therapy in locally advance cases. 


431 BLOOD VESSELS WITH DIFFERENT CHARACTERISTICS HAVE 

DISTINCT IMPACT ON SURVIVAL OF GLIOBLASTOMA 

MULTIFORME PATIENTS 

M. Kase 1 , A. Minajeva 2 , K. Niinepuu 2 , S. Kase 3 , A. Adamson 2 , M. Saretok 2 , 

M. Vardja 4 , T. Asser 5 , J. Jaal 6 

1 Dept. of Radiotherapy, North Estonia Medical Centre, Oncology and 

Haematology Clinic, Tallinn, ESTONIA, 2 Faculty of Medicine, University of Tartu, 

Tartu, ESTONIA, 3 Nursing, Health Care College, Tartu, ESTONIA, 4 Dept of 

Radiotherapy and Oncological Therapy, Tartu University Hospital, Haematology 

and Oncology Clinic, Tartu, ESTONIA, 5 Dept of Neurosurgery, Tartu University 

Hospital, Tartu, ESTONIA, 6 Dept of Radiotherapy and Oncological Therapy, Tartu 

University Hospital, Tartu, ESTONIA 

Background: Glioblastoma multiforme (GBM) is the most aggressive type of brain 

tumor in adults. GBMs are highly angiogenic: next to capillaries and bigger blood 

vessels, microvascular proliferations (MP) forming glomeruloid structures can be 

found. The aim of our study was to evaluate the prognostic significance of different 

blood vessel types in GBM. 

Methods: Between Jan 2006 and Dec 2008, 42 patients (30–77 years) received 

postoperative radiotherapy and chemotherapy. Surgically excised GBM tissues were 

histologically examined for overall proportion of MP (low, medium, high) and the 

total number of blood vessels (per microscopic field). Also, immunohistochemical 

staining intensity of CD133 and ICAM-1 were determined in endothelial cells 

(arbitrary score 0–3). Finally, blood vessel parameters were correlated with patients 

overall survival. 

Results: The overall proportion of MP was low-medium in 39% and high in 61% 

of GBM patients. The number of blood vessels per microscopic field was 2.5 ± 1.4 

(mean ± SD). A positive association was found between the number of blood 

vessels and endothelial CD133 staining intensity (p = 0.03). However, between the 

number of blood vessels and endothelial ICAM-1 staining intensity, a negative 

correlation was detected (p = 0.04). Median survival time of the study group was 

10.0 months (95% CI 9.0–11.0). The proportion of MP did not significantly affect 

survival (log rank test, p = 0.07). However, the survival time clearly depended on 

the number of blood vessels in GBM tissue (log rank test, p = 0.03). Median 

survival times for patients with low (

432 GAMMA KNIFE RADIOSURGERY AS A MAIN MODALITY IN 

TREATING INTRACRANIAL LESIONS OF NF II PATIENTS 

K. Abdel Karim, 1 , N.M. Elmashad 2 ,W.Reda 1 , A. El Shehaby 1 

1 Gamma Knife Center, Nasser Institute, Cairo, EGYPT, 2 Clinical Oncology 

Department, Tanta University, Tanta, EGYPT 

Objective: Gamma knife radiosurgery GKS was used for the treatment of the 

patients with Neurofibromatosis type II (NFII) for years to achieve better tumor 

control and to avoid the post operative neurological deficits. This study aimed at 

exploring the effect of GKS on the tumor control rate, the avoidance of new 

neurological deficits, and the associated morbidity. 

Methods: We revised the data of 50 intracranial NFII patients (either vestibular 

schwannomas or meningiomas) who were treated consequently between July 2001 

and October 2009 in our center, the data of 43 patients were evaluable. The mean 

follow up period was 43.7 months (range 6 to 96). We treated 22 females (51.2%) 

and 21 males (48.8%) with a mean age of 27.6 years (range 9–53 years). Eight 

patients (18.6%) had a family history of NFII, 29 patients (67.4%) had previous 

surgeries. A hundred and seventy NFII lesions were treated in 169 treatment 

procedures, 83/170 were vestibular schwannomas and 87 were meningiomas. The 

mean number of treated lesions per patient was 3.97 (range 1–14). The mean 

marginal dose was 11.9 Gy (range 8 to 13 Gy), with a mean isodose of 52.5%, mean 

percent coverage was 95.7% (ranged 71-100%). The mean target volume was 11.1 cc 

(range 0.1 to 26.11 cc). 

Results: Regarding the overall radiological response, 16 lesions (9.4%) had 

regressed, 146 (85.9%) remained stable, and 8 (4.7%) had progressed. For 83 

schwannomas, 7 lesions (8.4%) had regression, 72 (86.7%) remained stable, and 4 

(4.8%) developed progression. For the 87 meningiomas, 9 (10.3%) had regressed, 

74 (85.1%) were stable, and 4 (4.6%) had progressed. The Overall survival rate 

(OS) for all patients was 95.3% (only 2 died), the mean tumor control rate of 

95.1%. The overall Freedom from neurological deficits was 97.7%. Only one patient 

complained of Grade III facial palsy which was temporary and resolved after 

medical treatment. Using a median dose of 12 Gy maintained serviceable hearing 

in 56.6% of ears. 

Conclusion: Gamma knife radiosurgery for NFII patients can achieve good tumor 

control and preserved function with low risk of morbidity. 


433 PEMETREXED AND WHOLE-BRAIN RADIATION THERAPY 

FOR TREATMENT OF BRAIN METASTASES FROM NON 

SMALL-CELL LUNG ADENOCARCINOMA: A SINGLE 

INSTITUTON ANALYSIS 

C. Chargari 1 , Y. Moussaid 2 , C. Helissey 1 , J. Jacob 1 , O. Bauduceau 1 , 

B. Ceccaldi 1 , L. Védrine 1 , S. Le Moulec 1 

1 Oncology and Radiation Oncology, Hôpital d’Instruction des Armées du 

Val-de-Grâce, Paris, FRANCE, 2 Rabat, Hopital d’Instruction des Armées 

Mohamed V, Rabat, MOROCCO 

Background: Folate antimetabolite pemetrexed was approved for treatment of 

patients with metastatic non small-cell lung carcinoma (NSCLC). Its activity on brain 

metastases makes it attractive in combination with whole brain radiation therapy 

(WBRT), but this regimen could also potentially increase toxicity. 

Patients and treatment: We retrospectively assessed the use of pemetrexed 

concurrently with WBRT in 12 consecutive patients with brain metastases from 

NSCLC. Patients received pemetrexed 500 mg/m2, either alone (n = 4) or combined 

with cisplatin 75mg/m2 (n = 6) or carboplatin AUC5 (n = 2). Median total number of 

pemetrexed-based chemotherapy cycles was 3.5 (range: 1–8). In the course of 

chemotherapy, patients received WBRT delivering 30 Gy in 10 fractions (n = 8) or 20 

Gy in 5 fractions (n = 4). 

Results: Six patients improved neurologically with treatment (five complete and one 

partial responses). Four patients had their neurological symptoms stable. Best 

radiological response was complete response lasting until last follow-up in one 

patient. Five patients experienced partial response. One patient had stable disease. 

Progressions were identified in four patients, within a median time interval of 17 

weeks (range: 6–58 weeks). Three patients were not analyzable for tumor response 

because of rapid systemic progression leading to death. Two of them had improved 

neurologically. No high-grade WBRT-toxicity was reported but one patient 

developed symptoms suggestive of a limbic encephalopathy five weeks after WBRT 

completion. 

Conclusion: The combination of pemetrexed with WBRT was associated with a 

substantial improvement of neurological deficits and tumor responses in most 

patients. However, survival remained disappointing and there were concerns 

about toxicity in one patient. A clinical trial is required for better analyzing the 

potential synergistic effects of drug with radiation and evaluating neurological 

toxicity. 



434 LIMITED PREDICTIVE VALUE OF SCORING SYSTEMS FOR 

METASTATIC SPINAL CORD COMPRESSION (MSCC): 

RESTROSPECTIVE MONOCENTRIC STUDY 

E. Tabouret 1 , C. Cauvin 2 , S. Fuentes 3 , B. Esterni 4 , T. Adetchessi 3 , N. Salem 5 , 

A. Madroszyk 2 , A. Gonçalves 1 ,P.Viens 6 , G. Gravis-Mescam 1 

1 Medical Oncology, Paoli Calmettes, Marseille, FRANCE, 2 Medical Oncology, 

Institut Paoli Calmettes, Marseille, FRANCE, 3 Neuro-surgery, AP HM, Marseille, 

FRANCE, 4 Biostatistic, Paoli Calmette, Marseille, FRANCE, 5 Radiotherapy, Paoli 

Calmettes, Marseille, FRANCE, 6 Cancer Center, Institute Paoli Calmettes, 

Marseille Cedex, FRANCE 

Background: Incidence of MSCC is increasing, paralleling increasing life expectancy 

of patients (pts). We analyzed pts referred for surgery for MSCC to evaluate scoring 

system relevance, prognosis factors, efficiency and safety. 

Methods: From 2004 to 2010 148 pts (77 men) with oncologic (84%) and 

hematological (16 %) diseases had surgery for MSCC. Patients and tumoral 

characteristics were recorded. Prognostic value of Tomita, Tokuhashi scores, ASA 

score, Frankel score (FS) and pain was investigated. 

Results: Median age was 60 y (22–87). Lung (17%) and breast cancer (18%), were 

mainly represented. Multiple extra-bone metastases were observed in 39% of pts. 

Pain was present in 96% of pts and 66% were hyperalgic (pain score > 6). FS was 

decreased for 49% of pts and median Karnofsky Performance Scale (KPS) was 70%. 

Majority had laminectomy with spinal fixation: 73 %. Radiotherapy was done for 

68%. Median overall survival (OS) was 8.9 months (IC95: 4.4–13). Tokuhashi but not 

Tomita score was relevant. Survival predictive accuracy of TS was only 51%. By 

univariate analyses, moderate pain (p = 0.001), primary breast (p = 0.02) or 

hematological (p < 0.001) diseases are associated with higher OS than lung cancer 

(p = 0.004). Absence of extra-bone metastase (p < 0.001), KPS > 70 (p < 0.001), ASA 

score (p < 0.001), FS (p = 0.01), type of surgery (p = 0.03), post surgery 

chemotherapy (p < 0.001) presented prognostic value. By multivariate analysis 

extra-bone metastases (p = 0.004), KPS (p = 0.001) and ASA score (p = 0.007) 

remained significant. Pain decrease was observed for 75% of pts. After surgery, 92% 

of pts were ambulatory and FS was improved for 31%. Surgery complications 

occurred in 16.8% and only 7% of pts died within 30 days. 

Conclusion: Surgery for MSCC is associated with limited morbidity, improvement of 

patients’ autonomy and remission of pain. In our study, usual scores seem not 

relevant, whereas ASA score, KPS and extra-bone metastases are significant survival 

prognostic factors. 


435TiP A DUAL PHASE I/II STUDY OF TH-302 AND BEVACIZUMAB 

IN RESECTABLE RECURRENT GLIOBLASTOMA FOLLOWING 

BEVACIZUMAB FAILURE 

R.M. Zuniga 1 , J. Sun 2 , J.R. Floyd 1 , S.R. Yerragudi 1 , C. Hart 2 , C. Eng 2 , 

A.J. Brenner 1 

1 Cancer Therapy and Research Center, University of Texas Health Sceince 

Center at San Antonio, San Antonio, TX, UNITED STATES OF AMERICA, 

2 Clinical Operations, Threshold Pharmaceuticals, South San Francisco, CA, 


Introduction: Bevacizumab, a recombinant human monoclonal anti-VEGF antibody, 

exhibits anti-tumor activity in recurrent glioblastoma; however, the median progression 

free survival (PFS) of patients who progress on bevacizumab and are subsequently 

started on a non-bevacizumab containing regimen is only 1.6 months. Pre-clinical 

studies have shown that anti-angiogenic treatment leads to an increase in hypoxia in 

the tumor microenvironment leading to increased invasiveness. Hypoxia upregulates 

survival mechanisms, inhibits apoptosis, and stimulates invasiveness. TH-302 is a 

hypoxia-activated prodrug that once activated releases the alkylating agent Br-IPM. 

This drug has shown to potentiate, in vivo, the anti-tumor efficacy of other 

anti-angiogenic agents. This dual phase I/II study enrolled subjects with recurrent 

glioblastoma following bevacizumab failure that were planned for repeat craniotomy. 

Methods: Single center, dose-escalation, prospective study with TH-302 single dose at 

575 mg/m2 or placebo administered pre-operatively, followed by postoperative 

combination therapy of bevacizumab at 10 mg/kg every 2 weeks and TH-302 dose 

escalated 240–480 mg/m2 every 2 weeks (4 week cycle) until disease progression. 

Resected tumor tissue was evaluated for hypoxia induced pimonidazole adducts, 

endogenous CAIX staining, double-strand DNA damage by gamma-H2AX and MGMT 

expression. 

Results: Five patients underwent craniotomy and initiated TH-302 plus bevacizumab. 

No dose limiting toxicity was reported. There were no grade 3 or 4 adverse events 

(AEs) observed at 240mg/m2, and one grade 3 (skin ulceration) and no grade 4 AEs 

observed thus far in the second cohort at 340mg/m2. Of the initial 5 patients treated, 

one patient had a partial response (PR) and 3 patients had stable disease (SD) per 

RANO criteria. Histological assessment of resected tumors demonstrated extensive 

areas of hypoxia as measured by pimonidazole and a heterogeneous distribution of 

gamma-H2AX staining. 



Conclusions: TH-302 demonstrates good tolerability when combined with 

bevacizumab. The MTD has not been reached and only one grade 3/4 toxicity was 

observed. Dose escalation is ongoing, with planned expansion at the MTD. 

Disclosure: J. Sun: The author is an employee of pharmaceutical industry with a 

financial interest in the drug which is the subject of this abstract. C. Hart: The 

author is an employee of pharmaceutical industry with a financial interest in the 

drug which is the subject of this abstract. C. Eng: The author is an employee of 

pharmaceutical industry with a financial interest in the drug which is the subject of 

this abstract. All other authors have declared no conflicts of interest. 

437TiP A RANDOMISED PHASE II STUDY OF CARBOPLATIN AND 

BEVACIZUMAB IN RECURRENT GLIOBLASTOMA 

MULTIFORME (CABARET STUDY). COOPERATIVE TRIALS 

GROUP FOR NEURO-ONCOLOGY (COGNO) 

K. Field1 , M.A. Rosenthal1 , H. Wheeler2 , L. Cher3 ,E.Hovey4 , A.K. Nowak5 , 

C. Brown6 , A. Livingstone6 , K. Sawkins6 , R.J. Simes6 1 

Department of Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, 

AUSTRALIA, 2 Medical Oncology, Royal North Shore Hospital, Sydney, NSW, 

AUSTRALIA, 3 Neuro-Oncology, Austin Hospital, Melbourne, VIC, AUSTRALIA, 

4 

Medical Oncology, Prince of Wales Hospital, Sydney, NSW, AUSTRALIA, 

5 

Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA, AUSTRALIA, 

6 

Clinical Trials, NH&MRC Clinical Trials Centre, University of Sydney, Sydney, 

NSW, AUSTRALIA 

Background: Glioblastoma (GBM) is the most aggressive malignant glial tumor. 

There is no accepted standard management after disease progression. Much remains 

unknown about the optimal use of bevacizumab (bev), including the role of 

continuing beyond progression, and patterns of radiological progression during and 

after use. In addition, the new Response Assessment in Neuro-Oncology (RANO) 

criteria have yet to be validated prospectively. 

Methods: This study is a multi-centre, stratified randomised phase II trial. Patients 

have recurrent GBM after radiotherapy and temozolomide, have had no other 

chemotherapy for GBM, and have ECOG performance status 0–2. At least three 

months have elapsed since radiotherapy. In Part 1, patients are randomised 1:1 to 

intravenous bev 10 mg/kg 2-weekly and carboplatin AUC5 4-weekly or bev 

monotherapy. On progression, eligible patients are randomised to continue or cease 

bev (Part 2). The primary objective is to determine the effect of bev plus carboplatin 

versus bev alone on progression-free survival according to modified RANO criteria. 

Secondary endpoints are response rates, cognitive function, quality of life, steroid 

dose, toxicity, and overall survival. CogState, a validated neurocognitive testing 

system, is being used prospectively for the first time in this population and compared 

with mini-mental state examination. Exploratory endpoints include biomarker 

analyses, comparison of modified RANO and modified MacDonald criteria, 

predictive value of early MRI after 2 doses of bev, steroid dosing, and location and 

type of radiological progression during and after therapy. 

Results: Enrolment commenced in Nov 2010, completing Part 1 accrual in Mar 2012 

with 122 patients randomised from 17 Australian sites. Randomisation to Part 2 

continues. Feasibility and safety data will be presented; efficacy outcome results are 

not expected until 2013. 

Conclusions: The study results will significantly improve knowledge regarding the 

use of bevacizumab in the setting of recurrent GBM, as well as providing for the first 

time a prospective analysis of CogState neurocognitive testing for patients with brain 

tumours. 

Disclosure: M.A. Rosenthal: Roche Advisory Board member. H. Wheeler: Roche 

Advisory Board member. E. Hovey: Roche Advisory Board member. A.K. Nowak: 

Roche Advisory Board member and has received research funding through Roche 

Australia. R.J. Simes: Roche Advisory Board Member. All other authors have 



abstracts 

developmental therapeutics 

438O PHASE II ACTIVITY OF THE HSP90 INHIBITOR AUY922 IN 

PATIENTS WITH ALK-REARRANGED (ALK+) OR 

EGFR-MUTATED ADVANCED NON-SMALL CELL LUNG 


E. Felip 1 , E. Carcereny 2 , F. Barlesi 3 , L. Gandhi 4 , L.V. Sequist 5 , S-W. Kim 6 , H.J. 

M. Groen 7 , B. Besse 8 , D-W. Kim 9 , E. Smit 10 , M. Akimov 11 , E. Avsar 12 , 

S. Bailey 13 , W. Ofosu-Appiah 14 , E.B. Garon 15 

1 Medical Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN, 

2 Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans 

Trias i Pujol, Badalona, SPAIN, 3 Multidisciplinary Oncology and Therapeutic 

Innovations Department & Centre Investigation Clinique, Aix Marseille University, 

Marseille, FRANCE, 4 Oncology, Dana-Faber Cancer Institute, Boston, UNITED 

STATES OF AMERICA, 5 Medicine, Massachusetts General Hospital, Boston, 

MA, UNITED STATES OF AMERICA, 6 Oncology, Asan Medical Center, Seoul, 

KOREA, 7 Pulmonary Diseases, University Hospital Groningen (UMCG), 

Groningen, NETHERLANDS, 8 Departement of Medicine, Institute Gustave 

Roussy, Villejuif, FRANCE, 9 Department of Internal Medicine, Seoul National 

University Hospital, Seoul, KOREA, 10 Department of Pulmonary Diseases, Vrije 

Universiteit Medical Centre, Amsterdam, NETHERLANDS, 11 Oncology 

Translational Medicine, Novartis Pharma AG, Basel, SWITZERLAND, 12 Oncology 

Translational Medicine, Novartis Pharmaceuticals, East Hanover, NJ, UNITED 

STATES OF AMERICA, 13 Biometrics and Data Management, Novartis Pharma 

AG, Basel, SWITZERLAND, 14 Oncology, Novartis Oncology, Florham Park, NJ, 

UNITED STATES OF AMERICA, 15 Translational Oncology Research, David Geffen 

School of Medicine at UCLA, Los Angeles, UNITED STATES OF AMERICA 

Background: AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. 

HSP90 is a chaperone of client proteins relevant in NSCLC pathogenesis, including 

ALK and EGFR. Oncogenic fusion genes giving constitutive ALK activity (ALK+) 

occur in up to 6% of NSCLCs, and EGFR mutation (mut) occurs in 10–20% of cases. 

We report data from a Phase II study of AUY922 in patients (pts) with previously 

treated, advanced NSCLC, stratified by molecular status. 

Methods: Pts with advanced NSCLC who progressed following ≥1 prior line of 

chemotherapy, received AUY922 (70 mg/m 2 )asaonce-weekly,1-hrinfusion.Ptswere 

assigned to 1 of 4 strata: ALK + , EGFR-mut, KRAS-mut, or EGFR/KRAS/ALK wild-type. 

A Bayesian partially exchangeable multinomial model was used in the statistical analysis 

of the study. Primary endpoint was confirmed objective response rate or stable disease at 

18 wks. Secondary endpoints included OS, PFS, and safety/tolerability. 

Results: On 6 April 2012 cutoff, 121 pts had been treated (ALK+ [n = 22; both 

crizotinib (CRZ) treated and naïve], EGFR-mut [n = 35], KRAS-mut [n = 28], EGFR/ 

KRAS/ALK wild-type [n = 33], undetermined [n = 3]); pts were heavily pretreated 

(61% had received ≥3 prior regimens). Clinical activity of AUY922 was seen in pts 

with ALK+ and EGFR-mut NSCLC, with partial responses in 6/21 (29%) pts and 7/ 

35 (20%) pts, respectively. 4/6 ALK+ responders were CRZ-naïve and 2/6 were 

pretreated. Estimated median PFS rates (FAS) were 42% and 34% at 18 wks in ALK+ 

and EGFR mut pts, respectively. In EGFR-mut pts who had progressed just after 

EGFR tyrosine kinase inhibitor (TKI) therapy, median PFS rate at 18 wks was 45% 

vs 21% in pts who had not received a TKI as their immediate pre-AUY922 therapy. 

The most frequent adverse events (AEs) were eye disorders (77%), diarrhea (74%), 

and nausea (46%). Most AEs were grade (Gr) 1/2; Gr 3/4 AEs were rare (all 3 patients) were: fatigue (n = 4; 3 grade 1/2, 1 

grade 3), nausea (n = 4; grade 1). No treatment-related serious AEs were observed. 

No DLTs were observed; the 120 mg dose level remains under evaluation. At 90 mg 

(n = 3), Day 29 geometric mean Cmax, Ctrough, AUC(0-24hr), and t1/2 were: 402 ng/ 

mL, 170 ng/mL, 6130 ng*hr/mL, 29 hr, respectively. At the time of analysis, 8 pts had 

≥1 set of tumor response measurements starting ≥8 weeks after first dose. Partial 

responses were observed in 4 of 4 ALK+ pts (60 mg n = 1; 90 mg n = 3, including the 

crizotinib-naïve ACUP pt). Anti-tumor activity at 120 mg remains to be evaluated. In 

summary, AP26113 was well tolerated with preliminary anti-cancer activity in ALK+ 

pts naïve to or failing prior crizotinib. The phase 2 expansion will include 4 cohorts: 

ALK+ NSCLC that is 1) naïve or 2) resistant to prior ALK-targeted therapy; 3) 

EGFRm NSCLC that is resistant to EGFR-targeted therapy; 4) other cancers with 

abnormalities in ALK or other AP26113 targets. ClinicalTrials.gov: NCT01449461. 

Disclosure: G.J. Weiss: GJW has received funds and other support related to 

participation in this clinical trial from ARIAD Pharmaceuticals, Inc. through his 

employer, Scottsdale Healthcare. GJW has served on Speakers Bureaus for 

Genentech, Pfizer, and Eli Lilly. N.I. Narasimhan: NIN is an employee of ARIAD 

Pharmaceuticals, Inc. D.J. Dorer: DJD is an employee of ARIAD Pharmaceuticals, 

Inc. V.M. Rivera: VMR is an employee of ARIAD Pharmaceuticals, Inc. J. Zhang: JZ 

is an employee of ARIAD Pharmaceuticals, Inc. T. Clackson: TC is an employee of 

ARIAD Pharmaceuticals, Inc. F. Haluska: FH is an employee of and owns stock/stock 

options in ARIAD Pharmaceuticals, Inc. A.T. Shaw: ATS has received consulting 

fees/honorarium from ARIAD, Pfizer, Chugai, and Daiichi. ATS has received support 

in the form of grants paid to her employer by Novartis and AstraZeneca. D.R. 

Camidge: DRC has received consulting fees/honorarium from ARIAD and has served 

on advisory boards for Pfizer, Chugai, Novartis, and ARIAD. All other authors have 





440O RESULTS OF A FIRST-IN-HUMAN PHASE I STUDY OF THE 

ALK INHIBITOR LDK378 IN ADVANCED SOLID TUMORS 

A.T. Shaw 1 , D.R. Camidge 2 , E. Felip 3 , S. Sharma 4 , D.S.W. Tan 5 , D. Kim 6 , 

T. De Pas 7 , J.F. Vansteenkiste 8 , A. Santoro 9 , G. Liu 10 , M. Goldwasser 11 , 

D. Dai 12 , A.L. Boral 13 , R. Mehra 14 

1 Medicine, Harvard Medical School, Boston, MA, UNITED STATES OF 

AMERICA, 2 School of Medicine, University of Colorado, Denver, CO, UNITED 

STATES OF AMERICA, 3 Oncology, Vall d’Hebron University Hospital, Barcelona, 

SPAIN, 4 Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt 

Lake City, UT, UNITED STATES OF AMERICA, 5 Department of Medical 

Oncology, National Cancer Center, Singapore, SINGAPORE, 6 Department of 

Internal Medicine, Seoul National University Hospital, Seoul, KOREA, 7 Medical 

Oncology Unit of Respiratory Tract and Sarcomas, Istituto Europeo di Oncologia, 

Milano, ITALY, 8 Respiratory Oncology Unit (pulmonology), University Hospital 

Gasthuisberg, Leuven, BELGIUM, 9 Department of Medical Oncology and 

Hematology, Istituto Clinico Humanitas, Rozzano, ITALY, 10 Ontario Cancer 

Institute, Princess Margeret Hospital, Toronto, ON, CANADA, 11 Novartis 

Institutes for BioMedical Research, Novartis Pharmaceuticals, Cambridge, MA, 

UNITED STATES OF AMERICA, 12 Oncology Clinical Pharmacology, Novartis 

Pharmaceuticals, East Hanover, NJ, UNITED STATES OF AMERICA, 13 Clinical 

Research, Novartis Institutes for Biomedical Research, Inc, Cambridge, MA, 

UNITED STATES OF AMERICA, 14 Department of Developmental Therapeutics, 

Fox Chase Cancer Center, Philadelphia, PA, UNITED STATES OF AMERICA 

Background: Translocations of the anaplastic lymphoma kinase (ALK) gene occur in 

3–8% of NSCLC. LDK378 is a novel, potent small molecule ALK inhibitor that produces 

tumor regressions in ALK-driven (ALK+) NSCLC xenografts. A Phase 1 study is being 

conducted with the primary objective of determining the MTD and safety profile in 

patients (pts) with ALK+ cancers. Other objectives are to assess safety, PK, and 

antitumor activity in pts with ALK+ NSCLC, either previously untreated with ALK 

inhibitors, or relapsed following ALK inhibitor treatment, and other ALK+ cancers. 

Methods: LDK378 was administered orally once-daily on a continuous 21-day 

schedule, in adult pts with advanced malignancies harboring a genetic alteration in 

ALK who progressed on standard therapy or for whom there was no effective 

therapy. Dose escalation was guided by a Bayesian logistic regression model to 

determine the MTD, and started at 50 mg/day. 

Results: As of 25 April2012, 56 pts (primary site: lung 50 pts [37 with prior crizotinib]; 

breast 4 pts; other 2 pts; median age 53 (22–76) years; 88% ECOG PS 0/1) had received 

LDK378 at doses of 50–750 mg/day. Of 47 pts evaluable for response (per investigator), 

there were 24 (51%) responses. All responses were in ALK+ NSCLC (FISH positive in 

≥15% of tumor cells). In 26 pts with NSCLC who had progressed following crizotinib and 

were treated at ≥400 mg/day there were 21 (81%) responses. Dose limiting toxicities (DLTs) 

have occurred in 2/14 pts at 400 mg/day, 2/9 pts at 600 mg/day, and 1/9 pts at 750 mg/day. 

DLTs included diarrhea, vomiting, nausea, dehydration, and ALT elevation. The MTD was 

750 mg/day. At the cutoff date, 36 (64%) pts remain on treatment. Discontinuations were 

due to adverse events (AEs) in 1 (2%), and disease progression in 19 (34%) pts. The most 

frequent AEs (all grades) were nausea 33 (59%), vomiting 30 (54%), and diarrhea 27 (48%) 

pts. The most frequent Grade 3/4 AE was diarrhea (5 [9%] pts). Oral absorption of 

LDK378 was rapid with a T max of 5–6 hours, and half-life was about 36 hours. 

Conclusions: Daily oral LDK378 is well tolerated and the MTD was 750 mg/day. 

Striking activity was seen in ALK+ NSCLC pts treated at doses ≥400mg, who had 

previously progressed following crizotinib. 

Disclosure: A.T. Shaw: I have a consultant/advisory role for Pfizer, Novartis, Chugar, 

Ariad, and Daiichi. D.R. Camidge: I have a compensated consultant/advisory role 

with Novartis Pharmacuticals Inc. S. Sharma: I have a compensated consultant/ 

advisory role for Novartis (LEAD Summit). I have received honoraria for Novartis 

LEAD Summit. I have received research funding from Novartis (Phase Ib clinical 

trial). D.S.W. Tan: I have received research funding from Novartis. M. Goldwasser: 

Employment or leadership position to disclose: Associate Director Biostatistics: 

Novartis Pharmaceuticals. D. Dai: Employment or leadership position to disclose. 

Clinical Pharmacology Expert: Novartis Pharmaceuticals; Stock ownership: Myself; 

Novartis Pharmaceuticals. A.L. Boral: I am an employee of Novartis Institutes for 

Biomedical Sciences (Executive Director). I have stock ownership (Novartis). All 


441O A PHASE I/II STUDY OF ALK INHIBITOR CH5424802 IN 

PATIENTS WITH ALK-POSITIVE NSCLC; SAFETY AND 

EFFICACY INTERIM RESULTS OF THE PHASE II PORTION 

M. Nishio1 , K. Kiura2 , K. Nakagawa3 , T. Seto4 , A. Inoue5 , M. Maemondo6 , 

T. Hida7 , M. Harada8 , H. Yoshioka9 , T. Tamura10 1 

Thracic Oncology Center, Cancer Institute Hospital of JFCR, Tokyo, JAPAN, 

2 

Department of Respiratory Medicine, Okayama University Hospital, Okayama, 

JAPAN, 3 Medical Oncology, Kinki University School of Medicine, Osaka, JAPAN, 

4 

Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, JAPAN, 

5 

Department of Respiratory Medicine, Tohoku University, Sendai, JAPAN, 

6 

Department of Respiratory Medicine, Miyagi Cancer Center, Natori, JAPAN, 

7 8 

Thoracic Oncology, Aichi Cancer Center, Nagoya, JAPAN, Respiratory Medicine, 

National Hospital Organization Hokkaido Cancer Center, Sapporo, JAPAN, 

9 10 

Respiratory, Kurashiki Central Hospital, Kurashiki, JAPAN, Division of Internal 

Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN 

Background: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase constitutively 

activated following chromosomal gene translocation in a subset of non-small cell 

lung cancer (NSCLC). CH5424802, an oral ALK inhibitor, was well tolerated with 

promising efficacy in patients (pts) with ALK-positive NSCLC in the phase I portion 

(ASCO 2012). Here we report the interim results of the ongoing phase II portion. 

Methods: The primary objective of the phase II portion was to investigate the efficacy 

and safety at the recommended dose (RD) determined in the phase I portion. Pts with 

ALK-positive NSCLC, measurable disease, and no prior ALK inhibitor therapy were 

treated with CH5424802 at 300 mg bid until progressive disease or intolerable toxicity. 

Results: As of March 23, 2012, 34 pts have been enrolled: median age; 46 years, M/F; 

16/18, ECOG PS 0/1; 17/17, never-smoker; 62%, number of prior chemotherapy 1/2/ 

3/ > 4; 18/6/0/10. Among the first 15 pts, the response rate was 73.3% with 1 CR and 

10 PRs. Main treatment-related adverse events (AEs) among the 34 pts were AST 

increased (7 pts), ALT increased (6), neutropenia (5), rash (4), nausea (4), myalgia 

(3), dysgeusia (3), constipation (3), blood CPK increased (3), blood bilirubin 

increased (3), and blood ALP increased (3), which were mostly Grade 1 except for 

neutropenia. Grade 3 treatment-related AEs were two cases of neutropenia. For 

treatment-related eye disorders which are frequent in crizotinib, only one Grade 1 

case (vision blurred) was observed. No treatment-related AEs led to dose reduction. 

At the time of submission, 30 pts are on study (range 1 - 8 months). 

Conclusion: CH5424802 demonstrated clinically meaningful antitumor activity with 

well tolerated toxicity profile. A phase I/II study in ALK-positive NSCLC pts 

previously treated with or without crizotinib is ongoing in the US. 

Disclosure: M. Nishio: Corporate-sponsored research:Chugai pharmaceutical Co., 

Ltd., Pfizer. K. Kiura: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., 

Pfizer. K. Nakagawa: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., 

Pfizer. T. Seto: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. 

A. Inoue: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. M. 

Maemondo: Corporate-sponsored research:Chugai pharmaceutical Co., Ltd. T. Hida: 

Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. M. Harada: 

Corporate-sponsored research:Chugai pharmaceutical Co., Ltd., Pfizer. H. Yoshioka: 

Corporate-sponsored research:Chugai pharmaceutical Co., Ltd. T. Tamura: 

Corporate-sponsored research:Chugai pharmaceutical Co., Ltd. 

442O PI3K KINASE INHIBITOR GSK2126458 (GSK458): CLINICAL 

ACTIVITY IN SELECT PATIENT (PT) POPULATIONS DEFINED 

BY PREDICTIVE MARKERS (STUDY P3K112826) 

P. Munster 1 , R. van der Noll 2 , E. Voest 3 , J. Specht 4 , T.L. Werner 5 , E.C. Dees 6 , 

A.R. Tan 7 , A. Daud 8 , J. Schellens 9 , M.P. Lolkema 3 , M. Griffin 4 , N. Agarwal 10 , 

G.S. Falchook 11 , J.F. Kleha 12 , M. Durante 13 , D.A. Smith 12 , L. Adams 12 , 

J. Greshock 12 , S.R. Morris 12 , R. Kurzrock 11 

1 Medicine, Division of Hem/Onc, University of California, San Francisco, 

San Francisco, CA, USA, 2 Department of Pharmacology, The Netherlands 

Cancer Institute, Amsterdam, NETHERLANDS, 3 Department of Medical 

Oncology, University Medical Center Utrecht, Utrecht, NETHERLANDS, 

4 University of Washington Division of Medical Oncology, Fred Hutchinson Cancer 

Research Center, Seattle, WA, UNITED STATES OF AMERICA, 5 Department of 

Internal Medicine, Oncology Division, University of Utah School of Medicine, Salt 

Lake City, UT, UNITED STATES OF AMERICA, 6 Developmental Therapeutics 

Working Group, UNC Lineberger Cancer Comprehensive Cancer Center, Chapel 

Hill, NC, UNITED STATES OF AMERICA, 7 Breast Medical Oncology and Phase I 

Program, The Cancer Institute of New Jersey, New Brunswick, NJ, UNITED 

STATES OF AMERICA, 8 Melanoma Program, University of California, 

San Francisco, San Francisco, CA, UNITED STATES OF AMERICA, 9 Department 

of Pharmacology, The Netherlands Cancer Institute, Amsterdam, 

NETHERLANDS, 10 Hunstman Cancer Institute, University of Utah, Salt Lake City, 

UT, UNITED STATES OF AMERICA, 11 Department of Investigational Cancer 

Therapeutics, UT MD Anderson Cancer Center, Houston, TX, UNITED STATES 

OF AMERICA, 12 Research and Development, Oncology, GlaxoSmithKline, 

Research Triangle Park, NC, UNITED STATES OF AMERICA, 13 Research and 

Development, Oncology, GlaxoSmithKline, Collegeville, PA, UNITED STATES OF 

AMERICA 

Background: GSK458 is an oral, potent inhibitor of PI3K (α, β, γ, δ), mTORC1, and 

mTORC2. Cell lines with activation of the PI3K pathway are more likely to be 

sensitive to GSK458. 

Methods: Pts with advanced solid tumors received GSK458 until disease progression 

or intolerable toxicity. Dose escalation with once (QD) and twice daily dosing (BID) 

was explored. Pharmacodynamics (PD) (tumor biopsies and FDG–PET) in unselected 

populations, and clinical activity in specific populations (PIK3CA-mutant and wild-type 

[WT]) bladder cancer, renal cell carcinoma, PIK3CA-mutant metastatic breast cancer, 

and KRAS-WT metastatic endometrial cancer) were evaluated. 

Results: 170 pts (49% female; mean age 57 [22-85] yrs) received doses ranging from 

0.1 to 3 mg, the MTD for both QD and BID was 2.5 mg. The median (range) time 

above the target plasma concentration (20 ng/mL) was longer in BID versus QD 

dosing: 21hour (h) (14.8-24; n = 6) versus 8h (0-23.9; n = 18), respectively. Dose 

limiting toxicities were Grade 3 diarrhea. Most frequent (≥ 20%) drug related adverse 

events were diarrhea (28%), fatigue (24%) and nausea (23%). A dose response 

relationship between GSK458 plasma concentrations and increases in serum insulin 

levels was observed. 13 paired pre/post-dose tumor biopsies showed inconsistent 

changes in pAKT/total AKT, Ki67 and phospho-histone-H3. 9 pts had pre/post-dose 

FDG-PET; one pt had a mean SUV value decrease by ≥30% post-dose although none 

had responses per RECIST. Objective responses were seen in bladder cancer (1/3 

PIK3CA mutant and 2/15 wild-type) and renal cell (2/23: 1 CR duration 25+ months, 


1PR), but no responses were seen in PIK3CA-mutant breast cancer (1/10: stable for >6 

months) or KRAS-WT endometrial cancer (1/12: stable disease for > 6 months). 

Conclusions: Based on its superior pharmacokinetic profile, BID is the 

recommended schedule for GSK458 monotherapy. Surrogate PD markers (insulin) 

indicate on target activity. GSK458 showed promising activity in PIK3CA mutant 

bladder cancer and RCC. 

Disclosure: P. Munster: Phase I Research: GSKJ. Specht: Corporate-sponsored 

research: Pfizer, BMS, Genentech, BiPar Sciences, Boehringer IngelheimE.C. Dees: 

Corporate-sponsored research: GSK, Novartis, Genentech/Roche, MillenniumA. Tan: 

Corporate-sponsored research: GSKA. Daud: Membership on an advisory board or 

board of directors: Oncosec; Corporate-sponsored research: GSK, Pfizer, Merck, 

Oncosec, Exelixis G. Falchook: Corporate-sponsored research: GSK; GSK Travel 

reimbursement for ESMO 2010J. F. Kleha: Stock ownership: GSK; GSK EmployeeM. 

Durante: Stock ownership: GSK; GSK EmployeeD.A. Smith: Stock ownership: GSK; 

GSK EmployeeL. Adams: Stock ownership: GSK; GSK EmployeeJ. Greshock: Stock 

ownership: GSK; GSK EmployeeS.R. Morris: Stock ownership: GSK; GSK 

EmployeeAll other authors have declared no conflicts of interest. 

443PD PHARMACODYNAMIC (PD) – PHARMACOKINETIC (PK) 

STUDY OF FICLATUZUMAB(F), A MONOCLONAL ANTIBODY 

(MAB) DIRECTED TO THE HEPATOCYTE GROWTH FACTOR 

(HGF), IN PATIENTS (PTS) WITH ADVANCED SOLID TUMORS 

WHO HAVE LIVER METASTASES (METS) 

E. Elez 1 , J. Tabernero 2 , L. Prudkin 3 , S. Agarwal 4 , M. Han 4 , M. Credi 4 ,W.Yin 4 , 

N. Kuriyama 4 , J. Baselga 5 


2 Oncology Department, Vall d’Hebron University HospitalMedical Oncology 

Service, Barcelona, SPAIN, 3 Pathology, Vall d’Hebron University Hospital, 

Barcelona, SPAIN, 4 Oncology, AVEO Pharmaceuticals, Inc, Cambridge, MA, 

UNITED STATES OF AMERICA, 5 Hematology/Oncology, MGH Cancer Center, 


Background: F is a humanized IgG1 mAb directed to HGF that inhibits activation of 

the c-Met receptor, with potential anti-tumor activity. This study was to define the 

optimal dose using PD and PK assessments. 

Methods: Pts with solid tumors and liver mets, with phospho (p)-Met expression 

were sequentially enrolled into 2, 10, or 20 mg/kg (RP2D, defined in a previous 

study), of F given IV every 2 wks and were evaluated every 8 wks for response 

using RECIST 1.1. Target pathway modulation was assessed by measuring the 

following PD markers by IHC in biopsies of liver mets: p-Met, p-Akt, p-ERK, 

p-S6K, HGF, and c-Met; Ki67 and cleaved caspase-3; and CD31. PD-evaluable pts 

had measurable p-Met at Cycle 1 Day 1 pre-dose and at least one post-dose 

timepoint. Serum was collected to measure F, anti-drug antibody (ADA), s-Met, 

HGF, and HGF/F complex levels by ELISA. 

Results: Nineteen pts received F: 15 male/4 female; median age 60 years; ECOG PS 0/1 

(8/11 pts). The most frequent TEAEs, mostly Grade 1 to 3, were asthenia, edema, hepatic 

pain (32% each), cough (26%). There were no DLTs or ADA. Serum albumin decreased 

to below normal for most pts at EOT and recovered at the follow up visit. Best overall 

response was SD (5/18 pts) and disease progression (13/18 pts), and median duration of 

treatment was 6 wks (range 2-59). PK analysis revealed dose-proportional drug exposure 

with a low systemic clearance leading to a terminal half-life of 7.4 to 10.0 days, and a low 

volume of distribution approximating the plasma volume. F treatment increased the total 

serum HGF and HGF/F complex levels. Increasing dose of F resulted in progressive 

decreases in p-Met and p-AKT. At RP2D, the majority of pts experienced ≥ 25% 

decrease from baseline in p-Met, p-ERK, p-Akt, Ki67 and CD31. 

Conclusions: Ficlatuzumab(F) is well tolerated in this population. The PK of F in 

this study was consistent with that reported previously. Increase in post-dose serum 

HGF and HGF/F complex levels indicates target engagement. At RP2D, a majority of 

pts experienced decreases in key cell signaling PD markers. This study supports the 

selection of 20 mg/kg F dose as RP2D. 


444PD PHASE I DOSE-ESCALATION STUDY OF ORAL SELECTIVE 

C-MET INHIBITOR EMD 1214063 IN PATIENTS WITH 

ADVANCED SOLID TUMORS 

G.S. Falchook 1 , D.S. Hong 1 , H.M. Amin 2 ,S.Fu 1 , S.A. Piha-Paul 1 , 

M.B. Klevesath 3 , V. Jego 4 , A. Johne 5 , S. Stinchi 6 , R. Kurzrock 1 

1 Department of Investigational Cancer Therapeutics, UT MD Anderson Cancer 

Center, Houston, TX, UNITED STATES OF AMERICA, 2 Department of 

Hematopathology, UT MD Anderson Cancer Center, Houston, TX, UNITED 

STATES OF AMERICA, 3 Global Early Development Unit - Oncology, Merck 

KGaA, Darmstadt, GERMANY, 4 Biostatistics Geneva, Merck Serono, Geneva, 

SWITZERLAND, 5 Clinical Pharmacology, Merck KGaA, Darmstadt, GERMANY, 

6 Istituto Di Ricerche Biomediche, Merck Serono RBM, Colleretto Giacosa, ITALY 

Purpose: The cell surface receptor tyrosine kinase c-Met and its ligand, hepatocyte 

growth factor (HGF), mediate cell migration, survival and proliferation. EMD 


1214063 is a highly selective, reversible and ATP-competitive c-Met inhibitor that 

causes growth inhibition and regression of HGF-dependent and HGF-independent 

tumors in pre-clinical models. 

Methods: This is a first-in-man dose-escalation study to establish the MTD of EMD 

1214063. Eligible pts had advanced solid tumors not amenable to standard therapy. 

Following a 3 + 3 dose escalation scheme, pts were treated with once-daily oral EMD 

1214063 according to two 21-day-cycle schedules, either days 1-14 followed by a 

7-day rest (regimen 1, [R1]), or continuous 3 times weekly (regimen 2, [R2]). An 

optimised formulation was introduced in August 2011. Pd markers were evaluated in 

paired tumor biopsies using immunohistochemistry (IHC) and a Luminex based 

assay. 

Results: Until 3 November 2011, 50 pts had been treated; 27 in R1 and 23 in R2. 

The dose was escalated from 30 mg/day to 230 mg/day in R1 and to 115 mg/day in 

R2 with the initial formulation. For the optimised formulation, data are available for 

30 mg and 60 mg/day for R1, and for 60 mg/day in R2. Cmax and AUC increased 

with dose. The optimised formulation showed higher oral bioavailability. Two DLTs 

were reported, a G4 lipase and G3 amylase elevation in 1 pt in R1 at 115 mg/day, 

and a G3 lipase elevation in R2 at 115 mg/day. No treatment-related SAEs were 

observed. Treatment-related AEs of ≥G2 included nausea (n = 1), vomiting (n = 1), 

decreased appetite (n = 2), diarrhea (n = 1), and fatigue (n = 1) in R1, and 

neutropenia (n = 1) and fatigue (n = 1) in R2. Forty-four patients (88%) had no 

drug-related AE >G1. Analysis of pre- and on-treatment biopsies showed decreased 

phospho-c-Met staining intensity under treatment on IHC and >80% reduction in 

phospho-c-Met levels on the Luminex assay. Preliminary anti-tumor activity included 

an unconfirmed PR in 1 pt and SD ≥4 months in 7 pts. One pt with sarcomatoid 

bladder cancer and multiple MET copies due to polysomy of Chr 7 achieved SD for 

12+ months. 

Conclusion: The MTD has not yet been reached and dose escalation of EMD 

1214063 continues. Updated results will be presented. 

Disclosure: G.S. Falchook: Has a consultant/advisory relationship with EMS Serono, 

received research funding of EMD Serono, received travel reimbursement from EMD 

Serono. H.M. Amin: Received research funding of EMD SeronoM.B. Klevesath: 

Merck KGaA employeeV. Jego: Merck Serono employeeA. Johne: Merck Serono 

employeeS. Stinchi: Merck Serono employeeR. Kurzrock: Received research funding 

of EMD Serono and Merck KGaAAll other authors have declared no conflicts of 

interest. 

445PD CLINICAL ACTIVITY AND PHARMACOKINETICS (PK) OF 

CABOZANTINIB (XL184) IN PATIENTS WITH PROGRESSIVE 

MEDULLARY THYROID CARCINOMA (MTC) 

E.E.W. Cohen 1 , R. Elisei 2 , M.J. Schlumberger 3 , S.P. Müller 4 , P. Schöffski 5 , 

M. Brose 6 , M. Shah 7 , D.R. Miles 8 , L.T. Nguyen 8 , S. Sherman 9 

1 Dept of Medicine, University of Chicago Medical Center, Chicago, IL, UNITED 

STATES OF AMERICA, 2 Department of Endocrinology, University of Pisa, Pisa, 

ITALY, 3 Medical Imaging, Institut de Canc, Villejuif Cedex, FRANCE, 4 Klinik und 

Poliklinik für Nuklearmedizin, Universitätsklinikum Essen, Essen, GERMANY, 

5 Department of General Medical Oncology, University Hospitals Leuven, Leuven, 

BELGIUM, 6 Dept of Medicine, University of Pennsylvania Health System, 

Philadelphia, PA, UNITED STATES OF AMERICA, 7 College of Medicine, Ohio 

State University, Columbus, OH, UNITED STATES OF AMERICA, 8 Nonclinical 

Development, Exelixis, Inc., South San Francisco, CA, UNITED STATES OF 

AMERICA, 9 Department of Endocrine Neoplasia and Hormonal Disorders, 

University of Texas MD Anderson Cancer Center, Houston, TX, UNITED STATES 

OF AMERICA 

Background: Cabozantinib (cabo) is a potent oral therapy that inhibits MET, 

VEGFR2, and RET. In a phase 1 study, cabo demonstrated anti-tumor activity in 

patients with MTC, and a long terminal half-life of 120 hours. We report 

clinical activity and PK analyses from a Phase 3 study of cabo versus placebo 

(P) in patients with progressive, unresectable, locally advanced or metastatic 

MTC. 

Methods: Patients with MTC and documented RECIST progression within 14 

months (mo) of screening were randomized 2:1 to receive cabo (140 mg freebase qd, 

n = 219) or placebo (n = 111). Blood samples for PK were collected on days 1 and 29. 

Baseline tumor and blood samples were evaluated for RET mutation status. Tumor 

assessments occurred every 12 weeks, and the primary efficacy measure was 

progression-free survival (PFS), assessed by an independent radiology committee 

using RECIST. 

Results: Statistically significant PFS prolongation was observed, with median PFS for 

cabo of 11.2 mo versus 4.0 mo for P (HR 0.28, 95% CI 0.19-0.40, p < 0.0001). PFS 

results favored the cabo group across all RET mutation subgroups with hazard ratios 

0.24, 0.47, and 0.30 for RET mutation positive, negative, and unknown subgroups. 

The 12-mo progression-free landmark estimate is 47.3% for cabo and 7.2% for P; 

objective response rate was 28% for cabo vs 0% for P. Cabo demonstrated moderate 

accumulation, with plasma C max ∼3.6-fold increased at steady-state (Day 29) relative 

to Day 1. Plasma concentrations did not fluctuate markedly over the 24 hr dosing 

interval on Day 29. In a population-PK analysis, moderate inter-subject variability in 

clearance (CL/F) was observed (CV of ∼35%). No clinically significant covariates on 

PK were identified which would require dose adjustment, and PFS for cabo-treated 



subjects did not correlate with individual subject steady-state AUC predicted for 

uninterrupted 140 mg qd dosing. 

Conclusions: Cabo significantly prolonged PFS compared to placebo in a patient 

population with progressive MTC. PK analysis supports administration of cabo as a 

fixed dose without adjustment for patient covariates. 

Disclosure: M.J. Schlumberger: MJ Schlumberger has been a compensated 

consultant for Exelixis. M. Brose: Dr. Brose has received research funding and 

honoraria from Exelixis. M. Shah: Dr. Shah has received research funding from 

Exelixis. D.R. Miles: D. Miles is an employee and stockholder of Exelixis. L.T. 

Nguyen: Linh Nguyen is an employee and stockholder in Exelixis. S. Sherman: Dr. 

Sherman is a compensated consultant to Exelixis. All other authors have declared 


446PD PHASE I STUDY OF AFATINIB (BIBW 2992), AN ERBB 

FAMILY BLOCKER PLUS NINTEDANIB (BIBF 1120), A TRIPLE 

ANGIOKINASE INHIBITOR, IN PATIENTS (PTS) WITH 

ADVANCED SOLID TUMOURS 

J. Soria 1 , A. Hollebecque 1 , C. Massard 1 , E. Deutsch 1 , A. Varga 1 , N. Morsli 2 , 

M. Ould Kaci 2 , H. Staines 2 , K. Marzin 3 , R. Bahleda 1 

1 Dept. of Medicine, Institut Gustave Roussy, Villejuif Cedex, FRANCE, 2 Medical 

Affairs, Boehringer Ingelheim, Paris, FRANCE, 3 Pharmacokinetics, Boehringer 

Ingelheim, Biberach, GERMANY 

Background: Inhibiting multiple signalling pathways with the combination of 

afatinib, an oral irreversible ErbB Family Blocker, and nintedanib, an oral triple 

angiokinase inhibitor of VEGFR, PDGFR and FGFR, may lead to better efficacy. 

Methods: This Phase I study used a modified 3 + 3 design to determine the 

maximum tolerated dose (MTD) of afatinib, with dose escalating from 10 to 40 mg 

qd given in 2 schedules: continuous (C) or intermittent (I) (every other week), in 

combination with fixed-dose nintedanib (200 mg bid reduced to 150 mg bid after 

protocol amendment) in a 28-day cycle. Secondary endpoints were safety, efficacy, 

pharmacokinetics (PK), and circulating tumour cells (CTC) analysis. Treatment 

continued until disease progression or intolerability. 

Results: 45 pts with heavily pretreated advanced solid tumours were included: 26 

men; median age 56 years (range 37–73); main cancer types: lung (NSCLC), 

colorectal, breast, melanoma and ovary. Main adverse events were diarrhoea, 

asthenia, nausea, vomiting and transaminase elevation. Two MTDs were established: 

afatinib 40 mg qd (I) plus nintedanib 150 mg bid and afatinib 30 mg qd (C) plus 

nintedanib 150 mg bid (Table). Efficacy data showed evidence of antitumour activity 

with partial responses (RECIST) observed in 2 pts (HER2-negative breast cancer, and 

head & neck squamous cell carcinoma) and stable disease in 27 pts (lasting >3 

months in 8 pts). Preliminary PK data showed no drug–drug interaction. CTC 

analysis will be presented. 

Afatinib (C or I) 

(mg qd) 

Nintedanib 

(mg bid) 

Evaluable pts/ 

dose-limiting 

toxicity (DLT) DLT/Grade (G) 

10 C 200 3/0 

20 C 200 3/0 

30 C 200 7/2 diarrhoea G3, 

transaminase elevation 

G3 

40 C 200 3/3 diarrhoea G3, 


G3; creatinine increase 

G2 

30 I 200 6/2 diarrhoea G3, 


G3, creatinine increase 

G2 

40 I 200 6/2 dehydration G3, 


G4 

40 C 150 3/2 diarrhoea G3, renal 

failure G3 

40 I 150 6/0 MTD 

30 C 150 6/0 MTD 

Conclusion: At MTD, the combination of afatinib with nintedanib showed a 

manageable safety profile and evidence of activity in different heavily pretreated 

tumour types. 

Disclosure: J. Soria: Honoraria from Boehringer Ingelheim and Roche. N. Morsli: 

Employee of Boehringer Ingelheim. M. Ould Kaci: Employee of Boehringer 

Ingelheim. H. Staines: Employee of Boehringer Ingelheim. K. Marzin: Employee of 

Boehringer Ingelheim. All other authors have declared no conflicts of interest. 

447PD PRECLINICAL AND CLINICAL EVALUATION OF THE 

COMBINATION OF SORAFENIB AND EVEROLIMUS IN 

PATIENTS WITH ADVANCED SOLID TUMORS 

W.W. Ma1 , C. Weekes2 , D.K. Pawaskar3 , G. Fetterly1 , W.A. Messersmith2 , 

G.K. Dy1 , R.M. Straubinger3 , W.J. Jusko3 , S.G. Eckhardt4 , A.A. Adjei5 1 

Medicine, Roswell Park Cancer Institute, Buffalo, NY, UNITED STATES OF 

AMERICA, 2 Medicine, Univ of Colorado Health Sci Ctr, Aurora, CO, UNITED 

STATES OF AMERICA, 3 Pharmaceutical Sciences, State University of New York 

at Buffalo, Buffalo, NY, UNITED STATES OF AMERICA, 4 Medical Oncology, 

University of Colorado Denver, Denver, CO, UNITED STATES OF AMERICA, 

5 

Medicine Oncology, Roswell Park Cancer Institute, Buffalo, NY, UNITED 


Background: Using a patient-derived primary pancreatic cancer (PanCa) xenograft 

SCID mouse model, we found synergistic anti-tumor effects of sorafenib (S) 20 mg/ 

kg + everolimus (E) 1 mg/kg, and greater efficacy than either drug alone. No 

significant mouse toxicity was observed (weight loss, fur quality, GI toxicity). Here, we 

conducted a phase I and pharmacokinetic (PK) study of S + E in patients with advanced 

solid tumors, intending to expand to a phase II PanCa trial. Methods: Patients with 

advanced solid tumors were treated at dose levels (DL): [DL1] S 400 mg bid + E 5 mg 

daily; [DL2] S 400 mg bid + E 10 mg daily every 28-day cycle using a 3 + 3 dose 

escalation design. Patients started treatment with either S or E alone during a 1-week 

run-in, and the other agent added from Cycle 1 Day 1 onwards. Plasma samples were 

collected and analyzed for S and E, and PK was compared to preclinical studies. 

Results: Ten of 22 patients were evaluable for dose-limiting toxicity (DLT). Two of 6 

and 3 of 4 patients developed DLT at DL1 and 2 respectively, including grade (G) 3 

diarrhea, rash, hypophosphatemia, hand-foot syndrome and G4 fistula. Median 

cycles received were 1.5. Clinical E exposure (AUC profile) was significantly lower (1/ 

100th) than in preclinical combination studies whereas S exposure was comparable. 

Best response was stable disease for 6 cycles (168 days) in a uterine carcinosarcoma 

patient at DL1 (prior therapy PFS 114 days). Intention-to-treat analysis of 12 

advanced gemcitabine-refractory (GR) PanCa patients showed median survival of 2.7 

mo (95%CI 0, 6.8 mo). No PK interaction between S and E was observed. 

Conclusions: E at doses 5 mg and 10 mg daily combined with S 400 mg bid were not 

tolerable in patients. S toxicity appeared accentuated by E co- administration with no 

drug-drug PK interaction observed. Efficacy was observed in uterine carcinosarcoma but 

no significant efficacy in GR-PanCa. Although our preclinical model indicated efficacy 

of S + E in PanCa, it failed to predict the clinical toxicity profile. 


448PD A PHASE I STUDY OF THE COMBINATION OF RO4929097 

(RO) AND CEDIRANIB (CD) IN PATIENTS WITH ADVANCED 

SOLID TUMORS (PJC-004/NCI 8503) 

S. Sahebjam 1 , P. Bedard 2 , V. Castonguay 1 , H. Chen 3 , S.P. Ivy 3 , A.M. Oza 1 , 

E.X. Chen 1 , H.W. Hirte 4 , L. Siu 1 , S.J. Hotte 4 

1 Drug Development Program, Medical Oncology, Princess Margaret Hospital, 

Toronto, ON, CANADA, 2 Dept of Medical Oncology, Princess Margaret Hospital, 

Toronto, ON, CANADA, 3 Cancer Therapy Evaluation Program, National Cancer 

Institute, Bethesda, MD, UNITED STATES OF AMERICA, 4 Medical Oncology, 

Juravinski Cancer Centre, Hamilton, ON, CANADA 

Background: The NOTCH signaling pathway has been implicated in the 

tumorigenesis and resistance to anti-VEGF therapy, providing a rationale for the 

combination of RO, a gamma secretase inhibitor of NOTCH signaling, and Cd, a 

VEGFR-tyrosine multi-kinase inhibitor. 

Methods: The primary objectives of this study were to assess safety, tolerability, and 

recommended phase II dose (RP2D) of combination therapy in patients (pts) with 

advanced solid tumors. Secondary objectives were to determine preliminary anti-tumor 

efficacy, as per RECIST v1.1 criteria, as well as pharmacokinetic (PK) and 

pharmacodynamic (PD) studies. A standard 3 + 3 design was used. Cycle 1 is 42 days (D), 

where RO is given orally once daily D1-3, 8-10, 15-17, 22-24, 29-31, 36-38 and Cd is 

given orally once daily D22-42. Cycles 2 + are 21 days, with RO given D1-3, 8-10, 15-17 

and Cd given D1-21. Dose-limiting toxicity (DLT) was evaluated during cycle 1 (42 days). 

Results: Twenty pts (median age of 54 [18-87]; ECOG 0-1) have been treated at 3 

dose levels (DL): 7 pts at DL1 (RO = 10 mg; Cd =20 mg), 7 pts at DL2 (RO = 20 mg; 

Cd = 20 mg), and 6 pts at DL3 (RO = 20 mg; Cd = 30 mg). Primary tumors included: 

colorectal carcinoma (6), uterine sarcoma (4), renal cell carcinoma (3), and others 

(7). Pts received a median number of 3 cycles (range 1-20). The most common 

adverse events (AEs) of all grades possibly related to study drugs included (#pts): 

diarrhea (12), hypertension (HTN) (11), fatigue (11), and nausea (9). Grade 3+ AEs 

possibly related to study drugs included HTN, ALT and AST elevation, diarrhea, and 

hypophosphatemia. Two DLTs were observed: grade 4 HTN in DL1 which resolved 

after dose reduction and grade 4 AST elevation in DL2 which improved after 

discontinuing treatment. Of the 19 patients evaluable for response, the best response 

was stable disease (SD) in 12 pts and progressive disease in 7. Prolonged SD of ≥6 

cycles was observed in 4 pts, including 1 pt with low grade endometrial stromal 

sarcoma on DL1 who remains on study after 20 cycles. 

Conclusions: RO in combination with Cd is generally well tolerated at the 

DLs tested. The RP2D was defined as 20mg RO and 30mg Cd. PK data for 


RO and Cd, as well as PD data for circulating angiogenic factors will be 

presented. 


449PD PHASE 1 DOSE-ESCALATION TRIAL OF THE 

INVESTIGATIONAL HEDGEHOG (HH) PATHWAY INHIBITOR 

TAK-441 IN PATIENTS WITH ADVANCED SOLID TUMORS 

J.W. Goldman 1 , S.G. Eckhardt 2 , M. Borad 3 , M. Hidalgo 4 , D.P. Ryan 5 , A. Parikh 6 , 

S. Kuan 7 ,J.Yu 7 , S. Stewart 1 , L.S. Rosen 1 

1 Hematology / Oncology, UCLA Medical Center, Santa Monica, CA, UNITED 

STATES OF AMERICA, 2 Medical Oncology, University of Colorado School of 

Medicine, Aurora, CO, UNITED STATES OF AMERICA, 3 Hematology / Oncology, 

Mayo Clinic, Scottsdale, AZ, UNITED STATES OF AMERICA, 4 GIi Cancer Clinical 

Research Unit, CNIO- Spanish National Cancer Center, Madrid, SPAIN, 

5 Hematology / Oncology, Massachusetts General Hospital, Boston, MA, UNITED 

STATES OF AMERICA, 6 General Medicine, Takeda Pharmaceuticals 

International, Inc., Deerfield, IL, UNITED STATES OF AMERICA, 7 Clinical 

Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED 


Background: Dysregulation of the Hh pathway is a principal event in the 

carcinogenesis of multiple tumor types, including basal cell carcinoma. TAK-441 is 

an investigational, orally-available inhibitor of the G protein-coupled receptor 

Smoothened, a component of the Hh signalling cascade. 

Methods: This study (NCT01204073) was designed to determine safety, maximum 

tolerated dose (MTD) and maximum feasible dose (MFD) in patients with advanced 

solid tumors. Cycles consisted of 3 weeks continuous dosing, with a single-dose cycle 

1 lead-in, followed by 7 d pharmacokinetics (PK). Dose escalation (DE) proceeded in 

a modified 3 + 3 fashion. Radiographic tumor assessments were performed after 

cycles 2, 4, and every 4 cycles thereafter. 

Results: Thirty-two patients were enrolled in the DE phase, median age 59 y (range 

28–82), and treated with doses from 50–1600 mg daily. TAK-441 concentrations 

were quantifiable in plasma after the starting 50 mg dose, with total exposure 

increasing dose-proportionally to 800 mg. Maximum plasma concentration typically 

was reached 3 h post-dose. The median terminal disposition half-life was 15 h (range 

6–35 h). DLTs of Gr 3 fatigue and muscle spasms were observed in 1 pt at the 1600 

mg dose. Six subjects discontinued due to an adverse event (AE) including a patient 

who suffered a fatal cerebral hemorrhage in cycle 4 related to 50 mg TAK-441. Most 

common treatment-emergent AEs were muscle spasms (44%), dysguesia (41%), 

nausea (41%), fatigue (38%) and constipation (28%). The MFD is 1600 mg and the 

MTD has not been reached. Four patients remained on trial for >10 cycles, and 3 

patients continue on treatment. Response and PK/PD data will be presented. 

Conclusions: TAK-441 was well-tolerated up to an MFD of 1600 mg taken once 

daily. A dose expansion cohort has been initiated at 800 mg in patients with 

untreated basal cell carcinoma. 

Disclosure: S.G. Eckhardt: Consultancy, Research funding and Speakers Bureau/ 

Advisory Committee for Millennium/Takeda. S. Kuan: Employment with Millennium 

Pharmaceuticals, Inc. J. Yu: Employment and consultancy for Millennium. L.S. Rosen: 

Research support from Millennium. All other authors have declared no conflicts of interest. 

450PD A PHASE IB COMBINATION STUDY OF RO4929097 (RO), A 

GAMMA-SECRETASE INHIBITOR, AND TEMSIROLIMUS 

(TEM) IN PATIENTS (PTS) WITH ADVANCED SOLID TUMORS 

I. Diaz-Padilla 1 , S.J. Hotte 2 , S.P. Ivy 3 , A.M. Oza 1 , H.W. Hirte 2 , A.R.A. Razak 1 , 

E.X. Chen 1 , I. Brana Garcia 1 , L. Siu 1 , P. Bedard 1 

1 Dept. of Medical Oncology and Hematology, Princess Margaret Hospital, 

Toronto, ON, CANADA, 2 Medical Oncology, Juravinski Cancer Centre, Hamilton, 

ON, CANADA, 3 Cancer Therapy Evaluation Program, National Cancer Institute, 

Bethesda, MD, UNITED STATES OF AMERICA 

Background: The notch signalling pathway has a critical role in regulating cellular 

differentiation, proliferation, and apoptosis. RO is a potent and selective gamma-secretase 

inhibitor with antitumor activity in animal models. Pre-clinical experiments indicate that 

the PI3K/AKT/mTOR pathway may mediate resistance to gamma secretase inhibitors, 

providing a rationale for combination therapy with RO and TEM. 

Methods: A phase Ib dose-escalation study with a 3 + 3 design was conducted. 

Three dose levels (DLs) were planned. Objectives were to determine the 

recommended phase II dose (RP2D), safety, pharmacokinetics (PK) and 

pharmacodynamics (PD) of the combination. Eligible pts received once daily oral 

RO on a 3 day on/4 day off schedule every week (QW), and intravenous QW 

TEM. Initial doses were 10 mg RO and 25 mg TEM. Cycles were every 21 days, 

except for cycle 1, which was 28 days. Treatment-related dose-limiting toxicities 

(DLTs) were evaluated during cycle 1. 

Results: 17 pts (data cut-off 26-Apr-2012) have been treated on three DLs. Number of 

pts, DLTs and schedule are shown in Table 1. Demographics: M:F 6:11; median age: 60 

yrs (range 28-84); ECOG 0/1:4/13. Pts received a median of 3 cycles (range 1-12). The 

most common adverse events (AEs) related to the study drug combination included: 

fatigue (82%; G3 6%), mucositis, (71%; G3 6%), neutropenia (59%; G3 12%), anemia 

(59%;G30%),andhypertriglyceridemia(59%,G30%).TwoDLTs(G3rash,G3 

mucositis) were observed in the same patient in DL1 prompting dose expansion. No 

additional DLTs were observed. Of 15 patients evaluable for response, no objective 

responses were observed. 11 pts (73%) had stable disease (SD) as their best response; with 

3 pts (sarcoma, neuroendocrine, non-small cell lung cancer) on therapy for ≥6 cycles. 

Conclusions: RO can be safely combined with TEM. The RP2D was established as 

RO at 20 mg combined with 37.5 mg of TEM. PK and circulating angiogenic factors 

analyses will be presented. 

RO Dose 

(mg) 

TEM Dose 

(mg) 

No. of pts 

treated 

No. of pts 

with DLT DLT 

Dose Level 

1 † 

10 25 8 1 G3 rash, G3 

mucositis 

2 20 25 3 0 

3 ∧ 

20 37.5 6 0 

† 2 pts were not evaluable for DLT ∧ DL3 (RP2D) was expanded to 6 pts 



451P PHASE I AND PHARMACOKINETICS/PHARMACODYNAMICS 

(PK/PD) STUDY OF MEK INHIBITOR, RO4987655, IN 

JAPANESE PATIENTS WITH ADVANCED SOLID TUMORS 

S. Nakamichi 1 , H. Nokihara 1 , N. Yamamoto 1 , Y. Tamura 1 , K. Honda 1 , H. Wakui 1 , 

Y. Yamada 2 , N. Yamazaki 3 , S. Suzuki 4 , T. Tamura 1 

1 Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN, 

2 Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, 

JAPAN, 3 Division of Dermatological Oncology, National Cancer Center Hospital, 

Tokyo, JAPAN, 4 Division of Ophthalmic Oncology, National Cancer Center 

Hospital, Tokyo, JAPAN 

Background: RO4987655, an oral and selective inhibitor of MEK, is a key enzyme of 

the MAPK signaling pathway. This was a phase I, non-randomized, open-label, 

dose-escalation study in Japanese patients with advanced solid tumors. Primary 

objectives were determination of maximum tolerated dose (MTD) based on 

dose-limiting toxicities (DLTs), safety evaluation and PK analysis. Secondary 

objectives were PD analysis and exploratory analysis of RO4987655’s anti-tumor 

activity according to the RECIST 1.0 criteria. 

Methods: Patients received an oral single dose of RO4987655 (1, 2, 4, 5, and 6.5 mg) 

(Cycle 0) followed by continuous once daily dosing (QD, 1, 2, and 4 mg/day) then 

twice daily dosing (4, 5, and 6.5 mg BID, total daily dose: 8, 10, and 13 mg/day) in 

28-day cycles. A 3 + 3 dose-escalation design was used. Blood samples for PK analysis 

were collected in Cycle 0 (Day 1, 2, and 3) and in Cycle 1 (Day 1, 8, 15, and 22). PD 

was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). 

Results: As of March 2012, 25 patients were enrolled in 6 cohorts of 1, 2, 4, 8, 10, 

and 13 mg/day. Four DLTs were observed in the 13 mg/day (n = 2) and 10 mg/day 

(n = 2) cohorts, all of them reversible Grade 3 creatine phosphokinase (CPK) 

elevation. MTD was defined as 8 mg/day. Most commonly related adverse events 

(AEs) included dermatitis acneiform, CPK elevation, and eye disorders. Plasma 

exposure of RO4987655 appeared to increase in a dose-proportional manner with a 

plasma half-life (t1/2) of 14.0 to 24.4 hours. After multiple dose administration, 

steady-state conditions were reached by Cycle 1 Day 8 (240 hours). The inhibitory 

effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. 

Conclusions: The MTD of RO4987655 for Japanese patients was defined as 8 mg/ 

day. RO4987655 has a manageable safety profile with a favorable PK/PD correlation 

in Japanese patients with advanced solid tumors. 

Disclosure: S. Nakamichi: This phase I clinical trial is sponsored by Chugai 

Pharmaceutical Co., Ltd. H. Nokihara: This phase I clinical trial is sponsored by 

Chugai Pharmaceutical Co., Ltd. N. Yamamoto: This phase I clinical trial is 

sponsored by Chugai Pharmaceutical Co., Ltd. Y. Tamura: This phase I clinical trial 

is sponsored by Chugai Pharmaceutical Co., Ltd. K. Honda: This phase I clinical trial 

is sponsored by Chugai Pharmaceutical Co., Ltd. H. Wakui: This phase I clinical trial 

is sponsored by Chugai Pharmaceutical Co., Ltd. Y. Yamada: This phase I clinical 

trial is sponsored by Chugai Pharmaceutical Co., Ltd. N. Yamazaki: This phase I 

clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. S. Suzuki: This phase I 

clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. T. Tamura: This phase 

I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. 



452P A PHASE 1B STUDY TO EVALUATE THE SAFETY AND 

PHARMACOLOGY OF THE DUAL PI3K-MTOR INHIBITOR 

GDC-0980 IN COMBINATION WITH A FLUOROPYRIMIDINE, 

OXALIPLATIN, AND BEVACIZUMAB (BEV) IN PATIENTS WITH 


L.S. Rosen1 , J. Goldman1 , S. Stewart1 , J.M. Hubbard2 , M. Roos2 ,W.Lin3 , 

G. Shankar4 , J. Capdevila5 , E. Freas6 , S. Leong6 1 

Division of Hematology Oncology, UCLA, Santa Monica, CA, UNITED STATES 

OF AMERICA, 2 Oncology, Mayo Clinic, Rochester, MN, UNITED STATES OF 

AMERICA, 3 Bioocology Early Clinical Development, Genentech Inc, South 

San Francisco, CA, UNITED STATES OF AMERICA, 4 Biooncology Early Clinical 

Development, Genentech Inc, South San Francisco, CA, UNITED STATES OF 

AMERICA, 5 Medical Oncology, Hospital Vall d’Hebrón, Barcelona, SPAIN, 

6 

Medicine/oncology, University of Colorado, Denver, CO, UNITED STATES OF 

AMERICA 

Background: PI3K signaling is altered in many cancer types. In colorectal cancer 

(CRC), ∼30% of the tumors harbor PIK3CA mutations, and ∼20% of tumors have 

PTEN loss. GDC-0980 has demonstrated synergy with fluoropyrimidines, a common 

therapeutic agent in colorectal and advanced breast cancers. 

Methods: This was a standard 3 + 3 dose escalation design to determine the 

recommended phase 2 dose (RP2D) of GDC-0980 with capecitabine (CPC) (Arm A) or 

with mFOLFOX6 + Bev (Arm B) in patients (pts) with advanced solid tumors. In Arm A, 

GDC-0980 and CPC are given daily for 14 consecutive days in each 21-day cycle. In Arm 

B, GDC-0980 is given for 7 consecutive days in a 14-day cycle with mFOLFOX6 given on 

the first day. Bev is given on Day 1 starting in Cycle 5 during the dose escalation stage. 

Results: In Arm A 6 pts received 25mg GDC-0980 and 1650mg/m2 bid of CPC 

(A1); 3 pts received 40mg GDC-0980 and 1650mg/m2 CPC (A2); and 9 pts received 

40mg GDC-0980 and 2000mg/m2 CPC (A3). Common adverse events (AEs) in 

>20% pts were nausea, fatigue, decreased appetite, hyperglycemia, vomiting, diarrhea, 

stomatitis, mucositis and rash. One dose limiting toxicity (DLT) of G3 AST/ALT was 

observed in A1. The RP2D in Arm A is 40mg GDC-0980 + 2000mg/m2 CPC. One pt 

in A2 with HNSCC experienced a confirmed partial response (cPR, ≥6mo). In Arm 

B, 4 pts received 25 mg (B1) and 6 pts received 40mg GDC-0980 (B2) in combination 

with mFOLFOX6 and Bev (10 mg/kg). The RP2D in Arm B is 40mg GDC-0980 + 

mFOLFOX6 + Bev. Common AEs in >20% pts were nausea, vomiting, decreased 

appetite, diarrhea, fatigue, peripheral neuropathy and thrombocytopenia. One DLT of 

G4 thrombocytopenia was observed in cohort B2. Cohort expansion with CRC pts in 

Arm B is ongoing. Two pts in cohort B1 (cholangiocarcinoma, anal cancer) 

experienced cPRs (≥6mo). The PK of GDC-0980 and CPC or 5-FU, oxaliplatin and 

leucovorin suggests minimal drug-drug interaction. Biomarker analysis is ongoing. 

Conclusions: GDC-0980 combined with fluoropyrimidine-based regimens is well 

tolerated, with confirmed antitumor activity. The RP2Ds are identified. 

Disclosure: L.S. Rosen: Research support received from Genentech, the study 

sponsor. J. Goldman: Research support received from Genentech, the study sponsor. 

W. Lin: Genentech Employee. G. Shankar: Genentech Employee. S. Leong: Presently 

receiving research support for clinical trials from: Genentech, Pfizer, Astra Zeneca 

Presently recieving laboratory research support from Pfizer. All other authors have 


453P ANTI-PROGRAMMED DEATH-1 (PD-1) (BMS-936558/ 

MDX-1106/ONO-4538) IN PATIENTS (PTS) WITH ADVANCED 

SOLID TUMORS: CLINICAL ACTIVITY, SAFETY, AND 

MOLECULAR MARKERS 

S.L. Topalian1 , J.R. Brahmer1 , F.S. Hodi2 , D.F. McDermott3 , D.C. Smith4 , 

S. Gettinger5 , J.M. Taube1 , A. Gupta6 , J.M. Wigginton7 , M. Sznol8 1 

Melanoma Program, Sidney Kimmel Cancer Center at Johns Hopkins 

University, Baltimore, MD, UNITED STATES OF AMERICA, 2 Melanoma Center, 

Dana-Farber Cancer Institute, Boston, MA, UNITED STATES OF AMERICA, 

3 

Biology Therapy Program, Beth Israel Deaconess Medical Center, Boston, MA, 

UNITED STATES OF AMERICA, 4 Department of Internal Medicine, University of 

Michigan, Ann Arbor, MI, UNITED STATES OF AMERICA, 5 Section of Medical 

Oncology, Yale University School of Medicine, New Haven, CT, UNITED STATES 

OF AMERICA, 6 Discovery Medicine, Immuno-oncology, Bristol-Myers Squibb, 

Princeton, NJ, UNITED STATES OF AMERICA, 7 Discovery Medicine-clinical 

Oncology, Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA, 

8 

Section of Medicine Oncology, Yale Cancer Center, New Haven, CT, UNITED 


Purpose: Blockade of PD-1, a co-inhibitory receptor expressed by activated T cells, 

can overcome immune resistance and mediate tumor regression. This study describes 

the activity and safety of BMS-936558, an anti-PD-1 monoclonal antibody, in pts 

with advanced cancers. 

Methods: Pts received BMS-936558 IV q2wk at 0.1 − 10 mg/kg during dose 

escalation and/or cohort expansion. Tumors were assessed by RECIST v1.0. Pts 

received up to 12 cycles (4 doses/cycle) or until unacceptable toxicity, confirmed 

progressive disease, or complete response. 

Results: As of Feb 24, 2012, 296 pts with melanoma (MEL, n = 104), non-small 

cell lung (NSCLC, n = 122), renal cell (RCC, n = 34), colorectal (n = 19), and prostate 

(n = 17) cancer were treated. Median duration of therapy was 16 wks (range 2.0 − 

121.7 wks). MTD was not reached. Grade ≥3 drug-related AEs occurred in 14% of 

pts. AEs of special interest included pneumonitis, vitiligo, colitis, hepatitis, 

hypophysitis, and thyroiditis. There were 3 deaths due to pneumonitis. In evaluable 

pts, objective responses (ORs) or prolonged stable disease was observed in MEL, 

RCC, and NSCLC (Table). Some had a persistent reduction in overall tumor burden 

in the presence of new lesions and were not categorized as responders. To assess 

PD-1 ligand (PD-L1) as a potential predictive molecular marker, 

immunohistochemistry was performed on pretreatment tumor biopsies from 42 pts. 

Of 25 pts with PD-L1(+) tumors, 9 (36%) achieved OR vs 0/17 with PD-L1(-). 

Conclusions: BMS-936558 produces durable activity in advanced NSCLC, MEL, and 

RCC, supporting further clinical development. Preliminary data suggest a 

relationship between PD-L1 expression status on tumor cells and OR. Additional 

long-term follow-up data will be reported. 

Tumor 

type 

Dose, 

mg/kg 

No. 

pts a 

ORR, No. pts (%) 

[95% CI] 

SD ≥24 wks, 

No. pts (%) 

[95% CI] 

PFSR at 24 

wks, % 

[95% CI] 

MEL 0.1 − 10 94 26 (28)* [19 − 38] 6 (6) [2 − 13] 41 [30 − 51] 

NSCLC 1 − 10 76 14 (18) [11 − 29] 5 (7) [2 − 15] 26 [16 − 36] 

RCC 1 − 10 33 9 (27)* [13 − 46] 9 (27) [13 − 46] 56 [39 − 73] 

a 

Response-evaluable pts dosed by 07/01/2011 *1 CR ORR = objective response rate 

([{CR + PR} ÷ n] × 100); PFSR = progression-free survival rate; SD = stable disease 

Disclosure: S.L. Topalian: Consultant/Advisory Role: Bristol-Myers Squibb (myself, 

uncompensated); Amplimmune Inc (immediate family member, compensated). 

Research Funding: Bristol-Myers Squibb. F.S. Hodi: Consultant or Advisory Role: 

Bristol-Myers Squibb (myself, uncompensated). Research Funding: Bristol-Myers 

Squibb (myself). D.F. McDermott: Advisory Board Role: Bristol-Myers Squibb (Ad 

board participation). D.C. Smith: Research Funding: BMS Oncology (myself). J.M. 

Taube: Research Funding: Bristol-Myers Squibb (myself). A. Gupta: Employment or 

Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock 

Ownership: Bristol-Myers Squibb (myself). J.M. Wigginton: Employment or 

Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock 

Ownership: Bristol-Myers Squibb (myself). M. Sznol: Consultant or Advisory Role: 

Bristol-Myers Squibb (myself, compensated). Research Funding: Bristol-Myers Squibb 

(clinical trial funding, myself). All other authors have declared no conflicts of interest. 

454P PHASE IB DOSE-ESCALATION STUDY OF BEZ235 OR 

BKM120 IN COMBINATION WITH PACLITAXEL (PTX) IN 


L. Dirix 1 , M. Schuler 2 , J. Machiels 3 , D. Hess 4 , A. Awada 5 , N. Steeghs 6 , 

L. Paz-Ares 7 , R. von Moos 8 , B. Rabault 9 , J. Rodon 10 

1 Clinical Trials Oncology, Sint Augustinus Hospital, Antwerp, BELGIUM, 

2 Westdeutsches Tumorzentrum, Universitätsklinikum Essen, Essen, GERMANY, 

3 Department of Medical Oncology, Cliniques Universitaires Saint-Luc, Bruxelles, 

BELGIUM, 4 Medical Oncology, Kantonsspital St. Gallen, St. Gallen, 

SWITZERLAND, 5 Department of Medical Oncology, Institute Jules Bordet, 

Brussels, BELGIUM, 6 Medical Oncology, Netherlands Cancer Institute, 

Amsterdam, NETHERLANDS, 7 Medical Oncology, University Hospital Virgen del 

Rocio, Seville, SPAIN, 8 Medizinische Onkologie und Hämatologie, Kantonsspital 

Graubünden, Chur, SWITZERLAND, 9 Oncology, Novartis Pharma AG, Basel, 

SWITZERLAND, 10 Medical Oncology, Vall d’Hebron University Hospital, 


Background: The pan-PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor 

BEZ235 have demonstrated preclinical and clinical antitumor activity as single agents 

and in combination with other drugs. Here, we report interim results of BKM120 or 

BEZ235 + PTX in pts with advanced solid tumors. 

Methods: In the first 2 arms of this 4-arm Phase Ib dose-escalation study, pts with 

metastatic or locally advanced solid tumors received once-daily oral BKM120 or 

BEZ235 + wkly IV PTX. Dose-escalation was guided by a Bayesian logistic regression 

model with overdose control. The primary objective was to determine the MTD of 

BKM120 or BEZ235 + PTX. 

Results: 33 pts were treated with BKM120 (mg/d) + PTX (mg/m 2 ) at 6 dosing levels: 

40/70 (1 pt); 40/80 (5 pts); 60/80 (3 pts); 80/80 (4 pts); 100/80 (16 pts); and 120/80 

(4 pts). DLTs were observed in 4 pts (1/16 at 100/80 and 3/4 at 120/80), including 

asthenia, hyperglycemia, and depression. The MTD of BKM120/PTX was declared as 

100/80. Most common G3/4-suspected study treatment-related AEs (>5%) were 

neutropenia, hyperglycemia, and anemia. For the BEZ235 arm, 29 pts were treated 

with BEZ235 (mg/d) + PTX (mg/m 2 ) at 4 dosing levels: 400/70 (2 pts); 400/80 (3 

pts); 600/80 (4 pts); and 800/80 (20 pts). DLTs were observed in 4 pts (3/20 at 800/ 

80 and 1/4 at 600/80), including GI events, peripheral neuropathy, and febrile 

neutropenia. The MTD of BEZ235/PTX was declared as 800/80. Most common G3/ 

4-suspected study treatment-related AEs (>10%) were fatigue, diarrhea, and anemia. 

As of Feb 29, 29 pts were evaluable for response in each arm. In the BKM120/PTX 

arm, 1 CR (penile carcinoma [Ca]), 4 PRs (breast and ovarian Ca pts, each with 

multiple lines of prior therapy [12 and 3] and progression on prior PTX; cervical 


and vulvar Ca), and 11 SDs were observed. In the BEZ235/PTX arm, 1 PR (large-cell 

Ca of the lung, taxane-naïve), and 9 SDs were observed. 

Conclusion: BKM120 or BEZ235 + PTX were generally well tolerated and showed 

preliminary signs of efficacy. The MTDs of both BKM120/PTX and BEZ235/PTX 

were reached. For BKM120, the MTD in combination with PTX was the same as the 

single-agent MTD. Arms 3 and 4 will determine the MTD of BEZ235 or BKM120 + 

PTX and trastuzumab in pts with advanced HER2+ breast Ca. 

Disclosure: M. Schuler: Martin Schuler is an advisor for Novartis, and receives 

research funding from Novartis. J. Machiels: Jean-Pascal Machiels is on an advisory 

board for Boehringer, and receives a research grant from Sanofi. D. Hess: Dagmar 

Hess owns < 30,000 swiss francs of Novartis stocks. N. Steeghs: Neeltje Steeghs 

receives research funding from Novartis. L. Paz-Ares: Luis Paz-Ares has been an 

advisor for Lilly, Bayer, Roche and Pfizer. He has also received honoraria from all of 

the above. R. von Moos: Roger von Moos is a participant of advisory boards for 

Amgen, Novartis, Roche, BMS, and MSD, and receives unrestricted research grants 

and speaker honoraria from Amgen and Roche. B. Rabault: Bertrand Rabault is a 

employee of Novartis Pharma AG and owns stock in novartis pharma. All other 


455P EVOLUTION OF CLINICAL TRIAL DESIGN IN EARLY DRUG 

DEVELOPMENT: THE USE OF EXPANSION COHORTS (ECS) IN 

PHASE I CANCER TRIALS (PITS) 

A. Manji 1 , I. Brana Garcia 1 ,E.Amir 2 , I.F. Tannock 2 , P. Bedard 1 , A.M. Oza 1 , 

L. Siu 1 , A.R.A. Razak 1 

1 Drug Development Program, Division of Medical Oncology and Hematology, 

Princess Margaret Hospital, Toronto, ON, CANADA, 2 Medical Oncology, 

Princess Margaret Hospital, Toronto, ON, CANADA 

Background: ECs are frequently used to optimize the yield of PITs. However, their 

rationale and value have yet to be evaluated. Here, we explore the prevalence, 

characteristics and objectives of ECs in single-agent PITs. 

Methods: We conducted a systematic review using MEDLINE and EMBASE to 

identify all adult single-agent PITs published after 2006. Eligibility assessment and 

data extraction were performed by 2 reviewers. The primary endpoint was the 

proportion of PITs with ≥ 1 EC. Additional endpoints included factors associated 

with EC inclusion and whether the EC objectives were stated and achieved. 

Results: 4,557 articles were reviewed and 591 trials met eligibility criteria. 139 (24%) 

included ≥ 1 EC. Use of ECs in single-agent PITs increased between 2006 and 2011 

(12.2% to 35.7%, Spearman’s rho 0.20, p < 0.001). In PITs with ECs, a median of 22 

and 17 subjects were enrolled in the dose-escalation cohorts (DECs) and ECs 

respectively. In unadjusted analysis, PITs were more likely to include an EC if they 

were multi-center (OR 2.41, 95% CI 1.52-3.82, p < 0.001), industry-sponsored (OR 

1.80, 95% CI 1.12-2.91, p = 0.02), and evaluating non-cytotoxic agents (OR 2.12, 95% 

CI 1.30-3.47, p = 0.003). In multivariable analysis, these factors retained statistical 

significance except for industry sponsorship. Geographical location of study and 

tumor type were not significant. EC objectives were reported in 74% of trials and 

included safety (83%), efficacy (45%), pharmacokinetics (28%), pharmacodynamics 

(23%), and patient enrichment (14%). Among ECs assessing safety, the MTD was 

modified in 14% and new toxicities defined in 53%. Among ECs designed to assess 

efficacy, only 24 of 46 (52%) reported EC efficacy separately; of these, only 3 (13%) 

reported tumor responses in EC subjects not previously observed in the DEC. 

Conclusions: The utilization of ECs in PITs has increased with time and is more 

common for multi-center trials of non-cytotoxic agents. Safety and efficacy are 

common objectives but 26% failed to report explicit aims. Although the majority of 

ECs supplement PITs with meaningful safety data, their role in assessing preliminary 

efficacy requires better definition. 


456P MULTICENTER, DOSE-ESCALATION STUDY OF THE 

INVESTIGATIONAL DRUG TAK-733, AN ORAL MEK 

INHIBITOR, IN PATIENTS (PTS) WITH ADVANCED SOLID 

TUMORS: PRELIMINARY PHASE 1 RESULTS 

A.A. Adjei 1 , P.M. LoRusso 2 , A. Ribas 3 , J.A. Sosman 4 , G.K. Dy 1 , 

B. Chmielowski 5 , P. Lipman 6 , X. Zhou 7 , E. Gangolli 8 , V. Bozón 9 

1 Medicine Oncology, Roswell Park Cancer Institute, Buffalo, NY, UNITED 

STATES OF AMERICA, 2 Oncology, Karmanos Cancer Institute, Detroit, MI, 

UNITED STATES OF AMERICA, 3 Oncology, UCLA Jonsson Comprehensive 

Cancer Center, Los Angeles, CA, UNITED STATES OF AMERICA, 4 Hematology/ 

Oncology, Vanderbilt University Medical Center, Nashville, TN, UNITED STATES 

OF AMERICA, 5 Medicine, University of California Los Angeles, Los Angeles, CA, 

UNITED STATES OF AMERICA, 6 Biostatistics, Millennium Pharmaceuticals, Inc., 

Cambridge, MA, UNITED STATES OF AMERICA, 7 Clinical Pharmacology, 

Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED STATES OF 

AMERICA, 8 Translational Medicine, Millennium Pharmaceuticals, Inc., Cambridge, 

MA, UNITED STATES OF AMERICA, 9 Oncology, Clinical Research, Millennium 

Pharmaceuticals, Inc., Cambridge, MA, UNITED STATES OF AMERICA 

Background: TAK-733 is an investigational, orally available, selective, 

non-ATP-competitive, allosteric inhibitor of MEK1/2 shown to have anti-tumor 


activity in multiple xenograft models. In this first-in-human ph 1 study 

(NCT00948467), we evaluated safety, pharmacokinetics (PK), pharmacodynamics 

(PD), maximum tolerated dose (MTD) and efficacy of TAK-733 in pts with advanced 

solid tumors. 

Methods: Pts aged ≥18 y, with ECOG PS 0–2 and radiographically or clinically 

evaluable tumors were eligible. Pts received TAK-733 QD on d 1–21 in 28-d cycles; 

doses escalated in a modified 3 + 3 design based on dose-limiting toxicities (DLTs) in 

cycle 1 to determine MTD. Plasma and blood samples for PK and PD analysis were 

collected pre-dose on d 1, 8, 15 and 21 and post-dose d 1 and 21 in cycle 1. 

Results: As of March 16, 2012, 44 pts median age 58 (range 24 − 75) and 50% male, 

received TAK-733 (dose mg, [n]: 0.2, [1]; 0.4, [1]; 0.8, [2]; 1.6, [2]; 3.2, [4]; 4.4, [4]; 6, 

[4]; 8.4, [9]; 11.8, [8]; 16, [9]). 2 pts had DLTs (11.8 and 16.0 mg; both Grade 3 

acneiform rash); MTD has not been reached. Pts received a median of 2 cycles 

(range 1-11, 6 pts ≥6 cycles). Safety and PK data are shown in the table. Maximum 

inhibition (Emax) of ERK phosphorylationin peripheral blood lymphocytes ranged 

from 21-95% (TAK-733; 0.2-16 mg QD), median E max were 63%, 78%, and 92% at 

8.4, 11.8, and 16 mg, respectively. In 32 evaluable pts, 1 pt (16 mg dose) with 

melanoma (BRAF L597R) had partial response confirmed at cycle 6 (RECIST v1.1) 

and is still on treatment at cycle 8; 12 pts had a best response of stable disease. 

Conclusions: These preliminary data indicate that TAK-733 is generally well 

tolerated and pharmacodynamically active with signs of anti-tumor activity in pts 

with advanced non-hematologic malignancies. Dose escalation is continuing to 

determine the MTD. 

AEs, NCI-CTCAE v4.0 N = 44 

Drug-related AE, n (%) 

≥15% 

37 (84) 

Dermatitis acneiform 19 (43) 

Diarrhoea 8 (18) 

Grade ≥3 drug-related AE, n (%) 

≥5% 

7 (16) 

Dermatitis acneiform 2 (5) 

Creatine phosphokinase evaluation 2 (5) 

PK data N = 41 

Tmax, h 3 

T1/2, h 53 

Disclosure: P.M. LoRusso: Consultancy or advisory board (Millennium 

Pharmaceuticals Inc.), Research Funding (Millennium Pharmaceuticals Inc.). A. 

Ribas: Consultancy or advisory board (Millennium Pharmaceuticals Inc.), Honoraria 

(Millennium Pharmaceuticals Inc.). J.A. Sosman: Consultancy or advisory board 

(Millennium Pharmaceuticals Inc.), Honoraria (Millennium Pharmaceuticals Inc.). B. 

Chmielowski: Consultancy within past 2 years (GSK, Genentech, Prometheus, CytRx, 

Morphotek). Membership on Board of Directors, Speakers Bureau, Advisory 

Committee (BMS, Genentech, Prometheus). P. Lipman: Employment (Millennium 

Pharmaceuticals Inc.). X. Zhou: Employment (Millennium Pharmaceuticals Inc.). V. 

Bozón: Employment (Millennium Pharmaceuticals Inc.). All other authors have 


457P A PHASE I DOSE ESCALATION AND EXPANSION TRIAL OF 

BKM120, AN ORAL PAN-PI3K INHIBITOR, IN PATIENTS WITH 

ADVANCED SOLID TUMORS: ANALYSIS OF 

PHARMACODYNAMIC BIOMARKER DATA 

J. Rodon 1 , J. Bendell 2 , A.R.A. Razak 3 , M.J.A. De Jonge 4 , F. Eskens 5 ,E.Di 

Tomaso 6 , D.W. Sternberg 7 , L. Wang 8 , C. Sarr 9 , J. Baselga 10 

1 Medical Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN, 2 GI 

Oncology Research/drug Development Unit, Sarah Cannon Research Institute, 

Nashville, TN, UNITED STATES OF AMERICA, 3 Dept. of Medical Oncology and 

Hematology, Princess Margaret Hospital, Toronto, ON, CANADA, 4 Department 

of Medical Oncology, Erasmus University Medical Center, Rotterdam, 

NETHERLANDS, 5 Dept. of Medical Oncology, Erasmus University Medical 

Center, Rotterdam, NETHERLANDS, 6 Institutes for Biomedical Research, 

Novartis, Cambridge, MA, UNITED STATES OF AMERICA, 7 Oncology, Novartis 

Oncology, Florham Park, NJ, UNITED STATES OF AMERICA, 8 Oncology BDM, 

Novartis Institutes for Biomedical Research, Cambridge, MA, UNITED STATES 

OF AMERICA, 9 Modeling & Simulation, Novartis Pharmaceuticals, East Hanover, 

NJ, UNITED STATES OF AMERICA, 10 Hematology/Oncology, MGH Cancer 

Center, Massachusetts General Hospital, Boston, MA, UNITED STATES OF 

AMERICA 

Background: The MTD of single-agent BKM120 was previously declared as 100 mg/ 

day in a Phase I study in patients (pts) with advanced solid tumors (NCT01068483; 

Bendell et al. 2011). Here we report on the analysis of pharmacodynamic biomarkers 

from pts in the dose-escalation and dose-expansion arms of the Phase I study. The 

inhibitory effects of BKM120 were investigated (i) in the context of glucose 

metabolism regulation, a known PI3K-dependent process, and (ii) in the context of 

tumor biology, by surveying the phosphorylation of proteins downstream of PI3K. 

Methods: 83 pts received oral daily BKM120. Tumor samples were analyzed for 

PIK3CA mutation and PTEN expression. Blood C-peptide (glucose metabolism) was 



measured at Cmax (2–4 hrs post-dose) on Day 1 in 72 pts. Pathway phosphorylation 

in surrogate tissue was investigated in 51 paired skin samples by correlating changes 

in pS6 (baseline to Day 28) with the mean dose of BKM120 administered in each pt. 

In 8 pts where pre/post treatment biopsies could be obtained, pS6, pAKT, p4EBP1 

and Ki67 were quantified within limits of tissue availability. 

Results: Blood C-peptide at Cmax on Day 1 increased as a function of the 1st dose 

administered, with no change after 12.5 mg and mean increase of 72% (range: 56– 

84%) after 150 mg. Inhibition of pS6 on Day 28 (range: 20–60%) was observed in 

tumor tissue from 5 out of 8 pts. 4 of these 5 pts also demonstrated a decrease in 

either pAKT (range: 30–70%) or p4EBP1 (range: 27–35%) with 1 pt displaying a 

mean 30% decrease in all 3 markers. A decrease in proliferation as measured by 

Ki67 was observed in 4 pts (range: 13–60%) suggesting a potential biological 

impact in response to PI3K pathway inhibition. Inhibition of pS6 in skin increased 

moderately with the mean administered dose of BKM120 (mean inhibition of –28, 

–37, and –40%, for 12.5–60 mg, >60–90 mg, and >90 mg dose ranges, respectively) 

suggesting a relationship between treatment dose and the degree of PI3K pathway 

inhibition. 

Conclusion: This analysis supports the notion that daily BKM120 not only has the 

ability to induce inhibition of the immediate effector of PI3K (pAKT) but also to 

downregulate the pathway further downstream (pS6) at MTD. 

Disclosure: F. Eskens: Membership on an advisory board: Participant of LEAD 

summit meetings (Novartis). E. Di Tomaso: Employee of Novartis. D.W. Sternberg: 

Employee of Novartis. L. Wang: Employee of Novartis. C. Sarr: Employee of 

Novartis. Stock Ownership in Novartis Pharmaceuticals. J. Baselga: Novartis 

Scientific Ad Board (NVPBKM120); other pan‐PI3K inhibitors: Consulting for 

Exelixis; XL147; Roche‐Genentech Scientific Ad Board; GDC0941. All consulting 

relationships have CA’s in place which conform to the Partners/Harvard COI 

Policies. All other authors have declared no conflicts of interest. 

458P PHASE IB DOSE-ESCALATION STUDY OF THE AKT INHIBITOR 

GDC-0068 WITH DOCETAXEL (D) OR MODIFIED FOLFOX6 (F) 

IN PATIENTS (PTS) WITH ADVANCED SOLID TUMORS 

J. Bendell 1 , D. Roda 2 , J. Mateo 3 , A. Hollebecque 4 , L. De Mattos-Arruda 5 , 

R. Meng 6 , S. Isakoff 7 , L.R. Molife 8 , J. Tabernero 9 , A. Cervantes Ruiperez 10 

1 GI Oncology Research/Drug Development Unit, Sarah Cannon Research 

Institute, Nashville, TN, UNITED STATES OF AMERICA, 2 Department of 

Hematology and Medical Oncology, Hospital Clinico, Valencia, SPAIN, 3 Drug 

Development Unit, The Royal Marsden NHS Trust, Sutton, Surrey, UNITED 

KINGDOM, 4 Dept. of Medicine, Institut Gustave Roussy, Villejuif Cedex, 

FRANCE, 5 Medical Oncology, Vall d’Hebron Hospital, Barcelona, SPAIN, 

6 Exploratory Clinical Development, Genentech, So San Francisco, CA, UNITED 

STATES OF AMERICA, 7 Department of Hematology and Medical Oncology, 


8 Drug Development Unit, Royal Marsden Hospital, London, UNITED KINGDOM, 

9 Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, 

SPAIN, 10 Serv. Hematologia y Oncologia Medica, Hospital Clinico Universitario 

de Valencia, Valencia, SPAIN 

Background: Aberrant activation of the phosphoinositide 3-kinase (PI3K)/Akt 

pathway occurs in cancers and may lead to chemoresistance. GDC-0068 is a potent 

ATP-competitive small molecule inhibitor of all Akt isoforms. In preclinical models, 

GDC-0068 synergistically combined with taxanes and 5FU/platinum. This study 

evaluated safety, pharmacokinetics (PK), and efficacy of GDC-0068 combined with 

DorF. 

Methods: Eligible pts with metastatic solid tumors, treated with up to 3 regimens, 

received either D, 75 mg/m 2 Day1 and escalating GDC-0068 daily (QD) Days 2-15 

every 21 days (Arm A); or F, bolus 5FU 400 mg/m 2 , leucovorin 400 mg/m 2 , 

oxaliplatin (OX) 85 mg/m 2 Day 1, infusional 5FU 2400 mg/m 2 for 46 hours and 

GDC-0068 QD Days 1-7 every 14 days (Arm B). GDC-0068 dose was capped at 600 

mg QD, the single-agent MTD. Secondary endpoints were PK and predictive 

biomarker assessment. 

Results: 47 pts enrolled as of May 2012: Arm A (GDC-0068 in mg): 100 (n = 3), 200 

(n = 4), 400 (n = 7), 600 (n = 10, with expansion), and Arm B: 100 (n = 6), 200 (n = 

9), 400 (n = 6), 600 (n = 2, ongoing). Grade ≥ 2 adverse events (AEs) related to 

GDC-0068 in ≥ 10% of pts were nausea (17%), diarrhea (13%), fatigue (13%) in Arm 

A and nausea (17%) and diarrhea (13%) in Arm B. Fasting hyperglycemia due to 

GDC-0068 was only Grade 1 ( 6 months. Among 11 pts evaluable for IHC (immunohistochemistry) 

staining, 8 pts had high expression of PD-L1, a ligand of PD-1, on their tumor 

tissues, and 2 of them achieved PR. No pts with low PD-L1 expression showed 

objective response. 

Conclusion: ONO-4538 was well tolerated up to the 20 mg/kg and antitumor activity 

was observed within 1-10 mg/kg. 

Disclosure: N. Yamamoto: Chugai pharmaceutical co., ltd. Pfizer Kyowa-Hakko 

Kirin co., ltd. Y. Yamada: Bayer Yakult AstraZeneca. H. Nokihara: TAIHO 

PHARMACEUTICAL CO., LTD Merck Serono Pfizer. T. Tamura: Chugai 

Pharmaceutical co., ltd. Daichi-Sankyo co., ltd. Boehringer Ingelheim ABBOTT 

JAPAN Co., LTD Eisai co., ltd. Bristol-Myers Squibb Kyowa-Hakko Kirin co., ltd. All 


460P PHASE I AND II CLINICAL STUDY OF CANCER VACCINE 

CONSISTING OF 5 NOVEL EPITOPE PEPTIDES FOR PATIENTS 

WITH METASTATIC COLORECTAL CANCER (MCRC) 

S. Hazama 1 , Y. Nakamura 2 , K. Yoshida 3 , T. Tsunoda 3 , H. Tanaka 4 , K. Tahara 5 , 

R. Shimizu 1 , K. Okuno 6 , K. Yoshimatsu 7 , M. Oka 1 


Graduate School of Medicine, Ube, JAPAN, 2 Institute of Medical Science, 

University of Tokyo, Tokyo, JAPAN, 3 Cancer Immunology, OncoTherapy 

Science, Inc., Tokyo, JAPAN, 4 Digestive Surgery, Osaka City University, Osaka, 

JAPAN, 5 Surgery, Kure Kyosai Hospital, Kure, JAPAN, 6 Surgery, Kinki University, 

Osaka, JAPAN, 7 Surgery, Tokyo Womens Univercity, Tokyo, JAPAN 

Background: We have reported a phase I (PI) study for patients (pts) with mCRC 

using 5 novel HLA-A24-restricted peptides, which were derived from 3 oncoantigens 

(RNF43, TOMM34, KOC1), and from VEGFR1 and VEGFR2 at 2011 ASCO (oral 

paper). At 2012 ESMO, we will present the biomarkers for the efficacy of PI study, 

and an interim report about PII study of cancer vaccine consisting of 5 novel epitope 

peptides and FOLFOX for chemo naïve pts with mCRC. 

Methods: In a PI study conducted for mCRC, biomarkers were searched for the 

efficacy of vaccination. Eighteen mCRC pts who failed to standard therapy were 

enrolled in this study. Five peptides were injected to the inguinal or axillal region 

weekly at 0.5 mg to 3 pts, 1 mg to 3 pts, and 3 mg to 12 pts. Vaccinations were 

continuing until the pts refusal. Blood cell counts, CRP, and ELISPOT were 

performed before and after vaccinations. PII study was conducted to evaluate the 

efficacy of vaccination added on the standard FOLFOX therapy for chemo naïve pts 

with mCRC. All enrolled patients had received FOLFOX and vaccination without 


knowing HLA-A status double-blindly, and the HLA genotype will not key-opened 

until the final analysis point. The endpoints evaluate between HLA-A*2402 positive 

(24(+), n = 60) and HLA-A*2402 negative (24(-), n = 40) group, because the 

frequency of A*2402 in Japanese pts forecast about 60%. 

Results: In PI study, the total numbers of peptide specific response were 2 in 3 pts at 

0.5mg, 6 in 3 pts at 1.0 mg, and 37 in 12 pts at 3.0 mg. We decided that the RD was 

3.0 mg. One patient experienced a CR and 6 pts revealed SD. The median OS was 

15.2 months. The lymphocyte% (above 15%: p < 0.022) and CRP (below 1.0 mg/dl: p 

< 0.008) were primitive but important biomarkers to predict OS. In the low CRP 

group, pts with 3 or more peptides specific responses at 8 weeks survived longer than 

others(p = 0.032). In PII study, 86 pts were enrolled. The PFS of all pts without HLA 

key-open was seemed to be improved as compared to NO16966 study 9 month after 

the initial therapy. This result indicated the delayed effect which is characteristic in 

vaccine therapy. 

Conclusions: The PI study demonstrated that Lymphocyte%, CRP and CTL 

responses were predictive biomarkers for vaccination. The interim report about PII 

study will be presented at the meeting. 


461P MLN8237 (ALISERTIB), AN INVESTIGATIONAL AURORA A 

KINASE INHIBITOR, IN PATIENTS (PTS) WITH NON-SMALL 

CELL LUNG CANCER (NSCLC), SMALL CELL LUNG CANCER 

(SCLC), BREAST CANCER (BRC), HEAD AND NECK 

SQUAMOUS CELL CARCINOMA (HNSCC), AND 

GASTROESOPHAGEAL CANCER (GE): EMERGING PHASE (PH) 

2 RESULTS 

B. Melichar 1 , P. Lee 2 , R.H. Alvarez 3 , M. Degardin 4 , J. Bennouna 5 , 

C. Schusterbauer 6 , B. Zhang 7 , E. Benaim 8 , P. Rosen 9 

1 Oncology, University Fakultní Nemocnice Olomouc – Onkologická Klinika, 

Olomouc, CZECH REPUBLIC, 2 Oncology, Tower Cancer Research Foundation, 

Beverly Hills, CA, UNITED STATES OF AMERICA, 3 Division of Cancer Medicine, 

MD Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA, 

4 Département de Cancérologie Cervico-faciale, Centre Oscar Lambret, Lille, 

FRANCE, 5 Pharmacology and Clinical Oncology, Institut de Cancérologie de 

l’Ouest, Nantes, FRANCE, 6 Clinical, Millennium Pharmaceuticals, Inc., 

Cambridge, MA, UNITED STATES OF AMERICA, 7 Biostatistics, Millennium 

Pharmaceuticals, Inc., Cambridge, MA, UNITED STATES OF AMERICA, 8 Clinical 

Development, Millennium Pharmaceuticals, Inc., Cambridge, MA, UNITED 

STATES OF AMERICA, 9 Hematology and Medical Oncology, Providence Saint 

Joseph Medical Center, Burbank, CA, UNITED STATES OF AMERICA 

Background: Aurora A Kinase plays a key role in centrosome maturation and 

spindle formation in mitosis, and is frequently amplified or overexpressed in various 

human cancers. MLN8237 is an investigational, oral, selective AAK inhibitor being 

evaluated in pts with hematologic and non-hematologic malignancies. Here we 

report ph 2 results from an ongoing multicenter ph 1/2 trial of MLN8237 in pts with 

advanced solid tumors (NCT01045421). 

Methods: Pts aged ≥18 y with relapsed/refractory NSCLC, SCLC, BrC, HNSCC, 

or GE adenocarcinoma, ECOG PS 0–1, measurable disease by RECIST, and ≤2 

prior cytotoxic chemotherapy regimens (≤4 in BrC) were eligible. Ph 2 

enrollment followed a two-stage Simon’s design; to proceed to the second stage, 

at least two responses were required in the first 20 response-evaluable pts 

enrolled in that tumor cohort. The primary and secondary ph 2 objectives were 

overall response rate and safety profile, respectively. Response was assessed by 

RECIST v1.1. MLN8237 was administered orally as an enteric-coated tablet at the 

MTD of 50 mg BID for 7 d followed by 14-d rest in 21-d cycles (determined in 

ph 1). 

Results: As of March 29 2012, 226 pts have been treated in ph 2: HNSCC (n = 

54), BrC (n = 53), GE adenocarcinoma (n = 53); SCLC (n = 40), and NSCLC (n = 

26); median age was 61 y (range 30–88). Best responses achieved are: partial 

response in 17 pts (BrC, n = 6; SCLC, n = 4; H&N, n = 3; GE adenocarcinoma, n 

= 3; NSCLC, n = 1), and stable disease in 92 pts. Median cycles of treatment is 2 

(range: 1–15). 89% of pts reported drug-related adverse events (AEs); the most 

common included neutropenia (44%), fatigue (38%), alopecia (38%), diarrhea 

(30%), and anemia (27%). Grade ≥3 drug-related AEs were seen in 53% of pts 

and included neutropenia (36%), leukopenia (10%), and anemia (10%). 21 pts 

(9%) discontinued due to AEs; there were 19 on-study deaths (none 

drug-related). 

Conclusions: These emerging ph 2 data suggest antitumor activity for MLN8237, 

and further support a developing safety profile that is generally well tolerated across a 

range of solid tumors. 

Disclosure: B. Melichar: Honoraria Roche, Novartis, advisory board Roche. R.H. 

Alvarez: Consultancy (BMS, Roche), Honoraria (BMS), Research funding (GSK, 

Cylene Pharmaceuticals, Millennium Pharmaceuticals Inc., Novartis, Prometheus 


Therapeutics and Diagnostics, Eisai). J. Bennouna: Honoraria (AMGEN), 

Membership on Board of Directors, Speakers Bureau, Advisory Committee (Roche, 

AMGEN, Sanofi-Aventis). C. Schusterbauer: Employment (Millennium 

Pharmaceuticals, Inc.). B. Zhang: Employment (Millennium Pharmaceuticals, Inc.) 

and stock ownership (Takeda). E. Benaim: Employment (Millennium 

Pharmaceuticals, Inc.) and stock ownership (Takeda). P. Rosen: Research funding 

(Millennium Pharmaceuticals Inc.). All other authors have declared no conflicts of 

interest. 

462P A PHASE IB CLINICAL STUDY WITH 18F-FDG-PET RESPONSE 

EVALUATION OF THE COMBINATION OF TEMSIROLIMUS (T) 

AND PEGYLATED LIPOSOMAL DOXORUBICIN (PLD) IN 

BREAST, ENDOMETRIAL AND OVARIAN CANCER 

M.J. Sonderen 1 , I.M.E. Desar 1 , L. De Geus-Oei 2 , W.T.A. van der Graaf 1 , 

W.J.G. Oyen 2 , P.B. Ottevanger 1 , C.M.L. van Herpen 1 

1 Department of Medical Oncology/452, Radboud University Medical Centre 

Nijmegen, Nijmegen, NETHERLANDS, 2 Department of Nuclear Medicine, 

Radboud University Nijmegen Medical Centre, Nijmegen, NETHERLANDS 

Background: PLD is active in metastatic breast, endometrial and ovarian cancer. 

Preclinical data suggest that mTOR inhibitors can reverse resistance to doxorubicin. 

Therefore, the combination of T and PLD is promising. 

Methods: This phase I study assessed the MTD, safety and activity of the 

combination of T and PLD in advanced or recurrent breast, endometrial or ovarian 

cancer. After a 2 wk run in period with T iv once weekly, PLD iv once every 4 wks 

was added. The MTD was defined as the highest dose at which ≤ 1 DLT had been 

observed among 6 pts. FDG PET scans were performed at baseline (B), after 2 and 6 

wks to assess the effect on tumor metabolism. A CT scan was performed for RECIST 

evaluation at B and after 10 wks. PET scans were evaluated by SUV analysis and 

total lesion glycolysis (TLG). The fractional change in SUV and TLG between the 

first, second and third FDG-PET was calculated. 

Results: 20 pts were enrolled. On the 4 th dose level with 20 mg T and 40 mg/m 2 PLD 

2 DLTs occurred in 6 pts, a grade 3 thrombocytopenic bleeding and a grade 3 skin 

toxicity. Thus the MTD was assessed at 15 mg T and 40 mg/m 2 PLD. AEs occurring 

most frequently were (all grds/grd 3-4 (%)) fatigue (84/5), nausea (84/16) and 

mucositis (79/21). 3 pts showed PR and 9 SD (> 3 months). The mean PFS was 4.9 

months with 2 pts still on treatment. The fractional decrease in TLG from the first to 

the second FDG-PET for PR pts differed from those who had not (p= 0.018 for 

ΔTLG50). The fractional change in SUVmax from the second to the third FDG-PET 

differed between pts who had PD and those who had not (+14.0 versus -15.8, p = 

0.034). The degree of decrease in SUVmax between the FDG-PET made after 2 and 

6 wks was associated with better PFS (HR 1.068; p = 0.013). 

Conclusions: The combination of T and PLD is safe and tolerable. The MTD was 

assessed at PLD 40 mg/m 2 once every 4 wks and T 15 mg weekly. Early response 

evaluation with FDG-PET could predict PR and PD early after start of treatment. 

The activity of this combination in breast, endometrial and ovarian cancer pts is 

promising and warrants further studies with FDG-PET evaluation. 


463P DEVELOPMENT OF CANCER STEM CELLS THERAPEUTICS 

A.A. Epenetos 1 , C. Kousparou 2 , M. Deonarain 1 , S. Stylianou 2 

1 Life Sciences, Imperial College London, London, UNITED KINGDOM, 2 Cancer 

Research, Trojantec, Nicosia, CYPRUS 

Cancer Stem Cells, (CSCs), are responsible for the initiation, metastasis and 

recurrence of a variety of cancers and may be a key reason for the failure of current 

therapies. Cancer Stem cells operate through similar signaling pathways as normal 

stem cells such as Notch, Hedgehog,Wnt and others. Notch signaling is abnormal in 

many, if not all cancers as shown in cancer stem cell development. Furthermore, it 

may be that some cancers are ‘addicted’ to Notch signaling. This presents 

opportunities for tumour-specific intervention. As all the signaling cascades converge 

on the Notch transcriptional complex (NTC) in the nucleus, we have developed a 

novel synthetic protein acting as a Notch inhibitor operating at nuclear level. This 

protein is based on the cell penetrating protein (CPP) antennapedia (Antp) produced 

together with a dominant-negative truncated mastermind-like protein (DN-MAML) 

called TR4. TR4 has been shown in vitro and in vivo to have anti-Notch and 

anti-cancer activity with similar potency to many of the gamma-secretase inhibitors 

or monoclonal antibodies being developed by others against this pathway, but it is 

completely specific for the NTC. In summary, a specific Notch inhibitor has shown 

anticancer activity and could now be considered for clinical development. 

Disclosure: A.A. Epenetos: Receive directors fees from Trojantec ltd. All other 




464P A PHASE I STUDY OF DAILY AFATINIB, AN IRREVERSIBLE 

ERBB FAMILY BLOCKER, COMBINED WITH WEEKLY 

PACLITAXEL AND 2-WEEKLY BEVACIZUMAB IN PATIENTS 

WITH ADVANCED SOLID TUMOURS 

D. Enting 1 , J.E. Ang 2 ,C.O’Hanlon-Brown 1 , R. Kristeleit 3 , 

M. Uttenreuther-Fischer 4 , K. Pemberton 5 , K. Pelling 6 , D. Schnell 7 , J.S. de Bono 8 , 

J. Spicer 1 

1 Department of Oncology, King’s College School of Medicine and Guy’s 

Hospital, London, UNITED KINGDOM, 2 Drug Development Unit, Royal Marsden 

Hospital NHS Foundation Trust, Sutton, UNITED KINGDOM, 3 Drug Development 

Unit, Royal Marsden Hospital, Sutton, UNITED KINGDOM, 4 Clinical Development 

& Medical Affairs, Boehringer Ingelheim, Biberach, GERMANY, 5 Cinical Research 

/ Oncology, Boehringer Ingelheim, Bracknell, UNITED KINGDOM, 6 Statistics, 

Boehringer Ingelheim, Bracknell, UNITED KINGDOM, 7 Translational Medicine, 

Boehringer Ingelheim, Biberach, GERMANY, 8 Drug Development Unit, Royal 

Marsden Hospital NHS Foundation Trust, Surrey, UNITED KINGDOM 

Background: The clinical efficacy of cytotoxic agents can be enhanced both by ErbB 

inhibition and by bevacizumab (Bev). The primary objective of this study was to 

determine the maximum tolerated dose (MTD) of afatinib (A), an oral, irreversible 

ErbB Family Blocker, in combination with paclitaxel (P) and Bev. 

Afatinib 

(mg/day) 

Paclitaxel 

(mg/m 2 

Days 1, 8, 

15) 

Bevacizumab 

(mg/kg Days 1, 

15) 

All pts/ 

Evaluable 

pts/Pts with 

DLT 

DLT (all 

Grade 3) 

40 80 5 7/6/2 Fatigue/diarrhoea; 

fatigue 

30 80 5 5/5/2 Diarrhoea; 

paronychia 

20 80 5 3/3/0 

20 80 7.5 6/6/1 Mucositis 

(recommended 

dose) 

20 80 10 8/6/1 Dysphonia (MTD) 

Overall, the most frequent (any grade) adverse events (AEs) included diarrhoea 

(86%), fatigue (86%), rash (69%), mucositis (59%), and nausea (59%). Partial 

responses were confirmed in pts with non-small cell lung (n = 2) and cervical (n = 1) 

cancer. Eleven pts completed at least 6 treatment cycles of combination therapy. 

Methods: A Phase I open-label 3 + 3 design dose-escalation trial was undertaken to 

determine safety, pharmacokinetics (PK), and antitumour efficacy of A combined 

with P (fixed dose 80 mg/m 2 on Days 1, 8 and 15 of a 4-week cycle), and Bev (5 mg/ 

kg starting dose to be escalated to 10 mg/kg) administered on Days 1 and 15 in 

patients (pts) with advanced solid tumours. After at least 6 cycles of triplet 

combination therapy, pts benefiting and tolerating treatment were eligible to 

continue treatment with A and Bev. The PK data of P and Bev (± A), as well as the 

steady state PK of A combined with P and Bev will be presented. 

Results: Twenty-nine pts were enrolled (12 male; median age: 58 years [range: 21–73]; 

ECOG PS 0/1: 3/26). The MTD dose previously established for A (40 mg/day) in 

combination with P only (above schedule; Spicer et al. ESMO 2008) had to be 

de-escalated to 30 mg and then to 20 mg after 2/6 pts developed dose-limiting toxicities 

(DLTs) at 40 mg A and 2/5 at 30 mg A when combined with P and Bev 5 mg/kg. 

Conclusions: Promising antitumour activity was seen with the combination of A at 

20 mg/day with weekly P 80 mg/m 2 and 2-weekly Bev 7.5 mg/kg, the recommended 

dose for a Phase II study. At this dose, AEs of A combined with P and Bev were 

generally mild to moderate and manageable. 

Disclosure: M. Uttenreuther-Fischer: Employee of Boehringer-Ingelheim. K. 

Pemberton: Employee of Boehringer Ingelheim. K. Pelling: Employee of Boehringer 

Ingelheim. D. Schnell: Employee of SocraMetrics/Boehringer Ingelheim. J.S. de Bono: I 

have served as a paid consultant for Boehringer Ingelheim. J. Spicer: Honoraria from 


465P THE PRECLINICAL PHARMACOLOGICAL PROFILE OF 

ANAMORELIN/ONO-7643, A NEW GHRELIN RECEPTOR 

AGONIST FOR THE TREATMENT OF CANCER CACHEXIA 

C. Pietra 1 , Y. Takeda 2 , N. Tazawa-Ogata 2 , M. Minami 2 , X. Yuanfeng 3 , E. Duus 4 , 

R. Northrup 4 

1 Research and Preclinical, Helsinn Healthcare SA, Pambio Noranco, 

SWITZERLAND, 2 Discovery Research Laboratories, ONO Pharmaceutical, 

Osaka, JAPAN, 3 In Vitro Assay, HDB Biosciences, Shanghai, CHINA, 4 RD, 

Helsinn Therapeutics Inc., Bridgewater, NJ, UNITED STATES OF AMERICA 

Introduction: Ghrelin is the only known circulating orexigenic hormone which acts 

as the endogenous ligand for the ghrelin receptor (GRLN), and is considered a 

potential agent to treat cancer cachexia/anorexia. The aim of this study was to 

evaluate the in vitro and in vivo pharmacological activities of Anamorelin/ 

ONO-7643 (ANA), a new synthetic ghrelin receptor agonist, on food intake (FI), 

body weight (BW) and GH in rats. 

Material and methods: HEK293 cells expressing human recombinant ghrelin 

receptor were utilized in a Fluorescent Imaging Plate Reader (FLIPR), along with 

Fluo-8 dye to signal intracellular calcium. Ghrelin and ANA were incubated 

(0.001-1000 nM) to generate a concentration-response increase of Ca ++ . Binding 

experiments were also performed by using [ 125 I]Ghrelin. In vivo experiments were 

performed on male SD rats after oral treatment of ANA or vehicle. FI and BW were 

measured daily from Day 1 up to Day 7 of once-daily treatment. In other 

experiments, blood samples were collected at different time interval up to 6 hours 

post single dose for GH measurements. 

Results: Ghrelin and ANA showed a significant agonist activity on the ghrelin 

receptor in the FLIPR assay, with EC50 values of 0.67 nM and 0.74 nM, respectively. 

No significant antagonist activity was observed with ANA up to 1000 nM. In binding 

experiments, the affinity of ghrelin and ANA for ghrelin receptors were evaluated 

and resulted in a K i of0.58 nM and 0.70 nM, respectively. In the in vivo experiments, 

ANA (3, 10, 30 mg/kg p.o.) significantly (p < 0.05 vs vehicle ) increased FI and BW 

gain.The effect on FI was stable from Day 2 to Day 7 of treatment. ANA at the same 

doses increased GH AUC 0-6h and induced an increase in plasma GH levels. The 

effect was dose-dependent, and GH AUC 0-6h at 10 and 30 mg/kg p.o. were 

significantly higher (p < 0.05) than vehicle-treated animals. 

Conclusions: Anamorelin is a potent ghrelin agonist endowed with significant 

orexigenic activity demonstrating both an increase of FI and BW after subchronic 

treatment in rats. Plasma GH levels were increased after a single administration of 

ANA. These results support the continued investigation of Anamorelin as a potential 

treatment of cancer cachexia/anorexia. 

Disclosure: C. Pietra: Employee of Helsinn SA. Y. Takeda: Ono employee. N. 

Tazawa-Ogata: ONO employee. M. Minami: ONO Employee. E. Duus: Helsinn 

Therapeutics employee. R. Northrup: Helsinntheraputics employee. All other authors 


466P THE SAFETY AND EFFICACY OF SORAFENIB COMBINED 

WITH TRANSARTERIAL CHEMOEMBOLIZATION FOR 

PATIENTS WITH UNRESECTABLE HEPATOCELLULAR 

CARCINOMA 

W. Shao, N. Cong, J. Song 

Interventional Therapy, Shandong Cancer Hospital and Institute, Jinan, CHINA 

Background and aim: Transarterial chemoembolization(TACE) is widely used for 

unresectable hepatocellular carcinoma. However, the hypoxia caused by TACE in 

surviving tumor cell leads to release of angiogenic and growth factors contributing to 

poor outcome. Sorafenib can block tumor cell proliferation and angiogenesis. The 

hypothesis is that patients with unresectable HCC may benefit from sorafenib in 

combination with TACE. 

Methods: This is a retrospective study involving patients with unresectable HCC who 

had received at least one TACE session. Patients received sorafenib 400 mg twice per day 

and were monitored monthly. Dose reduction from 400mg to 200mg of sorafenib bid 

was permitted. The primary outcome is safety. The second outcome is overall survival. 

Results: Twenty one patients (mean age, 58 years; Child-Pugh class A, 100%; ECOG 

PS 0, 100%; BCLC B, 36.8%; BCLC C, 63.2%) were included from April, 2009 to 

February, 2011. The mean TACE sessions prior to or after sorafenib administration 

were 4.3 ± 2.9 and 1.5 ± 0.4 respectively. All patients were treated with sorafenib 

despite radiographic progression until there was deterioration in patient’s Child-Pugh 

class to C, ECOG PS score to 4, or had intolerant adverse events or death. Two 

patients quitted the study for intolerant diarrhea and withdrawn of consent, 

respectively. Of the other 19 patients, no grade 3 or 4 adverse events were observed. 

The most common toxicities were dermatology adverse effects (94.7%), diarrhea 

(63.2%) and alopecia (26.3%). Sorafenib dose was reduced temporarily in 14 patients 

(73.7%). Most of toxicities could be relieved after dose reductions and not aggravated 

again even the dose of sorafenib resumed to 400 mg bid. Five patients remained on 

sorafenib as of February 29, 2012, and were censored at that time point. The median 

survival was 12 months (9.2-14.8 months. 

Conclusion: The combination of sorafenib and TACE for unresectable HCC is safe 

providing that dose adjustment is permitted. The survival benefit is promising. 


467P PHASE I STUDY OF U3-1287, A HUMAN MONOCLONAL 

ANTIBODY TARGETING HER3, IN JAPANESE PATIENTS WITH 


H. Wakui1 , N. Yamamoto1 , S. Nakamichi1 , Y. Tamura1 , H. Nokihara1 , 

Y. Yamada2 , T. Tamura1 1 

Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN, 

2 

Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, 

JAPAN 

Background: HER3 is a key dimerization partner for HER-family members that 

activates oncogenic signaling pathways lead to cell survival and proliferation. 


Acquired-resistance to EGFR inhibitors may result from the activation of HER3 and/ 

or HER2, which share overlapping the signaling pathways. U3-1287 is a fully human 

anti-HER3 monoclonal antibody that has demonstrated anticancer activity in 

preclinical models. In a preceding US phase I study, the tolerability of U3-1287 was 

evaluated up to the dose of 20 mg/kg without dose-limiting toxicities (DLTs). In this 

study, we evaluated the tolerability, pharmacokinetics (PK) and potential antitumor 

activities of U3-1287 in Japanese patients with solid tumors up to the dose of 18 mg/kg. 

Methods: Patients received U3-1287 at a dose of 9 mg/kg or 18 mg/kg intravenously 

every 3 weeks (q3w). Tumor response, incidence of anti-U3-1287 antibodies 

(HAHA), and level of soluble HER3 (sHER3) were also evaluated. 

Results: Nine patients, 3 at 9 mg/kg and 6 at 18 mg/kg, were enrolled. Five 

patients were male and median (range) age of 67 (50-69) years. Tumor types were 

lung (2), colorectal (2), esophageal (2), breast (1), cervical (1), and sarcoma (1). No 

DLTs were reported. U3-1287-related AEs were ALT increase (3 patients), 

thrombocytopenia, diarrhea, stomatitis, cheilitis, rash, and AST increase (2 each). 

Plasma disappearance was bi-phasic and terminal half-life at the dose of 18 mg/kg 

was approximately 9 days. PK profiles were similar to those in the US phase I 

study. Four patients had best responses of stable disease. All patients tested were 

negative for HAHA formation. Level of sHER3 unexpectedly increased about 

four times in all patients. Mean sHER3 concentrations at baseline and day 15 were 

3.8 ng/mL and 16.5 ng/mL, respectively. These changes did not correlate with 

clinical response (at day15 in SD and PD patients; 16.7 ng/mL and 16.9 ng/ml, 

respectively). 

Conclusions: U3-1287 was well tolerated up to 18 mg/kg in Japanese patients with 

solid tumors. These data support a dosing regimen of 18 mg/kg q3w in future 

studies. 


468P PHASE I STUDY TO COMPARE SAFETY AND 

PHARMACOKINETICS OF AFATINIB, AN ORAL IRREVERSIBLE 

ERBB FAMILY BLOCKER, IN NON-CANCER SUBJECTS WITH 

HEPATIC IMPAIRMENT TO MATCHED HEALTHY SUBJECTS 

D. Schnell 1 , S. Buschke 2 , H. Fuchs 3 , R. Göldner 4 , M. Uttenreuther-Fischer 5 , 

P. Stopfer 6 , S. Wind 2 , A. Halabi 7 , R. Koenen 1 

1 Translational Medicine, Boehringer Ingelheim, Biberach, GERMANY, 

2 Pharmacokinetics, Boehringer Ingelheim, Biberach, GERMANY, 3 Drug 

Metabolism & Pharmacokinetics, Boehringer Ingelheim, Biberach, GERMANY, 

4 Statistics, Boehringer Ingelheim, Biberach, GERMANY, 5 Clinical Development & 

Medical Affairs, Boehringer Ingelheim, Biberach, GERMANY, 6 Clinical 

Pharmacokinetics/pharmacodynamics, Boehringer Ingelheim, Biberach, GERMANY, 

7 Medical Director, CRS Clinical Research Services Kiel GmbH, Kiel, GERMANY 

Background: Afatinib (BIBW 2992) is an oral, irreversible ErbB Family Blocker. It 

was found to be mainly excreted via faeces and is highly protein bound. To define 

the impact of different degrees of hepatic impairment (HI) on the pharmacokinetics 

(PK) and safety of afatinib, a dedicated Phase I trial was conducted. 

Methods: This single-dose, open-label, dose-escalation study in a matched group 

design included male or female subjects with HI (mild: Child Pugh A, score 5 or 6; 

moderate: Child Pugh B, score 7 to 9) and healthy volunteers (HV) matched to the 

HI subjects based on age, weight, sex and creatinine clearance. Dose escalation of 

afatinib from 30 to 50 mg was performed depending on tolerability and PK. Plasma 

and urine sampling was performed for up to 240 hours (h) and 72 h after afatinib 

administration, respectively. Primary endpoints were comparison of AUC 0-∞ and 

C max of afatinib between subjects with HI and matched healthy subjects. For all other 

parameters, descriptive statistics were calculated. Additionally, blood samples were 

drawn to determine in vitro plasma protein binding of afatinib. 

Results: Thirty-five subjects entered the trial: 3 subjects with mild HI received 

single-dose 30 mg afatinib and 32 subjects received single-dose 50 mg afatinib. 

Tolerability of afatinib was good, with 6/35 subjects showing AEs, which were related 

to afatinib in 3/35 subjects. Main PK parameters are given in Table 1. After a single 

dose of 50 mg, PK parameters were similar between patients with HI and their 

matched HV controls. 

Conclusions: Mild and moderate HI had no influence on the PK and tolerability of a 

single dose of 50 mg afatinib. Table 1: Comparison of main PK parameters after 

single-dose administration of 50 mg afatinib. 

Table: 468P 

50 mg afatinib, 

mild HI (N = 8) 

50 mg afatinib, HV 

matched to mild HI 

(N = 8) 

Disclosure: D. Schnell: Employee of SocraMetrics / Boehringer Ingelheim. S. Buschke: 

Employee of Boehringer Ingelheim. H. Fuchs: Employee of Boehringer Ingelheim. R. 

Göldner: Employee of Boehringer Ingelheim. M. Uttenreuther-Fischer: Employee of 

Boehringer Ingelheim. P. Stopfer: Employee of Boehringer Ingelheim. S. Wind: 

Employee of Boehringer Ingelheim. A. Halabi: Employee of CRS Clinical Research 

Services / Boehringer Ingelheim. R. Koenen: Employee of Boehringer Ingelheim. 

469P THE CLINICAL UTILITY OF A CHANGE IN THE ROYAL 

MARSDEN HOSPITAL PROGNOSTIC SCORE (RMHPS) IN 

PATIENTS (PTS) PRIOR TO PHASE I CLINICAL TRIAL 

THERAPY 

C.O. Michie1 , M. Ong1 , J. Mateo1 , A.M. Young1 , D. Olmos2 , J.E. Ang1 , 

L.R. Molife1 , U. Banerji1 , J.S. de Bono1 , S.B. Kaye1 1 

Drug Development Unit, Royal Marsden Hospital, Sutton, UNITED KINGDOM, 

2 

DDU/Prostate Unit, Royal Marsden HospitalNHS Foundation Trust, Sutton, 


Background: Previously we developed and validated the RMHPS to aid patient 

selection for phase I clinical trials 1 . However, its sensitivity in predicting short-term 

outcome is limited. Here we assessed whether, prior to trial entry, a worsening of 

RMHPS during screening improves specificity. 

Methods: Pts treated in phase I trials between Sep 09-11 at RMH Drug Development 

Unit were identified from a prospectively-collected database. RMHPS was calculated 

at 2 distinct timepoints; ≤1 wk prior to start of therapy and at an earlier 

timepoint ≤ 8 wks previously. RMHPS of 0-1 and 2-3 were denoted low and high 

respectively. Pts were divided into 4 groups based on the sequential RMHPS: 

low-low; low-high; high-low; and high-high. Median overall survival (OS) and time 

to study withdrawal were estimated by Kaplan-Meier method and prognostic 

variables compared by multivariate Cox regression analysis. 

Results: One hundred and thirty one pts were identified. The most common 

tumours were colorectal, ovary and breast. Median age and lines of prior 

chemotherapy was 57y and 2 respectively. 99% of pts had ECOG PS 0/1 at baseline 

while 89% had distant metastases. Pts were treated on study for a median of 70 days 

(d), with 74.8% discontinuing for progression, 8.4% for toxicity and 12.2% for other 

reasons. Study withdrawal


subcutaneous (SC) formulation of trastuzumab has shown non-inferiority vs. 

trastuzumab IV in a large Phase III study (Jackisch, et al. 2012). A proprietary 

single-use injection device (SID) has been developed to enable automated injection 

of trastuzumab SC formulation, thus offering potential for self-administration. In 

previous studies, trastuzumab SC was injected manually. 

Methods: This randomized, open-label study assessed the pharmacokinetic (PK) 

comparability and safety of a single 600 mg dose of trastuzumab SC injected 

manually (N = 60) or using the SID (N = 59) in healthy male subjects. PK and safety 

were assessed before dosing and up to day 63 after dosing, with cardiac safety 

monitoring up to Week 21. 

Results: The primary analysis showed that the study met the pre-specified criteria for 

comparability between modes of administration, as demonstrated by AUC0–21 days 

and Cmax values. Sensitivity analyses to assess possible variability due to body weight 

and actual dose delivered supported the co-primary analysis findings. The incidence 

of adverse events (AEs) of any grade was similar between arms with no grade 4 AEs, 

deaths, or cardiac, serious or SID-related AEs. Two grade 3 AEs occurred: pyrexia 

and head injury, both in the manual administration arm. Pain assessments and 

infusion-related/injection site reactions were similar. SID attachment and wearing 

comfort received top scores in all cases, while SID removal received the top score in 

all but two cases (acceptable). There were no SID failures. The incidence of 

antibodies to trastuzumab and recombinant human hyaluronidase was similar 

between arms, with no neutralizing antibodies detected and no relevant effects on PK 

observed. 

Conclusion: This study demonstrated comparability of two modes of administration 

for trastuzumab SC based on standard PK parameters, with comparable safety for 

trastuzumab SC administered manually and using the single-use injection device, 

which demonstrated consistent performance and tolerability. 

Disclosure: M. Lehle: Michaela Lehle is an employee of F. Hoffmann-La Roche Ltd. 

D. Heinzmann: Dominik Heinzmann is an employee of F. Hoffmann-La Roche Ltd 

and a stockholder in Roche Holdings. R. Mangat: Ranvir Mangat is an employee of 

Genentech Inc, and a stockholder of Roche Holdings. C. Li: Chunze Li is an 

employee of Genentech Inc, and a stockholder of Roche Holdings. L.A. 

Herráez-Baranda: Luis Herráez-Baranda is an employee of F. Hoffmann La-Roche 

Ltd. B.L. Lum: Bertram Lum is an employee of Genentech Inc, and a stockholder of 

Roche Holdings. All other authors have declared no conflicts of interest. 

471P A PHASE I, DOSE-ESCALATION STUDY OF MGCD265, A 

MULTI-TARGETED ORAL TYROSINE KINASE RECEPTOR 

INHIBITOR, FOR TREATMENT OF ADVANCED SOLID TUMORS 

H.I. Hurwitz 1 , C.K. Kollmannsberger 2 , M. Juretic 3 , J. Wang 3 , M. Fournel 3 , 

C. Bonfils 3 , C. Maroun 3 , R.W. Humphrey 3 , J. Besterman 3 , G. Shapiro 4 

1 Division of Hematology and Oncology, Duke University Medical Center, Durham, 

NC, UNITED STATES OF AMERICA, 2 BCCA Vancouver Cancer Centre, 

University of British Columbia Division of Medical Oncology, Vancouver, BC, 

CANADA, 3 Clinical Affairs, Methylgene, Inc, Montreal, QC, CANADA, 4 Oncology, 

Dana-Farber Cancer Institute, Boston, MA, UNITED STATES OF AMERICA 

Background: MGCD265 is a multikinase inhibitor with activity against Met, VEGFR 

1, 2 and 3, Tie-2 and Ron that has been shown in preclinical models to possess 

broad antitumor effects. 

Methods: Patients with advanced malignancies were enrolled in a phase I, 

open-label, dose-escalation study. Oral MGCD265 was administered daily over a 

3-wk cycle, at a starting dose of 24 mg/m2 once daily. QD and BID dosing were 

tested sequentially. The study’s primary aim was to determine the safety profile of 

MGCD265, including maximum tolerated dose (MTD) and dose-limiting toxicities 

(DLT). Pharmacokinetics, pharmacodynamics and antitumor activity were also 

evaluated. 

Results: To date, 61 patients have been enrolled, with dose escalation up to 313 mg/ 

m2 BID. Increasing dose frequency to BID increased exposure of MGCD265 by 

approximately twofold. Drug exposure achieved to date is in the range where tumor 

growth inhibition was observed with Met-sensitive preclinical models. 

Dose-dependent inhibition of Met phosphorylation was demonstrated in an ex vivo 

model using patient plasma, with up to 55% inhibition observed at doses to date. 

MTD has not yet been reached, and dose escalation continues. MGCD265 was well 

tolerated. DLTs were observed in 5 patients (N = 1 each): fatigue, diarrhea, lipase 

elevation, pituitary hemorrhage (all grade 3) and hypertension (grade 2, 

protocol-defined), all occurring in cycle 1 at daily doses ≥ 250 mg/m2. Drug-related 

grade 3 adverse events beyond cycle 1 were diarrhea, fatigue, elevated lipase and 

elevated alkaline phosphatase (N = 1 each). Of 51 response-evaluable patients to date, 

22 achieved stable disease (SD) for ≥2 cycles, and 7 achieved SD for ≥6 cycles (1 

patient up to 12 cycles). 

Conclusions: This study supports the safety of MGCD265 in patients with advanced 

malignancies. There are encouraging early signs of efficacy, with prolonged stable 

disease noted in several heavily pretreated patients. 

Disclosure: H.I. Hurwitz: Research funding from Methylgene, Inc. C.K. 

Kollmannsberger: Research funding from Methylgene, Inc. M. Juretic: Employee of 

Methylgene, Inc. J. Wang: Employee of Methylgene, Inc. M. Fournel: Employee of 

Methylgene, Inc. C. Bonfils: Employee of Methylgene, Inc. C. Maroun: Employee of 

Methylgene, Inc. R.W. Humphrey: Employee of Methylgene, Inc. J. Besterman: 

Employee of Methylgene, Inc. G. Shapiro: Research funding from Methylgene, Inc. 

472P CATUMAXOMAB SHOWS COMPARABLE ANTI-TUMOR 

ACTIVITY IN VITRO WITH IMMUNE EFFECTOR CELLS FROM 

DIFFERENT ETHNICITIES WITH DIFFERENT FCγR GENE 

POLYMORPHISMS 

F. Marmé 1 , K. Hasegawa 2 , H. Martinius 3 , J. Atz 3 , K. Fujiwara 2 

1 INF 460, Universitätsfrauenklinik Heidelberg & Nationales Centrum für 

Tumorerkrankungen (NCT), Heidelberg, GERMANY, 2 Department of Gynecologic 

Oncology, Saitama International Medical Center, Saitama, JAPAN, 3 Munich, 

Fresenius Biotech GmbH, Munich, GERMANY 

Background: Catumaxomab, the approved therapy for treatment of malignant 

ascites, exerts its anti-tumor effects via T-cell-mediated lysis, antibody-dependent 

cell-mediated cytotoxicity, and phagocytosis via activation of FcγR-positive accessory 

cells. It has been reported that FcγR-polymorphisms influence the IgG binding 

capacity of the receptor and that ethnic groups may differ with respect to 

responsiveness of immune effector cells to antibody-based therapies. The present 

nonclinical study therefore investigated potential inter-ethnic differences (Caucasian 

vs. Japanese, Korean, Black African and Hispanic Donors) and FcγR-gene 

polymorphisms with regard to the potency of catumaxomab in vitro. 

Methods: Blood samples of healthy subjects of different ethnic background (25 

donors of Caucasian, Korean, Black African and Hispanic ethnicity and 15 Japanese 

donors) were collected for comparative analyses. PBMCs were purified from whole 

blood samples and used as effector cells evaluating catumaxomab-mediated 

cytotoxicity towards EpCAM+ tumor target cells (HCT-8; colon) in vitro. 

Furthermore, the samples were genotyped for FcγR IIa and FcγR IIIa gene 

polymorphisms by PCR. 

Results: The comparative analysis of catumaxomab-mediated cytotoxicity obtained 

for the individual ethnic subgroups did not reveal major inter-ethnic differences 

although genetic polymorphisms for FcγR IIa/IIIa had been identified among 

donors. Even though a wider variability was observed among Caucasians, the 

potency range observed with immune effector cells of Japanese, Korean, Black 

African and Hispanic was found to be within the potency range observed for the 

Caucasian ethnicity. 

Conclusions: No impact of ethnic background or FcγRIIa/IIIa polymorphism on the 

immune cell-mediated pharmacological activity of the trifunctional antibody 

catumaxomab could be identified in vitro. Therefore, it can be assumed that patients 

with a different ethnic background may also benefit from catumaxomab therapy as 

already demonstrated for Caucasian patients. 

Disclosure: F. Marmé: consultant for Fresenius Biotech GmbH. K. Hasegawa: 

financial support for clinical studies from Fresenius Biotech GmbH. H. Martinius: 

works for Fresenius Biotech GmbH. J. Atz: works for Fresenius Biotech GmbH. K. 

Fujiwara: financial support for clinical studies from Fresenius Biotech GmbH. 

473P TREATMENT OF CHEMOTHERAPY-INDUCED ORAL 

MUCOSITIS BY SILYMARIN 

T.S. Altaei 

Pharmacology and Toxicology, Hawler Medical University, Erbil, IRAQ 

Background: Oral mucositis is a common and severe complication of head and neck 

radiation therapy. Silymarin is a polyphenolic flavonoid extracted from the milk 

thistle exhibits a strong antioxidant activity, and anti-inflammatory effects. The 

efficacy for the treatment was assessed in comparison with indomethacin. 

Patients and methods: A prospective, randomized, double blind; placebo controlled 

study was conducted in 65 of chemotherapy-induced oral mucositis patients; plasma 

IL-1β, leptin, and Trolox equivalent antioxidant capacity (TEAC) were assessed for 3 

orally treated groups; Silymarin 140mg, or Indomethacin 25mg, or placebo, 3 times 

daily for 14 days, radiation technique and dose were similar. The oral mucositis was 

assessed weekly according to OMAS and WHO scale, pain related to oral mucositis 

was scored subjectively by visual analog scale. 

Results: Patients’ characteristics showed no significant differences between tested 

groups. Statistical significance showed in; lower OMAS value at the time of 

using Silymarin, and lower mean time to healing of oral mucositis in Silymarin 

treated group compared to Indomethacin treated and placebo groups. Ulcer 

healing and pain relief were seen in 100% of Silymarin treated group but only 

40% of Indomethacin treated group compared to placebo after 5 days of 

treatment. Serum IL-1β, leptin were reduced significantly, and TEAC showed 

significant elevation in Silymarin treated group compared to baseline and other 

tested drugs. 

Conclusion: Silymarin could interrupt or block the mucositis process at multiple targets 

that protect the mucosa and promote healing of chemotherapy-induced mucositis by 

reducing the incidence, blocking the oxidative stress and anti-inflammatory actions. Key 

words: Silymarin, chemotherapy-induced mucositis, IL-1β,leptin. 



474P PHASE 1 STUDY OF THE SELECTIVE AKT INHIBITOR 

MK-2206 IN JAPANESE PATIENTS WITH ADVANCED SOLID 

TUMORS 

Y. Tanabe1 ,T.Doi2 , K. Tamura1 , K. Yonemori1 , M. Kodaira1 ,N.Fuse2 , 

H. Bando2 , Y. Maeda3 , T. Shimamoto3 , A. Ohtsu4 1 

Breast and Medical Oncology Division, National Cancer Center Hospital, Tokyo, 

JAPAN, 2 Gastroenterology & GI Oncology Department, National Cancer Center 

Hospital East, Chiba, JAPAN, 3 Japan Development, MSD K.K., Tokyo, JAPAN, 

4 

Research Center for Innovative Oncology, National Cancer Center Hospital East, 

Chiba, JAPAN 

Background: The AKT pathway, which mediates cell proliferation, survival, and 

angiogenesis, is commonly dysregulated in cancer. MK-2206 is an orally active, 

allosteric AKT 1/2 inhibitor with wide preclinical activity. This open-label, 

nonrandomized study investigated the safety, pharmacokinetics (PK), 

pharmacodynamics (PD), and antitumor activity of MK-2206 in Japanese patients 

with solid tumors who were refractory to standard therapy. 

Methods: Patients received once every other day (qod) or once-weekly (qw) doses of 

MK-2206 in 28-day treatment cycles, with a 1-week drug holiday following Cycle 

1. Dose-limiting toxicities (DLTs) were evaluated during Cycle 1, with cohorts of 3, 

6, or 9 patients, depending on the dose studied and adverse events (AEs) experienced 

by patients. Overall antitumor activity was assessed at designated time points every 

other treatment cycle after initial screening, following RECIST guidelines. 

Results: Treated patients (N = 24; male/female: 10/14; median age: 57 yrs; ECOG PS 

0/1: 16/8) received MK-2206 45 mg or 60 mg qod (n = 12) and 135 mg or 200 mg 

qw (n = 12). Grade 3 rash was the DLT at both 60 mg qod (1 of 9 patients) and 200 

mg qw (3 of 9 patients). Common reversible drug-related toxicities included rash 

(83.3%), stomatitis (58.3%), pyrexia (58.3%), and hyperglycemia (54.2%). MK-2206 

terminal half-life did not differ from non-Japanese patients (69–80 h vs 60–90 h), but 

Cmax, AUC, and Ctroughwere generally higher in Japanese patients (1.5- to 1.7-fold). 

ANOVA models that adjusted for body weight suggested that PK differences could be 

mostly attributed to between-study body weight differences. PD assays demonstrated 

inhibition of blood pAKT at Day 15 (27.6%–61.4%). Modest antitumor activity was 

observed with a best response of stable disease (SD) lasting longer than 42 weeks; 

patients who achieved SD had various diagnoses, including neuroendocrine 

carcinoma and esophageal cancer. 

Conclusion: MK-2206 at doses up to 60 mg or 200 mg has a long terminal half-life 

and can be safely administered on either qod or qw dosing schedules. Higher 

exposures were observed in Japanese patients, but this could be explained by body 

weight differences. 


475P FINAL ANALYSIS OF PHASE I AND PHARMACOKINETICS/ 

PHARMACODYNAMICS (PK/PD) STUDY OF RO5126766, A 

FIRST-IN-CLASS DUAL RAF/MEK INHIBITOR, IN JAPANESE 


K. Honda 1 , N. Yamamoto 1 , H. Nokihara 1 , Y. Tamura 1 , H. Asahina 1 , Y. Yamada 2 , 

S. Suzuki 3 , N. Yamazaki 4 , T. Tamura 1 


2 Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, 

JAPAN, 3 Division of Ophthalmic Oncology, National Cancer Center Hospital, 

Tokyo, JAPAN, 4 Division of Dermatological Oncology, National Cancer Center 


Background: RO5126766 is a highly selective and orally active dual inhibitor of Raf 

and MEK, key enzymes in the MAPK signaling pathway. This was a phase I, 

dose-escalation study in Japanese patients with advanced solid tumors. This Phase I 

study was aimed to assess maximum tolerated dose (MTD) based on dose-limiting 

toxicities (DLTs), safety evaluation, PK/PD analysis and exploratory analysis of 

anti-tumor activity. 

Methods: Patients received an oral single dose administration of RO5126766 (0.8, 

1.2, 1.8, and 2.25 mg) followed by continuous once daily dosing in 28-day cycles. A 

3 + 3 dose-escalation design was used. PD was evaluated by pMEK and pERK 

inhibition in peripheral blood mononuclear cells (PBMCs). Archival tumor tissue or 

biopsy samples were collected to analyze the mutation status of K-Ras and B-Raf 

only from patients who had consented to provide samples. 

Results: Twelve patients were enrolled into 4 sequential cohorts at 0.8, 1.2, 1.8, and 

2.25 mg/day. As 2.25 mg/day had already been defined as the MTD of the QD oral 

dosing regimen in another phase I study conducted in Europe, doses higher than 

2.25 mg/day were not administered. In the dose range tested, no DLTs were observed 

and the MTD was not defined. Frequent adverse events (AEs) included dermatitis 

acneiform, creatine phosphorkinase (CPK) elevation, and eye disorders. Plasma 

exposure of RO5126766 appeared to increase in a dose-proportional manner with a 

long plasma half-life (t 1/2) of 45.8 to 93.7 hours. Following multiple dose 

administration, steady-state conditions were reached by Cycle 1 Day 8 (240 hours). 

No clear associations between PK parameters and occurrence of skin disorders, CPK 

elevation, or eye disorder were found. The inhibitory effects of RO5126766 on both 

pMEK and pERK in PBMCs increased in a dose-dependent manner. These 


inhibitory effects were achieved at >80% over the dose level of 1.2 mg at steady state 

phase. Five out of 12 patients achieved stable disease including a melanoma case with 

over 20 % shrinkage. 

Conclusions: RO5126766 has a manageable safety profile up to 2.25 mg/day with a 

favorable PK/PD correlation in Japanese patients with advanced tumors. 

Disclosure: K. Honda: This phase I clinical trial is sponsored by Chugai 

Pharmaceutical Co., Ltd. N. Yamamoto: This phase I clinical trial is sponsored by 

Chugai Pharmaceutical Co., Ltd. H. Nokihara: This phase I clinical trial is sponsored 

by Chugai Pharmaceutical Co., Ltd. Y. Tamura: This phase I clinical trial is 

sponsored by Chugai Pharmaceutical Co., Ltd. H. Asahina: This phase I clinical trial 

is sponsored by Chugai Pharmaceutical Co., Ltd. Y. Yamada: This phase I clinical 

trial is sponsored by Chugai Pharmaceutical Co., Ltd. S. Suzuki: This phase I clinical 

trial is sponsored by Chugai Pharmaceutical Co., Ltd. N. Yamazaki: This phase I 

clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. T. Tamura: This phase 

I clinical trial is sponsored by Chugai Pharmaceutical Co., Ltd. 

476P TRASTUZUMAB-INDUCED EARLY CARDIAC DYSFUNCTION 

ASSESSED BY SPECKLE TRACKING ECHOCARDIOGRAPHY: 

CORRELATION WITH CHRONIC INFLAMMATION AND 

OXIDATIVE STRESS MARKERS 

M. Dessi’ 1 , G. Mantovani 1 , C. Madeddu 1 , L. Orgiano 1 , P. Alessandra 2 , 

C. Cadeddu 2 , G. Antoni 2 , R. Serpe 1 , G. Mercuro 2 

1 Department of Medical Oncology, University of Cagliari, Cagliari, ITALY, 

2 Department of Cardiovascular Diseases, University of Cagliari, Cagliari, ITALY 

Background: Trastuzumab (TZM) was shown to be very effective in patients with 

breast cancer overexpressing HER-2 in the neoadjuvant, adjuvant and metastatic 

setting. It has a mild cardiac toxicity which may increase when administered in 

combination with anthracyclines. The “Speckle Tracking Echocardiography” (STE), 

able to assess cardiac mechanics [cardiac torsion movements and the global, 

circumferential, radial and longitudinal Strain (S) and Strain Rate (SR)], and identify 

at an early stage left ventricular dysfunction, was used for cardiac monitoring. The 

present study aimed to assess the STE changes induced by TZM and correlate them 

with changes of chronic inflammation and oxidative stress markers. 

Methods: A phase IV, prospective, non-randomized study was designed: planned 

sample size 60 patients. Inclusion criteria: 18–70 yo women with HER-2 + ve breast 

cancer receiving TZM, LVEF ≥55%; ECOG PS score 0-2, no history of cardiac 

disease. The STE parameters (global, circumferential, radial and longitudinal S and 

SR) and chronic inflammation (IL-6 and TNF-α)/oxidative stress (reactive oxygen 

species and gluthatione peroxidase) markers were assessed at baseline, after each 

three-weekly TZM administration, up to the 8th TZM dose. 

Results: At September 2011, 30 patients (mean ± SD age 53 ± 10 y) were enrolled 

and completed the study. A significant reduction of the peak of radial and 

circumferential SR (p < 0.01 and p < 0.005) as first sign of systolic dysfunction was 

observed at the 3rd TZM dose. A significant reduction of the peak of longitudinal SR 

(p < 0.01) was observed at the 4th TZM dose. As for laboratory parameters, TNF-α 

increased significantly at the 2nd and 3rd TZM dose, whilst the remaining laboratory 

parameters did not change significantly. 

Conclusions: These preliminary results suggest that TZM treatment induces an early 

preclinical cardiac systolic dysfunction which correlates with an increase of TNF-α. 

The study is in progress to reach the planned sample size, monitor patients for an 

adequate follow-up time and eventually select patients candidates for an effective 

cardioprotective treatment. This study was Funded by AIRC - project number 8679. 


477P LIPOSOMAL PRODRUG OF MITOMYCIN C WITH THIOLYTIC 

ACTIVATION: IMPROVED THERAPEUTIC INDEX OVER 

MITOMYCIN C IN PRECLINICAL STUDIES 

A.A. Gabizon 1 , Y. Amitay 2 , H. Shmeeda 3 , S. Zalipsky 4 

1 Oncology, Shaare Zedek Medical Center, Jerusalem, ISRAEL, 2 Experimental 

Oncology, Lipomedix Pharmaceuticals Inc., Jerusalem, ISRAEL, 3 Experimental 

Oncology, Shaare Zedek Medical Center, Jerusalem, ISRAEL, 4 Consultant, 

Lipomedix Pharmaceuticals Inc., Jerusalem, ISRAEL 

We have developed a formulation of a mitomycin-C lipid-based prodrug (MLP) in 

pegylated liposomes (PL) in which MLP is activated by thiolytic cleavage to 

mitomycin C (MMC). PL-MLP (PROMITIL) was previously reported to have 

reduced toxicity and an improved therapeutic index as compared to MMC in human 

and mouse tumor models. In the following studies, we examined the 

pharmacokinetics, toxicity, and therapeutic activity of scaled-up batches of PL-MLP 

(prepared under the same protocol design as for clinical batches) in rodent and 

miniswine species. PL-MLP is a liquid suspension of vesicles of ∼100 nm diameter 

with MLP entrapped in the lipid bilayer at 10% molar ratio. Pharmacokinetic studies 

revealed major (>100-fold) differences in Cmax, AUC, plasma clearance and volume 

of distribution between MMC (i.v. 3 mg/kg) and PL-MLP (i.v. 6 mg/kg in 

MMC-equivalents). While MMC is cleared from blood within minutes and 

extensively distributed to peripheral tissues, PL-MLP is cleared very slowly with a 



mono-exponential half-life of ∼15 hours in rats and has a limited volume 

distribution roughly equivalent to the blood volume. In rat toxicity studies in rats, 

the MTD of PL-MLP was two to three-fold higher than that of MMC in 

mg-equivalent doses. Therapeutic studies in BALB/c mice inoculated i.p. with C26 

tumor cells show a clear survival advantage for treatment with PL-MLP over free 

MMC at all dose levels tested, whether treatment was administered by the i.v. or by 

the i.p. route. In the porcine model, no acute infusion reaction to i.v. administration 

of PL-MLP was observed. PL-MLP appears to be a stable formulation with minimal 

prodrug activation and release of MMC in circulation, yet significant antitumor 

activity, indicating in vivo prodrug activation in tumors. PL-MLP may represent an 

effective therapeutic tool in a broad spectrum of malignancies, including multi-drug 

resistant tumors, with improved safety over free MMC, and is due to be tested in a 

human phase I study in 2012. 

Disclosure: A.A. Gabizon: I am the founder and Chief Scientist of Lipomedix Inc., a 

company with a vested interest in the product discussed in this presentation. Y. 

Amitay: Paid employee of Lipomedix, a product of which is discussed here. All other 


478P PHASE I SAFETY AND TOLERABILITY OF ONCE DAILY ORAL 

AFATINIB (A) (BIBW 2992) IN COMBINATION WITH 

GEMCITABINE (G) IN PATIENTS (PTS) WITH ADVANCED 

SOLID TUMOURS 

S. Zanetta 1 , J. Bennouna 2 , N. Isambert 3 , H. De Mont-Serrat 4 , I. Tschoepe 4 , 

P. Squiban 4 , J. Delord 5 

1 Oncology Department, Centre Georges François Leclerc, Dijon, FRANCE, 

2 Oncology/ Pneumology, Institut de Cancerologie de l’Ouest-site René 

Gauducheau, Nantes, FRANCE, 3 Medical Oncology, Centre Georges François 

Leclerc, Dijon, FRANCE, 4 Medical Affairs, Boehringer Ingelheim, Reims, 

FRANCE, 5 Clinical Resarch Unit, Institut Claudius Regaud, Toulouse Cedex, 

FRANCE 

Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open 

label, Phase I, dose escalation trial investigated the safety, tolerability and 

pharmacokinetics of A in two parallel dose cohort expansion parts, in combination 

with either G (Part A) or docetaxel (Part B) in pts with relapsed or refractory solid 

tumours. Preliminary results from Part A are presented here. 

Methods: Eligible pts (confirmed diagnosis of advanced solid tumours, Eastern 

Cooperative Oncology Group Performance Status 0–1) received once-daily, oral 

dosing of A in combination with G, given intravenously at Day 1 and at Day 8 of 

every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. The primary objective 

was to establish the maximum tolerated dose (MTD) based on the occurrence of 

dose limiting toxicities (DLTs) observed in Cycle 1. Dose escalation was performed 

with cohorts of 3–6 pts using a 3 + 3 design. Initial starting dose level was A 30 mg/ 

day and G 1000mg /m 2 , escalating up to A 50 mg/day and G 1250 mg/m 2 , until the 

MTD was reached, and followed by a pharmacokinetic expansion cohort of 12 pts at 

the MTD level. 

Results: Nineteen pts were treated in the escalation part of the study with the 

following baseline characteristics: mean age (53.7 years), female (63.2%) and number 

of prior chemotherapies (≤2: 26%; >2: 74%). In Cycle 1, DLTs were experienced by 

one pt out of six receiving A 30 mg and G 1250 mg/m 2 , and in two pts at a dose 

level of A 40 mg/day and G 1250 mg/m 2 . Adverse events (AEs) observed in most pts 

were diarrhoea (89.5%) and rash (63.2%). MTD was exceeded at a dose level of A 40 

mg/day and G 1250 mg/m 2 . An intermediate dose level of A 40 mg/day and G 1000 

mg/m 2 is currently under evaluation with two pts enrolled to date. 

Conclusions: In pts with relapsed or refractory advanced solid tumours, the 

combination of A with G is well tolerated, with manageable AEs. Dose finding is 

ongoing and MTD, safety profile and preliminary evidence of activity are anticipated 

to be reported at time of presentation. 

Disclosure: J. Bennouna: I have received honoraria from roche, boehringer 

ingelheim, and amgen for advisory board. It is for myself. H. De Mont-Serrat: 

Employee of Boehringer Ingelheim. I. Tschoepe: Employee of Boehringer Ingelheim. 

P. Squiban: Employee of Boehringer Ingelheim. All other authors have declared no 


479P THE IMPACT OF PATIENT SOCIO-ECONONOMIC STATUS ON 

ACCESS TO EARLY PHASE CANCER TRIALS 

A. Mohd Noor 1 , S. Vizor 2 , B. McLennan 2 , D. Sarker 2 , H. Moller 1 , J. Spicer 1 , 

S. Papa 1 

1 School of Medicine, Cancer Research Division, King’s College London, London, 

UNITED KINGDOM, 2 Medical Oncology, Guy’s and St Thomas NHS Foundation 

Trust, London, UNITED KINGDOM 

Background: Little is known about the influence of sociodemographic factors on 

patient access to early phase cancer trials. The toxicity and efficacy of cancer drugs 

can vary according to sociodemographic factors, and these differences should be 

considered to ensure generalisability of results and equality of access. 

Method: We conducted a review of patients referred to the early phase trials unit at our 

centre in the five years to 2012. Electronic records were studied for demographic and 

cancer-specific data. Socio-economic status was defined by the Index of Multiple 

Deprivation (IMD; 1 - least deprived, 5 - most deprived) recorded for the regional Cancer 

Registry population according to postal code. Multivariate analysis (adjusting for gender, 

age and tumour type) was performed comparing 10,784 incident cancer cases in south 

east London with the patients referred to our unit, and with those enrolled in a trial. 

Results: 430 patients (195 female) were referred for consideration of an early phase 

trial, with a median age of 62 years (range: 22-86). Ethnicity was 74% white. 

Univariate analysis of ethnicity suggested the non-white population was less likely to 

be recruited (OR 0.48, 95% CI 0.26-0.88), but this relationship was lost with 

adjustment for age, gender, cancer type and IMD. Multivariate analysis showed that 

referral was less likely for patients in the more deprived quintiles (IMD-5: OR 0.53, 

95% CI 0.38-0.74). However, once referred to the unit, enrollment in a trial was not 

affected by IMD (IMD-5: OR 0.81, 95% CI 0.40-1.63). 

Conclusion: We show for the first time that social deprivation affects referral to an early 

phase cancer trials unit. The least deprived patients are almost twice as likely to be referred 

to the trial unit compared with the most deprived. This may be because patients in the 

higher deprivation quintiles are less suitable for a trial, for example due to comorbidities, 

or because of inequalities that could be addressed with patient or referrer education. 


480P SINGLE INSTITUTION PHASE I TRIAL OF THE NOVEL 

COMPOUND FIRST-IN-CLASS PDM08 IN REFRACTORY SOLID 

TUMORS (NCT01380249) 

J. Barriuso 1 , I. Soria 2 , V. Moreno 1 , M. Coronado 3 , I. Galicia 4 , M.A. Figueredo 2 , 

J. Frias 5 , J. Feliu 6 , A. Carcas 5 , J.L. Subiza 2 

1 Oncology Phase I Unit, La Paz University Hospital, Madrid, SPAIN, 2 Inmunology 

Department, San Carlos Hospital, Madrid, SPAIN, 3 Nuclear Medicine, La Paz 

University Hospital, Madrid, SPAIN, 4 UCICEC, La Paz University Hospital, 

Madrid, SPAIN, 5 Pharmacology, La Paz University Hospital, Madrid, SPAIN, 

6 Medical Oncology, La Paz University Hospital, Madrid, SPAIN 

Background: PDM08 is a synthetic derivative of the pyroglutamic acid with anti 

tumor effect in different murine cancer models. The absence of direct effect on 

tumour cells and the antitumor activity found in immunocompetent models 

indicates an immune response mediated mechanism. The aim was to assess the 

tolerability and safety profile of PDM08. 

Methods: PDM08 was administered twice a week for four-week cycles. An accelerate 

escalation phase was chosen with cohorts of 2 patients (pts) that had the possibility 

of escalate once to the next dose level if no grade ≥2 toxicity and no progressive 

disease were observed. An expansion cohort was planned at the MTD or the optimal 

biological dose (OBD). Extensive pharmacokinetic and pharmacodynamic (PD) data 

were collected. Preliminary efficacy was evaluated by PET-CT. 

Results: Since July 2011, 17 patients (pts) were recruited into 8 different dose levels 

(4pts were escalated) ranged from 0.560 mg to 56 mg. Pt characteristics were: males 

52.9%. Median age: 68 (28-76). ECOG 0: 64.7%. Median of previous treatments was 

3 ranged 2 to 5. 3 pts presented G1 headache. No DLTs were found. The best 

outcome was stable disease (SD) for 5 pts (4 colorectal and 1 endometrial), one 

being stable for 12 weeks, one 14 weeks and one remains stable after 21 weeks. 12.9% 

of the lesions evaluated by PET-CT showed a reduction in the maximum Standard 

Uptake Value (SUV) of 18-FDG. A pooled analysis of PD data from patients with 

the best response showed a statistically significant increased in serum levels of 

IL-17A, IL-13, IL-4, IL-5, TNFα, IL-22 and IL-1β (p < 0.05) from baseline. 

Interestingly patients without benefit showed higher basal levels of these cytokines. 

The analysis of blood cell populations in pts with SD found a trend to increase the 

absolute numbers of NKT (CD56, CD4), neutrophils (CD45, CD15, CD16b) and 

some specific markers of Myeloid-derived suppressor cells (CD11b, CD33). The OBD 

derived from PD changes was 56 mg. 

Conclusions: PDM08 is the first compound of a new class of drugs that can be 

dose-escalated safely in an accelerated manner and has promising activity. PD results 

suggest that PDM08 is boosting the innate immune response against cancer cells 

confirming preclinical data. 


481P TESETAXEL: ANALYSIS OF TWO DOSING SCHEDULES (ONCE 

WEEKLY VS. EVERY 3 WEEKS) USING A NOVEL ORAL 

TAXANE 

M. Beeram 1 , K. Papadopoulos 1 , A.W. Tolcher 1 , D. Rasco 1 , T. Cousin 2 , L. Itri 2 , 

A. Patnaik 1 

1 Developmental Therapeutics, The START Center for Cancer Care, San Antonio, 

TX, UNITED STATES OF AMERICA, 2 Developmental Therapeutics, Genta 

Incorporated, Berkeley Heights, NJ, UNITED STATES OF AMERICA 

Background: Tesetaxel (TST) is a novel oral taxane that is active in taxane-resistant 

models, is not a substrate for p-glycoprotein, and has limited preclinical neuropathy. 


TST is active in breast and gastric cancers when administered orally once every 3 

weeks (Q3W). Taxanes may have schedule-related activity and adverse reactions. We 

conducted a dose-ranging study comparing the safety, efficacy, and pharmacokinetics 

(PK) using two schedules. 

Methods: Patients (pts) had solid tumors, ECOG PS ≤ 2, and adequate organ 

function. In Schedule 1, TST was given once every 3 weeks from 18 to 27 mg/m2, 

escalated in increments of 3 mg/m2 to determine the MTD. In Schedule 2, TST was 

given once weekly for 3 weeks every 28 days, beginning at a total flat dose of 25 mg/ 

cycle with increases up to 75 mg/cycle. Dosing was then converted to a weight-based 

regimen at weekly doses of 12.5, 15, and 17.5 mg/m2 (i.e. total per cycle dose up to 

52.5 mg/m2). 3 pts were treated at each dose level until the MTD. 

Results: 27 pts were treated on Schedule 1. The MTD was 27 mg/m2 and 

neutropenia was dose-limiting. One pt with nasopharyngeal carcinoma had a PR and 

11 pts had stable disease, including several with taxane-resistant breast cancer. Cmax 

and AUC increased with increasing dose; however, the differences across the dose 

range examined were modest. No dose-related differences were apparent for other PK 

parameters. On schedule 2, 26 pts were treated in 8 dose cohorts. The MTD was 15 

mg/m2 (total cycle dose, 45 mg/m2). Constitutional symptoms (fatigue and anorexia) 

proved dose-limiting at 17.5 mg/m2/wk. Only 1 pt had Grade 3 neutropenia. One pt 

with MBC (who had progressed after 2 prior taxane regimens) had a PR; 1 pt with 

prostate cancer had prolonged PSA reduction. PK analyses showed low but 

progressive increases in trough TST concentrations (0.4–4.6 nmol/mL) 7 days after 

each succeeding dose, consistent with the prolonged T½ of this drug (∼180 hrs). 

There was no substantial drug accumulation over multiple cycles. 

Conclusions: Tesetaxel administered once every 3 weeks is active in pts with 

advanced gastric, breast and other solid tumors, including pts who have received 

prior taxanes. The weekly regimen is currently being evaluated in Phase 2. 

Disclosure: A.W. Tolcher: Corporate sponsored research. T. Cousin: Employee of Genta 

Inc. L. Itri: Employee of Genta Inc. All other authors have declared no conflicts of interest. 

482P PHASE 1 STUDY OF BPM 31510 (UBIDECARANONE) IN 

ADVANCED SOLID TUMORS: UPDATED ANALYSIS OF A 

NOVEL TREATMENT WITH PROMISING ACTIVITY 

S.P. Chawla 1 , A. Hendifar 1 , V.S. Chua 1 , D. Quon 1 , V. Narasimhan 1 , Y. Lavinski 2 , 

J. McCook 3 , R. Sarangarajan 3 , P. Song 3 , N. Narain 3 

1 Clinical Research, Sarcoma Oncology Center, Los Angeles, CA, UNITED 

STATES OF AMERICA, 2 Research, MutualHealth LLC, Newport Beach, CA, 

UNITED STATES OF AMERICA, 3 Clinical Research, Berg Pharma, Natick, CA, 


Background: BPM is a novel small molecule that targets aerobic glycolytic pathway, 

re-capitulates BCL-2 mediated apoptosis and disrupts tumor angiogenesis. 

Methods: A standard 3 + 3, dose-escalation study was designed with primary 

objectives of dose finding (MTD), toxicity and pharmacokinetic correlates (PK). 

Secondary objectives included response, response duration and clinical benefit. 

Results: 42 patients with advanced solid tumors (refractory to standard therapy) 

were enrolled in 8 dose cohorts (5.6 mg/kg to 104.3 mg/kg). The trial is still 

ongoing as the MTD has yet to be reached. 31 (74%) patients completed at least 

one cycle and are considered evaluable for efficacy and toxicity. Median number of 

treatment cycles administered were 2 (range, 1-7) with median duration of 14 

weeks (4-52 weeks). Of the 31 evaluable patients, 23 had grade I and 14 patients 

grade II elevation of INR without any significant clinical bleeding. Normalization 

of INR was observed in all the patients with vitamin K supplementation. Nine 

patients (29.0%) experienced mild headache during the first week of therapy, 

relieved with acetaminophen. There was no grade 3/4 treatment related toxicity. 

The pharmacokinetics of BPM was noted to be linear. The values for t1/2 ranged 

from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective 

tumor responses were noted at the dose of 58.6mg/kg with 1 complete response 

(myxoid liposarcoma) and 1 minor response (fibrosarcoma). With a median follow 

up of 14 weeks (4-52 weeks) clinical stabilization was observed in 61% of the 

patients. 

Conclusions: Interim data from this phase I study indicate that BPM is well tolerated 

with no dose limiting toxicity to date. There was no grade III/IV toxicity. Grade I/II 

toxicity included elevation of INR (without significant clinical bleeding) and mild 

headache. One patient had partial and one patient had minor response with 

stabilization of the disease in the majority. The current trial is in progress and there 

is strong rationale for further development of this unique compound which lacks the 

toxicity associated with chemotherapy. 

Disclosure: S.P. Chawla: I am an adviser to Berg Pharma LLC, Natick, MA; USA. A. 

Hendifar: I am an adviser to Berg Pharma LLC, Natick, MA; USA. V.S. Chua: I am 

an adviser to Berg Pharma LLC, Natick, MA; USA. D. Quon: I am an adviser to Berg 

Pharma LLC, Natick, MA; USA. Y. Lavinski: I am an employee of Berg Pharma LLC, 

Natick, MA; USA. J. McCook: I am an employee of Berg Pharma LLC, Natick, MA; 

USA. R. Sarangarajan: I am an employee of Berg Pharma LLC, Natick, MA; USA. P. 

Song: I am an employee of Berg Pharma LLC, Natick, MA; USA. N. Narain: I am an 

employee of Berg Pharma LLC, Natick, MA; USA. All other authors have declared 



483P DESIGNER PEPTIDE ANTAGONIST OF THE LEPTIN 

RECEPTOR WITH PERIPHERAL ANTINEOPLASTIC ACTIVITY 

S. Beccari1 , L.J. Otvos2 , G.L. Cetto3 , E. Surmacz2 1 

Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona-"Borgo 

Roma", Verona, ITALY, 2 Sbarro Institute for Cancer Research and Molecular 

Medicine, Temple University, Philadelphia, PA, UNITED STATES OF AMERICA, 

3 

Medicine, Azienda Ospedaliera Universitaria Integrata Verona-"Borgo Roma", 

Verona, ITALY 

Background: Obesity-related hormone leptin has been implicated in the 

development and progression of different cancer types. Studies in vitro and animal 

models documented that leptin promotes cancer cell proliferation and 

neoangiogenesis. Targeting leptin signaling could become a new therapeutic option 

for the treatment of cancer, especially in obese patients. In order to inhibit 

pro-neoplastic leptin activity, we developed peptidomimetics that are analogs of 

leptin/leptin receptor (ObR) interaction site, able to compete with leptin binding and 

capable of blocking leptin effects in vitro and in vivo. The lead compound (Allo-aca), 

however, crosses the blood-brain-barrier (BBB), inducing undesirable orexigenic 

effects and consequent weight gain. Redesign of Allo-aca to decouple its Central 

Nervous System (CNS) and peripheral activity should produce superior compound 

for cancer treatment. 

Objective: The aim of this study was to design and test Allo-aca derivatives for their 

biodistribution, BBB penetration and in vitro anti-neoplastic activity against breast 

and colorectal cancer cells. 

Results: Examination of several Allo-aca derivatives resulted in identification of the 

peptidomimetic D-Ser. D-Ser did not distribute across BBB but was present in the 

periphery of experimantal animals. D-Ser was shown to bind ObR, and inhibit 

leptin-dependent-proliferation of ObR-positive breast and colorectal cancer cells in 

vitro at the concentration of 1 nM. Its efficacy was demonstrated both in adhesion 

and in three-dimensional cultures, without showing any partial agonistic activity. 

Antiproliferative D-Ser action was associated with the inhibition of several 

leptin-induced pathways, including JAK/STAT3, MAPK/ERK1/2 and PI3K/AKT, 

Cyclin D1 and E-cadherin. 

Conclusions: D-Ser is the first novel leptin-based peptidomimetic featuring 

peripheral ObR antagonistic activity. D-Ser inhibits leptin-dependent growth of 

breast and colorectal cancer cells through downregulation of several key mitogenic/ 

survival pathways. The novel peptide may serve as a prototype to develop new 

oncotherapeutics, useful for the management of obesity-related cancers. 


484P LURBINECTEDIN (PM01183) IN COMBINATION WITH 

GEMCITABINE (GEM). PRELIMINARY RESULTS OF AN 

ONGOING PHASE IB STUDY 

E. Calvo 1 ,L.Ares 2 , M. Foster 3 , I. López Calderero 2 , A. Cubillo 1 , A. Velasco 4 , 

V. Boni 1 , D. Wilkins 3 , A. Soto-Matos 5 , S. Szyldergemajn 4 

1 Oncology, Hospital Sanchinarro/START, Madrid, SPAIN, 2 Oncology Service, 

Hospital Virgen del Rocio, Seville, SPAIN, 3 Oncology, University College of 

London Hospital, London, UNITED KINGDOM, 4 Clinical Operations, PharmaMar, 

Colmenat Viejo, Madrid, SPAIN, 5 Clinical, PharmaMar, Colmenat Viejo, Madrid, 

SPAIN 

Background: PM01183 is a new anticancer agent. It exerts a wide anti-tumour 

activity through minor groove DNA-binding. Pre-clinical evidence of synergism has 

been observed in combination with GEM. Single agent PM01183 has clinical activity 

in pancreatic and platinum-resistant ovarian cancer. Reversible neutropenia and high 

emetogenic potential are the main single agent toxicity. 

Methods: Informed and consented adult patients (pts) were included. The starting 

dose was PM01183 2.5 mg + GEM 800 mg/m 2 , on Days 1 and 8 q3wk. The dose was 

escalated in cohorts of 3-6 pts aiming to define the maximum tolerated dose (MTD). 

The highest dose reached with less than 1/3 of at least 9 pts having dose-limiting 

toxicities (DLTs) in Cycle 1 will be the recommended dose (RD). Age was restricted 

up to 75 years, PS-ECOG 0-1, have adequate major organ function and no more 

than 2 prior chemotherapy lines. Prior adjuvant GEM was allowed if relapse 

occurred >6 months. 

Results: As of MAY 2012, 23 pts were treated across 4 dose levels (DL), 8 (35%) 

were female, median age was 60 (37–72). NSCLC (n = 12; 52%), pancreatic/biliary 

tract (n = 5; 22%) and gynaecological (n = 4; 17%) were the most frequent tumour 

types. Dose escalation proceeded until the MTD was reached: DL 4 PM01183 3.5 mg 

+ GEM 1000 mg/m 2 . Three pts experienced DLTs: Day 8 omission (neutropenia), 

febrile neutropenia, neutropenic infection/sepsis and grade 4 thrombocytopenia. One 

fatal sepsis occurred at the MTD. DL 3 (PM01183 3.5 mg + GEM 800 mg/m 2 ) 

expansion as possible RD is ongoing. PM01183/GEM seems well tolerated at doses 

below the MTD. Other toxicities in addition to reversible myelosuppression were 

mild nausea/vomiting, asymptomatic LFTs increases, pneumonia, anaemia or fatigue. 

Evidence of activity includes: 2/12 partial (PR) + 1/12 complete response (CR) in 

NSCLC (2 pts are ongoing after 13+ and 10+ cycles) and 1/4 PR in gynecological. 

No pharmacokinetic interaction was observed. 



Conclusions: The combination of PM01183 and GEM seems feasible with an 

acceptable safety profile below the MTD: PM01183 3.5 mg+ GEM 1000 mg/m 2 .RD 

cohort expansion is currently ongoing. The combination is showing promising 

anti-tumour activity. Updated results will be presented in the meeting. 

Disclosure: A. Velasco: membership PharmaMar. A. Soto-Matos: PharmaMar 

membership. S. Szyldergemajn: PharmaMar membership. All other authors have 


485P CHALLENGE IN THE PHARMACOKINETIC EVALUATION OF 

DTS-108, A NEW TOPOISOMERASE I INHIBITOR, IN 

PATIENTS WITH ADVANCED CARCINOMAS 

O. Mir 1 , S. Faivre 2 ,C.Dreyer 3 , R. Coriat 4 , M. Bouattour 3 , F. Goldwasser 5 , 

E. Raymond 3 

1 Oncology Department, Teaching Hospital Cochin, AP-HPUniversit, Paris Cedex, 

FRANCE, 2 Internal Medicine, Hopital Beaujon, Clichy, FRANCE, 3 Oncology 

Department, Beaujon University Hospital, Clichy, FRANCE, 4 Oncology 

Department, CHU Cochin, Paris, FRANCE, 5 Oncology, Cochin Hospital, Paris, 

FRANCE 

Background: DTS-108 is a soluble pro-drug of SN38, the active metabolite of 

irinotecan, where the SN38 moiety is covalently linked to a 20AA peptide through a 

specific cross-linker that releases SN38 by esterase bond cleavage. DTS-108 was 

designed to achieve therapeutic levels of SN38, while reducing diarrhea. 

Methods: SN-38 and SN-38G levels were evaluate with fluorescence HPLC test and 

LC/MS/MS methods. The pharmacokinetics of DTS-108, the adverse event (AE) 

profile, the dose limiting toxicities (DLT) at cycle 1, the maximum tolerated dose 

(MTD), and the recommended phase II dose (RD) of intravenous DTS-108 (1-2 

hours) every two weeks (q2w) in patients (pts) with advanced/metastatic carcinomas 

was conducted. 

Results: Forty-Two pts received DTS-108 across 14 dosing cohorts (range: 3-416mg/ 

m2). All grade AEs were asthenia (43%), nausea (43%), diarrhea (41%), vomiting 

(33%), anemia (31%), rash (21%), anorexia (21%), alopecia (19%), abdominal pain 

(19%), and neutropenia (19%). Neutropenia was the dose limiting toxicity of 

DTS-108. Neutropenia started to be observed at doses >56 mg/m2. At 416 mg/m2, 3/ 

6 pts had grade 4 neutropenia. Fluorescence HPLC was initially used to quantify 

DTS-108 and its metabolites (SN-38 and SN-38G). Sample stability analysis of this 

method showed that SN38 values were inaccurate as DTS-108 degraded forming 

ex-vivo SN-38 during the blood collection, plasma storage, and/or sample extraction. 

New processes and analytical LC/MS/MS methods for testing SN-38 were 

implemented. At the dose of 313 mg/m2, mean DTS-108, SN38, and SN38G 

AUCINF (CV%) were 439293 (24%), 1992 (34%), and 4538 (46%) h*ng/mL. Tumor 

stabilization (RECIST) was observed in 9 pts and confirmed in 6 pts. 

Conclusions: SN-38 concentration using Fluorescence HPLC failed to monitor 

drug escalation in topoisomerase I inhibitor because of ex vivo degradation. SN-38 

exposures using LC/MS/MS methods are consistent with less variables values and 

allow drug monitoring. DTS-108 induced no dose-limiting diarrhea but 

neutropenia and infusion skin reactions. The dose level 313 mg/m2 was declared 

the MTD based on 5 of the 6 patients treated at this dose level having no 

dose-limiting neutropenia and the overall improvement in the management of 

infusion réactions. 


486P PHARMACOKINETICS (PK) AND SAFETY OF TESETAXEL, A 

NOVEL ORAL TAXANE, IN JAPANESE PATIENTS (PTS) WITH 


K. Tanaka 1 , T. Kurata 1 , Y. Fujisaka 2 , H. Kawakami 1 , H. Hayashi 1 , T. Cousin 3 , 

W. Okamoto 1 , T. Kudoh 1 ,T.Satoh 1 , K. Nakagawa 1 

1 Medical Oncology, Kinki University School of Medicine, Osaka, JAPAN, 

2 Medical Oncology, Kinki University Faculty of Medicine, Osaka, JAPAN, 3 Clinical 

Operations, Genta Incorporated, Berkeley Heights, NJ, UNITED STATES OF 

AMERICA 

Background: Tesetaxel is an orally administered taxane that, unlike IV analogs, is 

not a Pgp substrate (a primary mechanism of taxane resistance). This novel agent has 

a long plasma T½ (∼180 h), allowing administration once every 3 weeks (Q3W). 

Tesetaxel is particularly active in breast and gastric cancers, with response rates of 

50% and 20%, respectively, in 1st-line metastatic breast and 2nd-line gastric cancer. 

Among > 500 pts treated to date, no hypersensitivity reactions have occurred, and 

neurotoxicity has been distinctly uncommon. In Western pts, the maximally 

tolerated dose (MTD) of tesetaxel is 27 mg/m 2 Q3W, and neutropenia is dose 

limiting. We conducted a phase I intersubject dose-escalation study to evaluate safety 

and PK in Japanese pts. 

Methods: Eligibility criteria included age ≥ 20 years, advanced or metastatic solid 

tumors, ECOG PS ≤ 1, and adequate organ function. Tesetaxel 24 mg/m 2 was given 

on day 1 of a 21-day cycle to the first cohort. The dose was escalated to 27 mg/m 2 

and 31 mg/m 2 in successive cohorts absent dose-limiting toxicity (DLT). Serial blood 

samples were obtained for PK analysis and assayed by HPLC. 

Results: Twelve pts (9 men, 3 women; age 39-74 yr) were enrolled (3 each in the 24 

and 31 mg/m 2 cohorts and 6 in the 27 mg/m 2 cohort). Most pts were heavily 

pretreated; the median number of prior chemotherapy regimens was 

4. Neutropenia ≥ grade 3 occurred in 1 pt in the 24 mg/m 2 and 27 mg/m 2 cohorts 

and 2 pts in the 31 mg/m 2 cohort. DLT (febrile neutropenia) was observed in 1 pt at 

the 31 mg/m 2 dose. Mean PK data (see table) were similar in Western and Japanese 

pts, with an expected dose-dependent increase in exposure. 

Dose level Patients (n) C max T max AUC 0-168 h 

24 mg/m 2 

27 mg/m 2 

*31 mg/m 2 

Western (11) 29.7 2.5 594 

Japanese (3) 29.0 2.7 658 

Western (7) 31.2 2.1 869 

Japanese (3) † 

46.6 4.7 818 

Japanese (3) 57.0 2.0 1036 

† Results of PK analyses for last 3 pts enrolled not yet available * Dose not studied in 

Western pts 

Conclusion: This study indicates that tolerability and PK of tesetaxel is similar in 

Western and Japanese pts. Final data will be presented. 

Disclosure: T. Cousin: I am an employee of Genta Incorporated, the company that is 

developing tesetaxel. All other authors have declared no conflicts of interest. 

487P CORRELATION OF INFUSION-RELATED REACTIONS (IRR) 

AND OUTCOME IN PATIENTS RECEIVING NGR-HTNF 

TREATMENT 

G. Rossoni1 , V. Gregorc1 , A. Bulotta1 , M.G. Viganò1 , G. Todisco1 , A. Lambiase2 , 

C. Bordignon2 1 2 

Oncologia, IRCCS San Raffaele, Milano, ITALY, Clinical Development, MolMed, 

Milan, ITALY 

Background: NGR-hTNF (asn-gly-arg-human tumor necrosis factor) induces 

systemic release of cytokines and intratumoral infiltration of effector T cells. 

Intravenous infusion of NGR-hTNF is characterized by onset of IRR, mostly 

consisting of transient grade 1-2 chills. Incidence, predictors of development, and 

relationships with outcome of IRR were assessed across 5 phase 2 single-arm trials of 

NGR-hTNF. 

Methods: 205 patients (pts) with solid tumors received NGR-hTNF 0.8 µg/m 2 every 

3 weeks (q3w) given either alone in colon cancer (n = 45), liver cancer (n = 40), and 

mesothelioma (n = 55), or with doxorubicin in small-cell lung cancer (n = 28) and 

ovarian cancer (n = 37). Tumor assessment by RECIST was done q6w until 

progressive disease (PD). Logistic and Cox proportional-hazards regression models 

were used to analyze associations between IRR and outcome, in terms of response 

rate (RR, complete and partial response), disease control rate (DCR, rate of pts 

without PD at 6 weeks), and progression-free survival (PFS). 

Results: Overall, 137/205 pts (67%) experienced IRR on treatment, while 68 pts 

(33%) did not report IRR. In the IRR group, 63% of pts had grade 1 and 37% grade 

2. By time of onset, 88% of pts developed IRRs within first 6 weeks and 12% later. 

Baseline characteristics in the IRR v non-IRR groups were: median age 66 v 64; male 

50% v 56%; PS 1-2 34% v 35%, range of prior lines 1-4 v 1-5. Among baseline 

factors, only a low number of prior regimens predicted for IRR (odds ratio, OR 1.4 p 

= .02). The RR was 12% (95% CI 7-18) in the IRR group and 3% (1-10) in the 

non-IRR group (OR 4.4 p = .05), while DCR was 50% (42-59) in pts who had IRR 

and 34% (23-46) in pts who did not (OR 2.0 p = .02). On landmark analysis set at 

6-week time point, PFS was significantly improved in pts with IRR (hazard ratio, HR 

0.63 p = .007). Six-month PFS rates were 17% (11-23) for the IRR group and 6% 

(1-12) for the non-IRR group (log-rank p = .005). In multivariable analyses 

(adjusting for age, sex, PS, prior lines, and tumor types), the onset of IRR remained 

independent predictor of higher likelihood of response (OR 4.8 p = .05) and lower 

risk of progression or death (HR 0.62 p = .009). 

Conclusions: Occurrence of IRR may identify pts who are more likely to gain benefit 

from NGR-hTNF treatment. 

Disclosure: A. Lambiase: Employment- MolMed. C. Bordignon: Employment - 

MolMed. All other authors have declared no conflicts of interest. 

488P IMPACT OF SOLUBLE TUMOR NECROSIS 

FACTOR-RECEPTORS (STNF-RS) SHEDDING ON OUTCOME IN 

PATIENTS TREATED WITH NGR-HTNF 

P.A. Zucali 1 , M. Simonelli 1 , F. De Vincenzo 1 , E. Lorenzi 1 , A. Santoro 1 , 

A. Lambiase 2 , C. Bordignon 2 

1 Department of Oncology, Humanitas Cancer Center IRCCS, Rozzano, ITALY, 

2 Clinical Development, MolMed, Milan, ITALY 

Background: NGR-hTNF (asn-gly-arg-human tumor necrosis factor) displays a 

biphasic dose-response curve with activity shown at very low or high doses. 


Treatment-induced shedding of circulating sTNF-R1 or -R2 may block drug effects. 

The impact of this counterregulatory mechanism on NGR-hTNF activity was 

assessed in two phase I trials. 

Methods: Sixty patients (pts) with refractory solid tumors (median age, 60 years; M/ 

F 44/16; PS 0/1-2 25/35; median prior treatment lines, 3) received NGR-hTNF every 

3 weeks (q3w) given at low doses (0.2 to 1.6 µg/m 2 n = 14) or high doses (60 to 325 

µg/m 2 n = 46). Tumor assessment by RECIST was done q6w until progressive disease 

(PD). We assessed the associations between baseline-normalized plasma levels of 

sTNF-R2 after 1st treatment cycle and clinical outcomes in terms of disease control 

rate (DCR, rate of pts without PD after 6 weeks) and progression-free survival (PFS) 

Results: The levels of sTNF-R2 peaked significantly higher than sTNF-R1 (p < .0001) 

and increased dose proportionally (p = .0003), with a median distribution value of 

8.6 ng/mL (interquartile range 4.5-10.7). Using the 25th percentile as cut-off value, 

the sTNF-R2 levels were dichotomized in low (≤ 4.5 ng/mL n = 15) or high (> 4.5 

ng/mL n = 45). Mean number of cycles was 5.5 (range 1-29) and 2.5 (1-6) in pts with 

low or high levels, respectively. By univariate analyses, low sTNF-R2 levels were 

significantly associated with increased DCR (odds ratio, OR 3.8 p = 0.04) and 

improved PFS (hazard ratio, HR 0.29 p = .002). DCR was 58% (95% CI 32-81) and 

26% (16-41) in pts with low or high levels, respectively. Six-month PFS rates were 

29% in pts with low levels and 0% in pts with high levels (log-rank p = 0.0008). 

Median duration of disease control was 7.5 months in pts with low levels and 2.9 

months in pts with high levels (log-rank p = .007). After adjusting for age, sex, PS, 

and prior lines, a low sTNF-R2 level remained independent predictor of higher DCR 

(OR 5.2 p = .03) and longer PFS (HR = 0.27 p = .002). The highest sTNF-R2 levels 

(75th percentile) were associated with the worst survival rates (HR 2.6 p = .01) 

Conclusions: Early treatment-induced changes in sTNF-R2 shedding may identify 

pts who have a greater likelihood of benefit from NGR-hTNF. 

Disclosure: A. Lambiase: Employment - MolMed. C. Bordignon: Employment - 


489P FOOD EFFECT STUDY OF THE INVESTIGATIONAL AURORA A 

KINASE (AAK) INHIBITOR MLN8237 (ALISERTIB) IN PATIENTS 

WITH ADVANCED SOLID TUMORS 

G.S. Falchook 1 , X. Zhou 2 , L.S. Rosen 3 , K. Venkatakrishnan 2 , R. Kurzrock 1 , 

D. Mahalingam 4 , J. Goldman 5 , J. Jung 6 , C. Milch 2 , J. Sarantopoulos 7 

1 Investigational Cancer Therapeutics, The University of Texas M. D. Anderson 

Cancer Center, Houston, TX, UNITED STATES OF AMERICA, 2 Clinical 


STATES OF AMERICA, 3 Oncology, Premiere Oncology, Santa Monica, CA, 

UNITED STATES OF AMERICA, 4 Oncology, Institute for Drug Development, 

Cancer Therapy and Research Center at University of Texas Health Science 

Center San Antonio, San Antonio, TX, UNITED STATES OF AMERICA, 5 Division 

of Hematology Oncology, David Geffen School of Medicine, UCLA Medical 

Center, Santa Monica, CA, UNITED STATES OF AMERICA, 6 Biostatistics, 


AMERICA, 7 Oncology, Institute for Drug Development, Cancer Therapy and 

Research Center at Universtiy of Texas Health Science Center San Antonio, San 

Antonio, TX, UNITED STATES OF AMERICA 

Background: MLN8237 (alisertib) is an investigational, orally available, selective 

AAK inhibitor currently in clinical development for multiple oncology indications. 

The recommended phase 2 dose is 50 mg twice daily for 7 d in a 21-d cycle. This 

study was conducted to characterize the effects of food on single-dose 

pharmacokinetics (PK) of MLN8237 in pts with advanced solid tumors. 

Methods: Eligible pts were aged ≥18 y and had ECOG PS 0–1. Following overnight 

fasting for at least 10 h, pts received a single 50 mg dose of MLN8237 (enteric-coated 

tablet) under either fasted or fed conditions with a standard high-fat meal using a 

2-cycle, 2-way crossover design. PK samples were collected in Cycles 1 and 2 

pre-dose and following Day 1 dosing up to 48 h post-Day 1 dose. Ratio of geometric 

mean C max and AUC 0-last under fed conditions in reference to those under fasted 

conditions was calculated and the associated 90% CI were estimated using analysis of 

variances. Additional endpoints were safety and response. 

Results: 24 pts were enrolled: 33% male, 96% white, median age 58 y, and mean 

weight 64 kg. 14 pts were PK-evaluable (10 pts not PK-evaluable due to insufficient 

data). Following a single oral dose of MLN8237, median Tmax was 6 and 3 h for fed 

and fasted treatment, respectively. The geometric mean of AUC 0-last following single 

dose under fed conditions was 106% of that under fasted conditions (90% CI: 82%, 

137%). The geometric mean of C max under fed conditions was 83% of that under 

fasted conditions (90% CI: 66%, 106%). Following multiple dose administration, 23 

(96%) pts had a drug-related adverse event (AE). Most common drug-related grade 

3/4 AEs were neutropenia (50%), leukopenia (38%), and thrombocytopenia (21%). 3 

pts had drug-related serious AEs. One pt died (non-drug-related respiratory arrest). 

Stable disease was achieved in 12 pts, including 1 pt with melanoma who received 

∼11 cycles. 

Conclusions: Systemic exposures achieved following a single 50 mg dose of 

MLN8237 administered following a high-fat meal are similar to those observed in the 

fasted state. These data support the conclusion that MLN8237 may be administered 

without regard for the timing of meals in future clinical studies. 


Disclosure: G.S. Falchook: Research funding: Millennium Pharmaceuticals, Inc. X. 

Zhou: Employment: Millennium Pharmaceuticals, Inc. L.S. Rosen: Research support: 

Millennium Pharmaceuticals, Inc. K. Venkatakrishnan: Employment: Millennium 

Pharmaceuticals, Inc. R. Kurzrock: Research funding: Millennium Pharmaceuticals, 

Inc. J. Jung: Employment: Millennium Pharmaceuticals, Inc. C. Milch: Employment: 

Millennium Pharmaceuticals, Inc. Ownership interest: Takeda. All other authors have 


490P CLINICAL EVALUATION OF DENDRITIC CELL BASED 

VACCINES PULSED WITH WT1 AND/OR MUC1 FOR PATIENTS 

WITH ADVANCED OR RECURRENT CANCERS 

S. Tsujitani 1 , M. Tanii 2 , Y. Yonemitsu 3 

1 Department of Translational Medicine, National Center for Global Health and 

Medicine, Tokyo, JAPAN, 2 Department of Medical Oncology, Fukuoka Imax 

Clinic, Fukuoka, JAPAN, 3 R&D Laboratory for Innovative Biotherapeutics, Kyushu 

University, Fukuoka, JAPAN 

Background: Dendritic cell (DC)-based vaccines have been expected as one of new 

therapeutic approaches to treat cancer patients; however, their clinical outcome is not 

fully elucidated. We here report a single center retrospective study analyzing the 

survival of patients with various cancers. 

Patients and methods: DC-based vaccines pulsed with WT1 and/or MUC1 peptides 

has been carried out in 180 patients with advanced or recurrent cancers between 

September 2009 and September 2011. Previous standard chemotherapy failed in most 

patients and another chemotherapy was given with DC-based therapy. Intradermal 

injection of 1 x 107 mature DCs was repeated biweekly. After 1 course of treatment 

(7 times of injection), clinical efficacy was evaluated with RECIST criteria or tumor 

markers. 

Results: In 180 patients, 119 patients completed 1 course treatment. Patient with 0-1 

levels of performance status occupied 93% of 119 patients. One-year survival rate of 

the 119 patients was 57.6% and did not reach to MST. One-year survival rates were 

54% in lung cancer (n = 14), 35% in pancreas cancer (n = 14), 100% in colon cancer 

(n = 9), 50% in ovarian cancer (n = 9), 83% in breast cancer (n = 7) and 86% in 

gastric cancer (n = 5). In 20 patients with more than 1-year follow-up period and 

definite assessment of clinical response, 4 (20%) CR, 4 (20%) PR, 9 (45%) SD and 3 

(15%) PD were obtained. One-year survival rates were 100% in CR cases, 100% in 

PR, 67% in SD and 33% in PD. 

Conclusions: In patients with 1 course DC-based therapy, survival more than 1 year 

may be expected, particularly in those with definitive disease control after treatment. 

DC-based therapy may be suitable to patients with better performance status. 


491P BODY COMPOSITION IS LINKED TO TOXICITY AND 

OUTCOME IN PATIENTS (PTS) INCLUDED IN PHASE I TRIALS 

S. Cousin 1 , A. Hollebecque 1 , S. Koscielny 2 , A. Varga 1 , V. Baracos 3 , J. Soria 1 , 

S. Antoun 4 

1 Department of Medicine, Institut Gustave Roussy, Villejuif, FRANCE, 

2 Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif, 

FRANCE, 3 Department of Oncology, University of Alberta, Edmonton, AB, 

CANADA, 4 Emergency Department, Institut Gustave Roussy, Villejuif, FRANCE 

Background: Phase I clinical trials are dose- and toxicity–finding studies designed to 

identify the recommended phase II dose of new drugs. Thus, it appears crucial to 

distinguish toxicity directly related to the tested drug or to pts characteristics. 

Because previous studies have shown that sarcopenia could be linked to drug toxicity, 

we have evaluated the effects of body composition parameters on the toxicities 

incidence among phase I included pts. 

Methods: We have carried out a prospective single institution study which included 

all pts consecutively treated from January 2011 to July 2011 in our phase I unit, 

irrespective of the tumor type and/or drug nature. Clinical and biological nutritional 

parameters were recorded. Analysis of the computerized tomography (CT) images 

realized within 30 days before inclusion was used to evaluate cross-sectional areas 

(cm 2 ) of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and 

muscle tissue (MT). The 3 rd lumbard vertebra (L3) was chosen as a landmark since 

L3 and whole-body measurements are linearly related. Images were analyzed using 

Slice-O-Matic software V4.3 (Tomovision). Tissue cross-sectional areas were 

computed. Analysis was stratified on sex. Comparisons used Chi-2 test, 

Kruskal-Wallis test and log rank test. 

Results: The study population consisted in 64 men and 49 women. The median age 

was 57.3 years. Drug interruption due to toxicity (DIT) occurred in 15% of the pts. 

The only factor associated with DIT was low MT: 117 cm 2 versus 138 cm 2 (p= 

0.039). Pts who did not experiment DIT were more likely to have MT > median (56% 

versus 15%, p = 0.007). None of the following parameters were found to be associated 

with DIT: weight change >5%, >10%, Albumin< 35g/l, lacticodeshydrogenase > 250 

IU/l, transthyretin 6mg/l. Additionally, VAT < 



median was associated with poorer overall survival (OS) (p = 0.01) and shorter 

progression free survival (PFS) (p = 0.02). 

Conclusion: In a heterogeneous population of pts enrolled in various phase I trials, 

low muscle tissue was associated with the drug interruption due to toxicity. OS and 

PFS were linked to the VAT. Body composition is linked to toxicities risk and 

outcome in phase I pts. 


492P CLINICAL EFFECTS OF MGCD265, AN ORAL TYROSINE 

KINASE INHIBITOR, IN COMBINATION WITH ERLOTINIB OR 

DOCETAXEL FOR TREATMENT OF ADVANCED 

GASTROESOPHAGEAL AND NSCLC TUMORS 

A. Patnaik 1 , K. Papadopoulos 1 , A.W. Tolcher 1 , M. Beeram 1 , M. Tawashi 2 , 

M. Fournel 2 , C. Maroun 2 , R.W. Humphrey 2 , J. Besterman 2 , P.J. O’Dwyer 3 

1 Developmental Therapeutics, The START Center for Cancer Care, San Antonio, 

TX, UNITED STATES OF AMERICA, 2 Clinical Affairs, Methylgene, Inc, Montreal, 

QC, CANADA, 3 Abramson Cancer Center, University of Pennsylvania, 

Philadelphia, PA, UNITED STATES OF AMERICA 

Background: MGCD265, a multikinase inhibitor with nM IC50 against Met, VEGFR 

1, 2 and 3, Tie-2 and Ron, has been shown in preclinical models to possess broad 

antitumor effects. A phase I study was undertaken to assess therapy with MGCD265 

and docetaxel or erlotinib for treatment of solid tumors. 

Methods: Patients (pts) with advanced solid tumors were enrolled in an open-label, 

dose-escalation study using the standard 3 + 3 design. All pts received 3-wk cycles of 

MGCD265 (p.o. QD or BID) with docetaxel or erlotinib per standard of care, as 

defined by investigators. Endpoints were safety, pharmacodynamics, 

pharmacokinetics and antitumor activity of the combination therapy. 

Results: Of 89 pts enrolled, there were 12 cases of NSCLC (docetaxel group) and 9 cases 

of gastroesophageal (GE) cancer (erlotinib group). Of 10 response-evaluable NSCLC pts, 

all met criteria for stable disease (SD) for ≥2 cycles (including 2 pts with partial 

response). Five pts achieved SD for 5-16 mos, with four exceeding time on prior therapy. 

Two pts have not reached first evaluation. Treatment continues in 3 pts. Four of nine GE 

pts achieved SD. Three remained stable for 10-18 mos, exceeding time on prior therapy. 

Treatment continues in 1 pt. A plasma-based assay of Met phosphorylation showed up 

to 30% inhibition at doses to date. PK analysis is pending. Dose escalation continues. 

Toxicities were mostly mild to moderate. Nonhematologic adverse event (AEs) ≥ grade 

3 were reported in 20% of pts in each treatment arm, and were primarily GI-related. 

Expected docetaxel–associated hematologic AEs were also observed. 

Conclusions: Preliminary findings from a phase I study suggest that MGCD265 and 

docetaxel or erlotinib may hold promise for treatment of NSCLC and GE tumors. 

Clinical response was seen in the majority of NSCLC pts, with almost 50% achieving 

SD for ≥5 mos. Select GE pts achieved SD for more than 10 mos. AE rates with 

combination therapy were in the expected range. 

Disclosure: A. Patnaik: Research funding from Methylgene, Inc. K. Papadopoulos: 

Research funding from Methylgene, Inc. A.W. Tolcher: Research funding from 

Methylgene, Inc. M. Beeram: Research funding from Methylgene, Inc. M. Tawashi: 

Employee of Methylgene, Inc. M. Fournel: Employee of Methylgene, Inc. C. Maroun: 

Employee of Methylgene, Inc. R.W. Humphrey: Employee of Methylgene, Inc. J. 

Besterman: Employee of Methylgene, Inc. P.J. O’Dwyer: Research funding from 

Methylgene, Inc. 

493P PHARMACOKINETIC PROFILE OF MGCD265, AN ORAL 

TYROSINE KINASE INHIBITOR, WITH OR WITHOUT FOOD IN 

HEALTHY VOLUNTEERS 

E. Sicard 1 , M. Juretic 2 , M. Drouin 2 , G. Reid 2 , J. Wang 2 , W. Hunt 2 , C. Maroun 2 , 

J. Besterman 2 

1 Clinical Research, Algorithme Pharma, Laval, QB, CANADA, 2 Clinical Affairs, 

Methylgene, Inc, Montreal, QB, CANADA 

Background: MGCD265 is a novel targeted cancer therapeutic, currently in phase I/ 

II clinical trials, that inhibits Met and VEGF receptor tyrosine kinases. The abnormal 

activation of Met is involved in tumor development and metastasis, and VEGF 

kinase is responsible for inappropriate angiogenesis that nourishes the tumor. 

MGCD265 has demonstrated a favorable safety profile in patients with advanced 

malignancies and can safely be combined with other cancer therapeutics such as 

docetaxel and erlotinib. The objective of this Phase I study was to assess the 

bioavailability of MGCD265 under fasting and fed conditions in healthy volunteers. 

Methods: This was a randomized, laboratory-blinded, 2-period, crossover study. 

MGCD265 was administered as a single dose (100 mg) after a 10-hr overnight fast. For 

the fasting condition, fasting was continued for at least 4 hrs following drug 

administration. For the fed condition, subjects received a standardized meal 30 mins 

before drug administration. Blood samplings for the pharmacokinetic (PK) evaluation 

were done from pre-dose to up to 96 hrs post-dose. Safety was evaluated through the 

assessment of adverse events (AEs), laboratory tests, vital signs and 12-lead ECG. 

Results: Fourteen subjects were recruited [M/F: 8/6; median age: 51 years old (range 

41-65); median BMI: 25 kg/m2 (range: 19-29)]. One female subject discontinued 

early due to a fall (unrelated to MGCD265). Using nominal timepoints, on average, 

the fed condition was associated with an ∼3 fold increase in Cmax, AUCT, and 

AUCinf. The half-life of MGCD265 was found to be ∼34 hrs. Tmax was calculated 

to be 7 hrs and 10 hrs under fasting and fed conditions, respectively. MGCD265 

related AEs were mostly mild and included dry mouth in 3 subjects, somnolence in 1 

subject and moderate diarrhea in 1 subject. There were no clinically significant 

changes in vital signs, ECG or laboratory values. 

Conclusions: Exposure of MGCD265 increased significantly in the presence of a 

meal, with no added toxicity. The prolonged sampling time used in this study 

provided a more accurate estimation of MGCD265 half-life (∼34 hrs) compared to 

the estimate found in patients with advanced malignancies (∼23 hrs). 

Disclosure: E. Sicard: Research funding from Methylgene, Inc. M. Juretic: Employee 

of Methylgene, Inc. M. Drouin: Employee of Methylgene, Inc. G. Reid: Employee of 

Methylgene, Inc. J. Wang: Employee of Methylgene, Inc. W. Hunt: Employee of 

Methylgene, Inc. C. Maroun: Employee of Methylgene, Inc. J. Besterman: Employee 

of Methylgene, Inc. 

494P PHASE I SAFETY AND TOLERABILITY OF ONCE DAILY ORAL 

AFATINIB (A) IN COMBINATION WITH DOCETAXEL (D) IN 

PATIENTS (PTS) WITH RELAPSED OR REFRACTORY 

ADVANCED SOLID TUMOURS 

H. Senellart 1 , J. Bennouna 1 , N. Isambert 2 , H. De Mont-Serrat 3 , P. Squiban 3 , 

I. Tschoepe 3 , J. Delord 4 

1 Department of Medical Oncology, Centre René Gauducheau, Saint-Herblain 

Cedex, FRANCE, 2 Medical Oncology, Centre Georges François Leclerc, Dijon, 

FRANCE, 3 Medical Affairs, Boehringer Ingelheim, Reims, FRANCE, 4 Clinical 

Resarch Unit, Institut Claudius Regaud, Toulouse Cedex, FRANCE 

Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open 

label, Phase I, dose escalation trial investigated the safety, tolerability and 

pharmacokinetics (PK) of A, in two parallel dose cohort expansion parts, in 

combination with either gemcitabine (Part A) or D (Part B) in pts with relapsed or 

refractory solid tumours. Preliminary results from Part B are presented here. 

Methods: Eligible pts (advanced solid tumours, Eastern Cooperative Oncology Group 

Performance Status 0–1) received once daily, oral dosing of A with D, given 

intravenously on Day 1 of every 3 week cycle. Primary objective was to establish the 

maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities 

(DLT) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 pts 

using a 3 + 3 design. Initial starting dose level was A 30 mg/day and D 60 mg/m 2 , 

escalating up to A 50 mg/day and D 75 mg/m 2 until the MTD was reached, and 

followed by a PK expansion cohort of 12 pts at the MTD level. 

Results: To date, 27 pts have been treated in Part B, 18 pts in the escalation phase 

with A (30–50 mg/day) and D (60–75 mg/m 2 ), and 9 pts in the expansion phase 

with A 40 mg/day and D 75 mg/m 2 . Baseline characteristics were mean age (56.4 

years), female (44.4%), and number of prior chemotherapies (≤ 2: 48%; >2: 52%). 

Adverse events (AEs) were manageable and the MTD was not exceeded in the tested 

dose range up to A 50 mg/day and D 75 mg/m 2 . AEs were diarrhoea (92.6%) and 

asthenia (77.8%). Selected dose level for the expansion cohort (A 40 mg/d with D 75 

mg/m 2 ) was based on the potential for diarrhoea and rash during later cycles. At this 

dosage, events qualifying for DLT such as febrile neutropenia (2), diarrhoea Grade 3, 

hypokalaemia Grade 3, hyponatraemia Grade 3, increase of creatininaemia Grade 2 

and oral mucositis, were observed in 7 pts. 

Conclusions: Based on the rate of DLTs observed at 40 mg/day A + 75 mg/m 2 D, the 

decision was made to evaluate further the A 30 mg/day + D 75 mg/m 2 dose regimen 

in an additional cohort of 12 pts. Additional safety data and preliminary evidence of 

activity are anticipated to be available at the time of presentation. 

Disclosure: J. Bennouna: I have received honoraria from roche, boeringher, amgen 

for advisory board. It is for myself. H. De Mont-Serrat: Employee of Boehringer 

Ingelheim. P. Squiban: Employee of Boehringer Ingelheim. I. Tschoepe: Employee of 


495P CONTRIBUTION OF IMMUNOGENIC CELL DEATH (ICD) TO 

THE ANTI-TUMOR ACTIVITY OF CATUMAXOMAB 

(ANTI-EPCAM X ANTI-CD3) 

D. Goéré, C. Flament, N. Chaput-Gras, L. Zitvogel 

Surgical Oncology, Institut Gustave Roussy, Villejuif, FRANCE 

Background: The trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) is 

approved (EU) for the intraperitoneal treatment of malignant ascites. Catumaxomab 

is a trifunctional antibody targeting EpCAM on tumor cells, CD3 on T lymphocytes 

and binding to FcγR positive accessory cells thereby leading to the elimination of 

EpCAM+ tumor cells by different immune-mediated mechanisms. It has been 

reported that tumor cell death triggered by some immunogenic compounds or drugs 

used in the oncological armamentarium participates in the long term protection of 

patients treated with chemotherapy. The present nonclinical study investigated 

whether catumaxomab promotes immunogenic cell death (ICD) mechanisms which 

may contribute to its mode of action and its pharmacological activity in vivo. 


Methods: Either co-cultures of peripheral blood mononuclear cells from healthy 

volunteers and EpCAM+ tumor cells (allogeneic system) or ascites cells from patients 

with malignant ascites (autologous system) were incubated in the presence of 

catumaxomab for 24-48 hours. Analysis of T, NK, DC/monocyte cell activation and 

measurement of cytokine release in cell culture supernatants was performed. 

Subsequent analyses included investigation of cell death of EpCAM+ tumor cells and 

evaluation of ICD parameters (calreticulin, HMGB1, ATP). 

Results: The trifunctional antibody catumaxomab, in the presence of EpCAM+ 

tumor cells, induces activation of T lymphocytes, both CD4, CD8, with induction of 

Th1 and Th17 polarization accompanied by a by-stander NK cell triggering. In the 

absence of ICD chemotherapy (oxaliplatin, doxorubicin), no ICD markers 

(calreticulin, HMGB1, ATP) can be detected on EpCAM+ tumor cells. However, 

following a pre-sensitization by suboptimal doses of oxaliplatin, catumaxomab could 

promote enhanced exposure of calreticulin, HMGB1 and ATP release from EpCAM+ 

tumor cells (allogeneic system). 

Conclusions: Activation of T cells and induction of inflammatory lymphocytes mainly 

contributes to the catumaxomab-mediated elimination of EpCAM+ tumor target cells. 

ICD mechanisms including release of HMGB1 and ATP, exposure of calreticulin by 

targeted tumor cells may further promote the anti-tumor activity of catumaxomab. 


496P A PHASE 1 STUDY OF MM-111; A BISPECIFIC HER2/HER3 

ANTIBODY FUSION PROTEIN, COMBINED WITH MULTIPLE 

TREATMENT REGIMENS IN PATIENTS WITH ADVANCED 

HER2 POSITIVE SOLID TUMORS 

D. Richards 1 , F. Braiteh 1 , S. Anthony 1 , W. Edenfield 1 , B. Hellerstedt 1 , R. Raju 2 , 

P. Conkling 1 , C. McDonagh 3 , S. Frye 3 , V. Moyo 3 

1 Research, US Oncology, The Woodlands, TX, UNITED STATES OF AMERICA, 

2 Research, Alliance Oncology Research, Kettering, OH, UNITED STATES OF 

AMERICA, 3 Clinical Development, Merrimack Pharmaceuticals, Cambridge, MA, 


Background: Ligand-activated HER3 forms a potent signaling heterodimer with 

HER2 and is emerging as key tumorigenic node and mediator of drug resistance. 

MM-111 (111) is a novel molecule that inhibits ligand activated HER3 signaling in 

HER2+ tumors. Preclinically, MM-111 potentiates the anti-tumor activity of and 

mitigates resistance to trastuzumab, lapatinib and chemotherapies. This study 

evaluates the safety of MM-111 combined with standard of care (SOC) 

HER2-targeting regimens (Rx), namely; capecitabine (X), cisplatin (C), and 

trastuzumab (T) (Arm 1); lapatinib (L) + /- trastuzumab (Arm 2); and paclitaxel (P) 

with trastuzumab (Arm 3). 

Methods: This was a multi-arm Phase 1, dose escalation study of MM-111 in 

combination with SOC regimens to evaluate safety, pharmacokinetics (PK), and 

anti-tumor activity. Patients were required to have documented advanced HER2+ 

cancer, with adequate organ function. Each arm was designed to run as a separate 

Phase 1 study to address safety and tolerability and each arm utilized a "3 + 3" design 

with standard dosing of the SOC regimen. MM-111 was dosed weekly at 10mg/kg 

and escalated up to 20mg/kg where possible. 

Results: As of 30 March 2012, thirty patients had been enrolled across three arms. 

Dose-limiting toxicities (DLTs) included myelosuppression, infection, vomiting, 

diarrhea, mucositis, hypokalemia, hyponatremia, hypophosphatemia, hyperuricemia 

and one report of congestive heart failure (CHF). Serious Adverse Events (SAEs) 

included pneumothorax, confusion, hemiparesis, seizure, sepsis, diarrhea, disease 

progression and CHF (also DLT). The table below summarizes patient outcomes. 

Cohort 1 Arm 1 Arm 2 Arm 3 

Rx (Dose) X (1000) C (80) T (4/2) L (1000 mg) T (4/2) P (80) T (4/2) 

Units 

111 & T 

(mg/kg) 

XC&P 

(mg/m 

111 (10) 111 (10) 111 (10) 

2 ) 

N 6 3 8 

DLT 4 0 1 

SAE 4 1 2 

Cohort 2 XCT LT PT 

111 (5) 111 (20) 111 (20) 

N 3 7 3 

DLT 2 1 0 

SAE 0 4 0 

CR; PR; SD 

/N 

1 CR;2 PR;2 SD /9 2 PR/10 4 PR;5 SD /11 

MM-111 dosing required further reduction to 5mg/kg in arm 1 but was safely 

escalated to 20mg/kg in arms 2 and 3. 

Conclusion: Overall, MM-111 could be safely combined with SOC HER2 regimens. 

Additional safety, PK and efficacy data will be provided. 


Disclosure: C. McDonagh: Employed by Merrimack. Stock Ownership. S. Frye: 

employed by Merrimack. Stock Ownership. V. Moyo: Employed by Merrimack. Stock 

Ownership. All other authors have declared no conflicts of interest. 

497P DOSE-ESCALATION PHASE I STUDY OF CABAZITAXEL (CBZ) 

+ GEMCITABINE (GEM) IN PATIENTS (PTS) WITH METASTATIC 

OR UNRESECTABLE ADVANCED SOLID MALIGNANCY 

O. Rixe 1 , I. Puzanov 2 , P.M. LoRusso 3 , J. Yin 4 , S. Doroumian 5 , X. Zhi 6 , 

A.J. Olszanski 7 

1 Cancer Center, Georgia Health Sciences University, Augusta, GA, UNITED 

STATES OF AMERICA, 2 Division of Hematology-oncology, Vanderbilt University 

Medical Center, Nashville, TN, UNITED STATES OF AMERICA, 3 Department of 

Oncology, Karmanos Cancer Institute / Wayne State University, Detroit, MI, 

UNITED STATES OF AMERICA, 4 N/a, Sanofi, Bridgewater, NJ, UNITED STATES 

OF AMERICA, 5 Research and Development, Sanofi, Montpellier, FRANCE, 

6 Biostatistics, Sanofi, Bridgewater, NJ, UNITED STATES OF AMERICA, 7 Medical 

Oncology Department, Fox Chase Cancer Center, Philadelphia, PA, UNITED 


Rationale: Gem + taxane combinations have shown activity in some advanced 

cancers. Cbz (a novel taxane) + prednisone (P) improved overall survival vs 

mitoxantrone + P in pts with metastatic castration-resistant prostate cancer previously 

treated with docetaxel (de Bono 2010). 

Methods: A Phase I study (NCT01001221) was conducted to determine the 

maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz + Gem 

(parts 1a and 1b) and to evaluate antitumour activity at the MTD (part 2). Pts with 

histologically or cytologically confirmed metastatic or unresectable solid tumours 

without existing standard treatment were eligible. Cohorts of 3–6 pts were treated 

with Cbz (15–20 mg/m 2 1-h infusion) followed by Gem (700–1000 mg/m 2 )ond1 

and Gem alone on d8 (part 1a). The administration sequence on d1 was then 

reversed (part 1b), based on preliminary PK data. 

Results: Of the 12 pts in part 1a, 5 pts were treated at Cbz 20 mg/m 2 + Gem 1000 

mg/m 2 dose level (DL 20/1000), 5 pts at DL 15/900 and 2 pts at DL 15/700. In part 

1b, all 6 pts were treated at the lowest DL (700/15) allowed. At all DLs, ≥ 2 pts 

experienced a DLT, regardless of administration sequence. DLTs were febrile 

neutropenia (FN) (4 pts), Grade (Gr) 4 neutropenia (2 pts), Gr 4 thrombocytopenia 

(2 pts) and Gr 3 AST increase (1 pt). No MTD was established and part 2 was not 

performed. All pts experienced at least 1 treatment-emergent AE (TEAE); the most 

frequent all grade non-haematological TEAEs were fatigue 66.7%, decreased appetite 

50.0%, diarrhoea 44.4%, nausea 38.9% and weight decrease 33.3%. Gr 3–4 

haematological toxicities included neutropenia 66.7%, thrombocytopenia 33.3% and 

FN 22.2%. Nine pts continued study treatment and received 6–22 cycles; 3 pts had a 

partial response (melanoma, prostate small cell and appendiceal tumours), while 8 

pts experienced stable disease. PK analysis did not reveal a drug–drug interaction 

between Cbz and Gem. 

Conclusion: The MTD of Cbz + Gem could not be established due to DLTs. 

Antitumour activity was observed and drug administration sequence did not affect 

the toxicity profile. Further investigation of alternative dosing regimens is warranted 

in an effort to establish a tolerable combination. 

Disclosure: P.M. LoRusso: Has received research funding from Sanofi. J. Yin: Is a 

Sanofi employee and owns Sanofi stocks and shares. S. Doroumian: Is a Sanofi 

employee (pharmacokineticist) and owns Sanofi stocks and shares. X. Zhi: Is a Sanofi 

employee (statistician) and owns Sanofi stocks and shares. A.J. Olszanski: Research 

funding - Sanofi supplies support for the conduct of the study. All other authors 


498P FIRST-IN-HUMAN PHASE I ADMINISTRATION OF YS110, A 

HUMANIZED MONOCLONAL ANTIBODY DIRECTED AGAINST 

THE CD26 MOLECULE IN CANCER PATIENTS 

E. Angevin 1 , V. Trillet-Lenoir 2 , N. Isambert 3 , J. Alexandre 4 , F. Valleix 5 , T. Podoll 6 , 

I. Miyashita 7 , T. Yamada 8 , Y. Kaneko 9 , C. Morimoto 10 

1 Sitep, Institut Gustave Roussy, Villejuif, FRANCE, 2 Service D’oncologie 

Médicale, Hopital Lyon Sud, Pierre Bénite, FRANCE, 3 Unité De Phase I, Centre 

Georges François Leclerc, Dijon, FRANCE, 4 Service D’oncologie Médicale, 

Hopital Cochin, paris, FRANCE, 5 Clinical Research, FV-Clinical subcontractor for 

Harrison Clinical Research, Pontoise, FRANCE, 6 Oncology Department, Y’s 

Therapeutics, Redwood City, CA, UNITED STATES OF AMERICA, 7 Clinical 

Development, Kissei Pharmaceuticals, Tokyo, JAPAN, 8 Department of 

Pathology, Keio university School of Medicine, Tokyo, JAPAN, 9 Clinical 

Development, Y’s AC, Tokyo, JAPAN, 10 Division of Clinical Immunology, 

University of Tokyo, Tokyo, JAPAN 

Background: YS110 is a recombinant humanized IgG1 monoclonal antibody that 

selectively binds with high affinity to the extracellular domain of the CD26 antigen. 

CD26, a widely distributed 110-kDa transmembrane glycoprotein with intrinsic 

DPPIV activity and its truncated soluble form (sCD26/DPPIV) also present in serum 



and fluids, is known to play an important role in tumor biology. CD26 is frequently 

highly expressed on multiple cancer cell types, especially mesothelioma and renal cell 

carcinoma (RCC). In addition to its role in proteolysis via the DPPIV activity, CD26 

also acts as a receptor involved in T-cell co-stimulation and immune regulation. 

Preclinical evaluations of YS110 have demonstrated anti-tumor effects in cancer cell 

lines and xenografts expressing the CD26 antigen without significant side effects in 

toxicology studies (up to 100 mg/kg as single dose or 30 mg/kg for 5 weekly doses in 

cynomolgus monkeys). 

Phase I design and endpoints: The ongoing YSCMA-EU-0001 trial is a Phase I/II 

study of YS110 escalating dose administered intravenously once every 2 weeks for 3 

doses (Days 1, 15, 29). Patients must have progressive locally advanced inoperable 

and/or metastatic histologically confirmed solid tumors, refractory to prior standard 

therapies, with confirmed CD26 + tumor expression (≥ 20% of the tumor cells by 

central IHC evaluation). The primary endpoint is to determine the Maximum 

Tolerated Dose/Recommended Dose of YS110 and the pattern of DLTs. Secondary 

endpoints are the determination of the PK/PD parameters (i.e. analysis of cytokine 

release, immunophenotyping, circulating DPPIV activity and sCD26 antigen level). 

Preliminary antitumor efficacy is evaluated by RECIST1.1 criteria at Day 43. Patients 

demonstrating objective response or stable disease receive additional treatment cycles. 

Status of the study: As of May 1 st 2012, 22 patients (13 mesothelioma, 9 RCC) have 

been treated with 3 bi-weekly infusions over 29 days at 0.1, 0.4, 1 and 2 mg/kg. Based 

on PK data for them, the next cohort of 3 patients will be dosed at 2 mg/kg with 

weekly infusions over 29 days starting in May 2012. Safety, PK/PD, and preliminary 

efficacy data will be presented. 

Disclosure: T. Podoll: Compensated employment position : President of Y\\’s 

Therapeutics Compensated Consultant role. I. Miyashita: Compensated Employment 

role: Director Kissei Pharmaceuticals Co, Ltd. Y. Kaneko: Compensated employment 

role : managing board of directors Y’s AC Stock ownership: Y’s AC. C. Morimoto: 

Compensated Consultant role : Kissei Pharmaceuticals Co, Ltd Stock ownership: Y’s 

Therapeutics Honororia: Kissei Pharmaceuticals Co, Ltd Research funding: Y’s 

Therapeutics. All other authors have declared no conflicts of interest. 

499P INCIDENCE AND RELEVANCE OF PROTEINURIA IN 

BEVACIZUMAB (BV)-TREATED PATIENTS (PTS): POOLED 

ANALYSIS FROM RANDOMIZED CONTROLLED TRIALS (RCTS) 

R. Lafayette 1 , B. McCall 2 , N.F. Li 3 , L. Chu 4 , P. Werner 5 , A. Das 6 , R.J. Glassock 7 

1 Nephrology, Stanford Glomerular Disease Center, Stanford, CA, UNITED 

STATES OF AMERICA, 2 Product Development, Oncology, Genentech, Inc., 

South San Francisco, CA, UNITED STATES OF AMERICA, 3 Biostatistics, 

Genentech, Inc., South San Francisco, CA, UNITED STATES OF AMERICA, 

4 Global Product Development Biometrics, Genentech, Inc., South 

San Francisco, CA, UNITED STATES OF AMERICA, 5 Statistical Programming 

and Analysis (spa), F. Hoffmann-La Roche AG, Basel, SWITZERLAND, 6 PDCO, 

Genentech, Inc., South San Francisco, CA, UNITED STATES OF AMERICA, 7 The 

David Geffen School of Medicine, UCLA, Laguna Niguel, CA, UNITED STATES 

OF AMERICA 

Background: Proteinuria (PU) is a recognized adverse event with BV treatment (tx); 

however it is not known if BV-related PU is associated with clinical outcomes. This 

analysis was undertaken to define the relationship between PU with BV tx and 

sequelae, including changes in kidney function. 

Methods: A pooled safety database, comprising 22 phase 2/3 RCTs of BV across 

tumor types, was used to characterize PU events. Analysis pools were created based 

on data availability in individual studies. Raw and time-adjusted PU rates and data 

on the association between PU and arterial thromboembolic events (TEs), venous 

TEs, and infection were derived from Pool 1 (17 RCTs; n = 14,548). Data from Pool 

2 (8 RCTs; n = 9,158) were used to estimate the association between lab-reported PU 

and changes in kidney function based on serum creatinine (sCr) levels. Severity of 

kidney function change was categorized using the RIFLE classification for acute 

kidney injury (AKI). Potential predictors of PU were also assessed. 

Results: In Pool 1, the incidence rate of any-grade (gr) PU was 8.2% (733/8917) and 

4.6% (257/5631) in BV and control pts, respectively; gr ≥3 PU occurred in 1.4% and 

0.2%, respectively. Pts developing PU had a numerically increased rate of any-gr 

infection irrespective of tx (driven mostly by urinary tract infection); however, no 

association was found between PU and TEs (arterial or venous). In Pool 2, PU gr 

and tx appeared to slightly shift the rate of post-baseline AKI (Table). Evaluated risk 

factors (age, sex, history of hypertension or diabetes) were not found to be 

significantly predictive for gr ≥3 PU. 

Conclusions: The use of laboratory events and pooled data confirm a modest 

increase in PU with BV tx. The development of PU in BV-treated pts was associated 

with a modest increase in the risk of infection, but not TEs, and a trend toward a 

decrease in kidney function. Whether these associations are causal cannot be 

determined by this analysis. 

Tx group 

BV (n = 

5098) 

No BV (n = 

3186) 

Worst 

post-BL gr 

of PU a 

Pts without 

PU at BL, 

n 

Worst post-BL kidney function (RIFLE 

classification), n (%) 

Normal Risk b 

Injury c 

Failure d 

0 2960 2277 (76.9) 585 (19.8) 66 (2.2) 25 (0.8) 

1 1381 1021 (73.9) 307 (22.2) 31 (2.2) 20 (1.4) 

2 562 391 (69.6) 137 (24.4) 18 (3.2) 14 (2.5) 

3 59 34 (57.6) 19 (32.2) 4 (6.8) 2 (3.4) 

0 2144 1736 (81.0) 349 (16.3) 39 (1.8) 18 (0.8) 

1 769 618 (80.4) 123 (16.0) 19 (2.5) 9 (1.2) 

2 166 124 (74.7) 32 (19.3) 7 (4.2) 3 (1.8) 

3 2 1 (50.0) 1 (50.0) — — 

a CTCAE grade. No patients had gr 4 PU. 

b Increased sCR ×1.5 or estimated creatinine clearance (eCrCl) decrease >25%. 

c Increased sCr ×2 or eCrCl decrease >50%. 

d Increased sCr ×3, eCrCl decrease >75% or sCr ≥4 mg/dL. 

Note: missing values for each row are not shown. 

BL, baseline. 

Disclosure: B. McCall: Dr. McCall is an employee of and holds stock options in 

Genentech, Inc. N.F. Li: Dr. Li is an employee of and holds stock options in 

Genentech, Inc. L. Chu: Ms. Chu is an employee of and holds stock options in 

Genentech, Inc. P. Werner: Dr. Werner is an employee of F. Hoffmann-La Roche 

Ltd. A. Das: Dr. Das is an employee of and holds stock options in Genentech, Inc. R. 

J. Glassock: Dr. Glassock is a consultant to Genentech. All other authors have 


500P THE LEEDS FORMULA: A NEW, MORE ACCURATE AND 

WIDELY APPLICABLE FORMULA FOR ESTIMATING RENAL 

FUNCTION, ACCOUNTING FOR VARIABILITY IN CREATININE 

ASSAY MEASUREMENT 

F. Collinson 1 , W. Gregory 1 , C. Twelves 2 , C. Handforth 3 , M. Bosomworth 4 , 

G. Hall 3 

1 Clinical Trials Research Unit, University of Leeds, Leeds, UNITED KINGDOM, 

2 Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine & St 

James’s Institute of Oncology, Leeds, UNITED KINGDOM, 3 St James’s Institute 

of Oncology, St James’s University Hospital, Leeds, UNITED KINGDOM, 4 Blood 

Sciences, St James’s University Hospital, Leeds, UNITED KINGDOM 

Introduction: Many formulae are used to estimate renal function, but none account 

for the significant variation in creatinine (Cr) measurement between the 26 assays 

currently used in the UK. The UK National External Quality Assessment Service has 

published assay-specific Cr adjustors, but the calculated ’standardised Cr’ (SCr) 

dangerously overestimates GFR when used in formulae such as Cockroft and Gault 

(C&G) and Wright (W). We aimed to develop a simple formula to accurately 

estimate GFR in oncology patients, using easily available patient characteristics and 

the SCr, hence accounting for inter-assay variation. 

Methods: Isotopic GFR (iGFR) was measured using Tc 99m DTPA clearance. Serum 

Cr was measured using the O’Leary Jaffe assay and from this SCr derived. Clinical 

parameters (age, sex, height, weight, SCr, urea and albumin) were used in regression 

modelling (STATA) to investigate the relationship of individual parameters with 

iGFR. From this a novel formula was derived to estimate iGFR (the Leeds formula). 

This formula was then prospectively validated on a second cohort of patients. 

Results: In the discovery set 423 oncology patients were included with a range of 

malignancies, a median age of 49 (range 18-91) years and serum Cr between 50-130 

µmol/l who underwent iGFR measurement between 1/4/06 and 31/3/09. A model 

incorporating SCr, age, sex, height, weight, urea and albumin predicted iGFR 

(median calculated GFR 92 ml/ min, range 25-217; r 2 of 0.74) more accurately than 

alternative established GFR formulae e.g. C&G and W formulae (r 2 0.4-0.6) . 

Prospective validation on a separate cohort of oncology patients (496 patients 

between 1/4/09 and 31/3/11) validated the Leeds formula with an r 2 of 0.71 for 

correlation with iGFR. 

Conclusions: The Leeds formula uses readily available clinical information to 

estimate GFR more precisely than existing formulae and has the advantage of being 

applicable to Cr results from any laboratory provided the assay type is known. Many 

oncologists do not appreciate the resultant effect of inter-Cr assay variability on 

estimated renal function (GFR) and hence chemotherapy dosing. 



501 PRECLINICAL DATA INVESTIGATING THE USE OF 

SARACATINIB IN RENAL CELL CARCINOMA 

K. Sharpe1 ,Y.Lu1 , D. Berney1 , C. Rofe1 , T. Powles2 1 

Molecular Oncology, Barts Cancer Institute, London, UNITED KINGDOM, 

2 

Barts Cancer Institute, St Bartholomew’s Hospital QMUL, London, UNITED 

KINGDOM 

Background: SRC, a non-receptor tyrosine kinase, has been shown to effect pathways 

implicated in anti-VEGF drug resistance. Anti-VEGF drugs provide standard of care 

in renal cell carcinoma (RCC) and therefore we investigated the potential of the SRC 

inhibitor saracatinib in preclinical models of RCC. 

Methods and results: In vitro MTS assays were performed on a panel of RCC cell 

lines which demonstrated saracatinib significantly reduced cell viability in all RCC 

cell lines tested in a dose-dependent manner. Follow-up experiments performed 

using two separate isogenic cell lines confirmed that mutation of the VHL gene 

impaired saracatinib’s ability to reduce cell viability. In vitro migration assays 

confirmed saracatinib’s ability to reduce motility and migration and this effect did 

not correlate with VHL status. Using the VHL-null 786-O xenograft model we 

investigated the impact of saracatinib in vivo. Saracatinib (25 mg/kg) significantly 

slowed tumour growth compared to vehicle-treated tumours. Furthermore, when 

combined with the anti-VEGF drug cediranib, combination therapy (25 mg/kg + 

3mg/kg) significantly slowed tumour growth when compared to cediranib 

monotherapy (3mg/kg). Combination therapy significantly reduced vessel density (as 

measured by CD31 immunohistochemistry [IHC]) and increased the percentage of 

apoptotic cells (cleaved-caspase 3 IHC) compared to vehicle-treated tumours. 

Moreover, combination therapy increased the percentage of apoptotic cells compared 

to cediranib monotherapy but this result did not reach statistical significance. IHC 

analysis showed that saracatinib (25mg/kg) significantly reduced tumour 

phospho-STAT3 levels. 

Conclusions: These data demonstrate saracatinib’s potential to reduce RCC cell 

viability and motility in vitro and slow tumour growth in vivo both as monotherapy 

and in combination with an anti-VEGF agent. A randomised phase II trial is 

ongoing to investigate the potential of combining saracatinib and cediranib in VEGF 

TKI refractory RCC. 

Disclosure: K. Sharpe: Kevin Sharpe receives an MRC CASE stipend which 

AstraZeneca contributes towards. T. Powles: Thomas Powles has participated in 

advisory boards for Pfizer and GSK and has received research funding from these 

institutions. All other authors have declared no conflicts of interest. 

502 ASSOCIATION BETWEEN PERIPHERAL BLOOD LYMPHOCYTE 

COUNT (PBLC) AND OUTCOME IN PATIENTS WITH SOLID 

TUMORS TREATED WITH NGR-HTNF 

A. Bulotta1 , V. Gregorc1 , G. Rossoni1 , G. Todisco1 , M.G. Viganò1 , A. Lambiase2 , 

C. Bordignon2 1 2 

Oncologia, IRCCS San Raffaele, Milano, ITALY, Clinical Development, MolMed, 

Milan, ITALY 

Background: NGR-hTNF (asn-gly-arg-human tumor necrosis factor) induces 

antitumor effects by selectively damaging tumor neovasculature and increasing 

intratumoral infiltration of effector T cells. We investigated whether pretreatment 

PBLC values were associated with treatment outcomes in 5 phase II single-arm trials 

on 205 patients (pts) who were refractory/resistant to standard therapies. 

Methods: NGR-hTNF 0.8 µg/m 2 was given every 3 weeks (q3w) alone in pts with 

malignant pleural mesothelioma (MPM n = 55), hepatocellular carcinoma (HCC n = 

40), and colorectal cancer (CRC n = 45), or combined with doxorubicin in small-cell 

lung cancer (SCLC n = 28) and ovarian cancer (OC n = 37). Tumor assessment by 

RECIST was done q6w until progression. Kaplan-Meier methods and Cox models 

were used to determine univariate and multivariate associations between baseline 

PBLC and progression-free survival (PFS) and overall survival (OS). 

Results: Median baseline PBLC value was 1.4/mL (range 0.3-6.9; interquartile range 

1.0-1.8) in 198 pts with available pretreatment counts. The first distribution quartile 

was used as cut-off value to dichotomize PBLC into high (≥ 1.0; n = 144, 73%) or 

low (< 1.0; n = 54, 27%) levels. Baseline characteristics (high v low levels): median 

age 65 v 65; male 51% v 52%; PS 1-2 31% v 39%, range of prior treatment lines 1-5 v 

1-5. Mean number of cycles was 4.5 (range 1-24) in pts with high and 3.3 (1-13) in 

pts with low levels (p = .02). In univariate analyses, pts with high PBLC had 

significantly improved PFS (HR = 0.68 p = .02) and OS (HR = 0.51 p = .0001). 

Six-month PFS rates were 21% (95% CI 14-28) in the high and 9% (1-17) in the low 

PBLC groups (log-rank p = .02), while 1-year OS was 52% (44-60) in pts with high 

and 28% (16-40) in pts with low levels (p = .0001). After adjusting for major baseline 

factors (age, gender, PS, prior lines, and tumor type), a high PBLC remained 

independent predictor of longer PFS (HR = 0.60 p = .01) and OS (HR = 0.52 p 

= .0003). Median OS in pts stratified by PBLC < 1.0/mL, 1.0 to 1.8/mL, and > 1.8/mL 

were 7.7, 9.1, and 16.7 months, respectively (p < .0001 for trend). 

Conclusions: Pretreatment PBLC value may be used to identify which patients are 

likely to gain treatment benefit from NGR-hTNF. 


Disclosure: C. Bordignon: Employment - MolMed. All other authors have declared 


503 A PHASE I,II TRIAL OF AUTOLOGOUS DENDRITIC CELL 

TUMOR VACCINE COMBINED WITH IRRADIATION PATIENTS 

WITH REFRACTORY METASTATIC COLORECTAL CANCER 

Y.J. Choi, Y.M. Seol, H.J. Kim, J.S. Chung, G.J. Cho 

Hemato- Oncology, Pusan National University Hospital, Busan, KOREA 

Purpose: A dendritic cell vaccine has been developed as a novel strategy for 

generating antitumor immunity in the treatment of cancer. The purpose of this study 

was to assess the maximal tolerated dose, safety, clinical efficacy and immunologic 

response of a new dendritic cell vaccine (DC-Vac) combined with irradiation in 

patients with metastatic colorectal cancer. 

Methods (Materials): 22 patients with metastatic colorectal cancer were assigned to 

study that received 3, 6, or 12 × 106 DC-Vac 3 times at 2 week intervals and 

additional 2 times at 4 weeks intervals. On the day before and on the day of each 

vaccination, each patient received a 4 Gy radiation dose to the target tumor. On the 

day of vaccination, the indicated dose of autologus DCs was injected in to the 

irradiated tumor using ultrasound-guided needle injection procrdure. We also 

evaluated immunologic and tumor responses. 

Results: The maximum dose of DC-Vac (12 × 106) was shown to be safe. In 5 of 9 

patients, the vaccine resulted in increased interferon (IFN)-_ production by CD8+ 

cells after exposure to tumor lysate. The response evaluation was performed in 15 of 

the 17 patients who received at least 4 injections. Stable and progressive disease was 

found in 4 and 11 patients, respectively. 

Conclusions: The DC-based immunotherapy and radiotherapy is theoretically 

synergistic for the local control and systemic control. The DCVac/IRⓡ 

immunotherapy combined with irradiation was tolerable and safe in the evaluated 

cases of refractory metastatic colorectal cancer. Future work should include well 

designed a phase II clinical trials. 


504 SECOND CYCLE OF CATUMAXOMAB TREATMENT IN 

PATIENTS WITH MALIGNANT ASCITES: RESULTS FROM THE 

SECIMAS STUDY 

G. Oskay-Özcelik 1 , I.B. Vergote 2 , A. Santoro 3 , F. Marmé 4 , P. Rosenberg 5 , 

J. Sehouli 6 

1 Gynäkologisch-Onkologische Schwerpunktpraxis, Praxis Hindenburg, Berlin, 

GERMANY, 2 Obstetrics & Gynaecology, University Hospital Gasthuisberg, 

Leuven, BELGIUM, 3 Oncology Hematology, Humanitas Cancer Center, Istituto 

Clinico Humanitas, Rozzano, ITALY, 4 Inf 460, Universitätsfrauenklinik Heidelberg 

& Nationales Centrum für Tumorerkrankungen (NCT), Heidelberg, GERMANY, 

5 Onkologiska Kliniken Universitetssjukhuset, University Hospital Linköping, 

Linköping, SWEDEN, 6 Department of Gynecology, Charite Medical University, 

Berlin, GERMANY 

Purpose: The SECIMAS study investigated the feasibility of a second cycle of 4 

intra-peritoneal (i.p.) infusions of catumaxomab in patients who responded to 

treatment with 4 i.p. catumaxomab infusions in the CASIMAS study. 

Patients and methods: Eligible patients had to have completed 4 i.p. prior infusions 

of catumaxomab in the CASIMAS study and required their first therapeutic puncture 

after > 60 days. Primary endpoint was the proportion of patients who were able to 

receive at least 3 infusions. Secondary endpoints were safety including a composite 

safety score (CSS) summarizing the worst CTCAE grades for the main TEAEs 

(pyrexia, nausea, vomiting, and abdominal pain) and the development of anti-drug 

antibodies (ADA). Efficacy endpoints were puncture-free survival (PuFS), time to 

puncture (TTPu) and overall survival (OS). 

Results: Eight of 9 selected patients from the CASIMAS study were treated with a 

2nd of catumaxomab. Eight (100%) patients received all 4 infusions within 20 

days, thus the primary endpoint was met with a high compliance rate. The 

median CSS was comparable for these 8 patients with 3.4 after the first cycle and 

3.0 after the second cycle. Less patients in the SECIMAS study had AEs with 

CTC >3 (25%) compared to CASIMAS (70.1%). All 8 (100%) patients were 

ADA-positive at study entry and remained ADA-positive throughout treatment. 

PuFS was 47.5 days (28;181) and TTPu 60 days (34;na) after the 2nd cycle, while 

it was 37 days (24;61) and 102 days (69;159), respectively after the first cycle. OS 

was 406.5 days (281;480) in the SECIMAS study and 201 days (169;241) in the 

CASIMAS study. 

Conclusions: The study demonstrates that despite the advanced stage of disease and 

the presence of ADA, a second cycle of i.p. catumaxomab treatment is feasible and 

well tolerated in selected patients suffering from malignant ascites and requiring 

treatment for ascites after a first cycle of catumaxomab. These patients actually seem to 

benefit from the second cycle catumaxomab in the same range as after the first cycle. 

Disclosure: I.B. Vergote: consultant for Fresenius Biotech GmbH. A. Santoro: 

financial support for Fresenius Biotech GmbH. F. Marmé: financial support for 



clinical studies from Fresenius Biotech GmbH. P. Rosenberg: financial support for 

clinical studies from Fresenius Biotech GmbH. J. Sehouli: consultant for Fresenius 

Biotech GmbH and financial support for clinical studies. All other authors have 


505 BASELINE PLASMA BIOMARKER SIGNATURE IS ASSOCIATED 

WITH IMPROVED SURVIVAL IN ADVANCED NSCLC PATIENTS 

ON LINIFANIB 

E.M. Mc Keegan 1 , P.J. Ansell 1 , G. Davis 2 , S. Chan 2 , R.K. Chandran 2 ,S.Gawel 2 , 

M.D. McKee 1 , J.L. Ricker 3 , D.M. Carlson 1 , V. Devanarayan 3 

1 Global Pharmaceutical Research and Development, Abbott, Abbott Park, IL, 

UNITED STATES OF AMERICA, 2 Abbott Diagnostics Division, Abbott, Abbott 

Park, IL, UNITED STATES OF AMERICA, 3 GPRD, Abbott, Abbott Park, IL, 


Background: Linifanib is a potent and selective VEGF and PDGF receptor inhibitor 

that has activity in unselected, advanced NSCLC patients (pts) both as monotherapy 

in the relapsed setting and with carboplatin (C) and paclitaxel (P) in the first-line 

setting. A baseline plasma biomarker signature identifying NSCLC pts most sensitive 

to linifanib is needed. 

Methods: An exploratory retrospective analysis of 4 randomized clinical trials 

(linifanib or other treatments: ABT-510 [thrombospondin mimetic], pemetrexed +/- 

ABT-751 [tubulin inhibitor], docetaxel +/- ABT-751) in relapsed NSCLC was 

conducted. Evaluable baseline plasma samples were obtained from 116 pts who 

received linifanib and 125 pts on other treatments. A signature combining 

established tumor markers (carcinoembryonic antigen [CEA] and fragments of 

cytokeratin 19 [CYFRA 21-1]) was derived using a sequential BATTing approach. 

The signature was then tested across a randomized trial of CP + placebo, linifanib 7.5 

mg, or linifanib 12.5 mg in first-line advanced, non-squamous NSCLC. 

Results: In 2/3L NSCLC, the signature was associated with improvement in survival 

on linifanib monotherapy (HR = 0.51 vs. signature negative; P = 0.0017), but no 

improvement in survival on other treatments (P = 0.72). In the first-line setting with 

CP, the signature was associated with significant PFS improvement with linifanib and 

a trend towards significant overall survival improvement at high dose (Table). 

Signature positive patients 

CP + 

Placebo 

N=19 

Median PFS, m 

[95% CI] 

Median OS, m 

[95% CI] 

CP + Linifanib 

7.5 mg 

N=24 

5.4 [1.5, 6.9] 10.2 [3.9, NR] 

HR = 0.49*, 

11.3 [9.2, 

17.4] 

P = 0.049** 

12.5 [6.2, NR] 

HR = 1.02*, 

P = 0.758** 

CP + Linifanib 

12.5 mg N = 26 

8.3 [4.8, NR] 

HR = 0.38*, 

P = 0.029** 

17.4 [12.9, NR] 

HR = 0.54*, 

P = 0.137** 

NR= not reached *Adjusted for ECOG PS and gender. **Stratified log-rank test; 

P-value compared with CP + placebo. 

Conclusion: A baseline plasma biomarker signature is associated with improved 

survival in advanced NSCLC patients on linifanib. Incorporation of this signature 

should be considered in any further investigation of linifanib in NSCLC. 

Disclosure: E.M. Mc Keegan: Employee and shareholder of Abbott. P.J. Ansell: 

Employee and shareholder of Abbott. G. Davis: Employee and shareholder of Abbott. 

S. Chan: Employee and shareholder of Abbott. R.K. Chandran: Employee and 

shareholder of Abbott. S. Gawel: Employee and shareholder of Abbott. M.D. McKee: 

Employee and shareholder of Abbott. J.L. Ricker: Employee and shareholder of 

Abbott. D.M. Carlson: Employee and shareholder of Abbott. V. Devanarayan: 

Employee and shareholder of Abbott. 

507 PHASE I, OPEN-LABEL, RANDOMIZED, CROSSOVER STUDY 

EVALUATING THE EFFECTS OF LINIFANIB ON QTC INTERVALS 

IN PATIENTS WITH SOLID TUMORS 

Y. Chiu 1 , P.M. LoRusso 2 , J.L. Ricker 3 ,X.Li 1 , R. Pradhan 1 , D.M. Carlson 3 

1 Clinical Pharmacology and Pharmacometrics, Abbott, Abbott Park, IL, UNITED 

STATES OF AMERICA, 2 Eisenberg Center for Translational Therapeutics, 

Barbara Ann Karmanos Cancer Institute, Detroit, MI, UNITED STATES OF 

AMERICA, 3 GPRD, Abbott, Abbott Park, IL, UNITED STATES OF AMERICA 

Background: Linifanib (ABT-869) is a novel, orally active and selective inhibitor of 

VEGF and PDGF family of receptor tyrosine kinases that has shown antitumor 

activity in multiple types of solid tumors. This study was conducted to evaluate the 

potential effects of linifanib on QTc prolongation in patients (pts) with advanced 

solid tumors. 

Methods: Enrolled pts (N = 24; ≥18 years) had measurable disease refractory to 

standard therapies, ECOG PS 0-1, and adequate organ function. Pts received 2 

sequences of regimens of 0.25 mg/kg orally administered linifanib up to a 

maximum dose of 17.5 mg. Pts received a morning dose on Days 1 and 7 under 

fasting and fed conditions in a crossover fashion. Serial triplicate ECG recordings 

were obtained on Day –1, and over 24 hours on Day 1 and 7; single recordings 

were obtained at screening and study completion or discontinuation. Plasma 

samples were collected for 72 hours on Day 1 and 7 for pharmacokinetic 

analysis. Effects of linifanib on cardiac repolarization were analyzed using a 

linear mixed effects model on time-matched baseline adjusted QTcF intervals. 

The primary end point was the time-matched difference for on-treatment QTcF 

from baseline (ΔQTcF). An intersection-union test was performed within the 

framework of the corresponding linear mixed effects model. The relationship 

between ΔQTcF and plasma linifanib concentration was explored using a linear 

mixed effects model. 

Results: In the 24 pts evaluated, baseline QTcF ranged from 360.9 ms to 468.6 ms. 

After linifanib administration, the mean ΔQTcF ranged from –4.04 ms to 0.73 ms for 

the fasting regimen, and from –5.94 ms to –1.37 ms for the fed regimen. The upper 

95% confidence bound was 4.30 ms (ie, 500 ms or change of >30 

ms from baseline. 

Conclusion: At the maximum tolerated dose of 0.25 mg/kg, linifanib had no effect 

on cardiac repolarization in pts with advanced solid tumors. 

Disclosure: Y. Chiu: Full-time Abbott employee and stockholder. P.M. LoRusso: 

Patricia LoRusso’s institution receives research funding from Abbott. J.L. Ricker: 

Full-time Abbott employee and stockholder. X. Li: Full-time Abbott employee and 

stockholder. R. Pradhan: Full-time Abbott employee and stockholder. D.M. Carlson: 

Full-time Abbott employee and stockholder. 

508 ELECTROPHYSIOLOGICAL INVESTIGATION OF THE EFFECTS 

OF METOPROLOL AND DILTIAZEM ON PAZOPANIB INDUCED 

PROLONGED CARDIAC REPOLARISATION AND 

PROARRYTHMIC EFFECTS: EXPERIMENTAL STUDY 

T. Akman1 , O. Erbas2 , L. Akman3 , A.U. Yilmaz1 1 

Medical Oncology, Dokuz Eylul University Faculty of Medicine, Izmir, TURKEY, 

2 

Department of Physiology, Ege University Medical School, Izmir, TURKEY, 

3 

Department of Obstetrics and Gynecology, Ege University Medical School, 

Izmir, TURKEY 

Objective: Pazopanib is a potent multi-targeted tyrosine kinase inhibitor which 

is approved for the treatment of advanced RCC patients. While exploring the 

therapeutic index of TKIs, oncology investigators are confronted with drug 

adverse effects such as cardiac toxicities. QT prolongation has taken attention 

because of the risk of serious cardiac arrhythmias such as torsade de pointes 

(TdP) and sudden cardiac death. In several studies QTc prolongation was 

observed with TKIs such as sunitinib, vandetanib, dasatinib, crizotinib. 

However there are no data showing QTc prolongation with pazopanib 

treatment. In this study, we aimed to demonstrate the pazopanib induced 

proarrythmic electrophysiological effects and investigate the possible protective 

effects of metoprolol and diltiazem to ECG changes in an experimental 

model. 

Method: In this study 24 Sprague-Dawley adult male rats were used. Rats were 

randomly assigned to 4 groups (n = 6). To the first group (normal group), 

intraperitoneal injection of 6 ml/kg of saline were given and to the other groups 100 

mg/kg pazopanib were given via orogastric tubes. 3 hours after oral administration of 

pazopanib, to the second group (control group) saline, to the third group 1 mg/kg 

metoprolol and to the fourth group 1mg/kg diltiazem were applicated 

intraperitoneally. 1 hours after application of these drugs, under anesthesia, QTc was 

calculated by taking ECG in derivation I. 

Results: The mean QTc interval was 126,2 ± 2.99 s in group 1, 159.66 ± 6.02 s in 

group 2, 106.66 ± 2.64 in group 3 and 123.33 ± 1.72 s in group 4. Groups 3 and 4 

had significantly shorter QTc intervals compared to group 2 (p < 0.001). 

Conclusion: This is the first experimental study evaluating the use of 

prophylactic therapy with metoprolol and diltiazem in pazopanib induced QT 

prolongation. In this present experimental study we demonstrated the 

beneficial prophylactic effects of metoprolol and diltiazem in pazopanib 

induced QT prolongation. More evidence is needed to evaluate the 

effectiveness and safety of these drugs. Future prospective and 

randomized studies will be needed to confirm recommendations for high risk 

patients. 



509TiP LUX-LUNG 8: A RANDOMIZED, OPEN-LABEL, PHASE III 

TRIAL OF AFATINIB VS. ERLOTINIB IN PATIENTS WITH 

ADVANCED SQUAMOUS CELL CARCINOMA OF THE LUNG 

AS SECOND-LINE THERAPY FOLLOWING FIRST-LINE 

PLATINUM-BASED CHEMOTHERAPY 

G. Goss 1 ,S.Lu 2 , E. Felip 3 , A. Ardizzoni 4 , V. Georgoulias 5 , S. Gadgeel 6 , 

V. Chand 7 ,Y.Gu 7 , Y.S. Olivo 8 , J. Soria 9 

1 Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, CANADA, 

2 Shanghai Lung Tumor Clinical Center, Shanghai Chest Hospital, Shanghai, 

CHINA, 3 Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN, 

4 Onco-hematology Department of Internal Medicine, A.O. Universitaria di Parma, 

Parma, ITALY, 5 Medical Oncology, University Hospital of Heraklion, Heraklion, 

GREECE, 6 Medical Oncology, Karmanos Cancer Center, Detroit, MI, UNITED 

STATES OF AMERICA, 7 Clinical Development - Oncology, Boehringer Ingelheim 

Pharmaceuticals, Inc., Ridgefield, CT, UNITED STATES OF AMERICA, 8 Clinical 

Trial Management, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, 

UNITED STATES OF AMERICA, 9 Dept. of Medicine, Institut de Cancérologie 

Gustave Roussy, Villejuif Cedex, FRANCE 

Background: Patients with advanced squamous cell carcinoma (SCC) of the lung 

have limited treatment options. Although treatment with the EGFR tyrosine kinase 

inhibitor erlotinib is indicated in the second- or third-line or maintenance setting, 

the benefit is limited. Afatinib is a novel, selective, orally bioavailable, ErbB family 

blocker, irreversibly blocking EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4). 

Based on its promising preclinical profile and clinical activity in trials of SCC of the 

head and neck and lung, we seek to determine if the irreversible inhibition of the 

ErbB family translates into clinical benefit for patients with SCC of the lung. 

Methods: This trial will compare the efficacy of afatinib versus erlotinib as 

second-line treatment for patients with SCC of the lung, as measured by 

progression-free survival. Key patient eligibility criteria include: advanced NSCLC 

squamous or mixed histology, completion of at least 4 cycles of platinum-based 

doublet chemotherapy, eligible to receive EGFR-directed therapy as second-line 

therapy, ECOG PS 0–1, adequate organ function, availability of archived tumour 

tissue for correlative studies and no prior EGFR-directed therapy. Secondary 

endpoints are comparison of overall survival, objective response rate, disease control 

rate, tumour shrinkage, assessment of health-related quality of life and safety in both 

treatment groups. Eligible patients will be randomized (1:1) to receive either afatinib 

or erlotinib and stratified based on race (East Asian vs. other). Eight hundred 

patients are planned to be enrolled globally. Independent radiological assessment of 

the primary endpoint will be completed in a treatment-blinded manner. An 

independent data monitoring committee will monitor safety and efficacy of the trial. 

Disclosure: G. Goss: Consultant or advisory relationship to Boehringer Ingelheim, 

compensated prior to conduct of the study. S. Lu: Consultant or advisory 

relationship, compensated, AstraZeneca China for Iressa. A. Ardizzoni: Other 

remuneration: GSK DSMC PRAME Study. V. Georgoulias: Consultant or advisory 

relationship, uncompensated for GSK, Novartis, Sanofi, Janssen-Cilag, Amgen. 

Honoraria and research funding from GSK, Novartis, Sanofi, Janssen-Cilag, Amgen. 

S. Gadgeel: Consultant or advisory relationship for Boehringer Ingelheim. V. Chand: 

Employee of Boehringer Ingelheim Pharmaceuticals, Inc. Y. Gu: Employee of 

Boehringer Ingelheim Pharmaceuticals, Inc. Y.S. Olivo: Employee of Boehringer 

Ingelheim Pharmaceuticals, Inc. J. Soria: Honoraria from Boehringer Ingelheim and 


510TiP DENDRITIC CELL THERAPY FOR PATIENTS WITH 

REFRACTORY SOLID TUMOURS 

P.P. Bapsy 1 , B. Sharan 2 , C. Kumar 2 , A. Mahmood 2 , B. Rangarajan 3 , S. Atilli 4 , 

M. Jain 5 , S. Subramanian 6 , S. Rajappa 7 , M. Srivastava 8 

1 Oncology, Apollo Hospitals, Bangalore, INDIA, 2 Research and Development, 

APAC Biotech Pvt. Ltd, Gurgaon, INDIA, 3 Medical Oncology, Mazumdar Shaw 

Cancer Centre, Bangalore, INDIA, 4 Oncology, Bibi General Hospital, Hyderabad, 

INDIA, 5 Medical Oncology, Ruby Hall Clinic, Pune, INDIA, 6 Oncology, V S 

Hospital, Chennai, INDIA, 7 Medical Oncology, Basavatarakam Indo-American 

Cancer Centre, Hyderabad, INDIA, 8 Clinical Research, Nextvel Consulting LLP, 

Bangalore, INDIA 

Background: Dendritic Cell (DC) therapy initiates immune response against tumor. 

Study ongoing in 7 sites in India has objective to assess toxicity and efficacy in 

refractory solid tumours. 

Materials: DC therapy is prepared using Peripheral Blood Mononuclear Cells 

(PBMCs), cultured with cytokines (IL4 and GMCSF) and exposed to patient’s 

antigen retrieved from their own tumor tissue. Mature DCs are harvested on Day 8 

and checked for surface markers (CD 80 + (PE)CD 86+ (APC) and CD 83 + ( FITC) 

positive) and adequate counts (>1 million DCs) per dose. Patients with recurrent 

disease on symptomatic care were enrolled and 6 doses of DC were administered 

over 14 week’s period. Response criteria used are RECIST-version 1.1 (Response 

Evaluation Criteria for Solid Tumours) and irRC (Immune Related Response 

Criteria). Per protocol, Objective Response (OR) covers Stable Disease (SD), Partial 

Response (PR) and Complete Response (CR). 

Results and observations: 51 patients (ovary-9, colon and rectum- 7, head & neck -6, 

lung-5, Prostate- 5, sarcoma-4, breast-4, stomach-3, cervix-3, squamous cell carcinoma 

of heel-1, pancreas-1, melanoma-1, renal cell-1 and Cholangiocarcinoma-1) were 

enrolled and evaluated for safety. 220 infusions have been completed. All patients 

tolerated therapy well except one who had single episode of rigors during one infusion. 


Other adverse events reported were due to disease progression. Response assessment 

was done at Week 8 (before dose 4), Week 14 (before dose 6) and Week 26 from start 

of therapy. 33 patients’ Week 8 assessment is 22/33 (67%) OR by irRC and 9/33 (27%) 

by RECIST. Among OR, 1 shows PR for 2 consecutive visits. 20 patients’ Week 14 

assessment is 9/20 (45%) continuing with OR by irRC and 6/20 (30%) are OR by 

RECIST. Trends suggest patients with chronic disease (average period of disease of 45 

months), less metastatic sites, fewer prior chemotherapy failure and cancers like ovary, 

prostate and breast, have responded well. 19 patients are on trial, 6 are alive after 

withdrawal and are being followed up for survival and 26 died due to disease 

progression. Survival data is yet to mature. 

Conclusions: DC therapy is safe and extremely well tolerated. The response data is 

encouraging. More survival data is needed to conclude survival benefit. 

Disclosure: P.P. Bapsy: I am medical monitor for the study (consultant), involved 

with the study design, scientific inputs and safety monitoring aspects of the study. I 

am being paid a monthly professional fee for this activity. B. Sharan: I work for 

APAC Biotech (sponsor) as Research Director in the R & D Department and am 

being paid my monthly salary. C. Kumar: I work as Asst Director R & D for the 

sponsor APAC Biotech Pvt. Ltd. I get mothly salary for my job. A. Mahmood: I 

work as Senior Research Scientist in the R&D Department of APAC Biotech Pvt. Ltd 

and get my monthly salary. B. Rangarajan: I am Investigator for the trial and being 

compensated for my role as Clinical Research Investigator. S. Atilli: I am Investigator 

for the trial and being compensated for my role as Clinical Research Investigator. 

M. Jain: I am Investigator for the trial and being compensated for my role as Clinical 

Research Investigator. S. Subramanian: I am Investigator for the trial and being 

compensated for my role as Clinical Research Investigator. S. Rajappa: I am 

Investigator for the trial and being compensated for my role as Clinical Research 

Investigator. M. Srivastava: I am providing advisory consultancy to APAC Biotech 

Pvt. Ltd for study operations and being paid professional fees. 

1708PD MOLECULAR PROFILE AND ANTI-TUMOR ACTIVITY IN 

NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS (PTS) 

IN A PHASE 1 STUDY OF CABOZANTINIB (XL184) IN JAPAN 

H. Nokihara 1 , N. Yamamoto 1 , S. Nakamichi 1 , H. Wakui 1 , Y. Yamada 2 , J. Frye 3 , 

A. Decillis 4 , T. Tamura 5 


2 Medical Oncology, National Cancer Center Hospital, Tokyo, JAPAN, 3 Medical 

Affairs, Exelixis, Inc., South San Francisco, CA, UNITED STATES OF AMERICA, 

4 Clinical Development And Medical Affairs, Exelixis, Inc., South San Francisco, 

CA, UNITED STATES OF AMERICA, 5 Division of Internal Medicine and Thoracic 

Oncology, National Cancer Center Hospital, Tokyo, JAPAN 

Background: Cabozantinib is a potent targeted therapy that inhibits MET, VEGFR2, 

and RET. Anti-tumor activity in patients (pts) has been observed in a broad range of 

tumors including NSCLC. The primary objective of this phase 1 study is to determine 

the maximum tolerated dose (MTD) / recommended phase 2 dose in Japanese pts. 

Methods: Pts with advanced solid malignancies are enrolled in successive cohorts to 

receive escalating doses of cabozantinib orally once daily in a 3 + 3 trial design. Dose 

limiting toxicities (DLTs) are determined using Cycle 1 data. Response is assessed 

using modified RECIST v1.0. Results: As of 1 June 2012, 14 pts were enrolled 

including 5 pts with non-small cell lung adenocarcinoma. Pts have been treated at 3 

dose levels: 40, 60 and 80 mg. The NSCLC pts had a median of 4 prior regimens 

(range, 2 – 6). Four of the 5 NSCLC pts had a confirmed partial response (cPR) 

including a 51 yo female whose pre-treatment tumor sample lacked an EGFR 

activating mutation Analysis of tumor obtained pre-treatment and at progression 

demonstrated a KIF5B-RET fusion. 

Smoking Molecular 

Treatment Best 

Age Gender History Profile 

Duration (mos) Response 

64 Female Never EGFR mutation 15+ cPR 

51 Female Former EGFR wt, RET 

fusion positive 

9 cPR 

58 Female Never EGFR wt 10 cPR 

43 Male Former ALK fusion positive 4 cPR 

64 Female Never EGFR wt, ALK 

fusion negative 

6.5 SD 

DLT of Grade 3 hypertension was reported in 2 pts. The MTD using a capsule 

formulation is 60 mg. Adverse events were generally mild to moderate and include 

hypertension, palmar-plantar erythrodysesthesia, diarrhea, mucositis, rash, edema 

and headache. Laboratory abnormalities include elevated AST/ALT, lipase and TSH; 

and neutropenia and thrombocytopenia. Preliminary PK analysis showed that dosenormalized 

exposure in Japanese pts is approximately 2-fold higher than in non- 

Japanese pts. Despite relatively higher exposures, cabozantinib 60 mg daily appears to 

be a well tolerated dose. Conclusions: Cabozantinib appears well tolerated. Signs of 

antitumor activity include response and prolonged stable disease in NSCLC pts. 

Accrual and additional molecular characterization is ongoing. 

Disclosure: H. Nokihara: Taiho Pharmaceutical Co., Ltd, Merck Serono, Pfizer. N. 

Yamamoto: Chugai pharmaceutical co., ltd., Pfizer, Kyowa-Hakko Kirin co., ltd. Y. 

Yamada: Bayer, Yakult, AstraZeneca. J. Frye: Paid employee of Exelixis Exelixis stock 

ownership. A. Decillis: Paid Employee of Exelixis Exelixis Stock Ownership. T. 

Tamura: Chugai Pharmaceutical co., ltd., Daichi-Sankyo co., ltd., Boehringer 

Ingelheim, Abbott Japan Co., Ltd, Eisai co., ltd., Bristol-Myers Squibb, Kyowa-Hakko 

Kirin co., ltd. All other authors have declared no conflicts of interest. 


familial cancer and genetic syndromes 

511PD GERMLINE MUTATIONS IN CDH1 AND THE HEREDITARY 

DIFFUSE GASTRIC AND LOBULAR BREAST CANCER 

SYNDROME 

P.R. Benusiglio 1 , D. Malka 2 , A. De Pauw 3 , B. Buecher 3 , E. Rouleau 4 , C. Colas 5 , 

S. Grandjouan 6 , M. Blayau 7 , S. Delaloge 8 , O. Caron 1 

1 Clinical Cancer Genetics, Department of Medical Oncology, Institut Gustave 

Roussy, Villejuif, FRANCE, 2 Gastrointestinal Oncology, Department of Medical 

Oncology., Institut Gustave Roussy, Villejuif, FRANCE, 3 Cancer Genetics, Institut 

Curie, Paris, FRANCE, 4 Cancer Genetics, Centre Rene Huguenin, Saint-Cloud, 

FRANCE, 5 Cancer Genetics, La Pitie Salpetriere, Paris, FRANCE, 

6 Gastroenterology, Hopital Cochin, Paris, FRANCE, 7 Molecular Genetics, CHU 

de Rennes - Hôpital Pontchaillou, Rennes, FRANCE, 8 Breast Cancer Unit, 

Department of Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE 

Background: Germline mutations in the E-cadherin gene (CDH1) are found in up to 

48% of families with hereditary diffuse gastric cancer (HDGC), a syndrome 

characterized by multiple cases of DGC in a family. In 2010, experts updated CDH1 

testing criteria and included individuals and families with diagnoses of both DGC 

and lobular breast cancer (LBC), as an excess of LBC had been observed in HDGC 

families. We describe the characteristics associated with CDH1 mutations in a group 

of French patients and show that individuals or families with multiple LBC but no 

DGC should be offered genetic testing. 

Methods: We studied all index cases in which a CDH1 mutation had been identified 

between 2006 and 2011 in the Paris region. 

Results: We found 17 index cases with a CDH1 mutation, ten males and seven 

females, age was 17–63. Eight had familial DGC, four had sporadic DGC at a young 

age, one was a healthy male with two relatives with DGC, and one was a female with 

LBC and two siblings with DGC. Additionally, three females (18%) with no personal 

or family history of DGC had suffered from bilateral LBC under age 50. Only one 

was tested at diagnosis. She was offered prophylactic gastrectomy, and foci of DGC 

were seen on the surgical specimen. She is now doing well. The two others, who had 

initial negative BRCA1/2 screening, were only tested for CDH1 mutations years later 

after they had developed symptomatic DGC. 

Discussion: Three of our cases were females with bilateral LBC but no personal 

or family history of DGC. Two of them were only tested for CDH1 mutations 

once they had developed symptomatic DGC. Prophylactic gastrectomy is now 

systematically offered to mutation carriers, and these two cases would have been 

spared highly-lethal, symptomatic DGC, had they benefited from preventive 

surgery. The 2010 CDH1 testing criteria should be expanded and include cases or 

families with multiple LBC but no DGC. More precisely, any patient or family 

with multiple LBC under age 50 should be tested for CDH1 mutations, as 

carriers are offered life-saving surgery and adapted breast surveillance. Finally, we 

propose for consideration the name “hereditary diffuse gastric and lobular breast 

cancer” to define the cancer susceptibility syndrome associated with mutations 

in CDH1. 


512PD PORTUGUESE HIGH-RISK BREAST/OVARIAN CANCER: 

SURVIVAL ANALYSIS 

P. Machado 1 , A. Clara 2 ,A.Mayer 3 , S. Fragoso 1 , S. Santos 1 , A. Luís 4 , 

A. Opinião 4 , J. Parreira 5 , C. Simões 5 ,F.Vaz 4 

1 Molecular Biology Research Unit, Portuguese Institute of Oncology of Lisbon, 

Lisbon, PORTUGAL, 2 Medical Oncology, Portuguese Institute of Oncology, 

Lisbon, PORTUGAL, 3 Southern Portuguese Cancer Registry (ROR-SUL), 

Table: 512PD 

Female breast cancer Ovarian cancer 



Portuguese Institute of Oncology of Lisbon, Lisbon, PORTUGAL, 4 Medical 

Oncology, Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia 

de Lisboa, Lisbon, PORTUGAL, 5 Breast Cancer Risk Evaluation Clinic, Instituto 

Português de Oncologia de Lisboa, Lisbon, PORTUGAL 

Introduction: Even if only 5–10% of breast cancer (BC) is due to genetic 

predisposition (mainly related to BRCA1/2 mutations), its incidence, the high risk of 

these families and the possible prophylactic interventions make the study of these 

cases relevant. Scarce data suggest different survival in BRCA1 and BRCA2 associated 

ovarian cancer (OC). We aimed to analyze the survival of our BRCA1/2 BC and OC 

survivors. 

Patients and methods: Review of all BRCA1/2 cancer survivors identified until 

September 2011. All patients underwent pre and post-test counselling and were 

pre-screened for the c.156_157insAlu BRCA2 Portuguese founder mutation 

[Machado et al, 2007]. Negative patients were further analysed by CSCE and MLPA. 

Date of diagnosis and survival was obtained for 3 BRCA positive patients subgroups: 

BRCA1, BRCA2 (non c.156_157insAlu) and Alu (c.156_157insAlu). The control 

group (BRCAwt ) consisted on index patients screened during the same period, who 

were not BRCA1/2 positive and for whom we found information in the Southern 

Portuguese Cancer Registry (ROR-Sul). 

Results: Nine hundred and eighty consecutive index patients were screened and 

139 BRCA1/2 positive families were identified: 44 BRCA1 and 95 BRCA2 (44 

c.156_157insAlu). A total of 99 BC (88 female + 11 male) and 18 OC were identified 

in these families. Mean age at diagnosis and overall survival data for the 3 BRCA 

subgroups and control, regarding BC and OC are resumed in table1. Further clinical 

characterization (stage, presence of multiple cancers, prophylactic surgeries) is under 

way. Table1. Overall survival in pts with BC and OC: BRCA1/2 carriers vs 

wtBRCA1/2. 

Conclusion: BC was the more frequent type of cancer in these patients and 

BRCA1/2 carriers show a higher overall survival comparatively to BC pts with wt 

BRCA (P = 0,0197). The overall survival for OC is better for BRCA2 carriers 

((P = 0,0310). OC numbers are small and more follow up of these and future 

identified carriers are needed. 


513PD BRCA STATUS, MOLECULAR PROFILE AND CLINICAL 

VARIABLES IN PRIMARY BILATERAL BREAST CANCERS: A 

POPULATION-BASED CANCER REGISTRY STUDY 

A. Musolino 1 , M.A. Bella 1 , M. Michiara 2 , P. Zanelli 3 , N. Naldi 1 , B. Bortesi 1 , 

P. Sgargi 2 , R. Camisa 1 , T.M. Neri 3 , A. Ardizzoni 1 

1 Medical Oncology Unit, University Hospital of Parma, Parma, ITALY, 2 Medical 

Oncology Unit, University Hospital of Parma and Cancer Registry of Parma 

Province, Parma, ITALY, 3 Medical Genetics Unit, University Hospital of Parma, 

Parma, ITALY 

Introduction: Incidence of primary bilateral breast cancer (BBC) is rare and does 

not exceed 5%. BRCA1/2 mutation carriers diagnosed with breast cancer have a 

strong life time risk of developing contralateral breast cancer. Objectives To address 

both the proportion of BBC associated with BRCA1/2 germline mutations and the 

contribution of germline mutations to the clinical features and outcome of these 

tumors. 

Materials and methods: We identified 263 BBC patients (pts) from a cohort of 9585 

women with a first primary breast cancer systematically collected by the Cancer Registry 

of Parma Province from 1978 to 2006. Among these, 55 women, unselected for family 

history, were subjected to BRCA1/2 testing. In addition, 55 unilateral breast cancer pts, 

which tested negative for BRCA1/2 mutations, were evaluated as control group. 

Results: BRCA mutations were detected in 13 (24%) of 55 BBC pts. Family history of 

breast cancer was identified in 8% of these pts compared with 7% of non-carriers 

BRCA1 BRCA2 Alu BRCAwt BRCA1 BRCA2 Alu BRCAwt 

N 33 20 35 302 2 8 8 12 

Mean age at diagnosis (y) 43,5 40,1 45,9 68,3 47,2 55,8 

Mean OS (months) 107,59 145,23 144,70 78,47 40,45 57,92 86,48 64,14 

N of deaths 5 4 7 51 1 4 1 7 



abstracts

(P = 0.64). Synchronous BBC was significantly rarer in BRCA carriers than in 

non-carriers. In addition, BRCA-positive pts were younger at diagnosis than 

BRCA-negative ones. The combination of high histologic grade, ER, PR, and HER2 

negativity in both bilateral tumors was more frequent among BRCA-1 positive 

tumors than BRCA-2 positive and non-BRCA tumors (P < 0.001). Taken collectively, 

BRCA-positive BBC correlated with triple negative status compared to non-BRCA 

BBC and unilateral breast cancer controls (P < 0.001). There were no survival 

differences between BRCA-positive and non-BRCA tumors. 

Conclusions: Our data show that the combination of BBC occurrence and breast 

tumor phenotype can provide an efficient model for identifying individuals with high 

risk for BRCA mutations and support the hypothesis that BBC in BRCA carriers is 

qualitatively distinct from non-BRCA BBC and from sporadic, unilateral breast 

cancer. Further studies of incident cases are needed to better define the prognostic 

value of BRCA mutations. 


514P GASTRIC CANCER IN PORTUGUESE FAMILIES WITH BRCA2 

GENE MUTATIONS 

M.T.A. Alexandre 1 , A. Luís 2 , A. Opinião 2 , S. Bento 3 , C. Simões 3 , J. Parreira 3 , 

S. Fragoso 4 , P. Machado 4 , S. Santos 4 ,F.Vaz 2 

1 Medical Oncology, Instituto Português de Oncologia de Lisboa, Lisbon, 

PORTUGAL, 2 Medical Oncology, Breast Cancer Risk Evaluation Clinic, Instituto 

Português de Oncologia de Lisboa, Lisbon, PORTUGAL, 3 Breast Cancer Risk 

Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Lisbon, 

PORTUGAL, 4 Molecular Biology Research Unit, Instituto Português de Oncologia 

de Lisboa, Lisbon, PORTUGAL 

Background and objective: BRCA 1/2 are tumor suppressor genes responsible for a 

high number of hereditary breast and ovarian cancers. BRCA 2 mutations are also 

associated with higher risk of other cancers: prostate, melanoma, pancreatic, gastric and 

bile duct cancer. BRCA2 mutations are more frequent than BRCA1 mutations in Portugal 

and GC has, historically, a high incidence in this country. Our objective was to analyze the 

frequency and characteristics of GC in confirmed BRCA2 Portuguese families. 

Methods: Retrospective analysis of all BRCA2 families registered in our Clinic. All 

cases of GC, on the mutated side of the family, for 3 consecutive generations, were 

registered. The control group consisted of breast cancer families with standard risk of 

breast cancer (FSRBC) (with probability


compare the family history record and the hereditary cancer perception risk according 

to National Cancer Institute (NCI) criteria before and after the creation of a 

multidisciplinary heredofamilial cancer unit (HFCU) in our medical oncology service. 

Methods: We retrospectively analyze the clinical records from new incoming patients 

of our medical oncology service in two cohorts: Cohort 1, from January 2009 to 

December 2009 (616 patients, before HFCU creation); and cohort 2, from May 2010 to 

April 2011 (after HFCU creation, first 312 patients analyzed). Family history record 

(yes/no) and NCI general hereditary cancer criteria (unusually early age; one or more 

first-degree relatives affected with the same or a related tumor; synchronous, bilateral 

or metachronous cancer in the same patient; atypical presentations) were collected. 

Results were compared using chi- square test. p

abstracts 

gastrointestinal tumors, colorectal 

518O MAINTENANCE TREATMENT WITH IMMUNOMODULATOR 

MGN1703 FOLLOWING INDUCTION WITH STANDARD 1ST 

LINE THERAPY PROLONGS PROGRESSION-FREE SURVIVAL 

IN PATIENTS WITH METASTATIC COLORECTAL (MCRC): 

RESULTS OF THE PHASE II/III IMPACT TRIAL 

D. Arnold 1 , H.J. Schmoll 2 , J. Riera-Knorrenschild 3 , F. Mayer 4 , H. Kroening 5 , 

W. Scheithauer 6 , D. Nitsche 7 , M. Tschaika 8 , M. Schmidt 8 , B. Wittig 9 

1 University Cancer Centre Hamburg, Hubertus Wald Tumour Centre KMTZ, 

Hamburg, GERMANY, 2 Dept. Hematology/ Oncology, University of Halle Martin 

Luther University Hospital, Halle, GERMANY, 3 Clinic for Hematology, Oncology 

and Immunology, Universitaetsklinikum Giessen und Marburg, Marburg, 

GERMANY, 4 Medizinische Klinik und Poliklinik II, Eberhard-Karls-Universität 

Tübingen, Tübingen, GERMANY, 5 Schwerpunktpraxis für Haematologie und 

Onkologie, Schwerpunktpraxis für Haematologie und Onkologie, Magdeburg, 

GERMANY, 6 Department of Medicine I, Medical University of Vienna, Vienna, 

AUSTRIA, 7 Innere Medizin I, Hämatologie und Onkologie, Barmherzige 

Schwestern Linz, Linz, AUSTRIA, 8 Clinical Development, Mologen AG, Berlin, 

GERMANY, 9 Foundation Institute Molecular Biology and Bioinformatics, Freie 

Universität Berlin, Berlin, GERMANY 

Introduction: Standard chemotherapy is increasingly discontinued after successful 

“induction” in patients (pts) undergoing 1 st line treatment for mCRC. MGN1703 

is a synthetic DNA-based immunomodulator acting as an agonist of TLR-9 that 

has shown preclinical activity in mCRC. This study has been conducted to assess 

clinical efficacy, immunogenicity, and safety of MGN1703 as maintenance vs. 

placebo. 

Methods: The IMPACT study is an international, multicenter, randomized 

double-blind placebo-controlled phase II/III study. Pts with mCRC showing disease 

control (CR, PR or SD) after 4.5 to 6 months of 1st-line standard therapy with 

FOLFOX/XELOX or FOLFIRI +/- bevacizumab (investigatoŕs choice) were included. 

Results: Interim analysis of the unblinded data revealed a strong therapeutic effect 

compared to anticipated PFS. Therefore, patients were withheld from further 

randomization, according to a decision of the steering committee. In the ITT 

population (N = 55 pts), hazard ratio (HR) was 0.53 in favor of MGN1703 (p = 

0.062). In the per-protocol population (excluding screening failures; N = 50), HR was 

0.43 (p = 0.015). In the pre-defined target population (2 out of 3 factors: CEA


Conclusions: The analysis of this randomized phase III trial has not shown a benefit 

for adding cetuximab to FOLFOX4 in patients with resected stage III mKRAS CC 

with global results very close to those observed in KRAS wild type pts. Supported by 

Merck-Serono, Sanofi-Aventis. 

Disclosure: G. Folprecht: - Honoraries, for lectures and advisory boards from Merck 

KGaA and Bristol Mayers Squibb. -study grant from Merck KGaA -involved in clinical 

trials with Imclone and Merck KGaA J. Taieb: advisory board and consutancy for Sanofi 

Aventis and Merck Serono. All other authors have declared no conflicts of interest. 

521O DEFICIENT MISMATCH REPAIR (DMMR) AND BRAF 

MUTATION (MT) STATUS IN PATIENTS (PTS) WITH 

METASTATIC COLORECTAL CANCER (MCRC): A 

META-ANALYSIS OF THE CAIRO, CAIRO2, COIN AND FOCUS 

STUDIES 

S. Venderbosch 1 , T. De Haan 2 , D.A.M. Heideman 3 , T.S. Maughan 4 , C.G. Smith 5 , 

P. Quirke 6 , S.D. Richman 6 , I.D. Nagtegaal 1 , C.J.A. Punt 7 , M. Koopman 8 

1 Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, 

NETHERLANDS, 2 Epidemiology, Biostatistics and Health Technology 

Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, 

NETHERLANDS, 3 Department of Pathology, VU University Medical Centre, 

Amsterdam, NETHERLANDS, 4 Oncology, Gray Institute for Radiation Oncology 

& Biology University of Oxford, Oxford, UNITED KINGDOM, 5 School of Medicine, 

Cardiff University, Cardiff, UNITED KINGDOM, 6 Pathology and Tumour Biology, 

Leeds Institute of Molecular Medicine, Leeds, UNITED KINGDOM, 7 Department 

of Medical Oncology, Academic Medical Center, Amsterdam, NETHERLANDS, 

8 Medical Oncology, University Hospital Utrecht, Utrecht, NETHERLANDS 

Introduction: In stage II-III CRC the overall incidence of BRAF mt and dMMR is 

8% and 10-20%, resp. The incidence of BRAF mt in sporadic dMMR is high (24%, 

Roth et al., JCO 2010), and BRAF mt, in contrast to dMMR, has a negative 

prognostic value. The incidence of dMMR and BRAF mt in mCRC is approx. 4% 

and 8%, resp. No data from large series of mCRC pts are available on the prognostic 

value of BRAF mt in combination with dMMR. 

Methods: We performed a meta-analysis of 4 mCRC trials: CAIRO, CAIRO2, COIN 

and FOCUS. The primary outcome measure was the hazard ratio (HR) for 

progression free survival (PFS) and overall survival (OS) in relation to BRAF and 

MMR status. For the meta-analysis a cox regression analysis was performed on 

individual pt data. 

Results: In total 3064 pts were analysed, of whom 151 (4.9%) exhibited dMMR, and 

263 (8.6%) BRAF mt. A BRAF mt was observed in 211 (7.2%), and 52 (34.4%) of the 

pts with a proficient mismatch repair system (pMMR) and dMMR, resp. PFS was 

significantly worse for dMMR vs. pMMR pts (HR 1.22; 95% CI, 1.03-1.46), but not 

OS (HR 1.13; 95% CI, 0.94-1.36). PFS and OS were significantly worse for BRAF mt 

vs. BRAF wildtype (wt) pts (HR 1.28; 95% CI, 1.12-1.46 and HR 1.81; 95% CI, 

1.57-2.09, resp.). Within the pMMR group, BRAF mt pts had a significantly worse 

PFS and OS compared to BRAF wt pts (HR 1.32; 95% CI 1.09-1.61, and HR 1.88; 

95% CI 1.53-2.30, resp.). Within the dMMR group no significant differences were 

found for PFS and OS in BRAF mt pts vs. BRAF wt pts (HR 1.05; 95% CI 0.65-1.68, 

and HR 1.49; 95% CI 0.91-2.43, resp.). Within the BRAF mt group PFS and OS were 

not significantly different between pMMR and dMMR pts (HR 0.96; 95% CI 

0.63-1.47, and HR 1.03; 95% CI 0.67-1.59, resp.). Within the BRAF wt group, PFS 

and OS were not significantly different for pMMR vs. dMMR pts (HR 1.32; 95% CI 

0.99-1.75, and HR 1.22; 95% CI 0.90-1.65, resp.). 

Conclusion: In this meta-analysis of mCRC pts we observed a higher incidence of 

BRAF mt in dMMR than reported for early-stage CRC pts. In mCRC pts, dMMR is 

associated with a worse PFS compared to pMMR. The prognostic role of BRAF mt 

in mCRC is restricted to pMMR pts. Our data confirm the worse prognostic value of 

BRAF mt vs BRAF wt. 


522PD DEVELOPMENT AND VALIDATION OF A ROBUST 

MOLECULAR DIAGNOSTIC TEST (COLOPRINT) FOR 

PREDICTING OUTCOME IN STAGE II COLON CANCER 

PATIENTS 

T. Bachleitner-Hofmann 1 , I. Simon 2 , R. Salazar 3 , J. Tabernero 4 , R. Rosenberg 5 , 

J. van der Akker 6 ,Y.Li 7 , B. Chan 7 , G. Lanza 8 , A. Glas 6 

1 Department of Surgery, Medical University of Vienna, Vienna, AUSTRIA, 

2 Research and Development, Agendia NV, Amsterdam, NETHERLANDS, 3 G-I 

Unit. Medical Oncology Dpt., Institut Catal, Barcelona, SPAIN, 4 Oncology 

Department, Vall d’Hebron University Hospital, Barcelona, SPAIN, 5 Department 

of Surgery, Klinikum Rechtas der Isar, Munich, GERMANY, 6 Product Support, 

Agendia NV, Amsterdam, NETHERLANDS, 7 Product Support, Agendia Inc, 

Irvine, CA, UNITED STATES OF AMERICA, 8 5istituto di Anatomia E Istologia 

Patologica, University di Ferrara, Ferrara, ITALY 

Background: Only between 25 to 35% of stage II and IIIA colon cancer patients will 

experience a relapse of their disease and may benefit from adjuvant chemotherapy. 

ColoPrint is a gene expression classifier that can predict disease relapse in patients 

with early-stage colorectal cancer and helps to identify patients with higher risk of 

relapse. 

Methods: ColoPrint was developed using whole genome expression data and 

was validated in public datasets and an independent patient cohort of 206 

patients (Salazar et al., JCO 2011). The signature was translated to a 

customized 8-pack microarray. Positive and negative hybridization control genes 

monitor the quality of hybridization and a colon specific normalization gene 

set (n = 461) guarantee reliability of results. Reproducibility and precision 

studies with 20 times 6 samples were performed by multiple operators on 

multiple days. Additional independent patient cohorts were validated on the 

customized arrays. Uni- and multi-variate analyses were performed on the 

pooled stage II patient set (n = 320), the subset of T3/ MSS patients (n = 227) 

and stage IIIA (n = 16). 

Results: The prognostic classifier was evaluated in reproducibility and stability 

assays and stringent quality controls were established following the successful 

lead of the FDA-cleared MammaPrint assay. Results of all tests met the pre-set 

criteria. In the analysis of all stage II and IIIA patients, ColoPrint classified 

two-third of patients as being at low risk. The 3-year Relapse-Free-Survial (RFS) 

RFS was 92% and 77% for low and high risk patients respectively with a HR of 

2.9 (p = 0.001). Clinical and pathological risk parameters from the NCCN 

guidelines can be combined with ColoPrint for even more personalized risk 

assessment. ColoPrint is also able to distinguish risk groups in the subgroup of 

patients with T3 and MSS phenotype (HR= 2.7, p = 0.01) and IIIA (HR= 3.6, 

p=0.08). 

Conclusions: ColoPrint was technically and clinically validated and is now available 

for diagnostic use. ColoPrint significantly improves prognostic accuracy, thereby 

facilitating the identification of patients at higher risk who might be considered for 

additional treatment. 

Disclosure: I. Simon: Employee of Agendia (maker of ColoPrint). J. van der Akker: 

Employee of Agendia (maker of ColoPrint). Y. Li: Employee of Agendia (maker of 

ColoPrint). B. Chan: Employee of Agendia (maker of ColoPrint). A. Glas: Employee 

of Agendia (maker of ColoPrint). All other authors have declared no conflicts of 

interest. 

523PD THE 12-GENE COLON CANCER RECURRENCE SCORE (RS) 

PREDICTS RECURRENCE IN STAGE II AND III COLON 

CANCER PATIENTS TREATED WITH 5FU/LV (FU) AND 5FU/ 

LV + OXALIPLATIN (FU + OX): VALIDATION IN NSABP C07 

M.J. O’Connell 1 , M. Lee 2 , M. Lopatin 3 , G. Yothers 4 , K.M. Clark-Langone 5 , 

C. Millward 6 , S. Paik 1 , S. Sharif 1 , S. Shak 2 , N. Wolmark 1 

1 NSABP, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, 

UNITED STATES OF AMERICA, 2 Oncology Development, Genomic Health, Inc., 

Redwood City, CA, UNITED STATES OF AMERICA, 3 Biostatistics, Genomic 

Health, Inc., Redwood City, CA, UNITED STATES OF AMERICA, 4 Biostatistical 

Center, NSABP, Pittsburgh, PA, UNITED STATES OF AMERICA, 5 Development 

Laboratory, Genomic Health, Inc., Redwood City, CA, UNITED STATES OF 

AMERICA, 6 Pathology, Genomic Health, Inc., Redwood City, CA, UNITED 


Background: Standardized tools which accurately quantify recurrence risk are 

needed for optimal adjuvant treatment of colon cancer. The 12-gene RS has been 

validated in stage II colon cancer pts from QUASAR and CALGB 9581. We 

conducted a large prospectively-designed clinical validation study of RS, w/ 

pre-specified endpoints, methods, and analysis plan, in stage II and III colon cancer 

pts randomized to FU or FU + Ox in C-07. 

Methods: 50% of C-07 pts w/ tissue were randomly selected, stratified on stage and 

recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually 

microdissected fixed tumor tissue. Data were analyzed by Cox regression controlling 

for stage and treatment (TRT). 

Results: RT-PCR was successful in 892/921 pts (97%): 449 FU, 443 FU + Ox; 264 st II, 

409 st IIIA/B, 219 st IIIC. The primary endpoint was met: RS predicted recurrence 

(HR/25 units = 1.96, 95% CI 1.50-2.55 p < .001). RS also predicted DFS (p < .001) and 

OS (p < .001). RS predicted recurrence (p = .001) independent of T and N stage, 

MMR, nodes examined, grade, and TRT. Predefined high RS group (25% of pts) had 

higher recurrence risk than low RS group (39% of pts): HR = 2.11, p < .001. Cox model 

5 yr recurrence risk (95%CI) in FU treated pts by RS group (low, high): st II 9% 

(6-13%), 18% (12-25%); st IIIA/B 21% (16-26%), 38% (30-46%); st IIIC 40% (32-48%), 

64% (55-74%). RS did not have significant interaction w/ stage (p = 0.90) or age (p = 

0.76). Relative Ox benefit was similar across range of RS (interaction p = 0.48); 

accordingly, in Cox model and Kaplan-Meier analyses, absolute Ox benefit increased 

w/ higher RS. In an exploratory analysis of 735 genes, 16 genes were identified as 

associated with relative Ox benefit after controlling false discovery rate at 20%. 

Conclusions: RS predicts recurrence risk in stage II and III colon cancer, capturing 

underlying biology and providing risk information beyond conventional factors. RS is 

not predictive of relative Ox benefit but enables better discrimination of absolute Ox 

benefit as a function of risk. Incorporating RS into the clinical context may better 

inform adjuvant therapy decisions for pts w/ stage III as well as stage II colon 

cancer. 


Disclosure: M. Lee: I am an employee and stockholder of Genomic Health, Inc. M. 

Lopatin: I am an employee and stockholder of Genomic Health, Inc. K.M. 

Clark-Langone: I am an employee and stockholder of Genomic Health, Inc. C. 

Millward: I am an employee and stockholder of Genomic Health, Inc. S. Shak: I am 

Chief Medical Officer and a stockholder of Genomic Health, Inc. All other authors 


524PD ERCC1, DEFECTIVE MISMATCH REPAIR STATUS AS 

PREDICTIVE BIOMARKER OF SURVIVAL FOR STAGE III 

COLON CANCER PATIENTS RECEIVING OXALIPLATIN 

BASED ADJUVANT CHEMOTHERAPY 

P. Li, G. Chen 

Colorectal Surgery, Cancer Center, Sun Yat-Sen Universtiy, Guangzhou, CHINA 

Background: Several trials showed excision repair cross-complementation group 1 

(ERCC1) expression status is a candidate marker for predicting efficacy of 

oxaliplatin (OX) treatment for metastatic colorectal cancer (CRC). Association 

between the expression of mismatch repair genes (MMR) and favorable 

postoperative survival in stage II CRC receiving 5-FU chemotherapy has been 

identified. whether the expression of ERCC1 protein and MMR status are associated 

with survival of stage IIIB colon cancer receiving OX-based chemotherapy is 

unclear. 

Patients and methods: We enrolled 255 patients with stage III colon cancer after 

radical surgery. There were 95 patients receiving full-course Mayo clinic 

chemotherapy and 160 patients received mFOLFOX6 or XELOX chemotherapy. 

Immunohistochemistry analysis of the expression of MMR and ERCC1 was 

performed in tumor tissue. A predictive model for 5-year disease-free survival (DFS) 

and overall survival (OS) was constructed by using Kaplan-Meier analysis, logistic 

and Cox regression. 

Results: The patients with positive ERCC1 tumors had lower 5-year DFS (54%) 

than those with negative ERCC1 tumors (72%) in combined therapy group (HR: 

1.98 95%CI: 1.19-3.31 p = 0.009).The OS was also lower in combined therapy 

group with positive ERCC1 tumors (60%) than those patients with negative 

ERCC1 tumors (78% HR: 2.44 95%CI: 1.37-4.34 p = 0.02). In multivariate analysis, 

ERCC1 expression remained an independent significant predictive factor for DFS 

and OS (DFS HR: 2.33 95%CI: 1.37-3.93 p < 0.001, OS HR: 2.87 95%CI: 1.59-5.16 

p < 0.001). The protein expression of ERCC1 showed no statistical significance of 

DFS or OS in fluorouracil group (DFS HR: 1.16 95%CI: 0.63-2.14 p = 0.62, OS 

HR: 1.16 95%CI: 0.63-2.14 p = 0.63). The MMR status had no statistical 

significance of DFS or OS between combined therapy group and single-drug 

group. 

Conclusion: ERCC1 status was shown to be a highly predictive selection 

criterion in relation to the treatment decision regarding the addition of OX to 

5-FU for stage IIIB colon cancer. MMR status had no predictive value in this 

setting. 


525PD HSA-MIR31-3P EXPRESSION AS A PREDICTOR OF 

ANTI-EGFR RESPONSE IN WILD-TYPE KRAS PATIENTS 

WITH METASTATIC COLORECTAL CANCER 

P. Laurent-Puig 1 , G. Manceau 1 , J. Bachet 2 , B. Chibaudel 3 , F. Liebaert 4 , 

O. Bouché 5 , F. Penault-Llorca 6 , M.D. Diebold 5 , T. André 3 , S. Imbeaud 7 

1 UMR-S775, Université Paris Descartes, Paris, FRANCE, 2 Gastroenterology 

Hepatology, Hôpital Pitié-Salpêtrière, Paris, FRANCE, 3 Department of Medical 

Oncology, Hôpital Saint Antoine, Paris, FRANCE, 4 R&D, Integragen, Evry, 

FRANCE, 5 Hepatology-Gastroenterology, Hopital Robert Debré, Reims, 

FRANCE, 6 Recherche, CJP-ERTICA, Clermont-Ferrand, FRANCE, 7 UMR-S674, 

Inserm, Paris, FRANCE 

In colorectal cancer, KRAS mutations are associated with resistance to anti-EGFR 

antibodies. A major challenge is to identify, in wild-type KRAS patients, markers 

that predict response to this therapy. We focused on miRNAs, which can play 

role in the resistance to anti-EGFR based chemotherapy for metastatic colorectal 

cancer (mCRC). We first analysed 1145 miRNAs in 84 colorectal tumors and 5 

normal colon mucosae. We then conducted a study with 3 subgroups of patients. 

Group 1 is a retrospective series of patients treated by cetuximab and irinotecan, 

group 2 is a prospective collection of patient treated by cetuximab or 

panitumumab based chemotherapy and group 3 is a series of patients 

prospectively treated by panitumumab and irinotecan as third-line. Using a Cox 

proportional hazards model, fitted using principal components analysis of group 

1, we identified a predictive signature of 11 miRNA linked to disease free survival 

(p < 0.01). Validation by RT PCR showed that all the survival information is 

associated with miRNA hsa-mir-31-3p. We tested expression of this miRNA and 


the presence or absence of mutation BRAF on group 1 of 33 patients, in a Cox 

model, and found a hazard ratio (HR) of 1.9 CI95% [1.1-2.9]. In the two 

prospective series (38 patients) the prognostic impact of hsa-mir31-3p the HR is 

estimated to 1.9 CI95% [1.1-3.1]. We applied the multivariate model obtained 

from group 1 to group 2 and 3 in order to predict the disease free survival of the 

patients. The accuracy of the prediction measured by the AUC is 0.77. The 

performance of the test remains stable from 10 weeks to 48 weeks. A Cox 

proportional hazards model based on the hsa-mir31-3p logged expression, fitted 

using principal components from group 1 and BRAF mutation status as a clinical 

covariate allowed us to classify group 2 and 3 according to a free progression 

survival risk score (P = 0.005) with a specificity of 62% [95% CI: 38%-82%] and a 

sensitivity of 82% [95% CI: 56%-96%] for the prediction model. We established a 

nomogram, taking into account mir-31-3p expression level, age, gender and BRAF 

mutation status, which predict the progression risk (P < 0.0001). It is the first tool 

for selecting individual patients with a wild-type KRAS tumor for anti-EGFR 

therapy. 

Disclosure: P. Laurent-Puig: Received clinical research grant from Integragen. 

F. Liebaert: Integragen S.A Employee. All other authors have declared no conflicts of 

interest. 

526PD DEVELOPMENT OF A PREDICTIVE SCORE USING 

AMPHIREGULIN (AREG), EPIREGULIN (EREG) AND 

EGFR-FISH EXPRESSION LEVELS TO DETERMINE 

TREATMENT EFFICACY IN MCRC PATIENTS RECEIVING 

CETUXIMAB-BASED THERAPY. ANALYSIS OF THE GERMAN 

AIO CRC-0104 TRIAL 

V. Heinemann 1 , R. Laubender 2 , D.P. Modest 1 , A. Jung 3 , L. Fischer von 

Weikersthal 4 , U. Vehling-Kaiser 5 , C. Giessen 1 , T. Kirchner 3 , U. Mansmann 2 , 

S. Stintzing 1 

1 Department of Medical Oncology and Comprehensive Cancer Center, University 

of Munich, Munich, GERMANY, 2 University of Munich, Institute of Medical 

Informatics, Biostatistics, and Epidemiology, München, GERMANY, 3 Institute of 

Pathology, Univsersity of Munich, Munich, GERMANY, 4 Oncological Practice, 

Gesundheitszentrum St. Marien, Amberg, GERMANY, 5 Onkologische 

Schwerpunktpraxis, Onkologisches und Palliativmedizinisches Netzwerk 

Landshut, Landshut, GERMANY 

Background: We investigated the expression of the EGFR ligands amphiregulin 

(AREG) and epiregulin (EREG) as well as the amplification of the EGFR-gene in 

tumor specimens of mCRC patients (pts) treated first-line with anti-EGFR targeted 

cetuximab together with CAPOX or CAPIRI. All three factors have shown the 

capability to separate patient groups of different prognosis. Here we used a composite 

score to calculate response probability. 

Methods: A total of 185 mCRC pts were randomized to cetuximab plus CAPIRI or 

plus CAPOX. The primary study endpoint was ORR. Age, gender, study arm, KRAS 

mutational status, BRAF mutational status, AREG, EREG and EGFR-FISH expression 

levels were used for multivariate logistic regression analysis. 

Results: AREG and EGFR-FISH significantly correlated with ORR. These factors 

were used to create a prediction model for ORR by using logistic regression 

model. The linear predictor of this model is given by LP = -7.63 + (0.35*log 

[AREG]) + (6.58*[EGFR-FISH]) which can be used to calculate the probability of 

ORR by exp(LP) / [1 + exp(LP)]. The discriminatory ability of this model was 

assessed by ROC analyses were the optimal cut-off of the linear predictor 

discriminating best between responders and non-responders with respect to ORR 

was identified by using the Youden index and is given by -0.095. The area under 

the ROC curve (AUC) is 0.79 (95% confidence interval: 0.63, 0.90). Using this 

formula, response and survival times with a cut-off of 50% of ORR probability 

were calculated. ORR was significantly higher in the positive cohort and reached 

81% vs. 42% in the negative cohort (p= 0.009). This led to significantly longer 

survival times in the positive cohort, with regard to PFS (8.6 mo vs 4.6 mo; HR 

0.44; p = 0.003) and OS (38.4 mo vs 17.2 mo; HR 0.37; p= 0.001). 

Conclusion: In this retrospective and exploratory analysis it was possible to predict 

ORR probability with the help of molecular markers. There is an acceptable 

discriminatory performance as measured by the AUC for predicting ORR by 

AREG and EGFR-FISH Hence, both molecular markers might be promising 

candidates for predicting ORR under cetuximab-based treatment regimens and 

prospective evaluation of these markers is needed for replicating and validating our 

findings. 

Disclosure: V. Heinemann: Honoraria and travel support: Merck, Roche, Amgen. R. 

Laubender: Travel support: Merck. D.P. Modest: Honoraria and Travel Support: 

Amgen, Roche. A. Jung: Honoraria and travel Support: Amgen, Roche. C. Giessen: 

travel Support: Merck, Roche. T. Kirchner: Research Grant, Honoraria and Travel 

Support: Merck, Amgen, Roche. U. Mansmann: Honoraia and Travel support: 

Merck, Amgen. S. Stintzing: Honoraria and travel support: Merck, Amgen, Roche. 




527PD PHARMACOGENETIC PREDICTORS OF SEVERE CHRONIC 

PERIPHERAL NEUROPATHY IN STAGE II-III COLON CANCER 

(CC) PATIENTS TREATED WITH OXALIPLATIN-BASED 

ADJUVANT CHEMOTHERAPY (CT). A GEMCAD STUDY 

A. Custodio 1 , J. Moreno 1 , J. Aparicio 2 , J. Gallego Plazas 3 ,C. 

Fernández Martos 4 , J. Maurel 5 , D. Ramos 6 , P. Cejas 1 , R. Madero 7 , J. Feliu 1 

1 Medical Oncology, La Paz University Hospital, Madrid, SPAIN, 2 Medical 

Oncology Department, La Fe University Hospital, Valencia, SPAIN, 3 Medical 

Oncology Department, Elche University Hospital, Elche, SPAIN, 4 Medical 

Oncology Department, Fundación Instituto Valenciano de Oncología, Valencia, 

SPAIN, 5 Medical Oncology, Hospital Clinic i Provincial, Barcelona, SPAIN, 

6 Pathology Department, La Fe University Hospital, Valencia, SPAIN, 7 Biostatistics 

Unit, La Paz University Hospital, Madrid, SPAIN 

Background: Oxaliplatin-based CT is now the standard adjuvant therapy after 

resection of stage III and selected high-risk stage II CC. However, this treatment is 

often associated with cumulative peripheral neuropathy. Predicting individual patient 

risk for developing severe neuropathy could improve the quality of care by allowing 

the individualization of treatment. Our aim is to identify single nucleotide 

polymorphisms (SNPs) in genes involved in oxaliplatin sensitivity to predict severe 

(grade 2-3) oxaliplatin-induced chronic peripheral neuropathy (OXCPN) among 

stage II-III CC patients who received adjuvant CT. 

Methods: DNA was extracted from formalin-fixed-paraffin-embedded samples from 

202 surgically treated high-risk stage II (29.7%) and stage III (70.3%) CC patients 

receiving adjuvant oxaliplatin and fluoropyrimidines CT (25.24% FOLFOX, 74.75% 

CAPOX) from January 2004 to December 2008. Median follow-up was 51.4 months 

(7-96). Genotyping was performed for 35 SNPs in 18 genes involved in oxaliplatin 

metabolism (ERCC and XRCC groups), cell cycle and drug transport using 

MassARRAY (SEQUENOM) technology. A total of 177 stage II-III CC patients also 

treated with oxaliplatin-based CT were enrolled as a validation set. 

Results: Forty-eight (23.8%) patients experienced grade 2-3 OXCPN. The cyclin H 

(CCNH) (rs2230641) C/C genotype was associated with a higher risk of severe 

OXCPN (57.1% C/C, 24.2% C/T, 21.3% T/T; RR: 5.197, p = 0.041). In addition, 

patients harboring the CCNH (rs2230641) C/C and/or ATP-binding cassette 

subfamily G member (ABCG2) (rs3114018) A/A haplotype had a higher risk of 

grade 2-3 OXCPN compared to the CCNH (rs2230641) any T and ABCG2 

(rs3114018) any C haplotype (36.5% vs. 19.6%, respectively; RR:2.36; 95% CI, 

1.17-4.78; p = 0.022). The ability to predict severe OXCPN of this combined analysis 

was then independently validated in the second cohort (RR: 2.82; 95% CI, 1.41-5.63; 

p = 0.003). 

Conclusions: Our data suggest that SNPs in CCNH and ABCG2 can predict the 

development of severe OXCPN in stage II-III CC patients. The analysis of these 

SNPs may be useful in personalized adjuvant CT. 


528PD THE EFFECT OF CHEMOTHERAPY HOLIDAY ON THE 

OVERALL SURVIVAL OF PATIENTS WITH ADVANCED 

COLORECTAL CANCER: A META-ANALYSIS OF 

RANDOMIZED TRIALS 

A.A.L. Pereira 1 , J.F.M. Rego 2 , P.M. Hoff 1 , A. Sasse 3 , R.P. Riechelmann 2 

1 Centro De Oncologia - 2° Andar, Sirio Libanes Hospital, Sao Paulo, BRAZIL, 

2 Clinical Oncology, Instituto do Cancer do estado de Sao Paulo, Sao Paulo, 

BRAZIL, 3 Cevon Centre for Evidences In Oncology, UNICAMP - Universidade 

Estadual de Campinas, Campinas, BRAZIL 

Background: The impact of the duration of chemotherapy on the outcomes of 

patients with advanced colorectal cancer is controversial. Our objective was to 

perform a systematic review and meta-analysis of randomized controlled trials (RCT) 

that compared chemotherapy continuously administered until disease progression 

versus chemotherapy interruption in patients with metastatic colorectal cancer. 

Methods: We systematically searched for all RCT in which metastatic colorectal cancer 

patients were randomized to continuous therapy until progression or chemotherapy 

discontinuation after maximal response or fixed number of cycles. Trials were located 

through searches of PubMed, Cochrane Library and of ASCO/ESMO abstracts up to 

February 2012. Two authors independently extracted the data, and consensus was 

achieved when there was disagreement. Meta-analyses were performed using 

random-effects model. Hazard ratios (HR) were used for the meta-analysis and were 

expressed with 95% confidence intervals (CI). Statistical heterogeneity of data was 

evaluated with the chi-square test, and expressed using the I2 index. 

Results: Our search retrieved 42 RCT, of which five were eligible, with 1815 patients 

included. The analysis of progression-free survival (PFS) was not possible due to the 

different definitions of PFS across trials. The median chemotherapy free interval in 

the discontinuation group was 3.9 months. The pooled analysis of overall survival 

included 1776 patients (one trial was not included because it did not present 

extractable data). The metanalysis showed a statistically significant survival benefit 

with continuously given chemotherapy (HR = 0.90, 95% CI = 0.82 to 0.99; p = 0.03; I2 

0%) in comparison to chemotherapy holiday strategy. Quality of life was reported in 

one trial and no difference was found in it. 

Conclusions: Chemotherapy delivered continuously until tumor progression appears 

to be associated with a modest but significantly better survival in patients with 

advanced colorectal cancer over chemotherapy interruption. Continued therapy may 

be available for selected patients with more aggressive disease. 


529PD RANDOMIZED PHASE III IN ELDERLY PATIENTS 

COMPARING LV5FU2 WITH OR WITHOUT IRINOTECAN FOR 

1ST-LINE TREATMENT OF METASTATIC COLORECTAL 

CANCER (FFCD 2001-02) 

E. Mitry 1 , L. Venat-Bouvet 2 , J. Phelip 3 , E. Maillard 4 , J. Jouve 5 , X. Adhoute 6 , 

D. Gargot 7 , M. Gasmi 8 , L. Bedenne 9 , T. Aparicio 10 

1 Oncologie Médicale, Institut Curie, Paris, FRANCE, 2 Oncology, CHU de 

Limoges, Limoges, FRANCE, 3 Gastroenterology, CHU, St-Etienne, FRANCE, 

4 Biostatistiques, FFCD, Dijon, FRANCE, 5 Hepatogastrolentorology Department, 

CHU Le Bocage, Dijon, FRANCE, 6 Gastroenterology, Hôpital Haut-Leveque, 

Pessac, FRANCE, 7 Gastroenterology, Centre hospitalier, Blois, FRANCE, 

8 Hepatogastroenterology Department, Hôpital Nord, Marseille, FRANCE, 9 FFCD, 

Dijon, FRANCE, 10 Gastroenterology, CHU, Avicenne, FRANCE 

Background: Metastatic colorectal cancer (mCRC) most frequently occurs in elderly 

patients (pts), but these are less frequently treated with chemotherapy (CT) than 

younger ones. We report the final results of the first phase III study in elderly pts 

with mCRC receiving a 5FU-based CT with or without irinotecan. 

Methods: Elderly pts (75+) with previously untreated mCRC were randomly 

assigned to receive a 5FU-based CT, either alone or in combination with 

irinotecan (FU arms: LV5FU2 or simplified LV5FU2, IRI arms: LV5FU2-CPT11 

or FOLFIRI, reduced dosage for cycles 1 and 2). Stratification criteria were: center, 

Charlson index, Karnofsky index, previous adjuvant CT, sex, age, alkaline 

phosphatases. Primary endpoint was progression free survival (PFS). 240 events 

(282 pts) were required to demonstrate an improvement of median PFS from 5.5 

to 7.9 months (m) in the IRI arm (bilateral α = 5%, β = 80%). Secondary 

endpoints were overall survival (OS), safety, objective response rate (ORR), QOL 

and geriatric evaluation. Kaplan-Meier estimation, log-rank tests and Cox model 

(HR with 95%CI) were used. 

Results: Between 06/2003-05/2010, 142 pts were randomly assigned to FU and 140 

to IRI. Median age was similar in both arms 80 years (range 74-92). Main 

characteristics were well-balanced. Median duration of treatment was 3.5 m in FU 

and 4.5 m in IRI. At least one CT dose reduction was observed for 30.9% pts in FU 

and 52.6% pts in IRI. No significant difference was observed for the median PFS: FU 

5.2 m vs IRI 7.3 m, HR = 0.84 (0.66-1.07), p = 0.15. ORR was superior in IRI arm (p 

= 0.002): FU 27.4% (95% CI: 20.1-35.8) vs IRI 46.3% (95% CI: 37.6-55.1). Median 

OS was 14.2 m in FU vs 13.3 m in IRI, HR = 0.96 (0.75-1.24). More patients 

presented grade 3-4 toxicities in IRI arm (76.3% vs 52.2%), mainly neutropenia 

(38.5% vs 5.2% of pts), diarrhea (22.2% vs 5.2% of pts) and febrile neutropenia (6.7% 

vs 0.7% of pts). Toxic deaths occurred in 2 pts in each arm. 

Conclusion: In this elderly population, adding irinotecan to an infusional 5FU-based 

CT seems to increase PFS but does not improve survival and was associated with an 

increased toxicity. 

Disclosure: E. Mitry: Aventis, Pfizer: sponsor of the trial. All other authors have 


530PD CAPECITABINE (CAPE) +/- BEVACIZUMAB (BEV) IN THE 

ADJUVANT TREATMENT OF COLORECTAL CANCER (CRC) - 

FIRST AND FINAL TOXICITY RESULTS FROM THE 

INTERNATIONAL PHASE III QUASAR2 TRIAL 

R.S. Midgley 1 ,S.Love 1 , V. Potter 2 , E. Segelov 3 , D.R. Ferry 4 , A. Weaver 5 , 

C. Scudder 1 , P. Julier 1 , S. Grumett 6 , D.J. Kerr 7 

1 Department of Oncology, University of Oxford, Oxford, UNITED KINGDOM, 

2 Department of Oncology, Nottingham University Hospitals NHS Trust, 

Nottingham, UNITED KINGDOM, 3 St Vincents Clinical School, University of New 

South Wales, Sydney, NSW, AUSTRALIA, 4 Medical Oncology, Russells Hall 

Hospital, Dudley, UNITED KINGDOM, 5 Department of Oncology, Oxford 

University Hospitals Trust, Oxford, UNITED KINGDOM, 6 Department of 

Oncology, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UNITED 

KINGDOM, 7 Nuffield Department of Clinical Laboratory Sciences, University of 

Oxford, Oxford, UNITED KINGDOM 

Background: Bevacizumab is an anti-VEGF antibody approved for use in metastatic 

colorectal cancer (CRC). However 2 trials have suggested lack of efficacy in 

combination with dual agent chemotherapy in the adjuvant setting and there has 

been some indication that the spectrum of toxicity may be different compared to that 

observed in patients with advanced disease. 

Methods: The international phase III trial, QUASAR2, randomised stage III and 

high risk stage II CRC patients who had undergone potentially curative resection to 

receive oral Cape (1250mg/m 2 bd, days 1-14 q 21d) alone for 6/12 or Cape (6/12) 


plus intravenous Bev(7.5mg/kg q 21d) for 12/12. This abstract overviews the final 

toxicity data (15/12 minimum follow up per patient) from the Q2 trial. 

Results: 1952 patients were consented and randomised and, after excluding patients 

who did not receive at least one cycle of treatment, 963 patients receiving Cape alone 

and 959 patients receiving Cape plus Bev were analysed. Baseline characteristics 

(gender / age / stage of disease) were balanced across the 2 arms. See frequency of 

selected toxicities, as % patients, in table below. 

Discussion: As expected, the rates of hypertension (all grade or high grade) and 

proteinuria and wound healing (all grade) were significantly higher among patients 

receiving Bev. Although the addition of Bev did not increase diarrhoea rates, the 

frequency and severity of HFS was increased. This is not well recognised. Although 

cardiac chest pain was not increased by the addition of Bev, both arterial and venous 

thrombo-embolism (ATE/VTE) rates were increased although the difference only 

reached significance for VTE in this study. This is in contrast to most results in the 

advanced disease setting and may be a result of an interaction between post-operative 

risk of VTE and pro-thrombotic potential of Bev. Of note, an excess of ‘possibly 

treatment-related’ deaths was found in patients receiving Bev (1.9% vs 0.8%:RR2.3:CI 

1.0-5.2) and this just reached significance (p = 0.05). All results will be expanded in 

detail in the presentation / poster. 

Cape/ Bev Cape RR/CI/p 

Hypertension (all grades) 33.4 7.8 4.3/3.4-5.4/p < 0.001 

Hypertension (g3/4) 3.8 0.6 6.0/2.6-14.2/p < 0.001 

Proteinuria (all grades) 20.5 5.1 4.0/3.0-5.4/p < 0.001 

Poor wound healing (all grades) 3.1 1.8 1.8/1.0-3.2/p = 0.05 

Diarrhoea (g3/4) 10.8 10.6 1.0/0.8-1.3/p = 0.9 

Hand-foot syndrome (g3/4) 26.8 20.9 1.3/1.1-1.5/p = 0.002 

Cardiac chest pain SAE 2.7 2.6 1.0/0.6-1.8/p = 0.9 

Arterial Thromboembolism SAE 1.1 0.6 1.8/0.7-5.0/p = 0.2 

Venous Thromboembolism SAE 4.3 2.3 1.9/1.1-3.1/p = 0.01 

Disclosure: R.S. Midgley: Auther has received no strings attached educational 

unrestricted grant for clinical research and has sat on advisory boards for Roche. 

V. Potter: Auther has received a travel grant and has sat on an advisory board for 

ROche. E. Segelov: Author has sat on an advisory board for Roche Autralia. 

D.R. Ferry: Auther has received travel grants, research grants and has sat on advisory 

boards for Roche. S. Grumett: Auther has received traval grants and has sat on 

advisory boards for Roche. D.J. Kerr: Auther has received no strings attached 

educational unrestricted grant for clinical research and has sat on Advisory Boards 

for ROche. All other authors have declared no conflicts of interest. 

531P SHOULD PALLIATIVE RESECTION OF PRIMARY TUMOR BE 

PERFORMED IN PATIENTS WITH ADVANCED COLORECTAL 

CANCER? A SYSTEMATIC REVIEW & META-ANALYSIS 

S. Ahmed 1 , R.K. Shahid 2 , A. Leis 3 , K. Haider 1 , P. Pahwa 3 

1 Medical Oncology, Saskatoon Cancer Centre University of Saskatchewan, 

Saskatoon, SK, CANADA, 2 Medicine, University of Saskatchewan, Saskatoon, 

SK, CANADA, 3 Community Health & Epidemiology, University of Saskatchewan, 

Saskatoon, SK, CANADA 

Background: Colorectal cancer (CRC) is a leading cause of cancer death. Surgical 

resection of the primary tumor in patients with advanced CRC remains controversial. 

Limited data is available regarding potential benefits and risk of primary tumor 

resection in such patients. 

Objectives: To compare survival of patients with advanced CRC who underwent 

surgical resection of primary tumor with patients without resection. The review also 

aims to determine post-operative mortality & non-fatal complications rates, primary 

tumor complications rate (PTCR), non-resection surgical procedures rate (NSPR) 

and quality of life (QOL). 

Methods: A literature search was conducted by using CENTRAL (2012), Medline 

(1946-2012), and EMBASE (1947-2012). Selection Criteria: Studies involving patients 

with advanced colorectal adenocarcinoma who underwent primary tumor resection 

were selected using pre-specified eligibility criteria with restriction to publication 

dates from 1980, English language and human studies. Data Collection and analysis: 

Screening, evaluation of relevant articles and data abstraction was done in 

duplication and agreement was assessed. Articles that met the inclusion criteria were 

assessed for quality by using Ottawa-Newcastle score. Data was collected and 

synthesized as per protocol. 

Results: Of total of 3379 reports, 15 retrospective observational studies were selected 

with patients population of 12456. Among 12456 patients, 8620 (69%) underwent 

surgery with a median overall survival of the 15.2 months (range: 10-30.7) compared 

with 11.4 months (range: 3-22) of the non-resection group. Hazard ratio (HR) for 

survival was 1.44 (95% CI: 1.26-1.64) favoring surgical intervention. Mean 30 days 

post-operative mortality and non-fatal complications rates were 4.9% (95% CI: 0-9.7) 

& 25.9% (95%CI: 20.1-31.6) respectively. Mean PTCR & NSPR in the control group 

were 29.7% (95%CI: 18.5-41.0) and 27.6% (95 CI: 15.4-39.9) respectively. No study 

provided QOL data. Sub-group analysis that were defined a priori revealed HR of 

1.46 (95% CI: 1.20-1.78) favoring surgical intervention in patients treated with 

modern chemotherapy. 

Conclusions: The retrospective data favors primary tumors resection in advanced 

CRC. Future prospective randomized trials are warranted to confirm the findings. 


532P PTEN AND ADVANCED COLORECTAL CANCER (CRC): 

ANALYSIS FROM THE PHASE III AGITG MAX TRIAL OF 

CAPECITABINE ALONE OR IN COMBINATION WITH 

BEVACIZUMAB +/- MITOMYCIN C 

T. Price 1 , J. Hardingham 1 , C. Lee 2 , A. Townsend 1 , J. Wrin 1 , K. Wilson 2 , 

A. Weickhardt 3 , R.J. Simes 2 , C. Munroe 3 , N. Tebbutt 4 

1 Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville 

South, SA, AUSTRALIA, 2 CTC, University of Sydney, Sydney, NSW, 

AUSTRALIA, 3 Oncology, Ludwig Institute, Melbourne, VIC, AUSTRALIA, 

4 Medical Oncology, Austin Hospital, Heidelberg, VIC, AUSTRALIA 

Background: The tumour suppressor gene PTEN may have a role as a biomarker for 

anti-EGFR therapy in CRC. As PTEN expression also has a relationship with VEGF 

expression via HIF-1 alpha, and the PI3K/mTOR pathways, we have explored the 

potential that PTEN loss may be predictive of outcome with an anti-VEGF agent. We 

also assess the prognostic value of PTEN as this remains controversial. 

Methods: Patients enrolled in the Phase III MAX trial of capecitabine (C) +/bevacizumab 

(B) (+/- mitomycin C (M)) with available tissues were analysed for 

PTEN expression (loss v no loss) as assessed using a Taqman® copy number assay to 

measure copy number variation at the PTEN locus. The predictive value of PTEN 

status for bevacizumab efficacy was examined. PTEN status was also correlated with 

progression-free survival (PFS) and overall survival (OS) outcomes, and a second sub 

analysis grouping PTEN by KRAS/BRAF status was also performed. 

Results: Of the original 471 patients enrolled in the trial, tissues from 302 (64.1%) 

patients were analysed. Baseline characteristics of those with and without tissues were 

comparable. PTEN loss was observed in 38.7% of patients. There was no relationship 

between PTEN loss and KRAS or BRAF mutation (KRAS/BRAF MT v WT with 

PTEN loss; 34%/37% v 41%/39% respectively). PTEN loss was associated with rectal 

primary (p = 0.01) and lower rates of lung metastasis (p = 0.03). By using the 

comparison of C v CB + CBM, PTEN status was not significantly predictive of the 

effectiveness of B for PFS or OS (Table). PTEN status is also not prognostic for PFS 

or OS in multivariate analyses adjusting for other baseline factors (Loss v No Loss 

PFS HR 0.9 (0.7-1.16), OS HR 1.04 (0.79-1.38)). PTEN was also not prognostic when 

assessed by KRAS and BRAF status. 

Conclusions: PTEN status did not significantly predict different benefit with 

anti-VEGF therapy. PTEN status was not prognostic for survival in advanced 

colorectal cancer. 

C vs CB + CBM Loss No loss P value (for interaction) 

PFS HR 0.51 0.33 - 0.79 HR 0.72 0.52-0.98 P = .26 

OS HR 0.75 0.47-1.19 HR 1.00 0.70-1.43 P = .35 

Disclosure: T. Price: Uncompensated Advisory board Merck, AMGEN and Roche. 

Travel grants Merck and AMGEN. N. Tebbutt: Uncompensated Ad board Roche. All 


533P SOMATIC K-RAS MUTATION IS PREDICTIVE IN COLORECTAL 

CANCER, BUT IS IT PROGNOSTIC? A SYSTEMATIC REVIEW 

AND META-ANALYSIS 

I.B. Tan, T. Seah, S.L. Koo, S. Choo, C.K. Tham, D. Chong 

Medical Oncology, National Cancer Centre, Singapore, SINGAPORE 


Background: Consistent data from retrospective molecular analysis performed in 

multiple phase 3 Randomized controlled trials (RCTs) have established that somatic 

KRAS mutation (K-RAS-mt) is a strong predictor of non-response to anti-epidermal 

growth factor receptor antibody (anti-EGFR) therapy in colorectal cancer. However, 

K-RAS’s role as a prognostic marker remains undefined. We performed a systematic 

review and meta-analysis to determine the prognostic significance of somatic K-RAS 

mutation. 

Methods: We searched MEDLINE, EMBASE, and CENTRAL databases, ESMO and 

ASCO meeting proceedings for Phase 3 RCTs in colorectal cancer for which 

retrospective molecular analysis of K-RAS mutation was performed on archival 

patient samples. Studies were pooled according to setting of treatment (adjuvant, 1 st 

line metastatic, refractory). Meta-analysis was performed using random-effects model. 

The outcomes of interest were disease-free survival in the adjuvant setting and 

overall survival (OS) for advanced disease. 

Results: 14 Phase 3 trials which enrolled 18,991 patients were identified, of whom 

13,143 had K-RAS status ascertained (69.2% range: 48%-100%) In pooled data of 



patients who did not receive anti-EGFR therapy and had K-RAS status ascertained, 

patients with K-RAS-wt patients had better survival outcomes compared to 

K-RAS-mt patients. In the adjuvant setting (Disease Free Survival HR 0.75 95% CI: 

0.66-0.87, p < 0.001), 1 st line metastatic (Overall Survival: HR 0.85 (95% CI: 

0.76-0.96), p < 0.01) and refractory disease (Overall Survival: HR 0.75 95% CI: 

0.64-0.89, p < 0.01). 

Conclusion: Beyond being a predictive marker of non-response to EGFR antibodies, 

among patients with early stage, 1 st line metastatic and refractory colorectal cancer 

who do not receive anti-EGFR therapy, K-RAS is a negative prognostic marker. 


534P PROGNOSTIC IMPACT OF PHOSPHO-ER-ALPHA (PER-α) IN 

SURGICALLY RESECTED COLON CANCER 

I. López Calderero 1 , A.C. Moya 2 , A.A. Gonzalez 3 , A.C. Carranza 4 , M.C. Conde 1 , 

S. Molina-Pinelo 2 , M.D.P. Herrera 2 , M.L.L. Miron 1 , P.E. Garcia 1 , 

R. Garcia-Carbonero 1 

1 Oncology Service, Hospital Virgen del Rocio, Seville, SPAIN, 2 Laboratorio de 

Biologia Molecular del Cancer, Instituto de Biomedicina de Sevilla, Seville, 

SPAIN, 3 Departamento de Anatomía Patológica, Hospital central de Asturias, 

Oviedo, SPAIN, 4 Pathology Department, Hospitales Universitarios Virgen del 

Rocio, Seville, SPAIN 

Background: Preclinical models and randomized clinical trials suggest a protective 

role for estrogens against colorectal cancer (CRC). ER-β is the prevalent estrogen 

receptor in normal colonic mucosa, while its expression is significantly reduced in 

CRC. An increased ER-α/β ratio has been documented in colon carcinomas and this 

is associated with increased proliferation and decreased apoptosis. The aim of our 

study was to evaluate the expression of activated ER-α and its prognostic 

implications in a series of patients with surgically resected stage II-III CRC. 

Methods: Phosphorylated ER-α [Ser167] expression was evaluated by 

immunohistochemistry (IHC) in tissue microarrays (TMA) of 218 CRC 

paraffin-embedded tumor samples. A pER-α score was calculated for each sample 

according to staining intensity and proportion of stained cells assessed by two 

pathologists blinded to the clinical data. Univariate and multivariate analyses were 

performed to assess the correlation of pER-α score with clinicopathological features 

and survival. 

Results: pER-α staining was negative in 39 tumors (18%), 1+ in 164(75%), 2+ in 

11(5%), and unavailable in 4(2%). Half of the samples had positive staining in 

>10% of tumor cells. A high pER-α score was more common in women 

(female:56% vs male:45%; p = 0.07), older patients (>65years:56% vs 120mg/dl:66% vs 

A, overall response rate (partial reponse and stable disease) was 25% 

for the patients with the A/A genotype, 73% for the C/A genotype and 85% for C/C 

(p = 0.032). Progression free survival (PFS) was 2.5 months for patients harbouring 

the A/A genotype compare to 8 months for the patients with A/C and C/C 

genotypes (p = 0.0001); overall survival was also superior for patients containing the 

allele C genotypes (5 months for AA and 18 months for C/A and C/C); p = 0.001. 

For the polymorphism g.75395312G > A, the G/G genotype overall response rate was 

100% compare to 69% for the A/G and A/A genotypes (p = 0.048). PFS did not 

reach statistical significance for this polymorphism. None of the two Tag SNPs for 

the EREG ligand were found to correlate with response. 

Conclusions: AREG polimorphisms may help to identify refractory mCRC patients 

who will benefit from irinotecan plus anti-EGFR treatment. 


537P DIFFERENCES IN KRAS AND BRAF MUTATION PREVALENCE 

IN METASTATIC COLORECTAL CARCINOMA USING 

HIGH-SENSITIVITY TAQMELT VS ARMS-SCORPION PCR 

ASSAYS 

S. Zazo 1 , T. Caldes 2 , N. Pérez González 1 , J. Madoz 1 ,J.Satre 2 , R. Manso 1 , 

D. Ferrandez 3 , T. Ramos 4 , J. Garcia-Foncillas 5 , E. Diaz-Rubio 2 

1 Pathology Department, Fundacion Jimenez Diaz, Madrid, SPAIN, 2 Medical 

Oncology, Hospital Clinico San Carlos, Madrid, SPAIN, 3 Roche Farma, Roche 

Farma Spain, Madrid, SPAIN, 4 Roche Diagnostics, Roche Diagnostics, 

Barcelona, SPAIN, 5 Oncology, Fundación Jiménez Díaz, Madrid, SPAIN 

Background: Activating KRAS mutations are present in approximately 35-40% of 

patients with metastatic colorectal cancer (mCRC) and have been significantly 

associated with lack of response to anti-EGFR antibody therapies. Although current 

guidelines recommend testing for frequent KRAS codons 12/13 mutations (G12D, 

G12A, G12V, G12S, G12R, G12C and G13D), emerging data indicate that additional 

KRAS and BRAF mutations might be also predictive of non-responsiveness to 


anti-EGFR treatment. The present study is aimed to analyze the prevalence of 

Iow-frequent KRAS and BRAF V600 mutations in caucasian mCRC population. 

Methods: A two institution retrospective cohort of 1238 consecutive KRAS wild 

type mCRC patients previously studied for frequent 7 mutations in codons 12/13 

by the CE-IVD marked ARMS-scorpion real-time polymerase chain reaction PCR 

(Therascreen, Qiagen) was assayed by the diagnostic TaqMelt PCR assay cobas 

KRAS Mutation and cobas BRAF V600 Mutation Tests (Roche), which are 

designed to detect 19 mutations in KRAS codons 12, 13 and 61 (including G12F, 

G13C, G13R, G13S, G13A, G13V, G131, Q61H, Q61K, Q61R, Q61L, Q61E and 

Q61P) and BRAF V600 (V600E, V600K and V600D) mutations. DNA was 

obtained by cobas DNA preparation kit from one single 5um formalin-fixed 

paraffin-embedded tissue section. Discrepances in data are planned to confirm by 

next-generation sequencing. 

Results: In all samples, sufficient DNA was obtained for KRAS and BRAF mutational 

studies. Among 1238 KRAS codons 12/13 wild-type patients by ARMS-scorpion 

PCR, 166 (13.4%) showed KRAS mutations, 117 (9.5%) in codons 12/13, and 49 

(4%) in codon 61. BRAF V600 mutations were detected in 9% cases. In 

ARMS-scorpion PCR KRAS mutated patients, mutations were confirmed by cobas in 

all cases. 

Conclusions: The cobas Mutation Tests are robust and reproducible assays that, 1) 

requires a very small amount of tissue; 2) detects up to 13.4% mutations in codons 

12, 13 and 61 of the KRAS gene in wild-type mCRC population; and, 3) 9% of 

patients showed BRAF mutations in same population. 


538P THE ROLE OF COX-2 AND KI-67 OVEREXPRESSION IN THE 

PREDICTION OF PATHOLOGIC RESPONSE OF RECTAL 

CANCER TO NEOADJUVANT CHEMORADIATION THERAPY 

A. Taghizadeh Kermani 1 , A. Jafarian 2 , J. Esmaeili 2 , N. Mohammadian Roshan 2 , 

M. Seilanian Toosi 1 , A. Omidi Ashrafi 2 , M. Karimi Shahri 2 

1 Oncology, MUMS, Mashhad, IRAN, 2 Pathology, MUMS, Mashhad, IRAN 

Background: The response to neoadjuvant chemoradiotherapy (CRT) is not the 

same among all cases with advanced rectal cancer. Aims: In this study, we 

investigated the association between overexpression of two molecular markers 

(COX-2 and Ki-67) and tumor response to neoadjuvant therapy. Design: A 

retrospective cohort study. 

Materials and methods: Forty five patients with stage II-III rectal carcinoma were 

enrolled. All patients were treated with neoadjuvant therapy (45-50.4 Gy plus 

Capecitabin) between 2002 and 2009 in our institute. The pretreatment specimens 

were IHC stained for COX-2 and Ki-67 markers. The tumor response to neoadjuvant 

treatment was evaluated using a 5 point tumor regression grade (TRG) system. The 

induced inflammation and necrosis after chemoradiotherapy were also investigated. 

Statistical analysis: Statistical analysis was performed using SPSS version 11.5 and 

statistical significance was determined at P < 0.05. 

Results: The pathologic response to neoadjuvant treatment from complete response 

as (TRG = 1) through no response as (TRG = 5) was found in 10 (22.2%), 8 (17%), 6 

(13.3%), 16 (35.6%), and 5 (11.1%) cases. In comparison with poor responders 

(TRG: 4,5), patients with good response to neoadjuvant treatment (TRG: 1,2) were 

associated with lower pretreatment mean COX-2 staining extent (72.9% vs. 22.8%, 

P < 0.001) as well as lower mean Ki-67 staining extent ( 70.7% vs. 28.5%, p < 0.001). 

High COX-2 staining and high Ki-67 index were significantly associated with more 

inflammation. Patients with high COX-2 expression showed also significantly more 

necrosis in their postsurgical specimens. 

Conclusions: Overexpression of COX-2 and high Ki-67 index were associated with a 

poorer response to neoadjuvant chemoradiotherapy. These markers might be helpful 

to define those patients with rectal carcinoma who benefit more from neoadjuvant 

treatments. 


539P PTK7 OVEREXPRESSION IS ASSOCIATED WITH REDUCED 

METASTASIS-FREE SURVIVAL (MFS) IN COLORECTAL 

CANCER 

A. Gonçalves 1 , A. Lhoumeau 2 , G. Monges 3 , J. Delpero 4 , J.L. Raoul 2 , J. Borg 2 

1 Medical Oncology, Institut Paoli-Calmettes, Marseille, FRANCE, 2 Molecular 

Pharmacology, Institut Paoli-Calmettes, Marseille, FRANCE, 3 Biopathology, 

Institut Paoli-Calmettes, Marseille, FRANCE, 4 Surgical Oncology, Institut 

Paoli-Calmettes, Marseille, FRANCE 

Background: Protein tyrosine kinase-7 (PTK7) is a receptor tyrosine kinase (TK), 

with no identified natural ligand and a catalytically inactive intracellular TK domain. 

PTK7 expression is up-regulated in many human cancers, including colorectal cancer 

(CRC), but little is known about its role in cancer biology. Here, we have examined 

PTK7 protein expression in tumor and matched normal tissues from CRC patients 

by immunohistochemistry (IHC) and addressed the phenotypic impact of PTK7 

down-regulation in CRC cell lines. 


Methods: A TMA containing both tumor and matched normal tissues was built 

from a cohort of 192 patients with CRC collected between 1990 and 1998 at the 

Institut Paoli-Calmettes, Marseille, France. PTK7 expression was analyzed by IHC 

using polyclonal goat antibody anti-CC4 (R&D systems, USA). Percentage of stained 

cells was measured and staining intensity was scored as 0 (absent), 1 (weak), 2 

(moderate) and 3 (strong). PTK7-expressing CRC cell lines were transfected with 

PTK7- or control- shRNA and evaluated for cell proliferation, cytotoxic-induced 

apoptosis and cell migration. 

Results: Patient population had the following characteristics: median age, 63 ys 

(range 29-89); sex ratio = male (52%), female (48%); site = colon (90%), rectum 

(10%); stage = I-III (64%), IV (36%); median follow-up = 104 months. Staining 

intensity (0-1 = 65% of cases, 2 = 19% of cases, 3 =16% of cases, in tumor tissues 

versus 0-1 = 86% of cases, 2 = 11% of cases, 3= 3% of cases, in normal tissues; p = 

1,91.10-8) as well as average percentage of stained cells (30% in tumor tissues versus 

2% in normal tissues; p = 5.74.10-14) were higher in tumor compared to normal 

tissues. In stage I-III population (n = 122), 5-year MFS was lower in PTK7-positive 

(>10% of cells stained with intensity > 2) compared to PTK7-negative CRC (54% 

[95%CI: 38-75%] versus 75% [95%CI: 65-88%], p = 0.034, log-rank test). This impact 

was maintained in multivariate analysis and similar trends were observed in overall 

survival, while not reaching statistical significance. In vitro, PTK7 inhibition by 

shRNA significantly reduced cell migration. 

Conclusion: PTK7 protein is overexpressed in CRC and is associated with reduced 

MFS, possibly due to an impact on cell migration. 


540P THE INTRA-TUMOR STROMA MICROENVIRONMENT IN 

THERAPY MANAGEMENT FOR COLON CANCER PATIENTS 

W. Mesker 1 ,V.G.Pelt 1 , H. Gelderblom 2 , V. H. Krieken 3 , D.J. Kerr 4 , R. Tollenaar 1 

1 Surgery, Leiden University Medical Center (LUMC), Leiden, NETHERLANDS, 

2 Medical Oncology, Leiden University Medical Center (LUMC), Leiden, 

NETHERLANDS, 3 Pathology, University Medical Center St. Radboud, Nijmegen, 

NETHERLANDS, 4 Dept of Clinical Pharmacology, University of Oxford, Oxford, 


There is need to identify patients with colon cancer who benefit treatment. We 

previously have found that the stroma-tissue surrounding cancer cells plays an 

important role in tumor behavior and is reported as an independent prognostic 

parameter. Patients with a high stroma percentage within the primary tumor have a 

poor prognosis. Validation of the parameter was performed in the VICTOR trial. 

Recently the stroma percentage in lymph nodes and metastases was found a 

heterogenous process. Moreover the stroma groups respond differently to 

chemotherapy regimens. 

Methods: Tissue samples consisting of 5 µm Haematoxylin and Eosin (H&E) stained 

sections from the most invasive part of the primary tumor were analyzed for their 

tumor-stroma percentage. Stroma-high (>50% stroma) and stroma-low (≤50% 

stroma) groups were evaluated with respect to survival time and response to therapy. 

For patients with and without adjuvant therapy (CT) (n = 150) the primary tumor 

(PT) lymph nodes (LN) and liver metastases were analyzed. 

Findings: What is the profit of additional LN analysis? The CT treated stroma-low 

patient group showed an improved survival (5-yr OS 75% vs 83%, DFS 76% vs 83%, 

TTR 84% vs 100%). In the stroma-high patient group we did not notice any 

improvement of survival (5-yr OS 77% vs. 72%, DFS 68% vs. 68%, TTR 81% vs. 

77%). Which stroma group responds better to therapy? The stroma-high group 

showed a better response to therapy compared to the stroma-low group (increase 

5-yr OS 22% vs. 8%, DFS 18% vs. 8%, TTR 21% vs. 13%). 

Interpretation: The intra-tumor stroma percentage has proven to be a prognostic 

factor. It supports selective treatment for stroma-high and stroma-low patients. 

Preliminary results show that adjuvant therapy is more efficient for patients with a 

high stroma percentage. 


541P THE HISTOLOGICAL IMPORTANCE OF SIGNET RING CELL 

AND MUCINOUS ADENOCARCINOMA ON OUTCOMES IN 

PATIENTS WITH COLORECTAL CANCER 

S. Campos-Gomez 1 , V. Rosas Camargo 1 , R.A. Ramirez Fallas 1 , J.H. 

Flores Arredondo 2 , L. Morales Juarez 1 , S.I. Perez Alvarez 1 ,D. 

Valdez Bocanegra 1 , D. Huitzil Melendez 1 

1 Medical Oncology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador 

Zubiran, Mexico DF, MEXICO, 2 Research Department, The Methodist Hospital 

Research Institute, Houston, TX, UNITED STATES OF AMERICA 

The diagnosis of signet ring cell carcinoma (SRC) and mucinous 

adenocarcinoma (MC) represents approximately 1% and 15% of all colorectal 

cancers (CRC) respectively. Both entities have an aggressive biological behavior, 

but SRC tends to be the worst. A retrospective revision of cases was done in our 

institution to evaluate the clinical relevance, including metastasic patterns and 



overall outcome of patients with a SRC and MC component in patients with 

colorectal cancer. 

Methods: Clinical charts of all patients with a diagnosis of primary CRC were 

reviewed between 2001 and 2011 at our institution; those with a histological 

component of SRC and MC adenocarcinomas were registered. The analysis of 

primary tumor site, stage at presentation, tumor grade, metastasic sites, symptoms 

and survival for each group were performed and compared. 

Results: A total of 530 patients with primary CRC were identified. Signet cell was 

accounted for in 4% of patients with colorectal cancer, 14% had MC and the rest 

pure adenocarcinoma (72%). Median age of diagnosis for non-signet/non-mucinous 

adenocarcinomas was 61 years in comparison to 47 years for mucinous and signet 

cell carcinoma. SRC presented at more advanced stages III/IV at diagnosis (72%) 

more often than mucinous (46%) and highest tumor grade (SRC, 47%; MC 28%). 

There was no significant difference in location of primary cancer in both histologic 

types, presenting principally in ascending colon (28% vs 38%) and the rectum (28% 

vs 26%). Patients with a component of SRC and MC metastasized in a large 

proportion to the peritoneum and ovaries (80%) followed by ovary and lung. The 

most frequent symptom was abdominal pain (57%) in both groups. SCR carcinoma 

had significantly worse overall five-year relative survival than MC (25% vs 60%; p < 

0.002). Median survival of SRC compared to mucinous was 30 vs 88 months 

respectively. 

Conclusion: SRC in colorectal cancer has a very poor prognosis in comparison to 

other histologic types. The clinical and pathologic course is outright aggressive and 

presents in a younger population of patients with a higher tumor grade and in more 

advanced stages than MC. Both groups share patterns of metastasis predominantly to 

peritoneum and ovaries. 


542P DOWN-REGULATION OF γ-GLUTAMYL HYDROLASE GENE 

EXPRESSION IN TUMOR TISSUES IS ASSOCIATED WITH 

RESPONSE TO ORAL URACIL AND TEGAFUR/LEUCOVORIN 

CHEMOTHERAPY IN PATIENTS WITH COLORECTAL CANCER 

S. Sadahiro1 , T. Suzuki1 , A. Tanaka1 , K. Okada1 , A. Kamijo1 , H. Nagase2 , 

J. Uchida2 1 

Gastrointestinal Surgery, Tokai University School of Medicine, Isehara, JAPAN, 

2 

Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima, 

JAPAN 

Background: 5-Flurouracil (5-FU)/leucovorin (LV) and oral uracil and tegafur 

(UFT)/LV are widely used as standard adjuvant chemotherapy for colorectal cancer 

(CRC). We previously reported that right-sided tumors with high thymidine 

phosphorylase (TP) gene expression on pre-chemotherapy tumor biopsy are 

associated with a response to UFT/LV chemotherapy in patients with CRC. In the 

present study, we examined the relation between chemotherapy-induced gene 

expression changes (post-chemotherapy/pre-chemotherapy gene expression ratio) in 

CRC tissues and the efficacy of UFT/LV treatment. 

Material and methods: The subjects were 73 patients with CRC who were 

scheduled to undergo surgery. UFT (300 mg/m 2 /day) and LV (75 mg/day) were 

administered for 2 weeks before surgery. We assessed pathological response based 

on the extent of residual cancer cells and granulation tissue. The mRNA 

expressions of 6 pyrimidine-related enzymes and 8 reduced folate-related enzymes 

were quantitatively evaluated using a RT-PCR assay in paired samples of 

pre-chemotherapy tumor-biopsy specimens and post-chemotherapy resected-tumor 

specimens. 

Results: Pathological responses were observed in 19.2% (14/73) of the patients. 

Gene expression of γ-glutamyl hydrolase (GGH) was generally down-regulated 

after chemotherapy, and the extent of GGH down-regulation among the 

responders was significantly greater than that among the non-responders, with 

the least p value of 0.0009 among the genes studied. The extent of GGH 

down-regulation among right-sided tumors with high sensitivity to UFT/LV 

chemotherapy was significantly greater than that among left-sided tumors (p = 

0.0135). Moreover, on combined analysis of tumor site and sex, the extent of 

GGH down-regulation among left-sided tumors in men that showed low 

sensitivity to UFT/LV chemotherapy was significantly smaller than that among 

othertumors(p=0.0018). 

Conclusion: Down-regulation of GGH gene expression in primary CRC tissues after 

UFT/LV chemotherapy is associated with a response to chemotherapy in patients 

with CRC. 

Disclosure: H. Nagase: He is an employee of Taiho Pharmaceutical Co. J. Uchida: 

He is an employee of Taiho Pharmaceutical Co. All other authors have declared no 


543P P16(INK4A) GENE HYPERMETHYLATION AND KRAS 

MUTATION ARE INDEPENDENT PREDICTORS OF FOLFIRI 

AND CETUXIMAB CHEMOTHERAPY IN PATIENTS WITH 

METASTATIC COLORECTAL CANCER (MCRC) 

S.H. Kim 1 , K.H. Park 2 , S.J. Shin 1 , K.Y. Lee 3 , T.I. Kim 1 , N.K. Kim 3 , S.Y. Rha 1 , 

J.K. Roh 1 , J.B. Ahn 1 

1 Internal Medicine, Yonsei University College of Medicine, Seoul, KOREA, 

2 Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University 

College of Medicine, Seoul, KOREA, 3 Surgery, Yonsei University College of 

Medicine, Seoul, KOREA 

Background: P16 (INK4a) inhibits cyclin dependent kinases (CDKs) and plays various 

roles in cancer and senescence. P16 aberrancy is frequently detected in various 

cancers and may contribute to multidrug resistance. Hypermethylation of CpG island 

of p16 occurs in a significant proportion in colorectal cancer (CRC) and also is one 

of the CpG island methylator phenotype (CIMP) markers. 

Patients and method: We analyzed tumor samples from 49 patients with metastatic 

colorectal cancer (mCRC) who were treated with 5-fluorouracil, leucovorin, 

irinotecan (FOLFIRI) and cetuximab (1st line 22 pts, 2nd line 27 pts). 

Pyrosequencing was used to identify KRAS mutation and hypermethylation of 6 

CpG island loci (p16, p14, MINT1, MINT2, MINT31, hMLH1) in DNA extracted 

from formalin-fixed paraffin-embedded specimens. To analyze the relation between 

methylation status of CIMP markers including p16 and clinical outcome, logistic 

regression and Cox regression were performed. 

Result: Hypermethylation of p16 gene was detected in 14 of 49 patients (28.6%) and 

was significantly associated with KRAS mutation (Fisher’s exact, P = 0.01) and CIMP+ 

(Fisher’s exact, P = 0.002). Patients with p16 unmethylated tumors had significant 

longer time to progression (TTP, median 9.0 vs 3.5 months; log-rank, P = 0.001) and 

overall survival (OS, median 44.9 vs 16.4 months; log-rank, P = 0.008) than those with 

p16 methylated tumors. KRAS mutation was also associated with shortened TTP 

(median 8.9 vs 4.4 months; HR = 3.1, P = 0.008) and OS (median 44.9 vs 16.1 months; 

HR = 5.2, P < 0.0001). Patients with both KRAS and p16 aberrancy (n = 6) had 

markedly shortened TTP (median 2.8 months) compared with those with either KRAS 

or p16 aberrancy (n = 11; median 8.6 months, P = 0.021) or those with neither of them 

(n = 32; median 9.0 months, P C and c1843A > G) and two synonymous 

(c2221T > C and c1317C > T) common and putatively functional polymorphisms in 

the LRIG1 gene were selected. There were significant associations between LRIG1 

c1317C > T and c3158A > C polymorphisms and clinical outcome. OS was lower for 


patients harboring a T/T genotype than for patients with the C/C or C/T genotypes 

(p= 0.01). In the case of the c3158A > C polymorphism, patients harboring a C/C 

genotype had a lower OS than patients with an A/A or A/C genotypes (p = 0.047). 

Conclusions: In this study, we identified common germline variants in LRIG1 gene 

predicting clinical outcome in patients with mCRC receiving first-line 

oxaliplatin-based chemotherapy. 


545P MMP-9 AND VEGFR EXPRESSION HAS PROGNOSTIC 

SIGNIFICANCE AFTER RESECTION FOR PRIMARY TUMOR 

AND METASTATIC SITE IN COLORECTAL CANCER 

M.A. Lee 1 , S.T. Oh 2 , W.K. Kang 2 , S.W. Kim 3 

1 Medical Oncology, Seoul St. Mary’s Hospital, of the Catholic University, Seoul, 

KOREA, 2 Surgery, Seoul St. Mary’s Hospital, Seoul, KOREA, 3 Gastroenterology, 

Seoul St. Mary’s Hospital, Seoul, KOREA 

Background: Resection for metastatic lesion has been commonly done in stage 

colorectal cancer, showing better survival outcome than other GI malignancy. 

Although R0 resection in primary and metastatic lesion is done in stage IV cancer, 

recurrence should be developed and cure is rare. In the present study, we reviewed 

and analyzed the protein expression and the recurrence to determine the prognostic 

factor in stage IV colorectal cancer. 

Method: Tissue specimens from 130 patients with metastatic colorectal cancer were 

analyzed. All patients were diagnosed as metastatic colorectal cancer between Jan, 

2000 and Aug, 2008 at Seoul St. Mary’s hospital, the Catholic University. We 

performed immunohistochemical staining using tissue microarray for Wnt 3a, Wnt 

5a, VEGFR, and MMP-9. We analyzed the clinicopathological characteristics through 

the medical record and the association with protein expressions. 

Result: Of the 130 patients, Male was 78 (60%), and female was 52 (40%). 

Median age was 59.5 years old (range: 27-81). Colon cancer was 76 (58.5%) and 

rectal cancer was 54 (41.5%). 94 patients were initially diagnosed as stage IV, 

but took curative resection for primary lesion and metastasectomy. The other 36 

patients had recurrent disease as distant metastasis after curative surgery, and 

then took metastasectomy. The Wnt 5 expression showed the tendency of 

positive perineural invasion (p = 0.065), but there was no correlation between 

protein expression and other pathological factors. As a prognostic factor for 

recurrence, Negative MMP expression showed significantly longer time t o 

recurrence (TTR) than positive group (13mon vs, 10 months, p = 0.010) and 

VEGFR expression showed a correlation with TTR (15.7 mon for negative vs. 

11.1 mon for positive, p = 0.060). There was no correlation between recurrence 

and pathological findings such as lymphatic, vascular or perineural invasion, and 

other protein expressions. 

Conclusion: VEGFR and MMP-9 expression showed prognostic significance for 

recurrence in stage IV or recurrent colorectal cancer after metastasectomy. Unlikely 

the stage III colorectal cancer, pathological findings such as lymphovascular or 

perineural invasion did not have association with recurrence. 


546P NEUROPILIN-1 (NRP1) EXPESSION IN TUMOR METASTASIS 

OF PRIMARY AND COLORECTAL CANCER: IMPLICATIONS 

FOR ANTIANGIOGENIC THERAPY 

M.J. Ortiz-Morales1 , C. Morales2 , A. Gómez3 , G. Pulido4 , M.T. Cano Osuna5 , 

J. Jiménez6 , P. Sánchez6 , M. Medina7 , J. De La Haba Rodriguez8 ,E. 

Aranda Aguilar8 1 

Medical Oncology, Hospital Universitario Reina Sofía, Córdoba, SPAIN, 

2 

Medicine University, Department of Cell Biology, Physiology and Immunology, 

Córdoba, SPAIN, 3 Medical Oncology, Hospital Reina Sofía, Córdoba, SPAIN, 

4 

Medical Oncology, Universitary Hospital Reina Sofía, Córdoba, SPAIN, 

5 

Oncologia Medica, Hospital Universitario Reina Sofia, Cordoba, SPAIN, 

6 

Medical Oncology, Universitay Hospital Reina Sofia, Córdoba, SPAIN, 

7 

Pathological Anatomy, Universitary Hospital Reina Sofía, Córdoba, SPAIN, 

8 

Medical Oncology, Reina Sofía Hospital. Biomedical Research Institute (IMIBIC), 

Cordoba, SPAIN 

Introduction and objective: Vascular development is critical in tumor biology and 

targeted therapies against angiogenesis process have proven their therapeutic efficacy. 

Neuropilin-1 (NPR1), a membrane glycoprotein that works as a receptor for 

semaphorins, is also a co-receptor for VEGF-A165 and it is expressed in endothelial 

cells and in many other tumors. Very few studies about this protein in primary and 

secondary tumors have been reported with contradictory conclusions 1,2 . The aim of 

this study is to analyze the relationship between the expression of NRP1 in colorectal 

cancer patients in primary tumor and metastases and clinical and pathologic features, 

treatment response, progression-free interval and overall survival. 

Patients and methods: From 1995 to 2010, 70 patients with available biological 

material in paraffin of primary tumor and metastases (liver and/or lung) have been 

selected. NRP1 expression was performed using immunohistochemistry with 


neuropilin-1 Rabbit Monoclonal Antibody Catalog # 2621-1 (ATOM) at 1:75 

dilution. Vascular endothelium was used as positive control and tumor sample 

without antibody as negative control. Clinical and pathological data of patients, 

treatments administered, toxicity, response, progression-free interval and overall 

survival were registered. 

Results: The mean age of patients was 63 years. 51 patients (85%) were 

adenocarcinoma and 46 patients (76%) were moderately differentiated. 34 patients 

(56.7%) presented metastatic disease at the moment of primary tumor diagnosis. 

NRP1 expression exists in 100% (120) of samples analyzed. 

Conclusions: In our study, in contrast to latest published data 2 , no differences about 

intensity and frequency of expression of NRP1 were found between primary and 

metastatic samples. It is not possible to establish any relationship between tumor 

response to treatment and evolution. References: 1. Parikh AA, Fan F, Liu WB, et al. 

Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of 

angiogenesis. Am J Pathol 2004;164:2139-51. 2. Jubb AM, Strickland LA, Liu SD, 

Mak J, Schmidt M, Koeppen H. Neuropilin-1 expression in cancer and development. 

J Pathol 2012;226:50-60. 


547P PROGNOSTIC SIGNIFICANCE OF COMBINED POSITIVITY OF 

LYMPHATIC, VASCULAR, AND PERINEURAL INVASION 

(TRIPLE POSITIVE) IN STAGE II/III COLORECTAL CANCER; A 

NEW PARADIGM WORTH TO INVESTIGATE? 

F. Dane 1 , M.A. Ozturk 1 , M. Koçar 1 , B.M. Atasoy 2 , B. Aktas 1 , F. Telli 1 , 

M. Kanıtez 1 , M. Bes¸irog˘ lu 1 , P.F. Yumuk 1 , S.N. Turhal 1 

1 Internal Medicine Dpt., Medical Oncology Div., Marmara University Faculty of 

Medicine, Istanbul, TURKEY, 2 Radiation Oncology Dpt., Marmara University 

Faculty of Medicine, Istanbul, TURKEY 

Background: Despite the studies showing the impact of each lymphatic, vascular or 

perineural invasion on prognosis separately, the exact effect of these parameters in 

together (triple positive) on prognosis is not known. In this study, we assessed the 

pathological features and the survival outcomes of triple positive colorectal cancer 

patients. 

Methods: The files of stage II/III colorectal cancer (CRC) patients (n = 532) who 

received adjuvant systemic treatment following curative resection in our center were 

analyzed, retrospectively. Tumors with vascular, lymphatic, and perineural invasions 

were called triple positive (TP), all others were called non-triple positive (NTP) 

tumors. Patients with unknown vascular, lymphatic or perineural invasion status (n 

= 93) were excluded from the analysis. Adjuvant therapy was consisted of either 

fluorouracil or oxaliplatin-based chemotherapy (CT) regimens. Rectal cancer patients 

were given adjuvant radiation therapy also. Survival was determined using the 

Kaplan-Meier method, with differences determined by multivariate analysis using the 

Cox multiple hazards model. Results were compared using the log-rank test. 

Results: A total of 439 patients (243 male: 196 female) with stage II/III colorecral 

cancer who received adjuvant therapy were evaluated retrospectively. The median age 

was 60 (range: 23–84 years). Median follow-up was 36 months. Fifteen percent of the 

patients were TP. The rate of TP tumors were 4%, 13,6%, and 29% in T2, T3, and T4 

tumors, respectively (p:0.001). The rate of TP tumors were 5,6%, 13,9%, and 40,5% 

in N0, N1, and N2 tumors, respectively (p:0.0001). There were no relation between 

TP tumors rates and age, gender or tumor localization (p > 0.05). Five years DFS and 

OS rates were 37,7% vs 64,7% (p:0.0001) and 53,4% vs 78,1% (p:0.0001) for TP and 

NTP tumors, respectively. 

Conclusion: Our findings revealed that patients with TP tumors have inferior 

survival outcomes when compared to NTP tumors. However results of multivariate 

analyses for DFS and cancer specific OS did not support the preanalysis hypothesis 

of TP being a poor prognostic sign in early stage CRC patients. Nevertheless, we 

believe that accurate answer to this question can be given via retrospective analysis of 

prospectively collected data from multi-center clinical trials. 


548P MUTATION OF EITHER RAS OR BRAF CORRELATES WITH 

MGMT METHYLATION AND MUTATION OF PIK WITH PTEN 

METHYLATION, BUT NONE OF THESE IS ASSOCIATED WITH 

STAGE IN COLORECTAL CANCER 

B. Metzger1 , M.A. Dicato2 , G. Mahon3 , S. Obertin3 , J. Kayser3 1 

Laboratory, Foundation for Research on Cancer, Luxembourg, LUXEMBOURG, 

2 

Hematology-Oncology, Hospital Centre of Luxembourg, LUXEMBOURG, 

3 

Foundation for Research On Cancer, Hospital Centre of Luxembourg, 

LUXEMBOURG 

Background: In a previous study of 222 patients we showed how epigenetic and 

genetic changes during oncogenic progression could possibly explain the adenomacarcinoma 

sequence: first, methylation of promoters of H-cadherin gene followed by 

MGMT methylation, K-ras oncogene G to A point mutations, activation of B-raf 

gene by a V600E mutation finally methylation of E-cadherin. (ASCO 2011, 



abstr.3608) We extended the study by examining PTEN, PIK exon 9 and 20 for 

mutations and methylation and correlated all the genes to tumor stage. We divided 

TNM into early stage I & II and late III & IV. 

Method: Ethical approval was obtained. DNA was extracted from tumor samples 

obtained from CRC patients by resection. The PTEN methylation was analyzed by 

methylation-specific PCR. and analyzed by gel electrophoresis after Sybr green 

staining and UV-photography. 

Results: Data were available for 117 patients. Correlation coefficients were calculated 

and their significance assessed using Chi-squared: RAS/BRAF either mutant (mut) 

with late stage, P = 0.123 (suggestive), RAS/BRAF either mut with MGMT 

methylated, P = 0.017 (significant); PIK mut with PTEN methylated, P = 0.044 

(significant); and PIK mut with CDH13 methylated, P = 0.123 (suggestive). 

Concerning RAS/BRAF and stage, 86% of RAS/BRAF either mut tumours, were late 

stage, while only 53% of wild type (wt) tumors were late stage. For RAS/BRAF and 

MGMT, 76% of RAS/BRAF either mut were MGMT methylated, but 53% of wt 

tumors were methylated. PIK mut tumors were also PTEN methylated, and CDH13 

methylated. Results are tumor specific as all blood controls were unmethylated resp. 

wt. 

Conclusion: With PIK, PTEN and CDH13 no significant correlation was noted 

with either MGMT unmethylated or methylated nor with RAS/BRAF either wt or 

mut. RAS/BRAF correlated significantly with MGMT (p = 0.017), methylated PIK, 

PTEN and CDH13 did not correlate with early or late stage. There was a 

tendency, of RAS/BRAF mut to be associated with late stage. Of all these markers 

none correlates in a significant fashion with early or late stages and as of now, 

despite multiple genetic and epigenetic data sets, no predictive statement can be 

made. 


549P PROGNOSTIC ROLE OF KRAS MUTATIONS DETECTED BY 

HIGH-SENSITIVITY TAQMELT PCR ASSAY IN METASTATIC 

COLORECTAL CANCER 

J. Garcia Foncillas 1 , S. Zazo 2 , C. Carames 1 , G. Serrano 1 , A. Leon 1 , A. Campos 3 , 

J.I. Martin-Valades 1 , C. Cañadas 2 , T. Hernandez-Guerrero 1 , F. Rojo 2 

1 Department of Oncology, University Hospital “Fundacion Jimenez Diaz”, Madrid, 

SPAIN, 2 Pathology, Hospital Universitario. Fundación Jimenez Diaz, Madrid, 

SPAIN, 3 Department of Oncology, Hospital Infanta Elena, Madrid, SPAIN 

Background: KRAS mutation is present in approximately 35-40% of patients with 

metastatic colorectal cancer (mCRC) and has been established as a predictive marker 

of resistance to anti-EGFR therapy, but its role as prognostic factor is not yet clear. 

This study is aimed to analyze the prevalence and the impact in prognosis of 

expanded number of KRAS mutations in caucasian mCRC population and the 

sensitivity of the TaqMelt PCR assay cobas KRAS Mutation Test. 

Methods: A single institution retrospective cohort of 669 consecutive mCRC patients 

between 2000-9 with clinical follow-up was studied for frequent 7 mutations in 

codons 12/13 by ARMS-scorpion real-time PCR (Therascreen, Qiagen) and TaqMelt 

PCR assay cobas KRAS Mutation Test (Roche), which are designed to detect 19 

mutations in KRAS codons 12, 13 and 61. DNA was obtained by cobas DNA 

preparation kit (Roche) from one single 5um FFPE tissue section and by QIAamp 

DNA FFPE Tissue Kit (Qiagen) from 50um of tissue. 

Results: KRAS mutation was detected by the cobas KRAS Mutation Test in 41.2% 

of mCRC patients and was correlated with poor overall survival (OS) (p = 0.013), 

OS from the metastatic diagnosis for metachronous disease (p = 0.025), disease-free 

survival for metastatic disease (p = 0.012) and time to progression (p = 0.046). 

KRAS mutation was significantly associated with tumor grade (p = 0.025) and liver 

as first site of dissemination (p = 0.047). However, KRAS mutations detected by 

Therascreen did not impact on prognosis. The median of DNA concentration 

obtained by cobas and QIAamp was 120ng/ul and 80ng/ul, respectively. The 

frequency of invalid cases was 5.7% (cobas) and 17.9% (Therascreen). Finally, 

cobas identified 19.2% additional KRAS mutations not detected by Therascreen. 

Next Generation Sequencing by 454 GS FLX+ System analysis is ongoing to 

validate discrepant mutations. 

Conclusions: The cobas KRAS Mutation Test is a robust and reproducible assay that, 

1) obtains superior DNA recovery from very small amount of FFPE tissue; 2) detects 

up to 19.2% of mutations not detected by other methods; and, 3) KRAS mutations 

detected by cobas correlate with poor outcome in mCRC. 


550P TP, TS AND DPD AS POTENTIAL PREDICTORS OF OUTCOME 

FOLLOWING CAPECITABINE PLUS OXALIPLATIN (XELOX) VS. 

BOLUS 5-FLUOROURACIL/LEUCOVORIN (5-FU/LV) AS 

ADJUVANT THERAPY FOR STAGE III COLON CANCER: 

UPDATED BIOMARKER FINDINGS FROM STUDY NO16968 

(XELOXA) 

H. Schmoll1 , J. Tabernero2 , J.A. Maroun3 , F. De Braud4 , T. Price5 ,E.Van 

Cutsem6 , M. Hill7 , S. Hoersch8 , K. Rittweger9 , D. Haller10 1 2 

Internal Medicine, University Clinic Halle (Saale), Halle, GERMANY, Medical 

Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN, 3 Medical 

Oncology, The Ottawa Hospital Regional Cancer Centre, Ottawa, ON, CANADA, 

4 

Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, 

Milano, ITALY, 5 Oncology, The Queen Elizabeth Hospital, Adelaide, SA, 

AUSTRALIA, 6 Digestive Oncology, University Hospital Gasthuisberg/Leuven, 

Leuven, BELGIUM, 7 Medical Oncology, Kent Oncology Centre, Maidstone, 

UNITED KINGDOM, 8 Biostatistics, Dr. Manfred Köhler GmbH; working on behalf 

of Roche PDBB (Biostatistics), Freiburg, GERMANY, 9 Global Development, 

Hoffmann-La Roche Inc., Nutley, NJ, UNITED STATES OF AMERICA, 

10 

Hematology/oncology, University of Pennsylvania, Philadelphia, PA, UNITED 


Background: In NO16968, XELOX was superior in terms of disease-free survival 

(DFS) and overall survival (OS) to bolus 5-FU/LV as adjuvant therapy for stage III 

colon cancer [Schmoll et al. ASCO GI 2012]. Three key enzymes appear to have the 

potential to predict efficacy and/or safety of fluoropyrimidine-based treatment: 

thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine 

dehydrogenase (DPD). We evaluated the association between baseline TP, TS and 

DPD and outcome (DFS and OS). 

Methods: Patients (pts) with stage III colon cancer received either XELOX (8 cycles, 

24w) or bolus 5-FU/LV (Mayo Clinic, 6 cycles, 24w; Roswell Park, 4 cycles, 32w). 

The primary study endpoint was DFS; secondary endpoints included OS. TP, TS and 

DPD expression levels were determined in formalin-fixed, paraffin-embedded tissues 

by RT-PCR, and the median used as a cut-off point: high (above median) vs. low 

(below median). 

Results: The biomarker population included 498 (26%) of 1886 pts entered (XELOX, 

n = 242; 5-FU/LV, n = 256). Baseline demographics, tumour characteristics, cancer 

history and efficacy (DFS and OS) were similar to those in the main study 

population. Cox regression analysis for DFS is shown in the table. In the XELOX 

group pts with low tumour DPD and TP levels and a high TP/DPD ratio appeared 

to have significantly better DFS; this effect was not observed with 5-FU/LV. 

XELOX 5-FU/LV 

Covariate 

(high vs. low) HR 95% CI p value HR 95% CI p value 

DPD 2.45 1.55–3.86 0.0001 0.69 0.47–1.00 NS 

TP 1.73 1.10–2.72 0.0186 0.81 0.55–1.18 NS 

TS 0.90 0.58–1.40 NS 0.91 0.62–1.33 NS 

TP/DPD ratio 0.54 0.34–0.86 0.0091 0.76 0.51–1.13 NS 

Conclusions: These exploratory findings suggest that low tumour levels of DPD may 

be predictive for XELOX efficacy when given as adjuvant therapy in pts with resected 

stage III colon cancer. There was no correlation between DPD levels and outcome in 

the 5-FU/LV group. These data raise the possibility of predictive markers for XELOX 

but, until validated prospectively, would currently not have a role in treatment 

decisions. 

Disclosure: H. Schmoll: Consultant or Advisory Board: Roche Research Funding: 

Roche. J. Tabernero: Consultant or Advisory Board: Roche. J.A. Maroun: 

Consultant or Advisory Board: Roche. Honoraria: Roche. Research Funding: Roche. 

F. De Braud: Honoraria: Roche. T. Price: Consultant or Advisory Board: Roche. E. 

Van Cutsem: Research Funding: Roche. M. Hill: Consultant or Advisory Board: 

Roche. Honoraria: Roche. Research Funding: Roche. S. Hoersch: Employed by Dr. 

Manfred Köhler GmbH/Roche. K. Rittweger: Employed by Hoffmann-La Roche 

Inc. D. Haller: Consultant or Advisory Board: Roche. Honoraria: Roche. Research 

Funding: Roche. 


551P ADJUVANT CHEMOTHERAPY (AC) USE AND OUTCOMES IN 

STAGE II COLON CANCER (CC) WITH VS. WITHOUT POOR 

PROGNOSTIC FEATURES 

A. Kumar, H. Kennecke, H. Lim, R. Woods, D. Renouf, C. Speers, W. Cheung 

Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, CANADA 

Background: AC is frequently considered in patients (pts) with “high risk” stage II 

CC, defined by the presence of >/ = 1 poor prognostic features: obstruction or 

perforation, T4 stage,


(Siemens Syngo Via Oncology) and manual measurement of the LD (RECIST 1.1) 

and the LOD. Agreement between the tumor volume algorithm and volumetry for 

each rater and the corresponding inter rater agreement (IA) were investigated using 

Bland-Altman (BA) plots. Agreement between the RECIST-based and 

volumetry-based relative changes was quantified by intraclass correlation (ICC) 

where 1.0 would indicate perfect agreement. 

Results: 222 target lesions from 25 pts were measured at 99 TAs. BA plots indicated 

that the volume algorithm showed negligible constant bias for both raters (rater 1, 

0.09 with p = 0.25, and rater 2 -0.05 with p = 0.41). IA with regard to the volumetry 

showed a smaller constant bias (-0.16 with p = 0.17) compared with the volume 

algorithm (-0.31 with p = 0.04). The relative change in tumor size between baseline 

and first TA was investigated. The ICCs for RECIST-based versus volumetry-based 

relative changes for the 2 raters were 0.79 and 0.62. Application to mCRC patients 

from the CRYSTAL (n = 1198) and OPUS (n = 337) studies showed the ICCs for 

RECIST-based versus volume algorithm-based relative changes to be 0.60 and 0.77. 

Conclusions: The algorithm for estimating the tumor volume was validated as 

demonstrated by the negligible bias and the BA plots. The moderate ICCs for early 

changes in tumor size in the 25 Munich pts and those from the CRYSTAL and 

OPUS studies indicate clear differences between RECIST- and volume-based TAs and 

suggest that RECIST underestimates both tumor shrinkage and tumor growth. 

Disclosure: R. Laubender: RPL receives travel support and research funding by Merck 

KGaA. U. Sartorius: The author is an employee of Merck KGaA. M. Schlichting: The 

author is an employee of Merck KGaA. S. Stintzing: The author receives: Honoraria 

and travel support from Merck Serono and Roche AG Honoraria from Amgen GmbH. 

A. Graser: The author declares that he is a member of the Siemens speakers’ bureau 

and that he receives grant money from Bayer Pharma. V. Heinemann: The author 

declares: Honoraria (lectures) from Merck, Roche, Sanofi Honoraria (Ad Boards) from 

Merck, Roche, Sanofi Research support from Merck, Roche, Sanofi. 

555P EFFICACY AND SAFETY OF BEVACIZUMAB IN METASTATIC 

COLORECTAL CANCER (MCRC): FIRST-LINE ANALYSIS OF 

POOLED DATA FROM RANDOMIZED CONTROLLED TRIALS 

(RCTS) 

F.F. Kabbinavar 1 , H.I. Hurwitz 2 , N.C. Tebbutt 3 , B.J. Giantonio 4 , Z. Guan 5 , 

L. Mitchell 6 , D. Waterkamp 7 , J. Tabernero 8 

1 Thoracic Oncology and Kidney Cancer Programs, David Geffen School of 

Medicine at UCLA, Los Angeles, CA, UNITED STATES OF AMERICA, 2 Division 

of Hematology and Oncology, Duke University Medical Center, Durham, NC, 

UNITED STATES OF AMERICA, 3 Austin Health, University of Melbourne, 

Melbourne, VIC, AUSTRALIA, 4 The Abramson Cancer Center, University of 

Pennsylvania, Philadelphia, PA, UNITED STATES OF AMERICA, 5 Cancer Center, 

Sun Yatsen University, Guangzhou, CHINA, 6 Global Medical Affairs Biometrics, 

F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 7 Global Medical Affairs, 

F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 8 Medical Oncology / 

Gastrointestinal Tumors Group, Vall d’Hebron University Hospital / VHIO, 


Background: Bevacizumab (BV) with chemotherapy (CT) is a standard treatment for 

mCRC. This analysis pooled individual patient data from the clinical databases of six 

RCTs (phase 2 or 3) of BV to further define clinical outcomes with first-line 

treatment, including within subgroups. 

Methods: Patient data were pooled from first-line (AVF2107, NO16966, ARTIST, 

AVF2192, AVF0780, AGITG MAX) mCRC trials of BV. All analyses were based on 

the intent-to-treat population. Overall and progression-free survival estimates (OS, 

PFS) were calculated by Kaplan-Meier methods. To assess differences in time to 

response variables by treatment arm (CT vs BV + CT), stratified random (overall) 

and fixed (subgroup comparisons) models were used to estimate pooled hazard ratios 

(HRs) and 95% confidence intervals (CIs), with each study included as a stratum. 

Overall: BV + CT vs CT 

HR (95% CI) P value 

OS 0.81 (0.70 − 0.93) .0034 

PFS 

Subgroup comparisons: BV + CT vs 

CT 

0.58 (0.46 − 0.73)

experienced significantly more ≥ grade 2 neurotoxicity (51.2% vs. 12.5%, P = 0.001) 

(Table-1). Neurotropin was the only factor that affected the incidence of ≥ grade 2 

neurotoxicity in the Kaplan-Meier log rank and the multivariate Cox proportional 

hazards regression analysis. 

Conclusion: Neurotropin combined with oxaliplatin decreases chronic neurotoxicity 

effectively and safely. 


557P A RANDOMIZED, CONTROLLED TRIAL OF CETUXIMAB PLUS 

CHEMOTHERAPY FOR PATIENTS WITH KRAS WILD-TYPE 

UNRESECTABLE COLORECTAL LIVER-LIMITED METASTASES 

J. Xu, L. Ye, L. Ren, Y. Wei 

Department of General Surgery, Zhongshan Hospital Fudan University, 


Background: To assess the effect of cetuximab combined with chemotherapy in 

first-line treatment for unresectable colorectal liver metastases (CLM). 

Methods: After resection of the primary focus, patients (pts) with non-resectable 

synchronous liver-limited metastases from wild-type KRAS colorectal cancer were 

randomly assigned to received chemotherapy (FOLFIRI or mFOLFOX6) plus 

cetuximab (arm A) or chemotherapy alone (arm B). The primary end point was the 

rate of secondary resection for liver metastases. Secondary end points included tumor 

response and survival. 

Results: From June 2008 to December 2011, 116 pts were eligible (59 in arm A and 

57 in arm B). The 3-year overall survival (OS) rate and median survival time (MST) 

of the total pts was 32% and 27.5 months (mo), respectively. R0 resection rate for 

liver metastases was 30.5% (18/59) in arm A and 8.8% (5/57) in arm B, with 

significant difference (Odds ratio = 4.57, p< .01). In R0 resected 18 pts from arm A, 

the median disease free survival and MST was 11.4 and 46.6 mo. The pts in arm A 

had improved objective response (OR, 66.1% v 33.3%, Odds ratio = 3.90, p< .01), 

increased 3-year OS rate (43% v 21%, p= .01) and prolonged MST (32.8 v 22.8 mo, 

HR =0.49, p= .01) compared with those in arm B. Furthermore, for the pts without 

liver surgery, people from arm A also got more survival benefit than those from arm 

B on 3-year OS rate (25% v 17%, p= .047), MST (28.2 v 21.2 mo, HR =0.55, p= .047) 

and progressives free survival (8.3 v 5.2 mo, HR =0.64, p= .03). In addition, in arm 

A, pts who experienced resection of liver metastases were significantly improved 

3-year OS rate (74% v 25%, p= .02) and MST (46.6 v 28.2 mo, HR = 0.29, p= .02) 

than those without liver surgery, and the pts harboring BRAF wild-type tumors 

gained more benefit on MST (35.8 v 23.4 mo, HR =0.39, p= .045) rather than on OR 

( 70.0% v 44.4%, Odds ratio = 2.92, p > .05), when compared to those with mutated 

BRAF tumors. 

Conclusion: For initially unresectable CLM population with KRAS wild-type, 

cetuximab combined with chemotherapy could improve resectability of liver 

metastases, response rates and survival compared with chemotherapy alone 

(ClinicalTrials.gov number NCT01564810). 


558P UNDERSTANDING THE VALUE OF RESPONSE AND EARLY 

TUMOUR SHRINKAGE (ETS) IN PTS WITH WT KRAS MCRC 

TREATED WITH PANITUMUMAB (P) PLUS FOLFOX (F) 

J. Douillard 1 , S. Siena 2 , J. Tabernero 3 , M. Peeters 4 , C. Davison 5 , S. Braun 6 , 

R. Sidhu 7 

1 Medical Oncology, Centre René Gauducheau (ICO) Institut de Cancerologie de 

l’Ouest, Nantes, FRANCE, 2 Department of Medical Oncology, Ospedale 

Niguarda Ca’ Granda, Milan, ITALY, 3 Oncology Department, Vall d’Hebron 

University HospitalMedical Oncology Service, Barcelona, SPAIN, 4 Department Of 

Medical Oncology, University Hospital Antwerp, Antwerp, BELGIUM, 

5 Biostatistics, Amgen Ltd., Uxbridge, UNITED KINGDOM, 6 Medical 

Development, Amgen (Europe) GmbH, Zug, SWITZERLAND, 7 Medical 

Development, Amgen Inc., Thousand Oaks, UNITED STATES OF AMERICA 

Introduction: In clinical trials, tumour response is considered clinically 

meaningful when a lesion shrinks by ≥30%, according to RECIST (ORR). It 

has been purported that in pts with WT KRAS mCRC treated with an 

anti-EGFR mAb, both ORR and ETS (week 8 [W8]; ≥20%) predict improved 

OS compared with standard treatment. We explore the validity of these 

hypotheses. 

Methods: Using final analysis data from PRIME, we calculated median OS and PFS 

in pts with WT KRAS mCRC who did or did not achieve: a RECIST response (≥/< 

30%); or ETS (≥/ < 20%) at W8. We calculated the binary correlation coefficients 

(Phi) for the association between meeting the above shrinkage criteria at W8 (yes/ 

no) and OS at 2 years. 

Results: Consistent with the previously published finding that ORR is higher with P 

+ F vs F, at W8 more pts treated with P + F (vs F) had a RECIST response (Table). 

Irrespective of treatment arm, median OS and PFS were significantly longer in pts 

who achieved either ETS or a RECIST response (vs pts who did not; Table). Pts 


receiving P + F (vs F) showed longer median OS and PFS in each shrinkage group. 

OS trends favoured the P arm for pts achieving ETS (vs F alone; Table). However, 

outcomes were similar between arms in pts that achieved a RECIST response at W8. 

The correlation coefficients between meeting the ≥30% or ≥20% criterion and OS at 

2 years were 0.21 and 0.27, respectively. 

Conclusions: Regardless of treatment arm, pts achieving a RECIST response 

(≥30%) or ETS (≥20%) at W8 demonstrated improved PFS and OS compared 

with those who did not. Trends toward longer OS were observed in pts treated 

with P + F achieving ETS compared with F alone. Potential imbalances in 

post-protocol anti-EGFR mAb use and resection rate limit the interpretation of 

ORR in predicting OS. The poor Phi values found in PRIME between W8 

tumour shrinkage and 2-year OS suggest that ORR and ETS alone in the 

first-line treatment of mCRC are inappropriate surrogates for predicting OS. 

FOLFOX Panitumumab + FOLFOX 


significantly improved survival with an acceptable toxicity profile. However, more 

evidence is needed that current treatment options are tolerable and efficacious in 

older pts. Here, we assessed efficacy and safety according to age in the ML18147 

study. 

Methods: Pts with unresectable, histologically confirmed mCRC who progressed

functioning scales. Exploratory analyses included the change from baseline QoL 

scores by severity of skin reactions, the change in reported symptoms from baseline 

according to tumor response and treatment, and the effect of symptomatic status at 

baseline on response and survival. 

Results: QoL was evaluable in 627/666 pts (94%) with KRAS wild-type 

tumors, 52% received FOLFIRI, and 48% FOLFIRI plus cetuximab. No 

significant differences for GHS/QoL (p = 0.12) and social functioning scores 

(p = 0.43) were found between the treatment arms. In pts receiving cetuximab, 

themeanchangefrombaselineinGHS/QoLwas3.00inptswithoutskin 

reactions compared with -1.09 and -0.51 in those with grade I and grade 

II-IV early skin reactions, respectively. Social functioning score worsened in 

pts with no skin reactions (mean -6.41) compared with a slight improvement 

in those with grade I (mean 1.64) and grade II-IV (mean 1.48) early skin 

reactions, respectively. Tumor response was higher (58% vs 40%, p = 0.0002) 

and survival longer (hazard ratio 1.68, p < 0.0001) in asymptomatic versus 

symptomatic pts at baseline. FOLFIRI plus cetuximab increased tumor 

response in symptomatic (65% vs 52%, p = 0.0388) and asymptomatic pts at 

baseline (52% vs 31%, p = 0.0034), and in pts whose tumors had responded, 

maximum symptom relief from baseline occurred earlier (8 vs 16 weeks) 

compared with FOLFIRI alone. 

Conclusions: Adding cetuximab to FOLFIRI improved clinical outcome without 

negatively impacting on QoL, improving response despite baseline symptoms 

and leading to earlier symptom relief in pts whose tumors had responded. 

Symptom status at baseline was demonstrated to be a useful prognostic factor 

in mCRC. 

Disclosure: C. Köhne: The author reports honoraria from Pfizer and Merck KGaA. 

G. Folprecht: The author reports consultant/advisory roles for Merck KGaA, Roche 

and BMS, honoraria from Merck KGaA, Pfizer, Roche and Novartis and research 

funding from Merck KGaA. P. Rougier: The author reports, in relation to the topic 

concerned, honoraria for three years from Merck KGaA for participation at scientific 

boards and symposia. D. Curran: The author acted as a consultant (on statistical and 

QoL analysis) for Merck KGaA. U. Sartorius: The author is an employee of Merck 

KGaA. I. Griebsch: At the time of this research, the author was an employee of 

Merck KGaA. E. Van Cutsem: The author has received research funding from Merck 

KGaA. All other authors have declared no conflicts of interest. 

562P BEVACIZUMAB BEYOND PROGRESSION: HOW TO MONITOR 

TREATMENT EFFICACY? RESULTS OF A FUNCTIONAL 

IMAGING STUDY IN MURINE COLORECTAL CANCER 

L. Heijmen 1 , E.E.G.W. Ter Voert 2 , C.J.A. Punt 3 , L. De Geus-Oei 4 , A. Heerschap 2 , 

J. Bussink 5 , V. Zerbi 2 , W.J.G. Oyen 6 , O. Boerman 4 , H.W.M. van Laarhoven 3 

1 Medical Oncology, Radboud University Medical Centre, Nijmegen, 

NETHERLANDS, 2 Radiology, Radboud University Medical Centre, Nijmegen, 

NETHERLANDS, 3 Department of Medical Oncology, Academic Medical Center, 

Amsterdam, NETHERLANDS, 4 Nuclear Medicine, Radboud University Medical 

Centre, Nijmegen, NETHERLANDS, 5 Radiation Oncology, Radboud University 

Medical Centre, Nijmegen, NETHERLANDS, 6 Department of Nuclear Medicine, 

Radboud University Nijmegen Medical Centre, Nijmegen, NETHERLANDS 

Introduction: The BRiTE study suggested that bevacizumab beyond progression to 

first line therapy is beneficial for survival in advanced stage colorectal cancer. 

However, since response to bevacizumab cannot always be predicted by tumor size 

measurements, we studied utility of several functional imaging modalities to assess 

efficacy of bevacizumab beyond progression (BBP). 

Methods: 26 BALB/c nude mice with s.c. LS174T xenografts (diameter >0.4 cm) 

were treated with daily capecitabine (200 mg/kg), weekly oxaliplatin (3mg/kg) and 

2x/weekly bevacizumab (5 mg/kg). Tumor volume was assessed using caliper 

measurements. Tumors were considered progressive on the treatment regimen when 

volume was ≥1.5 times initial volume at 2 succeeding measurements. In 13 mice 

bevacizumab treatment was continued (BBP group), while the control group received 

saline injections. Within 3 days after progression, imaging was performed: FDG-PET, 

diffusion weighted imaging (DWI), T2*, dynamic contrast enhanced MRI 

(DCE-MRI). Measurements were repeated 7 and 10 days after the first 

measurements. Linear mixed models were used to assess differences between the 2 

groups over time. After the last measurement, tumors were snap-frozen and 

immunohistochemically examined for 9F1 (vasculature), glucose transporter 1 

(GLUT-1), carbonic anhydrase IX (CAIX) and Ki67 (proliferation) expression. 

Results: Tumor growth after progression was more pronounced in the control group 

(p < 0.01). FDG-PET showed a trend towards higher FDG uptake in the control 

group (p = 0.08). DWI, T2* and DCE-MRI parameters were not significantly 

different in the 2 groups. Immunohistochemical analyses showed a trend towards 

lower Ki67 expression (fraction 0.027 vs 0.041 p = 0.05) and higher CAIX fraction 

(0.21 vs. 0.10 p < 0.01) in the BBP group. The relative vascular area was lower in the 

BBP group (0.029 vs. 0.042 p = 0.03). Vascular density (104 vs. 127 vessels/mm 2 p= 

0.16) and GLUT-1 expression (0.08 vs 0.11 p = 0.48) did not significantly differ. 

Conclusion: Bevacizumab after progression had significant effects on tumor 

microenvironment. FDG-PET may be a sensitive functional imaging technique to 

assess the effects of bevacizumab. 



563P SKIN RASH AND OUTCOME IN COLORECTAL CANCER (CRC) 

PATIENTS TREATED WITH ANTI-EGFR MONOCLONAL 

ANTIBODIES 

F. Petrelli 1 , K.F. Borgonovo 2 , M. Cabiddu 3 , M. Ghilardi 4 , M. Cremonesi 3 , 

F. Maspero 3 , S. Barni 3 

1 UO Oncologia, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, ITALY, 

2 Medical Oncology Division, A.O. Treviglio-Caravaggio, Treviglio, ITALY, 3 Medical 

Oncology Division, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, ITALY, 

4 Medical Oncology Division, A.O. Trevilgio-Caravaggio, Treviglio, ITALY 

Introduction: The most common toxicity associated with anti-EGFR monoclonal 

antibodies (MoAbs) is an acneiform rash, that occurs in nearly all patients. One 

of the more interesting and useful clinical observations regarding EGFR-targeted 

therapy has been the association of clinical benefit with development of skin 

rash. We have performed a systematic review and a pooled analysis of the 

predictive value of skin rash for patients with advanced CRC treated with 

cetuximab (C) and panitumumab (P) in prospective clinical trials or in 

retrospective case series. 

Materials and methods: We searched PubMed and ASCO Meetings for 

publications reporting the correlation of skin rash with survival and/or response 

rate. The lower limit date for the search was February 11,2012 with no upper 

limit. The primary outcome was overall survival as a function of severity of 

cutaneous toxicity in patients treated with C or P (OS). Secondary endpoints were 

the predictive role of skin rash for progression free survival/time to progression 

and response rate (ORR). 

Results: Fourteen publications (for a total of 3,833 patients) were included in this 

meta-analysis. All included studies enrolled patients with advanced disease. For the 

primary endpoint (OS) 11 trials had available data; the occurrence of skin rash was 

significantly associated with reduced risk of death in patients treated with C or P 

(HR 0.51, P < 0.00001). For the association of risk of progression with skin rash (data 

available from 5 trials) the HR was significant too (HR 0.58, P < 0.00001). According 

to response rate analysis (15 trials available) skin rash was a significant predictor of 

activity with a RR of 2.23 (P < 0.00001) for patients with toxicity compared to 

patients with no or low-grade toxicity. ORR was 35% compared with 13% for 

high-grade compared to low-grade skin toxicity arms. The results appear similar for 

C and P trials for all the endpoints. 

Conclusion: Skin rash represents an early predictive biomarker of response, however 

the prognostic value of this event is presently unknown. 


564P QUALITY-ADJUSTED SURVIVAL IN PATIENTS WITH 

WILD-TYPE (WT) KRAS METASTATIC COLORECTAL CANCER 

(MCRC) RECEIVING FIRST-LINE THERAPY WITH 

PANITUMUMAB PLUS FOLFOX VERSUS FOLFOX ALONE 

J. Wang 1 , Z. Zhao 2 , B. Barber 2 , J. Zhang 1 , B. Sherrill 3 , S. Braun 4 , R. Sidhu 5 , 

M. Gallagher 2 , J. Douillard 6 

1 Biostatistics, RTI Health Solutions, Research Triangle Park, NC, UNITED 

STATES OF AMERICA, 2 Global Health Economics, Amgen Inc., Thousand 

Oaks, CA, UNITED STATES OF AMERICA, 3 Biometrics, RTI Health Solutions, 

Research Triangle Park, NC, UNITED STATES OF AMERICA, 4 Amgen (Europe) 

GmbH, Zug, SWITZERLAND, 5 Department of Clinical Research, Amgen Inc., 

Thousand Oaks, CA, UNITED STATES OF AMERICA, 6 Medical Oncology, Centre 

René Gauducheau (ICO) Institut de Cancerologie de l’Ouest, St Herblain, 

FRANCE 

Background: Panitumumab plus FOLFOX significantly improved progression-free 

survival (PFS) in patients with WT KRAS mCRC. The objective of this analysis was 

to use the quality-adjusted time without symptoms of disease or toxicity of treatment 

(Q-TWiST) method to compare quality-adjusted survival between the treatment 

arms. 

Methods: Patients with mCRC were randomized to panitumumab plus FOLFOX or 

FOLFOX alone in a phase III clinical trial. For each treatment arm, the area under 

the survival curve, which was estimated using the Weibull distribution, was 

partitioned into health states: toxicity (TOX), time without symptoms of disease 

progression or toxicity (TWiST, i.e., PFS minus TOX), and relapse period (REL, i.e., 

overall survival (OS) minus PFS); and adjusted using utility weights derived from 

patient-reported EuroQoL 5-dimensions measures. The null hypothesis of no 

difference between treatment groups was tested based on the normal approximation 

with standard errors calculated by the bootstrap method. Sensitivity analyses were 

performed using the standard Q-TWiST approach with means restricted to median 

OS. 

Results: Of 1,183 patients who were randomly assigned, 1,096 patients (93%) had 

available tumor KRAS status, of which 656 patients (60%) had WT KRAS tumors 

(panitumumab plus FOLFOX, n = 325; FOLFOX alone, n = 331) and were included 

in this analysis. Compared to patients treated with FOLFOX alone, the panitumumab 

plus FOLFOX group had significantly longer quality-adjusted PFS (8.5 versus 7.2 

months, respectively; 1.3 additional quality-adjusted months; p = 0.02) and 

quality-adjusted OS (22.4 versus 18.6 months; 3.8 additional quality-adjusted 



months; p = 0.04). When analysis was restricted to 24 months follow-up, the 

Q-TWiST advantage was smaller but still significant (14.0 versus 13.0 months; 1.0 

additional quality-adjusted month; p = 0.04). 

Conclusions: This Q-TWiST analysis showed that in patients with previously 

untreated WT KRAS mCRC, panitumumab plus FOLFOX significantly improved the 

duration of the quality-adjusted survival compared with FOLFOX alone. 

Disclosure: J. Wang: The study was funded by Amgen Inc. Z. Zhao: Employed and 

stock owner of Amgen Inc. B. Barber: Employed and stock owner of Amgen Inc. J. 

Zhang: The study was funded by Amgen Inc. B. Sherrill: The study was funded by 

Amgen Inc. S. Braun: Employed and stock owner of Amgen Inc. R. Sidhu: Employed 

and stock owner of Amgen Inc. M. Gallagher: Employed and stock owner of Amgen 

Inc. J. Douillard: The study was funded by Amgen Inc. 

565P BEVACIZUMAB (BEV) + CHEMOTHERAPY (CT) BEYOND FIRST 

PROGRESSION IN PATIENTS (PTS) WITH METASTATIC 

COLORECTAL CANCER (MCRC) PREVIOUSLY TREATED WITH 

BEV-BASED THERAPY: OVERALL SURVIVAL SUBGROUP 

FINDINGS FROM ML18147 

J.M. Vieitez de Prado 1 , C. Borg 2 , D. Arnold 3 , R. Greil 4 , E.J.D. Van Cutsem 5 , 

R. von Moos 6 , J. Bennouna 7 , I. Reyes-Rivera 8 , B. Bendahmane 9 , S. Kubicka 10 

1 Medical Oncology, Hospital Central de Asturias (HUCA), Oviedo, SPAIN, 

2 Medical Oncology, University Hospital Besançon, Besançon, FRANCE, 

3 Medical Oncology, Hubertus Wald Tumor Center, University Cancer Center 

Hamburg (UCCH), Hamburg, GERMANY, 4 Oncology Centre, III Medizinische 

Universitätsklinik Salzburg, Salzburg, AUSTRIA, 5 Digestive Oncology, University 

Hospital Gasthuisberg, Leuven, BELGIUM, 6 Medical Oncology, Kantonal 

Hospital Graubünden, Chur, SWITZERLAND, 7 Medical Oncology, Institut de 

Cancérologie de l’Ouest, Nantes, FRANCE, 8 Statistics, Genentech Inc., South 

San Francisco,CA, UNITED STATES OF AMERICA, 9 GPS Oncology, 

F. Hoffmann-La Roche, Basel, SWITZERLAND, 10 Internal Medicine, Cancer 

Center Reutlingen, Reutlingen, GERMANY 

Background: ML18147 evaluated the benefit of continuing BEV + standard CT as 

second-line (2L) treatment for pts with mCRC progressing after first-line (1L) 

BEV-containing therapy. Here we report results of pre-specified subgroup and 

exploratory KRAS mutation analyses. 

Methods: Pts with unresectable, histologically confirmed mCRC progressing within 3 

mo after discontinuing 1L BEV were randomised to 2L fluoropyrimidine + oxaliplatin 

or irinotecan (crossed over from 1L) ± BEV (2.5 mg/kg/wk equivalent). The primary 

endpoint was overall survival (OS). Subgroup analyses for OS were performed using 

the same statistical method as for the primary analysis. 

Results: 409 pts were randomised to BEV + CT and 411 to CT (1 pt not treated). 

Median OS was 11.2 mo for BEV + CT vs 9.8 mo for CT (unstratified HR = 0.81; 

95% CI 0.69–0.94; p = 0.0062). Subgroup analyses for OS were generally consistent 

with the overall population (Table). While the treatment effect in female pts 

appeared to be lower, the treatment-gender interaction test was not statistically 

significant. 

Category Subgroup N HR for OS 95% CI 

All All 819 0.81 0.69–0.94 

Gender Female 

294 0.99 0.77–1.28 

Male 

525 0.73 0.60–0.88 

Age 9mo 369 0.73 0.58–0.92 

First-line chemotherapy Oxaliplatin-based 343 0.79 0.62–1.00 

Irinotecan-based 476 0.82 0.67–1.00 

Time from last BEV dose ≤42 d 

630 0.82 0.69–0.97 

>42d 189 0.76 0.55–1.06 

Liver metastases only No 

592 0.81 0.67–0.97 

Yes 

226 0.79 0.59–1.05 

No. of organs with metastasis 1 

307 0.83 0.64–1.08 

>1 

511 0.77 0.64–0.94 

KRAS mutation data were available from an exploratory analysis in 616 pts (75%); 

median OS for KRAS wild-type (WT) pts was 15.4 mo for BEV + CT vs 11.1 mo 

for CT (HR = 0.69, 95% CI 0.53–0.90; p = 0.0052); in KRAS mutant (MT) pts 

median OS was 10.4 vs 10.0 mo, respectively (HR = 0.92; 95% CI 0.71–1.18; p = 

0.4969). Median PFS for KRAS WT pts was 6.4 mo for BEV + CT vs 4.5 mo for 

CT (HR = 0.61; 95% CI 0.49–0.77; p < 0.0001); in KRAS MT pts median PFS was 

5.5 vs 4.1 mo, respectively (HR = 0.70; 95% CI 0.56–0.89; p = 0.0027). No 

treatment interaction by KRAS status was seen for OS (p = 0.1266) or PFS (p = 

0.4436). 

Conclusions: ML18147 showed that BEV + CT continued beyond progression 

significantly improves survival vs CT alone. Findings from the subgroup analyses for 

OS were generally consistent with the overall population. 

Disclosure: J.M. Vieitez de Prado: Involved in corporate-sponsored trials for Roche. 

D. Arnold: Consultant / Advisory Board: Roche. Honoraria: Roche. Research 

funding: Roche. R. Greil: Honoraria: Roche Research support: Roche. E.J.D. Van 

Cutsem: Research funding: Roche. R. von Moos: Consultant/advisory board: Roche. 

Honoraria: Roche. Research funding: Roche. J. Bennouna: Consultant / advisory 

board: Roche. Honoraria: Roche. I. Reyes-Rivera: Employed by Genentech Inc. B. 

Bendahmane: Employed by F. Hoffmann-La Roche. S. Kubicka: Consultant / 

advisory board: Roche. Honoraria: Roche. All other authors have declared no 


566P RANDOMIZED PHASE II STUDY OF OXALIPLATIN AND S-1 

(OS) VERSUS OXALIPLATIN AND CAPECITABINE (XELOX) IN 

PATIENTS WITH METASTATIC OR RECURRENT COLORECTAL 

CANCER 

D.Y. Zang 1 , I.J. Chung 2 ,H.Oh 3 , K.U. Park 4 , K.H. Lee 5 , B. Han 1 , D.R. Choi 1 ,H. 

S. Kim 1 , J.H. Kim 1 

1 Internal Medicine, Hallym University Medical Center Hallym University College of 

Medicine, Anyang, KOREA, 2 Medical Oncology, Chonnam National University 

Hwasun Hospital, Jeollanamdo, KOREA, 3 Internal Medicine, Gangneung Asan 

Hospital, Gangneung, KOREA, 4 Internal Medicine, Dongsan Medical Center, 

Keimyung University, Daegu, KOREA, 5 Internal Medicine, Yeungnam University 

Hospital, Daegu, KOREA 

Background: Combination oxaliplatin and S-1 (OS) or oxaliplatin and capecitabine 

(XELOX) chemotherapy have shown significant efficacy in advanced colorectal 

cancer. To evaluate those efficacy and safety, we performed a randomized phase II 

study in patients with metastatic or recurrent colorectal cancer. 

Methods: Eligible patients were those who had measurable lesions and had no 

previous history of chemotherapy except adjuvant chemotherapy. Eight-eight patients 

were randomly assigned to receive oxaliplatin 130 mg/m 2 was administered 

intravenously on day 1 and S-1 80 mg/m 2 (OS, arm A) or capecitabine 2,000 mg/m 2 

(XELOX, arm B) was administered orally on days 1-14. Cycles were repeated every 

21 days. Patients were treated until proved to have disease progression or 

unacceptable toxicity. The primary endpoint of the study was to assess the overall 

response rate (ORR). 

Results: Characteristics of the patients were well-balanced between arms, except for 

primary disease site, where the percentage of colon, rectosigmoid, and rectum were 

42%, 16%, and 42% (arm A) and 58%, 22%, and 20% (arm B), and number of 

metastatic organs, where the percentage of less than 1 and more than 2 were 53% 

and 47% (arm A) and 67% and 33% (arm B). A total of 284 cycles (median 6, range 

1-39) in Arm A; 298 cycles (median 5, range 1-19) in arm B were administered. 

Eighty-three (41 for arm A and 42 for arm B) patients were evaluated for toxicity 

and response. The main toxicities were thrombocytopenia [grade 1/2/3/4 = 8/10/7/1 

patients (A); 10/10/7/5 (B)], neutropenia [grade 1/2/3/4 = 9/8/1/0 (A); 8/12/5/2 (B)], 

anemia [grade 1/2/3/4 = 21/13/3/1 (A); 20/11/4/0 (B)], peripheral neuropathy [grade 

1/2/3 = 11/10/0 (A); 11/8/3 (B)], and hand-foot syndrome [grade 1/2/3 = 2/0/0 (A); 

7/1/2 (B)]. There were 3 CR, 11 PR, 25 SD and 2 PD (A); 5 CR, 13 PR, 16 SD and 7 

PD (B). The confirmed ORR in the intention-to-treat population was 32.6% (95% CI: 

18.6-47.4%) in arm A and 40.0% (95% CI, 25.0-55.0%) in arm B. The median time 

to progression was 6.7 (95% CI, 4.8-8.7) months (A) and 8.0 (95% CI, 6.3-9.6) 

months (B). The median survival time was 19.0 (95% CI, 7.6-30.5) months (A) and 

22.1 (95% CI, 17.9-26.3) months (B). 

Conclusion: These data suggest that both OS and XELOX regimens are active and 

are well tolerated regimens in patients with metastatic or recurrent colorectal cancer. 


567P NEOADJUVANT MULTIDISCIPLINARY PHASE II STUDY 

(BRANCH) OF AN EARLY BEVACIZUMAB SCHEDULE PLUS 

CHEMO-RADIATION THERAPY IN RECTAL CANCER: 

EFFICACY, SAFETY, AND BIOMARKERS 

A. Avallone, E. Di Gennaro, L. Aloj, P. Delrio, B. Pecori, F. Tatangelo, A. Petrillo, 

V.R. Iaffaioli, S. Lastoria, A. Budillon 

Gastrointestinal Oncology, National Cancer Institute of Naples, Fondazione G. 

Pascale, Naples, ITALY 

Background: In BRANCH study we assess the safety and efficacy of an experimental 

schedule of early (4 days before) bevacizumab (BEV) added to neoadjuvant 

chemotherapy (CT) and radiotherapy (RT) in poor-risk locally advanced rectal 

cancer (pLARC) patients (pts) and explore the potential of circulating endothelial 

cells (CECs) and tumor lesion glycolysis (TLG) as surrogate markers of pathological 

response(PR). 

Patients and methods: 46 pts (cT4, cN + , cT3≤ 5 cm from the anal verge and/or 

positive circumferential margin, M1 resectable) received 3 biweekly courses of 


oxaliplatin (100 mg/m 2 )/raltitrexed (2.5 mg/m 2 ) on day 1, and 5-FU (800 mg/ 

m 2 )/folinic acid (250 mg/m 2 ) on day 2 during pelvic RT (45 Gy). BEV (5 mg/kg) 

was given biweekly 4 days before beginning of CT/RT for 2 courses. Toxicity 

was graded with NCI-CTC v.3. PR was defined using Mandard tumor regression 

grade (TRG). According to the Simon’s two-stage design, assuming an 

hypothesis of a 50% TRG1 (complete tumor regression) (α error = 0.05, β error 

= 0.20), at least 6/16 TRG1 should be obtained to continue accrual to 46 pts. 

CECs and TLG were evaluated at baseline (BL) on day 10 and before surgery, 

by flow cytometry and FDG-PET, respectively. Statistical analysis was by 

Mann-Whitney test. 

Results: We obtained 23 TRG1 (50%), 14 TRG2 (30%) and 8 TRG3-4 (17%). 

Grade ¾ neutropenia was the most common adverse event (13/46 pts, 28%). 

TLG reduction on day 10 vs BL was significantly higher in responders TRG1-2 

compared to non-responders TRG3-4 pts (median -72%, range -90% + 31% vs 

-38%, range -45% + 25%; p < 0.05). Median CECs at BL were higher in TRG1-2 

vs TRG3-4 pts (median 0.22/µl, range 0-3.98 vs 0/µl, range 0-0.174; p = 0.009). 

Moreover, in TRG1-2 pts CECs were significantly reduced on day 10 vs BL 

(median 0.014/µl, range 0-2.29; p = 0.002). This pattern was not seen in TRG3-4 

pts with a tendency toward increased levels (median 0.316/µl, range 0-2.64; p = 

0.097). In both TRG 1-2 and TRG 3-4 preoperative CECs and PET-CT studies 

were not predictive of PR. 

Conclusions: Current scheme of BEV plus CT and RT appears safe and active, 

yielding high rate of TRG1 and TRG2 responses in pLARC. Early FDG-PET and 

CECs evaluation emerged as potential biomarkers for treatment selection to be 

incorporated in design of future studies with this regimen. CEP and citochine data 

will be provided at the meeting. 


568P SAFETY AND EFFICACY OF INTRAVENOUS CETUXIMAB (CET) 

AND HEPATIC ARTERY INFUSION OF IRINOTECAN, 

5-FLUOROURACIL AND OXALIPLATIN IN PATIENTS WITH 

UNRESECTABLE LIVER METASTASES FROM WT KRAS 

COLORECTAL CANCER (CRC): RESULTS FROM OPTILIV 

EUROPEAN PHASE II TRIAL 

F. Levi 1 , V. Boige 2 , P. Rougier 3 , M. Hebbar 4 , D. Smith 5 , C. Focan 6 , 

R. Guimbaud 7 , C. Carvalho 8 , M. Bouchahda 1 , M. Ducreux 2 

1 Chronotherapy Unit, Medical Oncology Department, Inserm, U776, Paul 

Brousse Hospital, Villejuif, FRANCE, 2 Oncologie Digestive, Institut de 

Cancérologie Gustave Roussy, Villejuif, FRANCE, 3 Digestive Oncology, Hopital 

European George Pompidou, Paris, FRANCE, 4 Department: Unité D’oncologie 

Médicale, CHRU de Lille - Hôpital Huriez, Lille, FRANCE, 5 Oncologie Digestive, 

Hôpital Saint André, Bordeaux, FRANCE, 6 Département D’oncologie, 

CHC-Clinique Saint-Joseph, Liege, BELGIUM, 7 Oncologie Médicale, CHU 

Toulouse Purpan, Toulouse Cedex, FRANCE, 8 Unidade de Oncologia, Hospital 

Prof. Doutor Fernando Fonseca, Amadora, PORTUGAL 

Background: Hepatic artery infusion (HAI) of chronomodulated (Chrono) 

irinotecan (I), 5-Fluorouracil (F) and oxaliplatin (O), or flat O combined with 

intravenous (iv) F-Leucovorin allowed secondary metastases resections and prolonged 

survival in patients (pts) with CRC liver metastases despite prior failure of iv 

chemotherapy (Bouchahda, Cancer 2009; Goere, Ann Surg 2010). 

Purpose: To prospectively evaluate safety and efficacy of combining iv Cet with HAI 

of IFO in pts with CRC liver metastases. 

Methods: This Phase II trial involved pretreated pts with unresectable CRC liver 

metastases receiving iv Cet (500 mg/m 2 ) and Chrono or Conventional (Conv) HAI 

of I (180 mg/m 2 ), F (2800 mg/m 2 ), and O (85 mg/m 2 ) q2 weeks. Liver metastases 

were resected whenever adequately downstaged. 

Results: Accrual of 64 pts (42 M, 22F; age, 33-76 years; 4 ongoing) was 

complete at 9 centers (4 countries) on 13/03/2012. In 62 monitored pts: PS 0/1/ 

2 (61/36/3%), bilobar liver lesions (84%), a median of 9 metastases (1-50; largest 

diameter, 54 mm; range, 15-172) involving a median of 6 segments (1-8). Pts 

received one (44%), two (30%) or three (26%) prior iv chemotherapy lines. A 

median of 5 courses (1-13) was given to 59 pts (Chrono, 18; Conv, 41; 3 never 

treated), with artery occlusion as main cause of withdrawal (53%). Main grade 

3-4 toxicities per pt were neutropenia (39%), abdominal pain (25%), fatigue 

(17%), diarrhea (15%), and nausea (10%). Grade 3 sensory neuropathy occurred 

in 3% of the pts. Intent-to-treat objective tumor response rate was 45% [95% 

CL,31-59], including 2 radiological complete responses. Disease control rate was 

83%. Per-protocol secondary liver surgery rate was 33.3% [20.4-46.2]. One pt 

had pathologic complete response in 24/25 metastases in all liver segments (1-6 

cm) and has been disease-free for 25+ months and alive at 38+ months. Median 

progression-free survival (41 events) was 9.1 months [6.5-11.6]. Preliminary 

median survival (19 events) is 28.6 months [16.3-40.9]. 

Conclusions: The combination of intravenous cetuximab with triplet HAI 

chemotherapy offers a safe and highly effective treatment option for patients with 

chemotherapy- refractory CRC liver metastases. Support: ARTBC International, 

Villejuif; Merck-Serono & Pfizer (France). 



569P SOMORE TRIAL: COMBINING SORAFENIB (SOR) WITH 

CAPECITABINE (CAP) YIELDS HIGHLY ENCOURAGING 

SURVIVAL RESULTS AND ELEVATED METABOLIC RESPONSE 

RATE IN CHEMOREFRACTORY METASTATIC COLORECTAL 

CANCER (MCRC) 

A. Deleporte 1 , A. Hendlisz 1 , T. Delaunoit 2 , R. Marechal 3 , M. Peeters 4 , 

S. Holbrechts 5 , M. van den Eynde 6 , G. Houbiers 7 , M. Moreau 8 , P. Flamen 9 

1 Medical Oncology, Institut Jules Bordet, Brussels, BELGIUM, 

2 Gastroenterology, Entité Jolimontoise, La Louviere, BELGIUM, 3 Service 

Médico-Chirurgical de Gastroentérologie, Hopital Universitaire Erasme, Brussels, 

BELGIUM, 4 Medical Oncology, Universitair Ziekenhuis Antwerpen, Antwerpen, 

BELGIUM, 5 Medical Oncology, Hopital Ambroise Pare, Mons, BELGIUM, 

6 Medical Oncology, Cliniques universitaires St-Luc, Brussels, BELGIUM, 

7 Gastroenterology, Hopital Saint Joseph, Liege, BELGIUM, 8 Data Center, Institut 

Jules Bordet, Brussels, BELGIUM, 9 Nuclear Medicine, Institut Jules Bordet, 

Brussels, BELGIUM 

Background: Several phases I and II trials including mCRC and metastatic breast 

cancer patients have suggested an interesting clinical activity in solid tumors with a 

SOR-CAP combination. SoMore’s aim is to assess its potential benefit in 

chemorefractory mCRC and the predictive value of early metabolic response (MR) 

on survival. 

Methods: SoMore (EUDRACT 2010-023695-91) is a multicentric phase II in PS 

0-1 chemorefractory mCRC pts. Two co-primary objectives were defined 1) to 

demonstrate that overall survival (OS) at 6 months is > 30% (67 pts needed to 

have 90% power to detect a true rate of 50% at 1-sided level 2.5%); 2) to 

compare OS between early PET responders and non responders (62 deaths 

required before analysis -on pts assessable for MR- to detect a true HR < 0.385, 

assuming a 67% rate of early responders). Pts received a 1st cycle of SOR 

(600mg/day) CAP (1700 mg/m 2 /day, day 1-14 every 21 days), then subsequent 

cycles with a SOR dose of 800mg/day until progression or unacceptable 

toxicity. FDGPET-CT was performed at baseline and before second cycle. 

Investigator-independent centralized PET analysis was carried out with 

metabolic non response defined by < 15% FDG uptake decrease in a dominant 

proportion (≥50%) of predefined target lesions (SUVmax> 2.5 liver uptake; 

size > 15 mm). 

Results: Between February and October 2011, 92 eligible pts were recruited in 6 

centers: 50 male pts (54%), ECOG PS 0/1 : 51 (55%)/41 (45%), median age of 61 

years. A median of 5 treatment cycles were given (0-18 + , treatment ongoing in 11 

pts). No toxic death was observed. Grade III-IV toxic reactions were reported in 53% 

of the pts, mainly fatigue (17%), hand-foot skin reaction (13%), diarrhea (13%). 3/81 

pts stopped their treatment due to toxicity. OS rate at 6 months was 65/92 (71%, 

95% CI : 61%-79%), significantly higher than 50% (p < 0.001). PET showed a MR in 

65% [54%-74%] of the 79 evaluable pts. Data are not yet mature to analyze the 

predictive value of PET on survival. 

Conclusions: SoMore largely met one of its primary objectives with an observed 71% 

OS at 6 months for this heavily pretreated mCRC population with manageable 

toxicity. Data about PET assessment according to mOS and PFS will likely be mature 

at the time of the meeting and presented if available. 


570P EFFECT OF POST-PROTOCOL ANTI-EPIDERMAL GROWTH 

FACTOR RECEPTOR (EGFR) MONOCLONAL ANTIBODY (MAB) 

THERAPY ON SURVIVAL OUTCOMES IN PATIENTS WITH 

WILD-TYPE (WT) KRAS METASTATIC COLORECTAL CANCER 

(MCRC) TREATED WITH PANITUMUMAB (PMAB) PLUS 

CHEMOTHERAPY 

J-Y. Douillard 1 , M. Peeters 2 , A. Rong 3 , S. Siena 4 , S. Braun 5 , R. Sidhu 3 , T. Price 6 

1 Centre René Gauducheau, Nantes, FRANCE, 2 University Hospital Antwerp, 

Antwerp, BELGIUM, 3 Amgen Inc., Thousand Oaks, CA, UNITED STATES OF 

AMERICA, 4 Ospedale Niguarda Ca’ Granda, Milan, ITALY, 5 Amgen GmbH, Zug, 

Switzerland, 6 Queen Elizabeth Hospital and University of Adelaide, Woodville, 

AUSTRALIA 

Background: Results from two randomized, multi-centre, phase III studies of pmab 

plus chemotherapy (FOLFOX4 in 1 st -line [PRIME]; FOLFIRI in 2 nd -line [181]) 

demonstrated a trend toward improved overall survival (OS) in the experimental 

arms vs chemotherapy alone, analysing the ITT populations. We evaluated the 

hypothesis that crossover to post-protocol anti-EGFR mAb-containing therapy in the 

control arms may have attenuated OS outcomes. 

Methods: For this retrospective analysis, we used data of both PRIME and 181 

study final analyses prespecified to occur at 30 months after the last patient was 

enrolled. We conducted sensitivity analyses to estimate OS outcomes using 

statistical procedures: (1) estimating the effect of randomized treatment as if no 

patients in the chemotherapy arm received subsequent anti-EGFR mAb-containing 

therapy a ; (2) identifying the survival differences that would have been observed had 

all patients stayed on protocol treatment b ; (3) modifying the Cox 

proportional-Hazards model, allowing for a time-dependent covariate with value 0 



Table: 570P 

up to the point of subsequent therapy and a value of 1 from then on; (4) 

censoring patients at the time of subsequent anti-EGFR use and adjusting the 

informative censoring with the inverse probability-of-censoring weighted (IPCW) 

analysis d-f . 

Results: Table. 

Conclusions: Patients receiving chemotherapy alone crossed over earlier and more 

frequently to post-protocol anti-EGFR treatment versus those receiving combination 

therapy. All analyses produced results indicating that the lack of a statistically 

significant OS benefit estimate may have been due to selective crossover bias. The 

results also indicate that IPCW method may be particularly suited for detecting OS 

benefits that otherwise would not be detected with an ITT approach that ignores 

selective crossover bias. 

Disclosure: J. Douillard: AMGEN: Participation in Advisory Boards, speaker in 

Symposia compensated MERCK:Participation in Advisory Boards, speaker in 

Symposia compensated, Research support ROCHE: Participation in Advisory Boards, 

speaker in Symposia compensatedM. Peeters: Consultant/advisory role for Amgen 

and also received honoraria and research funding. A. Rong: Employee of Amgen and 

holds Amgen stock. S. Siena: Advisory role for Amgen, AstraZeneca, Merck Serono, 

Roche, Celgene. S. Braun: Employee of Amgen and holds Amgen stock. R. Sidhu: 

Employee of Amgen and holds Amgen stock. T. Price: Consultant/advisory role for 

Amgen and received honoraria. 

571P BEVACIZUMAB (BEV) + CHEMOTHERAPY (CT) BEYOND FIRST 

PROGRESSION IN PATIENTS (PTS) WITH METASTATIC 

COLORECTAL CANCER (MCRC) PREVIOUSLY TREATED WITH 

FIRST-LINE BEV + CT (ML18147): EFFICACY AND SAFETY 

ANALYSES BY OXALIPLATIN VS IRINOTECAN-BASED CT 

P. Österlund 1 , V. Alonso-Orduna 2 , C. Schlichting 3 , T. André 4 , J. Sastre 5 , 

R. Greil 6 , S. Kubicka 7 , I. Reyes-Rivera 8 , B. McCall 9 , E.J.D. Van Cutsem 10 

1 Medical Oncology, Helsinki University Central Hospital, Helsinki, FINLAND, 

2 Servicio De Oncología Médica, Hospital Universitario Miguel Servet, Zaragoza, 

SPAIN, 3 I. Chirurgische Klinik, Diakoniekrankenhaus Rotenburg GmbH, 

Rotenburg, GERMANY, 4 Medical Oncology, Hopital Saint-Antoine and Université 

Pierre et Marie Curie, Paris, FRANCE, 5 Medical Oncology, Servicio de Oncología 

Médica HC, Madrid, SPAIN, 6 Oncology Centre, III Medizinische Universitätsklinik 

Salzburg, Salzburg, AUSTRIA, 7 Internal Medicine, Cancer Center Reutlingen, 

Reutlingen, GERMANY, 8 Statistics, Genentech Inc., South San Francisco, CA, 

UNITED STATES OF AMERICA, 9 Product Development, Oncology, Genentech, 

Inc., South San Francisco, CA, UNITED STATES OF AMERICA, 10 Digestive 

Oncology, University Hospital Gasthuisberg, Leuven, BELGIUM 

Background: ML18147 is the first randomised study to show that continuing BEV + 

standard CT as second-line (2L) treatment significantly improves overall survival 

(OS) and progression-free survival (PFS) in pts with mCRC who progressed after 

receiving a standard first-line (1L) BEV-containing regimen. Here we evaluate 

outcome in the 2L setting using, as a stratification factor, 1L oxaliplatin vs 

irinotecan-based CT. 

PRIME 181 

Pmab + 

FOLFOX4 FOLFOX4 

Methods: Pts with unresectable, histologically confirmed mCRC who progressed 

within 3 months of discontinuing 1L BEV were randomised to 2L 

fluoropyrimidine-based CT ± BEV (2.5 mg/kg/wk equivalent). Choice of 2L 

oxaliplatin or irinotecan was dependent on the 1L regimen (crossover). OS, PFS, 

overall response rate (ORR) and adverse events (AEs) were analysed in the 2L setting 

using the 1L oxaliplatin or irinotecan-based CT as a stratification factor. 

Results: 820 pts were randomised from Feb 2006 to Jun 2010. Of these, 343 received 

1L oxaliplatin-based CT and 476 received 1L irinotecan-based CT, after which they 

crossed over to receive either oxaliplatin or irinotecan-based CT in 2L. BEV + CT 

beyond progression prolonged OS and PFS, regardless of whether oxaliplatin or 

irinotecan-based CT was used in 1L (Table). ORR was low in CT and BEV + 

CT-treated pts in both groups. AEs associated with BEV were generally similar in pts 

treated with either oxaliplatin or irinotecan-based CT. 

Outcome in 2L 

Pmab + 

FOLFIRI FOLFIRI 


ITT analysis for OS 

n = 325 n = 331 n = 303 n = 294 

Median OS, months 

(95% CI) 

23.9 (20.3– 27.7) 19.7 (17.6–22.7) 14.5 (13.0–16.1) 12.5 (11.2–14.2) 

HR (95% CI) 

Post-protocol anti-EGFR mAb therapy 

0.88 (0.73–1.06) 0.92 (0.78–1.10) 

Incidence, (%) 13 25 12 34 

Median time to use, 

months 

21.5 15.6 12.4 7.9 

OS sensitivity analyses on influence of post-protocol anti-EGFR mAb therapy 

Branson-Whitehead, 

0.84 (0.68-1.05) 0.90 (0.71, 1.14) 

2002 a 

Robins and Tsiatis, 

1992 b 

Allison, 1995 c 

IPCW d-f 

0.83 (0.66-1.04) 0.89 (0.71, 1.13) 

0.68 (0.55-0.83) 1.03 (0.87, 1.23) 

0.74 (0.56-0.97) 0.71 (0.53, 0.94) 

a Branson and Whitehead, 2002; b Robins and Tsiatis, 1992; c Allison, 1995; 

d Rimawi & Hilsenbeck, 2012; e Colleoni et al, 2011; f Robins & Finkelstein, 2000. Abbreviation: CI = confidence interval 

1L oxaliplatin-based CT 1L irinotecan-based CT 

CT (n = 

174) 

BEV + CT (n = 

169) 

CT (n = 

236) 

BEV + 

CT 

(n = 240) 

Median OS, months 10.0 12.0 9.3 10.9 

p-value 0.0524 0.0454 

HR (95% CI) 0.79 (0.62–1.00) 0.82 (0.67–1.00) 

Median PFS, months 4.2 6.2 3.8 5.4 

p-value 0.0005 1% 

of pts, % 

0.2414 0.7145 

Any 52 66 60 61 

Hypertension 0 1 2 2 

Bleeding/haemorrhage

572P PANERB STUDY: WHICH CATEGORY OF PATIENTS, 

SUFFERING FROM METASTATIC COLORECTAL CANCER, CAN 

BENEFIT FROM PANITUMUMAB TREATMENT AFTER 

CETUXIMAB-BASED REGIMEN FAILURE? 

J. Metges 1 , J.F. Ramée 2 , O. Dupuis 3 , P. Deguiral 4 , E. Boucher 5 , O. Cojocarasu 6 , 

M. Ferec 7 , M. Porneuf 8 , J. Douillard 9 , F. Grude 10 

1 Medical Oncology, C.H.U. Morvan Institut de Cancerologie et d’Hematologie, 

Brest Cedex, FRANCE, 2 Medical Oncology, Centre Catherine de Sienne, Nantes, 

FRANCE, 3 Medical Oncology, Centre Jean Bernard, Le Mans, FRANCE, 

4 Medical Oncology, Pole Hospitalier Mutualiste Saint Nazaire, Saint Nazaire, 

FRANCE, 5 Medical Oncology, Centre Eugène Marquis, Rennes, FRANCE, 

6 Oncology, Centre Hospitalier Du Mans, Le Mans, FRANCE, 7 Medical Oncology, 

CH Morlaix, Morlaix, FRANCE, 8 Medical Oncology, Ch Saint Brieuc, Saint 

Brieuc, FRANCE, 9 Medical Oncology, Centre René Gauducheau (ICO) Institut de 

Cancerologie de l’Ouest, St Herblain Cedex, FRANCE, 10 ICO Paul Papin, 

Observatoire Dédié au Cancer, Angers, FRANCE 

Background: Metastatic colorectal cancer (mCRC) management has been clearly 

improved by targeted therapies such as anti-HER1 drugs (panitumumab and 

cetuximab). As evaluation of their use sequentially after progression in the real 

world is strategic to assess health poliltics, no series of patients is currently 

available. The Observatory of cancer Bretagne-Pays de la Loire is a network of 50 

private and public cancer centers particularly focused on good practise for cancer 

drugs use. 

Methods: The aim of the study is to evaluate the use of Panitumumab Monotherapy 

(PM) after previous treatment with Cetuximab-Based Regimen (CBR) in an 

homogeneous series of kras wild type unresectable mCRC according to EMA 

approval. Sex, age, localization of the tumor, successive chemotherapeutic regimens, 

toxicities, response rate, progression free survival (PFS) and overall survival (OS) 

have been studied. 

Results: 106 patients (73 men, median age 64.4 years [36-86]) previously treated 

with CBR received PM at progression. The primary tumor site was colon (62%), 

rectum (35%) and both of them (3%). Patients received successively 1 to 9 lines 

of treatment for mCRC. Objective responses (OR) were observed in 46% of the 

patients under CBR and 17% responded again to PM. Disease stabilization was 

achieved in 17% of the patients treated with CBR and in 13% of the patients 

treated with PM. Amongst the patients who had an OR with CBR, 31% also had 

an OR with PM and 16% were stabilized with PM (clinical benefit 47%). In case 

of cetuximab resistance, only 14% of the patients had a clinical benefit with PM. 

The median PFS under CBR was 6.6 months IC95% [5.3-7.7] and 3.2 months 

IC95% [2.8 -3.5] under PM after CBR. The median OS for the patients who 

achieved a response with both targeted therapies was 25.4 months IC 95% 

[22.4-42.6] vs 15.0 months IC 95% [12.9-18.3] for the patients who did not (p < 

0.0001). 

Conclusion: Our study clearly showed that patients with progression after response 

to cetuximab regimen had a potential opportunity of clinical benefit (47%) with 

panitumumab monotherapy with a good response rate. OS was potentially increased 

in responders to the successive use of both targeted therapies. 

Disclosure: J. Metges: conference for Amgen, MerckSerono and Amgen. O. Dupuis: 

participation in a scientific evening as moderator account for MerckSerono. M. Ferec: 

participation paid to a board VIFOR invitations congress by Roche, Amgen. J. 

Douillard: AMGEN : participation in advisory boards and steering committees, 

speaker in symposia, compensated MERCKSERONO: Research Funding, 

participation in advisory boards and steering committees, speaker in symposia, 

compensated. All other authors have declared no conflicts of interest. 

573P PHASE II STUDY OF 1ST-LINE COMBINED CHEMOTHERAPY 

BEVACIZUMAB WITH MODIFIED RPMI REGIMEN FOR 

ELDERLY OR FRAIL PATIENTS WITH UNRESECTABLE OR 

METASTATIC COLORECTAL CANCER (OGSG0802) 

M. Yoshida 1 ,T.Kato 2 , S. Iwamoto 3 , Y. Miyake 2 , M. Nakamura 4 ,T.Sato 5 , 

D. Sakai 6 , M. Matsuoka 7 , T. Otsuji 7 , H. Furukawa 8 

1 Cancer Chemotherapy Center, Osaka Medical College, Takatsuki, JAPAN, 

2 Department of Surgery, Minoh City Hospital, Osaka, JAPAN, 3 Surgery, Kansai 

Medical University School Hirakata Hospital, Osaka, JAPAN, 4 Aizawa 

Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, JAPAN, 5 Kinki 

University Hospital, Faculty of Medicine, Medical Oncology, Osaka, JAPAN, 

6 Osaka Medical Center for Cancer and Cardiovascular Disease, Medical 

Oncology, Osaka, JAPAN, 7 Gastroenterology, Dongo Hospital, Nara, JAPAN, 

8 Surgery, Kinki University School of Medicine, Osaka, JAPAN 

Background/ Objectives: The first-line combined chemotherapy RPMI regimen with 

bevacizumab (Bmab) in AVF2192g trial for elderly or frail patients (Pts) could be 

active to progression free survival (PFS), the secondary endpoint, although it may not 

prolong overall survival (OS), the primary endpoint. According to the results of 

efficacy and safety studies, a fluoropyrimidine (FU) + Bmab regimen is regarded as an 

option for 1st-line chemotherapy. We planned a phase II study of modified RPMI 

regimen with Bmab for elderly or frail Pts. 


Methods: Pts with confirmed unresectable/metastatic colorectal cancer without 

previous chemotherapy, and fulfilling at least one of the following characteristics 

were enrolled: Age ≧65 years, ECOG performance status 1 or 2, serum albumin ≦ 

3.5g/dl, incompatible with receiving oxaliplatin or irinotecan, or prior abdominal/ 

pelvic radiotherapy. Pts received modified RPMI regimen (5-FU 600 mg/m 2 and 

l-leucovorin 200 mg/m 2 bolus day 1, 8, 15) and Bmab 5 mg/kg day 1, 15, q4w) until 

disease progression or study withdrawal. The primary endpoint was overall response 

rate (ORR), and the secondary endpoints were PFS, OS, safety and treatment 

completion rate of treatment. 

Results: 41 Pts (mean age 76 years [range 56–90]; 55% male) were enrolled to this 

trial from 13 institutions. 28 Pts (68%) had objective progression and a patient 

(2.4%) died without progression. The ORR, the primary endpoint, the rate of best 

response, the disease control rate (CR + PR + SD) were 36.6%, 56.1%, 85.4%, 

respectively. The median PFS was 9.0 months (95%CI, 7.5–19.6) by independent 

central review. Median OS was 30.2 months (95%CI, 23.8–Not achieved). Mean 5-FU 

and Bmab dose intensity were 86.9% and 83.6%, respectively. The incidences of all 

grade/grade 3-4 adverse events: leukopenia (66/7), neutropenia (58/24), 

thrombocytopenia (39/2), nausea (29/0), diarrhoea (34/5), anorexia (32/10), fatigue 

(49/5), stomatitis (29/7) and hypertension (24/5). Grade 3 febrile neutropenia and 

grade 4 pulmonary embolism was observed in one patient. 

Conclusions: The modified RPMI regimen with Bmab showed activity, and was well 

tolerated by elderly or frail Pts. ORR and the median PFS of this regimen were 

similar to historical data with FU + Bmab. This regimen may be a good option not 

requiring percutaneous port placement for elderly or frail Pts. . 

Disclosure: M. Yoshida: The author received few payments for lectures from Chugai 

Pharmaceutical Co., Ltd. Grants for research were also provided to the 

Chemotherapy Center of Osaka Medical College by this pharmaceutical companies. 


574P CLINICAL OUTCOME OF CETUXIMAB FOR METASTATIC 

COLORECTAL CANCER PATIENTS HARBORING KRAS 

CODON61, KRAS CODON146, BRAF, NRAS OR PIK3CA 

MUTATIONS 

E. Shinozaki 1 , H. Bando 2 , T. Nishina 3 , K. Yamazaki 4 , S. Kadowaki 5 , S. Yuki 6 , 

S. Kajiura 7 , K. Tsuchihara 8 , S. Fujii 9 , T. Yoshino 10 

1 Gastrointestinal Oncology, Cancer Institute Hospital of Japanese Foundation for 

Cancer Research, Tokyo, JAPAN, 2 Department of Gastroenterology and 

Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, 

Chiba, JAPAN, 3 Gastrointestinal Oncology, National Hospital Organization 

Shikoku Cancer Center, Matsuyama, JAPAN, 4 Gastrointestinal Oncology, 

Shizuoka Cancer Center, Shizuoka, JAPAN, 5 Division of Gastroenterology, 

Saitama Cancer Center, Saitama, JAPAN, 6 Department of Gastroenterology, 

Hokkaido University Hospital, Sapporo, JAPAN, 7 The Third Departoment of 

Internal Medicine, University of Toyama, Toyama, JAPAN, 8 Cancer Physiology 

Project, Research Center for Innovative Oncology, National Cancer Center 

Hospital East, Kashiwa, JAPAN, 9 Pathology Division, Research Center for 

Innovative Oncology, National Cancer Center Hospital East, Kashiwa, JAPAN, 

10 Department of Endoscopy & Gastrointestinal Oncology, National Cancer 

Center Hospital East, Kashiwa, Chiba, JAPAN 

Background: Retrospective pooled analyses have identified KRAS, BRAF, NRAS, and 

PIK3CA mutations as potentially negative predictive factors for colorectal cancer 

patients treated with Cetuximab (Cmab). We developed a novel kit that applies 

Luminex technology for detection of mutations in KRAS codon61, KRAS codon146, 

BRAF, NRAS, and PIK3CA in a single reaction (GENOSEARCH Mu-PACK). 

Methods: Formalin-fixed paraffin-embedded tumor samples and clinical data of 

colorectal cancer patients treated with Cmab-containing regimens were collected 

from 7 Japanese centers. KRAS, BRAF, NRAS and PIK3CA gene statuses were 

determined, both by our kit and by direct-sequencing (DS). Objective response, 

progression-free survival (PFS), and overall survival (OS) were evaluated in 

subgroups determined by mutation status. 

Results: A total of 83 samples were collected. The concordance rate between our 

kit and DS data was 100%. Our kit results identified 3 samples with mutations 

in KRAS codon 61 (3.6%), 2 in KRAS codon 146 (2.4%), 4 in BRAF (4.8%), 2 

in NRAS (2.4%), and 4 in PIK3CA (4.8%). We also identified 21 samples with 

mutations in KRAS codon 12, 13 (25.3%) by using Luminex technology. All of 

these mutations, except for PIK3CA, were mutually exclusive. The response rate 

for all patients in the study was 24.4%, whereas the response rate for the group 

of patients with all wild-type tumors was 40.8%. The median PFS values of 

patients with all wild-type tumors (N = 49), with KRAS codon12, 13 mutation 

(N = 21), and with any of KRAS codon61, KRAS codon146, BRAF, NRAS, or 

PIK3CA mutations (N = 12) were, respectively, 6.4 months (95%CI: 2.9, 10.0), 

2.7 months (95%CI: 1.2, 4.2), and 1.6 months (95%CI: 1.5, 1.7) (Log Rank test, 

P < 0.0001). The median OS values were, respectively, 15.6 months (95%CI: 10.1, 

20.2), 8.2 months (95%CI: 5.7, 10.7), and 6.3 months (95%CI: 1.9, 10.7) (Log 

Rank test, P < 0.0001). 

Conclusions: Patients with KRAS codon61, KRAS codon146, BRAF, NRAS, and 

PIK3CA mutations may not derive clinical benefits from Cmab, nor would patients 

with KRAS codon 12, 13 mutations. This newly developed detection kit is robust and 



practical for examining a patient’s KRAS codon61, codon146, BRAF, NRAS, and 

PIK3CA gene status. 


575P BIOPSY SPECIMENS OBTAINED 7 DAYS AFTER STARTING 

CHEMORADIOTHERAPY (CRT) PROVIDES RELIABLE 

PREDICTORS OF RESPONSE TO CRT FOR RECTAL CANCER 

T. Suzuki 1 , S. Sadahiro 1 , A. Tanaka 1 , K. Okada 1 , A. Kamijo 1 , S. Kawada 2 

1 Gastrointestinal Surgery, Tokai University School of Medicine, Isehara, JAPAN, 

2 Radiology, Tokai University School of Medicine, Isehara, JAPAN 

Background: Preoperative CRT is a standard treatment for locally advanced 

rectal cancer (LARC). The histologic response to CRT or the downstaging has 

been reported to be closely related to oncologic outcomes. Various biomarkers 

in biopsy specimens obtained before CRT have been investigated as 

predictors of response, however, reliable predictive biomarkers remain to be 

established. 

Methods: The study group comprised 101 consecutive patients with LARC who 

received preoperative CRT of 45Gy with oral uracil/tegafur (UFT) or S-1. We 

evaluated histologic findings on H-E staining and immunohistochemical expressions 

of Ki67, p53, p21, and apoptosis in biopsy specimens obtained before CRT and 7 

days after starting CRT. These findings were contrasted with the rate of histologic 

marked regression and the degree of tumor shrinkage. 

Results: In biopsy specimens obtained before CRT, the degree of tumor shrinkage 

on barium enema (BE) were significantly greater in patients with p21-positive 

tumors (52 ± 11%) than in those with p21-negative tumors (45 ± 16%) (p < 0.01). 

In biopsy specimens obtained 7 days after starting CRT, the histologic marked 

regression according to the tumor regression grade (TRG) criteria was significantly 

higher in apoptosis-positive patients (57.1%) and p21-positive patients (49.2%) 

than in apoptosis-negative patients (30.1%) and p21-negative patients (20.0%) (p = 

0.02 and p < 0.01, respectively). The degrees of tumor shrinkage based on BE and 

on MRI were both significantly higher in apoptosis-positive patients (55 ± 12%, 81 

± 15%) and p21-positive patients (52 ± 13%, 74 ± 19%) than in apoptosis-negative 

patients (45 ± 15%, 68 ± 19%) and p21-negative patients (41 ± 13%, 66 ± 19%) (p < 

0.01, p < 0.01, p < 0.01 and p = 0.04, respectively). Histologic changes in H-E 

stained biopsy specimens significantly correlated with marked regression as well as 

with tumor shrinkage based on BE and MRI (p < 0.01, p < 0.01 and p = 0.03, 


Conclusions: Immunohistochemical expressions of p21 and apoptosis together with 

histologic changes on H-E-stained biopsy specimens obtained 7 days after starting 

CRT are strong predictors of response to CRT. 


576P ADVERSE EVENTS IN ELDERLY PATIENTS ON ADJUVANT 

THERAPY WITH UFT/LV OR S-1 FOR STAGE III COLON 

CANCER: ACTS-CC TRIAL [TRICC0706] 

M. Ishiguro 1 , H. Uetake 1 , T. Ishikawa 1 , Y. Kusunoki 2 , F. Kinoshita 2 , 

N. Kashiwagi 2 , Y. Nagata 2 , Y. Matsubara 2 , K. Sugihara 3 

1 Department of Translational Oncology, Tokyo Medical and Dental University, 

Graduate School, Tokyo, JAPAN, 2 Translational Research Informatics Center, 

Foundation for Biomedical Research and Innovation, Kobe, JAPAN, 3 Department 

of Surgical Oncology, Tokyo Medical and Dental University, Graduate School, 

Tokyo, JAPAN 

Background: The ACTS-CC trial is a phase III trial designed to validate 

non-inferiority of S-1 to UFT/ LV, a standard adjuvant therapy for stage III colon 

cancer in Japan. We reported the safety profile of this trial (Brit J Cancer 2012). To 

clarify the characteristics of adverse events (AEs) in elderly patients, subgroup 

analysis was performed. 

Methods: 20-80 aged patients with stage III colon cancer were randomly assigned to 

receive UFT/LV (UFT: 300 to 600 mg/day and, LV: 75 mg/day on days 1-28, followed 

by 7 days rest, 5 courses) or S-1 (80 to 120 mg/day on days 1-28, followed by 14 days 

rest, 4 courses). We compared treatment status and safety among group A (age ≤ 70), 

group B (age 71-75) and group C (age 76-80). 

Results: A total of 1,504 patients (756 in S-1 group, 748 in UFT/LV group,) were 

analyzed. The numbers of patients of group A, B and C were 506 (69%), 160 

(20%) and 90 (11%), and the rates of patients with PS 1 in each group were 

2.6%, 4.3% and 16.8%, respectively. Pre-treatment value of Hemoglobin of group 

B and C was lower than that of group A, while there were no differences in that 

of neutrophils, platelets and creatinine. In S-1 treatment, incidences (any grades) 

of anemia (group A: 29%, B: 37%, C: 47%), anorexia (30%, 34%, 46%) and 

fatigue (25%, 29%, 39%) were higher in group C. In ≥ grade 3 AEs, incidences of 

anorexia (3%, 7%, 13%), diarrhea (4%, 3%, 7%) and fatigue (2%, 3%, 7%) were 

higher in group C. In UFT/LV treatment, incidence (any grades) of anorexia 

(22%, 33%, 30%) and anemia (24%, 32%, 35%) were higher in group B and C, 

while incidence of elevation of AST (23%, 15%, 12%) and ALT (25%, 15%, 12%) 

were higher in group A. The completion rates of S-1 treatment was lower in 

group C (group A: 78%, B: 77%, C: 69%), although those of UFT/LV did not 

differ among the groups. There was no difference in the rate of discontinuation 

due to AEs listed on the discontinuation criteria among the groups, while that 

due to AEs not listed on the criteria (i.e. physician’s judgment or patient’s 

request) was higher in group C. 

Conclusions: In elderly patients, subjective AEs such as anorexia and fatigue were 

common, and mild anemia was observed in one-third of ≥71 aged patients. 


577P EXTENSIVE LIVER RESECTIONS AND PREOPERATIVE 

REGIONAL INTRAARTERIAL CHEMOTHERAPY IN PATIENTS 

WITH LIVER COLORECTAL CANCER METASTASES AND 

UNFAVOURABLE PROGNOSTIC FACTORS 

S. Khays 1 , K. Mamontov 1 , A. Kotelnikov 2 , S. Lazarev 1 , A. Lazarev 3 

1 Liver and Pancreas Surgery, Altai Branch of N. N. Blokhin Russian Cancer 

Research Centre, Barnaul, RUSSIAN FEDERATION, 2 Liver and Pancreas 

Surgery, N. N. Blokhin Russian Cancer Research Centre, Moscow, RUSSIAN 

FEDERATION, 3 N. N. Blokhin Russian Cancer Research Centre, Altai Branch of 

N. N. Blokhin Russian Cancer Research Centre, Barnaul, RUSSIAN 

FEDERATION 

Objective: To analyze patients with negative prognostic factors, as well as overall and 

disease-free survival. 

Materials and methods: 101 patients with liver colorectal cancer metastases were 

enrolled in this local observational study. All patients undergone preoperative 

regional intraarterial chemo- or biotherapy (group 1 - FOLFOX 6, group 2 - 

FOLFOX 6 + bevacizumab) followed by liver resection. Synchronous metastases – in 

54 patients (53%). Metachronous metastases – in 47 (47%). Bilobate lesion – in 62 

patients (62%). Solitary metastasis – in 46 (46%). Multiple metastasis – in 55 (54%). 

Partial regression of tumor was observed in 26 patients (26%), stabilization – in 53 

(53%). Progression – in 21 (21%). Extensive liver resection with resection of 

contralateral lobe was performed in 39 patients (39%). Standard hepatectomy – in 71 

(70%). Extended hepatectomy – in 30 (30%). Extrahepatic metastases – in 23 patients 

(23%). Metastases in lymph nodes of hepatoduodenal ligament – 18 (18%). 

Results: Univariate analysis revealed three unfavorable factors: bilobate lesion of the 

liver (p = 0.04), multiple liver metastases (p= 0.00029), metastases to the 

hepatoduodenal ligament (p = 0.001). Multivariate analysis revealed two unfavorable 

prognostic factors: multiple liver metastases (p = 0.015), metastases to the 

hepatoduodenal ligament (p = 0.04). Overall survival with FOLFOX 6 + bevacizumab: 

Median – 33 months, 3-years - 36 ± 10, 5 years - 12 ± 7. With FOLFOX 6: Median – 

29 months, 3 years – 42 ± 7, 5 years – 14 ± 6. Overall survival in case of metastases to 

the lymph nodes of hepatoduodenal ligament. With metastases: Median – 27 

months, 3 years – no, 5 years – no. Without metastases: Median – 35 months, 3 

years - 49 ± 7, 5 years – 16 ± 6. Overall survival depending on the number of liver 

foci. Solitary foci: Median – 35 months, 3 years - 42 ± 10, 5 years – 23 ± 10. Multiple 

foci: Median – 28 months, 3 years – 51 ± 10, 5 years – 12 ± 7. 

Conclusion: The main criteria characterizing tumor aggressiveness are the number of 

liver foci and metastases to the hepatoduodenal ligament, which determine tumor 

spreading. 


578P COMPARISON OF PATHOLOGICAL RESPONSES (PR) 

OBSERVED ON COLORECTAL CANCER METASTASES (CRCM) 

RESECTED AFTER DIFFERENT PREOPERATIVE 

TREATMENTS 

M. van den Eynde 1 , M. Gizzi 2 , G. Pairet 3 , P. Lefesvre 4 , V. Lannoy 5 , J. Gigot 6 , 

B. Navez 6 , J. Canon 2 , C. Sempoux 3 , J. Carrasco 2 

1 Medical Oncology, Cliniques Universitaires St-Luc, Brussels, BELGIUM, 

2 Medical Oncology, Grand Hopital de Charleroi, Charleroi, BELGIUM, 

3 Pathology, Cliniques Universitaires St-Luc, Brussels, BELGIUM, 4 Pathology, IPG 

Loverval, Loverval, BELGIUM, 5 Centre du Cancer, Cliniques Universitaires 

St-Luc, Brussels, BELGIUM, 6 Surgery, Cliniques Universitaires St-Luc, Brussels, 

BELGIUM 

Background: Irinotecan (IR) or oxaliplatin (OX)-based regimens optionally 

combined with anti-VEGF or anti-EGFR Target Therapies (TT) are used as 

preoperative treatment for metastatic colorectal patients before resection of CRCM. 

Best combination remains unclear. The study purpose was to compare PR observed 

on resected CRCM after different preoperative treatments. 

Methods: 114 patients engaged for CRCM resection after 2005 were included in this 

retrospective analysis. PR was evaluated on 296 resected CRCM according to the 

pathological Tumor Regression Grading scale (TRG), grading PR from complete 

(TRG1) to absent (TRG5). Mean TRG of resected metastasis was compared based on 

Kruskall-Wallis and Mann-Whitney tests. Cumulative PFS were calculated by 

Kaplan-Meir method and compared by log-rank test. 


Results: 92/114 patients were preoperatively treated. Mean TRG after OX without TT 

was better than mean TRG after IR without TT (p = .044). No difference was 

observed between mean TRG after chemotherapy alone compared to mean TRG after 

chemotherapy + anti-VEGF (p = .53) or to mean TRG after chemotherapy + 

anti-EGFR (p = .39). Subgroup analysis revealed that mean TRG after IR + 

anti-EGFR was better than mean TRG after OX + anti-EGFR (p = .031), and that 

mean TRG after OX + anti-VEGF was better than mean TRG after IR + anti-VEGF 

(p = .001). PFS analysis for the 92 preoperatively treated patients revealed that 13 

patients with major PR (TRG ≤ 2), had a significantly improved PFS compared to 79 

patients with minor or no PR (TRG > 2) (median PFS= 33.7 vs 22.9 month p= .018). 

Conclusion: PR observed on resected CRCM after a preoperative treatment does not 

seem to be linked to the TT (anti-VEGF or anti-EGFR) but rather to the 

chemotherapy/TT association with a significant advantage for OX + anti-VEGF or 

IR + anti-EGFR combinations. 

Preoperative strategy Patients (n) Metastases (n) TRG mean 95% CI 

No treatment 22 54 4.33 4.11- 4.55 

Chemo alone 38 86 3.19 2.95 - 3.43 

OX 28 68 3.16 2.89-3.43 

IR 8 11 3.91 3.44-4.38 

Other 2 7 ND ND 

Anti-VEGF + chemo 38 120 3.32 3.10 - 3.54 

OX 8 27 2.63 2.18 - 3.08 

IR 29 80 3.53 3.27 - 3.78 


Anti-EGFR + chemo 16 36 2.97 2.50 - 3.44 

OX 9 16 3.56 2.98 - 4.15 

IR 6 19 2.47 1.77 - 3.18 



579P ASSESSMENT AND COMPARISON OF TREATMENT EFFICACY 

IN PATIENTS WITH COLORECTAL CANCER (CRC), USING A 

NOVEL METHODOLOGY TO ESTIMATE THE RATE OF TUMOR 

REGRESSION (D) AND GROWTH (G) 

M. Blanco Codesido 1 , J. Wilkerson 2 , L. Rodriguez Gayo 3 , M. Rodriguez Alonso 3 , 

P. Nava Garcia 3 , A. Matas Ochoa 3 , A.J. Muñoz Martín 3 , S. Álvarez Suárez 3 ,P. 

García Alfonso 3 ,T.Fojo 2 

1 Servicio De Oncología Médica, Hospital General Univ. Gregorio Marañon, 

Madrid, SPAIN, 2 Medical Oncology Branch Center for Cancer Research, 

National Cancer Institute, Bethesda, MD, UNITED STATES OF AMERICA, 

3 Servicio Oncología, Hospital Universitario Gregorio Marañon, Madrid, SPAIN 

Introduction: Novel methods of assessing treatment efficacy should prove helpful in 

drug development and in the management of cancer patients (pts). We have 

developed a novel method to analyze tumor response to therapy by quantifying the 

rate of tumor regression (d) and growth (g). We have shown g is slower when pts are 

on effective therapy and that g correlates with survival. We utilized this novel 

methodology in pts with a diagnosis of CRC to compare the efficacy of oxaliplatinand 

irinotecan-containing regimens (OCR, ICR). Unlike PFS, an incremental 

measure of efficacy, g is a continuous variable and can more accurately assess 

differences between treatments. Because calculations of g are indifferent to 

assessment intervals, estimating a tumor’s g allows comparison of efficacy across 

trials. 

Methods: Using tumor measurements obtained for RECIST assessments or serum 

CEA levels and a two-phase mathematical equation we determined d and g in 70 pts 

at each evaluation. 

Results: 70 pts (47 male, 23 female) with metastatic CRC were studied. The median 

g value with OCR (.00132) was statistically similar (p = 0.573) to that observed with 

ICR (.00148). Both therapies also had similar effects on d (OCR = 0.00529; ICR = 

0.00451; p = 0.716). Similar results were seen using serum CEA levels. Furthermore, 

in an individual pt, statistically valid g and d values could be estimated long before 

tumor quantity increased, providing an early indicator of treatment failure. 

Importantly, in the majority of pts receiving prolonged treatment the growth rate 

constant did not change, despite rising tumor quantities, indicating resistance is 

intrinsic. Additional data being gathered should allow us to compare relative effects 

on g in first and subsequent lines to discriminate between the effects observed in 

tumor shrinkage and the impact on tumor growth. 

Conclusions: In this cohort of CRC patients the data suggest both OCR and ICR 

have similar efficacy. The evidence in pts receiving long term therapy demonstrating 

no change in g over time suggest resistance is intrinsic and not acquired, and would 

support a strategy of continued treatment with a tolerable regimen given the similar 

efficacy of the commonly used combinations. 



580P HEPATIC ARTERIAL INFUSION (HAI) OF OXALIPLATIN PLUS 

INTRAVENOUS (IV) FLUOROURACIL (FU), LEUCOVORIN (LV) 

AND CETUXIMAB FOR FIRST-LINE TREATMENT OF 

UNRESECTABLE COLORECTAL LIVER METASTASES (CRLM): 

FINAL RESULTS OF A MULTICENTER PHASE 2 STUDY 

(CHOICE) 

D. Malka 1 , V. Boige 1 , M. Faron 2 , C. Caramella 3 , E. Boucher 4 , P. Rivera 5 ,T.De 

Baere 3 , D. Goéré 6 , J. Pignon 2 , M. Ducreux 1 

1 Oncologic Medicine, Institut Gustave Roussy, Villejuif, FRANCE, 2 Biostatistics 

and Epidemiology, Institut Gustave Roussy, Villejuif, FRANCE, 3 Radiology, Institut 

Gustave Roussy, Villejuif, FRANCE, 4 Medical Oncology, Centre Eugène Marquis, 

Rennes, FRANCE, 5 Medical Oncology, CHU, Toulouse, FRANCE, 6 Surgery, 

Institut Gustave Roussy, Villejuif, FRANCE 

Background: To determine the efficacy and tolerance of HAI oxaliplatin plus iv FU/ 

LV and cetuximab in patients (pts) with unresectable CRLM. 

Methods: Main eligibility criteria for this phase 2 study were: histologically proven 

colorectal adenocarcinoma; tumor wild-type (wt) KRAS status (protocol amendment 

in 09/2008); unresectable CRLM; no extrahepatic disease (except primary with 

absent/mild symptoms, and ≤ 3 nonspecific lung nodules ≤ 5 mm in diameter); no 

prior chemotherapy for metastatic disease; WHO performance status 0-1. After 

surgical or percutaneous insertion of an implantable HAI catheter, pts were treated 

with HAI oxaliplatin (100 mg/m 2 in 2 hrs) plus iv modified LV5FU2 regimen (LV, 

400 mg/m 2 in 2 hrs; FU, 400 mg/m 2 bolus then 2400 mg/m 2 in 46 hrs) every two 

weeks plus iv cetuximab (400 mg/m 2 then 250 mg/m 2 /week, or 500 mg/m 2 every two 

weeks) until disease progression, limiting toxicity, or CRLM resection. Primary 

endpoint was objective response rate (ORR) (RECIST 1.0). Secondary endpoints 

included toxicity (NCI CTC-AE v3.0), disease control rate (DCR), resection rate, 

progression-free survival (PFS), and overall survival (OS). 

Results: A total of 36 pts were included in 8 centers from 11/2006 to 12/2009. Most 

of the 35 eligible pts (male, 63%; median age, 54 yrs [range, 33-75]) had extensive 

disease (≥ 4 CRLM, 88%; bilobar CRLM, 91%). Pts received a median of 10 cycles 

(range, 1-41). Main severe toxicity was abdominal pain (40%), neutropenia (37%), 

peripheral neuropathy (34%) and rash (29%). Among 32 evaluable pts, ORR was 

87% and DCR was 97%. Among the evaluable pts with wt KRAS (n = 27) or wt 

KRAS/BRAF (n = 24) tumor status, ORR were 89% and 96% and DCR 96% and 

100%, respectively. Overall, 23 of the 35 pts (66%) underwent curative-intent 

resection and/or radiofrequency ablation (wt KRAS pts, 21 [70%]; wt KRAS/BRAF 

pts, 20 [74%]). After a median follow-up of 48 months, median PFS was 29 months 

(median OS, not reached). 

Conclusions: First-line HAI oxaliplatin plus iv LV5FU2 and cetuximab seems 

feasible and highly effective in pts with unresectable CRLM. 

Disclosure: D. Malka: Membership on an advisory board: Roche Research funding: 

Amgen, Merck Serono, Sanofi-Aventis. M. Ducreux: Membership on an advisory 

board: Roche, Pfizer, Sanofi-Aventis, Merck Serono, Amgen Research funding: Roche, 

Merck Serono, Pfizer. All other authors have declared no conflicts of interest. 

581P SENSITIVITY ANALYSES OF PROGRESSION-FREE SURVIVAL 

(PFS) OF AFLIBERCEPT-FOLFIRI VERSUS PLACEBO-FOLFIRI 

IN METASTATIC COLORECTAL CANCER (MCRC): RESULTS 

FROM THE VELOUR STUDY 

E. Van Cutsem 1 , J. Tabernero 2 , R. Lakomy 3 , J. Prausova 4 , P. Ruff 5 , 

V. Moiseyenko 6 , D. Ferry 7 , E. Boelle 8 , J. McKendrick 9 , C. Allegra 10 

1 Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, BELGIUM, 

2 Oncology Department, Vall d’Hebron University HospitalMedical Oncology 

Service, Barcelona, SPAIN, 3 Department of Clinical Oncology, Masaryk Memorial 

Cancer Institute, Brno, CZECH REPUBLIC, 4 Oncology, University Hospital Motol, 

Prague, CZECH REPUBLIC, 5 Medical Oncology, University of Witwatersrand 

Medical School, Johannesburg, SOUTH AFRICA, 6 Oncology, St-Petersburg 

Medical Academy, St-Petersburg, RUSSIAN FEDERATION, 7 Oncology, Box Hill 

Hospital, West Midlands, UNITED KINGDOM, 8 Research and Development, 

Sanofi, Vitry-sur-Seine, FRANCE, 9 Oncology, Box Hill Hospital, Victoria, 

AUSTRALIA, 10 Oncology, University of Florida, Gainesville, FL, UNITED STATES 

OF AMERICA 

Background: The VELOUR study [NCT00561470] in previously treated mCRC 

showed significant improvement in overall survival (13.5 vs 12.06 months; P = 

0.0032) and PFS (6.9 vs 4.67 months; P = 0.00007) with aflibercept-FOLFIRI vs 

placebo-FOLFIRI. Two sensitivity analyses (SAs) were performed to assess robustness 

of PFS observed in the primary analysis. 

Methods: In the primary PFS analysis, an Independent Review Committee (IRC) 

assessed disease progression per radiological tumor progression. The primary PFS 

analysis was performed at a conservative α level of 0.0001. In SA #1, patients with 

documented radiological progression or death occurring >9 weeks after the last valid 

tumor assessment without progression and patients who received further anti-cancer 

therapy without documented progression were censored at the last valid tumor 

assessment date. In SA #2, PFS was per the investigators’ assessment of lesions; 

clinical progression was considered as an event. 



Results: SA #1 (Table) showed significant improvement in PFS with 

aflibercept-FOLFIRI compared to placebo-FOLFIRI (P < 0.00001), thus confirming 

primary PFS analysis. SA #2 also showed an improvement in PFS with aflibercept vs 

placebo; difference was not significant (P = 0.0017) at the 0.0001 α level. 

Discrepancies between IRC and investigators’ assessments were noted in placebo (n 

= 273, 45.8%) and aflibercept (n = 231, 39.3%) arms. An unstratified log-rank test 

comparing primary PFS in the two arms was consistent with the stratified analysis, 

showing a significant difference in PFS with aflibercept (P = 0.00005). Aflibercept 

showed typical anti-VEGF side effects. 

Conclusion: The data from these PFS sensitivity analyses (SAs) are consistent with 

the primary analysis of PFS in VELOUR, further supporting the statistically 

significant and clinically meaningful improvement in PFS seen in the primary 

analysis. Funded by Sanofi & Regeneron 

Analysis: PFS 

(months) Placebo N = 614 Aflibercept N = 612 HR [99.99% CI] 

Primary: 4.67 4.07 – 5.55 6.90 5.88 – 7.85 0.758 [0.578 – 0.995] 

SA #1: 4.53 4.07 – 5.68 6.97 6.05 – 8.51 0.654 [0.477 – 0.895] 

SA #2: 4.50 4.04 – 5.55 6.24 5.49 – 7.19 0.814 [0.630 – 1.052] 

Disclosure: E. Van Cutsem: I have received research funding from Sanofi. 

J. Tabernero: I have an advisory relationship with sanofi, for which I have been 

compensated. R. Lakomy: I have received research funding from Sanofi. P. Ruff: I 

have received honorarium from Amgen, Merck AG, Roche, Sanofi and Pfizer. I have 

received research funding from Amgen, Merck AG, Sanofi and Pfizer. I have received 

travel grants from Amgen, Roche, and Pfizer. D. Ferry: I have an advisory 

relationship with Sanofi. I have received honorarium from Sanofi. E. Boelle: I am an 

employee of Sanofi. C. Allegra: I have an advisory relationship with Sanofi. All other 


582P A PHASE II STUDY OF COMBINED CETUXIMAB, IRINOTECAN, 

OXALIPLATIN AND UFT (ESCOUT) IN PATIENTS WITH 

ADVANCED COLORECTAL CANCER (ACRC) INCORPORATING 

ANALYSIS OF CIRCULATING TUMOUR CELLS (CTCS) 

M. Krebs 1 , S. Gollins 2 , I. Chau 3 , J. Hasan 4 , M. Braun 4 , K. Morris 1 , J. Beech 4 , 

G. Adaway 4 , C. Dive 1 , M.P. Saunders 4 

1 Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer 

Research, Manchester, UNITED KINGDOM, 2 Clinical Oncology, North Wales 

Cancer Treatment Centre, Wales, UNITED KINGDOM, 3 Medicine, Royal Marsden 

Hospital, Sutton, UNITED KINGDOM, 4 Medical Oncology, The Christie NHS 

Foundation Trust, Manchester, UNITED KINGDOM 

Introduction: Patients (pts) with ≥3 CTCs/7.5ml blood at baseline, enumerated by 

the CellSearch® (Veridex) system, have poor overall survival (OS)1. CTC guided 

treatment strategies may improve pt outcomes. This study investigated the efficacy of 

combining 4 active agents and evaluated CTC numbers for prognostic and 

pharmacodynamic utility. 

Methods: Pts with previously untreated, inoperable, ACRC and wtKRAS were 

eligible. Chemotherapy was administered every 28 days with Cetuximab 400 mg/m 2 

D1 & D15 and UFT 250 mg/m 2 with calcium folinate 30mg TDS D1-21. UFT dose 

was reduced by 1 caps/day for grade 2/3 diarrhoea. Irinotecan 180 mg/m 2 D1 and 

oxaliplatin 100 mg/m 2 D15 alternated to reduce long-term toxicity of each drug. 

Treatment was continued until disease progression. The primary end-point was 

response rate (RR) and secondary endpoints included progression free survival (PFS), 

OS, toxicity and CTC number. Blood samples (7.5ml) for CTC analysis were drawn 

at baseline and D15. CTCs were enumerated using the CellSearch® system. Results: 

Forty-eight pts were recruited; 46 were evaluable for response and 42 for CTC 

enumeration. A 67% RR was achieved with disease control in 91% - CR 2 pts (4%), 

PR 29 (63%) & SD in 11pts (24%). Two pts with inoperable colonic tumours had 

curative resections after chemotherapy; no patients had liver only disease. Grade 3 

toxicities included diarrhoea (21%), lethargy (17%), neutropenia (8%), parasthesia 

(17% G2, no G3) and alopecia (4% G2). Only 14 pts have died so OS is expected to 

increase with longer review. At baseline 50% pts had ≥3 CTCs suggesting this cohort 

comprised a poor prognostic group; median PFS/OS of these pts was 8.5/18.8 

months(m), considerably better than expected (cf 6.1/11.6m in Cohen1). Pts with 5 Ug/L 

(primary tumor is a “secretor”) whilst 50.5% did not have elevated pre-op CEA 

(“non-secretor”). The pre-op CEA value is prognostic (continuous variable, p < 

0.01). During follow-up, all non-secretors and 58% of secretors achieved a trough 

CEA < 5 Ug/L. Achieving a trough CEA 5 Ug/ 

L prior to relapse was observed in 51% of all patients. This new rise was more 

likely to be observed among patients whose initial primary was secretory (p < 

0.01). The median time from new rise in CEA to clinical relapse was 2.4 months. 

This was not different between initial secretors and non-secretors. At clinical 

relapse, 82% of initial secretors vs 47% of initial non-secretors had elevated CEA 

(p < 0.01). 

Conclusions: Pre-operative CEA levels prior to initial surgery influence CEA 

dynamics post curative resection in patients with recurrent colorectal cancer. Among 

secretors, fall to baseline CEA is associated with longer time to recurrence. Among 

all patients, a new rise in CEA is more likely to occur in patients whose initial 

primary is secretory. Once this new rise occurs, median time to recurrence is 2.4 

months and this duration is not dependent on initial secretory status. 


584P FDG-PET TUMOR LOAD PARAMETERS MEASURED BY TOTAL 

LESION GLYCOLYSIS AS PREDICTORS OF TREATMENT 

RESPONSE AND OUTCOME IN METASTATIC COLORECTAL 

CANCER 

H. El Mansy 1 , C. Garcia 2 , A. Deleporte 1 , L. Ameye 3 , A. Hendlisz 1 , P. Flamen 2 

1 Medical Oncology, Institut Jules Bordet, Brussels, BELGIUM, 2 Nuclear 

Medicine, Institut Jules Bordet, Brussels, BELGIUM, 3 Data Centre, Institute Jules 


Objectives: Early metabolic response measured by the change of FDG maximum 

Standardized Uptake Value (SUVmax) on PET-CT after 1 cycle of chemotherapy in 

patients with metastatic colorectal cancer (mCRC) can predict negative objective 

response and is correlated to Overall Survival (OS) (Hendlisz et al. 2011). The aim of 

this work is to assess the correlation between the change in FDG-PET whole body 

metabolic tumoral load parameters and the RECIST response, progression free 

survival (PFS), OS. 

Methods: FDG-PET/CT scans were performed at baseline and on Day 14, in 41 

patients with unresectable mCRC undergoing a biweekly chemotherapy regimen. 

Patients were followed-up for up to 28 months. The change in Functional Tumor 

Volume (FTV) and Total Lesion Glycolysis (TLG) (TLG = FTV x SUVmean) of all 

the lesions was calculated using a fixed threshold segmentation algorithm (threshold 

for segmentation = SUV mean of 30 mm sphere in the right lobe of the liver plus 3 

standard deviations) corrected to lean body mass (Wahl et al 2009). Predictive and 

prognostic value was tested through correlation with RECIST response (using 

independent dedicated CT), PFS and OS. A cutoff value for TLG responding patients 

was set at 40% or more decrease in the baseline value. 

Results: 39 patients were evaluable for analysis. The median OS was 20 months (95% 

CI, 10 to 28), the change in whole body FTV and TLG were significantly related to 

RECIST response (p-value: 0.015 and 0.0038), to PFS (P-value: 0.009, 0.018) and to 

OS (p-value: 0.002, 0.0027). Patients with > 40% decrease in TLG have better PFS: 

median 12 months compared to median 3 months in the rest of the patients [log 

rank test p-value 0.004; HR 0.31 (95% CI, 0.14 to 0.72)], and a better median OS 27 

months compared to 11 months [log rank test p-value 0.05; HR 0.38 (95% CI, 0.14 

to 1.04)]. 

Conclusions: Changes in the metabolic tumoral load parameters after one cycle of 

standard chemotherapy for mCRC are predictors of RECIST response, progression 

free and overall survival. 



585P CHANGES IN THE INTESTINAL ENVIRONMENTS OF 

PATIENTS WITH COLORECTAL CANCER OR ADENOMA 

S. Ohigashi 1 , K. Sudo 1 , H. Onodera 1 , D. Kobayashi 2 , O. Takahashi 3 , 

T. Takahashi 4 , T. Asahara 4 , K. Nomoto 4 

1 Gastroenterological Surgery, St. Luke’s International Hospital, Tokyo, JAPAN, 

2 General Internal Medicine, St. Luke’s International Hospital, Tokyo, JAPAN, 

3 Center for Clinical Epidemiology, St. Luke’s Life Science Institute, Tokyo, 

JAPAN, 4 Microbiological Research, Yakult Central Institute, Tokyo, JAPAN 

Background: An increasing amount of evidence suggests a role for microbiota in 

colorectal cancer (CRC). However, it remains unclear whether microbial dysbiosis is 

the cause or the result of CRC onset. We analyzed the intestinal environments to 

determine whether the changes differed with the stage of CRC. 

Patients and methods: We analyzed 13 groups of microbiota, 8 types of organic 

acids, and pH in fecal matter obtained from the following groups: individuals with 

CRC, individuals with adenoma, and individuals with normal intestinal tracts. 

Ninety-three patients with CRC and 49 healthy individuals (22 with adenoma and 27 

without adenoma) were enrolled. The fecal microbiota was identified using reverse 

transcription-quantitative PCR. 

Results: The counts of total bacteria (10.3 ± 0.7 vs. 10.8 ± 0.3 log 10 cells/g of feces; P 

< 0.001), 5 groups of obligate anaerobe (Clostridium coccoides group, C. leptum 

subgroup, Bacteroides fragilis group, Bifidobacterium, and Atopobium cluster), and 2 

groups of facultative anaerobes (Enterobacteriaceae and Staphylococcus) were 

significantly lower in the cancer group than in the healthy individuals. While the 

concentrations of short chain fatty acids (SCFA) such as acetic acid, propionic acid, 

and butyric acid were significantly decreased in the CRC group, the pH was 

increased in the CRC group (7.4 ± 0.8 vs. 6.9 ± 0.6; P < 0.001). Comparison among 

the CRC, adenoma, and non-adenoma groups revealed that fecal SCFAs 

concentrations and pH in the adenoma group were intermediate to the CRC group 

and the non-adenoma group. Within the CRC group, no differences in either 

microbiota or organic acids were observed among T-stages or Dukes stages. 

Conclusions: CRC patients showed significant changes in the fecal microbiota, SCFA 

concentrations, and pH. These changes are not a result of CRC progression but are 

involved in CRC onset. 


586P DOES THE COMPLIANCE TO ADJUVANT CHEMOTHERAPY 

DEPEND ON NEOADJUVANT RADIATION THERAPY 

MODALITY? 

K. Chan 1 , T. Vuong 2 , P. Kavan 2 , T. Niazi 2 , C. Holcroft 3 , E. Ferland 4 , J. Sturgeon 2 , 

D. Melnychuk 2 , T. Alcindor 2 , G. Batist 2 

1 Medicine, McGill University, Montreal, QC, CANADA, 2 Oncology, McGill 

University, Montreal, QC, CANADA, 3 Clinical Epidemiology, McGill University, 

Montreal, QC, CANADA, 4 Oncology, Pierre Boucher Hospital, Longueuil, QC, 

CANADA 

One of the standard approach for the locally advanced rectal cancer patients is 

neoadjuvant chemoradiation therapy (CRT), followed by total mesorectal excision 

(TME) and adjuvant chemotherapy (ACT). ACT compliance has been a major 

concern for these patients. In this study we assessed the possible impact of 

neoadjuvant radiation therapy (RT) modality on ACT compliance. 

Methods: We, retrospectively, analyzed the data of 114 locally advanced rectal cancer 

patients, after neoadjuvant RT and referred for consideration of ACT, at McGill 

University hospitals. ACT compliance was defined as pts who received at least 6 cycles 

of ACT and optimal dose compliance (ODC) was defined as pts who received at least 

85% of the recommended chemotherapy dose. Neoadjuvant RT modalities included 

high dose rate endorectal brachytherapy (HDREBT) alone with no chemotherapy; 

conformal external beam RT (3D-CRT) with chemotherapy and intensity-modulated 

RT (IMRT) with chemotherapy. We applied a chi-square test for 2-way categorical 

associations and multivariable logistic regression with compliance as the outcome. 

Results: The data of 114 consecutive locally advanced rectal cancer patients, mean age 

64y (range:32-85), were analyzed. 41 patients (36%) were treated with neoadjuvant 

HDREBT alone, 33 (29%) with 3D-CRT and chemotherapy, and 40 (35%) with IMRT 

and chemotherapy. The HDREBT dose was 26 Gy in 4 consecutive fractions alone and 

that of 3D-CRT and IMRT was 50 Gy in 25 fractions, Monday to Friday with 

concurrent 5-FU. 41 pts (36%) received FOLFOX, 13 (11%) XELOX, 11 (10%) 5-FU, 7 

(6%) Xeloda and 9 (8%) received other chemotherapy, while 33 pts refused the ACT. 

ACT compliance after HDREBT, 3D-CRT and IMRT were respectively: 70.7%, 45.5%, 

37.5% (p = 0.008). Age was a negative factor (p < 0.001) but not gender (p = 0.61) on 

ACT compliance. In a multivariate analysis and adjusting for age and gender, HDREBT 

continued to lead to better ACT compliance compared to 3D-CRT (p = 0.020) and 

IMRT (p < 0.001) and there was no difference clinically between EBRT and IMRT. 

Similarly, ODC rate for HDREBT, 3D-CRT and IMRT were respectively: 63.4%, 21.2% 

and 32.5% (p = 0.001). 

Conclusion: Our data suggests that neoadjuvant HDREBT yields significantly higher 

rates of ACT compliance and ODC compared to 3D-CRT with chemotherapy and 

IMRT with chemotherapy. 



587P POST-MARKETING SURVEY OF PANITUMUMAB IN 

JAPANESE PATIENTS WITH UNRESECTABLE COLORECTAL 

CANCER: INTERIM REPORT OF 3,005 PATIENTS 

K. Sugihara 1 , N. Boku 2 , A. Gemma 2 , N. Yamazaki 2 , K. Muro 2 , T. Hamaguchi 2 , 

T. Yoshino 2 , H. Ueno 3 , A. Ohtsu 2 

1 Surgical Oncology, Tokyo Medical and Dental University, Tokyo, JAPAN, 

2 Vectibix Safety Evaluation Committee, Vectibix Appropriate Use Committee, 

Osaka, JAPAN, 3 Pharmacovigilance Department, Takeda Pharmaceutical 

Company Limited, Osaka, JAPAN 

Background: Panitumumab (P-mab) was approved in April 2010 in Japan for 

treatment of unresectable, advanced or recurrent colorectal cancer with wild-type 

KRAS, both in monotherapy and in combination with chemotherapy for all lines of 

treatment. 

Objectives: To investigate the status of post-marketing use and adverse drug 

reactions (ADRs) of P-mab in Japan, and to assess the safety and efficacy of P-mab 

in Japanese patients. 

Methods: All-case surveillance (all patients were registered before starting P-mab 

therapy by the central registration method) was conducted since the product launch. 

All the patients were examined for eligibility requirements such as KRAS genotype, 

patient performance status and combination regimen and registered for this study 

before starting P-mab therapy. 

Results: Between June 2010 until November 2010, 3,091 patients were enrolled. 

Background information of the 3,005 patients that were collected by October 2011 

was as follows: male/female: 1,912/1,093, mean age: 65.0 years (range 18–90), 

colorectal cancer: 3,005, KRAS genotype wild/ mutant/ not determinable: 2,925/3/77, 

first line/ second line/third line or later treatment: 312/542/2,150, PS 0-1/2/3/4:2,743/ 

236/22/4 and P-mab monotherapy/combination with chemotherapy: 1,232/1,766. 

Combination regimens: FOLFOX/ FOLFIRI/ other anticancer agents were 563/1,004/ 

456. Overall incidence of ADRs was 83.7%, Grade 3 or higher ADRs were 24.7%. 

Incidence of ADRs of special interest for this surveillance: skin disorder / interstitial 

lung disease/ infusion reaction/ electrolyte abnormality/ cardiac disorder were 77.8%/ 

1.3%/ 1.5%/ 18.3%/ 0.2%. The median survival time of patients with P-mab 

monotherapy as third line treatment was 10.3 months. 

Conclusion: P-mab was administered to patients who met the eligibility 

requirements and the appropriate use was confirmed. The safety profile of P-mab in 

the post-marketing use was similar to that previously reported in the clinical trials. 

The risk/benefit balance for use of P-mab in patients with unresectable colorectal 

cancer remains favorable. 

Disclosure: K. Sugihara: Membership on advisory board: Takeda, Merck Serono, 

Chugai Sponsored research and honoraria: Takeda, Taiho, Chugai, Yakult, 

Bristol-Myers Squibb, Merck Serono, Daiichi-sankyo. Sponsored research: Kyowa 

Hakko Kirin No other conflict of interest. N. Boku: Membership on advisory board 

and honoraria: Takeda No other conflict of interest. A. Gemma: Membership on 

advisory board and honoraria: Takeda No other conflict of interest. N. Yamazaki: 

Membership on advisory board and honoraria: Takeda, Bristol-Myers Squibb, Merck 

Serono No other conflict of interest. K. Muro: Membership on advisory board: 

Takeda Honoraria: Takeda, Yakult, Chugai, Taiho, Bristol-Myers Squibb, 

Daiichi-sankyo, Merck Serono No other conflict of interest. T. Hamaguchi: 

Membership on advisory board: Takeda Honoraria: Takeda, Daiichi-sankyo No other 

conflict of interest. T. Yoshino: Sponsored research: Bayer, Taiho, Daiichi-sankyo, 

Quintiles Membership on advisory board: Takeda Honoraria: Chugai, Takeda, 

Bristol-Myers Squibb, Yakult, Merck Serono No other conflict of interest. H. Ueno: 

Emproyee of Takeda Pharmaceutical Co., Ltd. who sponsored this survey No other 

conflict of interest. A. Ohtsu: Membership on advisory board,consultant: Takeda, 

Daiichi-sankyo, Novartis Pharma, Chugai, Taiho Honoraria: Takeda, Daiichi-sankyo, 

Taiho, GlaxoSmithKline, Pfizer, Yakult, Bristol-Myers Squibb, Merck Serono No 

other conflict of interest. 

588P HRQOL DURING ADJUVANT CHEMOTHERAPY WITH 

CAPECITABINE IN PATIENTS AFTER SURGERY FOR COLON 

CANCER: ADDITIONAL STUDY OF JFMC37-0801 

Y. Kinugasa 1 , T. Shiroiwa 2 , M. Nakamura 3 , R. Nezu 4 , S. Hazama 5 , T. Fukuda 6 , 

M. Ishiguro 7 , J. Sakamoto 8 , S. Saji 8 , N. Tomita 9 

1 Colon and Rectal Surgery, Shizuoka Cancer Center, Shizuoka, JAPAN, 

2 Department of Hygiene and Public Health, Teikyo University School of Medicine, 

Tokyo, JAPAN, 3 Aizawa Comprehensive Cancer Center, Aizawa Hospital, 

Nagano, JAPAN, 4 Department of Surgery, Osaka Rosai Hospital, Osaka, JAPAN, 


Graduate School of Medicine, Yamaguchi, JAPAN, 6 Center for Public Health 

Informatics, National Institute of Public Health, Saitama, JAPAN, 7 Department of 

Surgical Oncology, Tokyo Medical and Dental University, Graduate School, 

Tokyo, JAPAN, 8 Japanese Foundation for Multidisciplinary Treatment of Cancer, 

Tokyo, JAPAN, 9 Division of Lower Gi, Department of Surgery, Hyogo College of 

Medicine, Hyogo, JAPAN 

Objectives: The JFMC37-0801 trial is a phase III trial designed to validate 

superiority of 1-year treatment with capecitabine to 6 months treatment as adjuvant 

chemotherapy for stage III colon cancer. Health related quality of life (HRQOL) and 



cost-effectiveness have been evaluated as an additional study. We analyzed impact of 

prolonged treatment with capecitabine on patients’ HRQOL. 

Methods: Capecitabine (2500 mg/m 2 /day) was orally given on days 1-14, followed by 

a 7-day rest. Enrolled patients were randomly assigned to group A (received 8 

courses of capecitabine) or group B (16 courses). In patients agreed to participate to 

the additional study, HRQOL was evaluated by self-administered questionnaire at the 

start of the protocol treatment, 3, 6, 9, 12, 15 and 18 months. The questionnaire 

includes Functional Assessment of Cancer therapy-C (FACT-C) and EuroQol 5 

Dimension (EQ-5D). 

Results: In 1306 patients enrolled to the JFMC37-0801 trial, HRQOL of 171 

participants (81 in group A, 90 in group B) were evaluated. Mean age of the patients 

in group A and B was 63.3 and 64.5 years-old, respectively. Among a total of 1197 

points of survey, 959 questionnaires (80.1%) were retrieved. Recovery rates of 

questionnaires tended to decrease with time after finishing treatment. Through the 

entire survey period, mean score of FACT-C (96.9-103) and EQ-5D (0.85-0.93) were 

satisfactory. In longitudinal analysis of the change from baseline score, the scores 

tended to increase after finishing the treatment period in both group A and group 

B. Significant difference between the score of group A and group B was not observed 

in each survey point. No difference by age and tumor stage was also observed. 

Conclusions: HRQOL of the patients received postoperative adjuvant chemotherapy 

with capecitabine was satisfactory through the survey period. There was no 

significant difference of HRQOL between 8 and 16 courses of capecitabine treatment. 

Disclosure: J. Sakamoto: Junichi Sakamoto is a director of the Japanese Foundation 

for Multidisciplinary Treatment of Cancer (JFMC). S. Saji: Shigetoyo Saji is a director 

of the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC). All 


589P SURVIVAL ANALYSIS OF 1,061 PATIENTS WITH 

SYNCHRONOUS COLORECTAL HEPATIC METASTASES 

J. Xu, Y. Zhong, D. Zhu, Y. Wei, L. Ren 



Objectives: To investigate survival and to identify prognostic factors in patients with 

synchronous colorectal hepatic metastasis. 

Methods: Clinical, pathologic and follow-up data were retrospectively collected from 

1,061 consecutive patients treated for synchronous colorectal hepatic metastases at 

Zhongshan Hospital between 2000 and 2010. The prognostic values of different 

factors were studied through univariate and multivariate analyses. 

Results: For patients with resectable hepatic metastases, the total expense per patient 

in the simultaneous resection group was lower than that in the staged resection 

group (25,693 RMB vs. 34,129 RMB, P < 0.050), and there were no significant 

differences in the complication rates (24.5% vs. 20.5%) or median overall survival 

(48.5 vs. 47.0 months) between the simultaneous and staged resection groups. For 

patients with unresectable hepatic metastases, resection of the primary tumor was 

associated with improved median overall survival (19.0 vs. 9.3 months, P < 0.001). Six 

factors were found to be independent predictors of poor survival by multivariate 

analysis: a poorly differentiated primary tumor, number of hepatic metastases ≥ 4, 

maximum hepatic metastasis size ≥ 5 cm, extra-hepatic metastases, no resection of 

the primary tumor and no surgical treatment of hepatic metastases. Giving one point 

to each of the above factors, all of the patients were divided into low-risk (0-1 

points), medium-risk (2-3 points) and high-risk (4-6 points) groups with 5-year 

survival rates of 51%, 16% and 0%, respectively (P < 0.001). 

Conclusions: Simultaneous resection of the primary tumor and hepatic metastases 

were accepted as prognostic factors in patients with resectable synchronous colorectal 

hepatic metastases. Resection of the primary tumor was recommended at the right 

time for asymptomatic patients with unresectable hepatic metastases. A prediction 

model using the above six factors can be used to guide the clinical management of 

patients with synchronous colorectal hepatic metastases. 


590P PHASE 1B STUDY OF A NOVEL ORAL PPAR-GAMMA 

AGONIST, EFATUTAZONE IN COMBINATION WITH FOLFIRI IN 

JAPANESE PATIENTS WITH METASTATIC COLORECTAL 

CANCER WHO FAILED THE FIRST-LINE THERAPY 

T. Yoshino 1 , S. Yuki 2 , K. Yamazaki 3 , N. Machida 3 , Y. Komatsu 4 , R. Oyama 5 , 

Y. Yachi 5 , H. Onuma 5 , A. Ohtsu 6 

1 Department of Gastroenterology & GI Oncology, National Cancer Center 

Hospital East, Kashiwa, JAPAN, 2 Department of GI, Hokkaido University 

Hospital, Hokkaido, JAPAN, 3 Division of Gastrointestinal Oncology, Shizuoka 

Cancer Center, Shizuoka, JAPAN, 4 Cancer Center, Hokkaido University Hospital, 

Hokkaido, JAPAN, 5 Clinical Developmental Department II, Daiichisankyo CO., 

LTD, Tokyo, JAPAN, 6 Research Center for Innovative Oncology, National Cancer 

Center Hospital East, kashiwa, JAPAN 

Background: Efatutazone is a highly-selective peroxisome proliferator-activated 

receptor gamma (PPAR-gamma) agonist of thiazolidinedione (TZD) class, which 

shows higher potency than rosiglitazone. The recommended dose (RD) is 0.50 mg 

twice-daily (BID) in accordance with pharmacokinetics (PK), pharmacodynamics 

(PD, adiponectin) and safety analyses in US and Japanese phase 1 studies. This study 

assessed the safety, tolerability, antitumor activity, PK, PD, and determined the RD 

of efatutazone in combination with FOLFIRI in Japanese patients. 

Materials and methods: This was an open-label, dose-escalation study using a 3 + 3 

design. Each patient participated in only 1 dose group and received oral efatutazone 

0.25 or 0.50 mg BID with every 2-week administration of FOLFIRI (Irinotecan 180 

mg/m 2 IV infusion over 90 minutes,l-LV 200 mg/m 2 IV infusion over 120 minutes, 

and 5-FU IV continuous infusion 2400 mg/m 2 over 46 hours). After determining the 

RD of efatutazone, 9 additional patients were enrolled for the further assessment of 

efatutazone. PK samples for efatutazone, Irinotecan and SN-38 were collected to 

assess the drug–drug interaction. PD samples were also collected. All patients 

provided written informed consent. 

Results: A total of 15 patients were enrolled (7 male and 8 female; median age of 63 

years old, range: 41–73 years). Dose-limiting toxicities were not observed, and the 

maximum tolerated dose (MTD) was not reached. Most patients experienced edema 

(80.0%) and weight increase (100.0%) which were manageable with diuretics. The 

most common haematological toxicities were neutropenia and anaemia, managed 

with supportive therapy and/or modification of FOLFIRI. Seven out of 15 patients 

showed stable disease (SD). Efatutazone increased plasma adiponectin levels. Plasma 

concentration of efatutazone increased according to dose. Efatutazone doesn’t affect 

plasma concentration of Irinotecan and SN-38. 

Conclusions: Efatutazone in combination with FOLFIRI is a novel anticancer 

therapy, which is tolerated in Japanese patients with metastatic colorectal cancer. 

Although the MTD was not reached, 0.50 mg BID, corresponding to the RD in 

western patients, was selected as the RD for Japanese patients based on safety 

analyses. Full safety data and clinical activity data will be presented. 

Disclosure: T. Yoshino: I have honoraria with Chugai, Takeda, Bristol-Myers 

Squibb, Yakult and Merck Serono. I have research funding from Bayer,Taiho, 

Daiichi-sankyo and Quintiles. I have received consulting fee from Takeda. Y. 

Komatsu: Y.Komatsu has honoraria with DAIICHI SANKYO COMPANY, 

LIMITED, YAKULT HONSHA CO., LTD, Pfizer. Y.Komatsu has research 

funding from DAIICHI SANKYO COMPANY, LIMITED, YAKULT HONSHA 

CO., LTD, Pfizer. R. Oyama: R.Oyama is an employee of Daiichisankyo CO., 

LTD. Y. Yachi: Y.Yachi is an employee of Daiichisankyo CO.,LTD. H. Onuma: 

H.Onuma is an employee of Daiichisankyo CO., LTD. A. Ohtsu: A.Ohtsu has an 

advisory role and/or honoraria with Takeda Pharmaceutical Co., Ltd, DAIICHI 

SANKYO, Novartis, CHUGAI PHARMACEUTICAL CO., LTD, TAIHO 

Pharmaceutical Co., Ltd, Glaxosmithkline, Pfizer, YAKULT HONSHA, Merck 

Serono, Bristol-Myers Squibb. All other authors have declared no conflicts of 

interest. 

591P COLON CANCER ADJUVANT MFOLFOX-6 – SURVIVAL IMPACT 

OF OXALIPLATIN REDUCED DOSE-INTENSITY 

A.F. Carneiro 1 , J. Godinho Bexiga 1 , D.S. Marques 1 , C. Faustino 1 , N. Sousa 2 , 

M. Machado 2 , P. Ferreira 1 , A. Raimundo 1 , R. Fragoso 1 

1 Medical Oncology, Instituto Portugues de Oncologia Centro do Porto, Porto, 

PORTUGAL, 2 Medical Oncology/Hematology, Instituto Portugues de Oncologia 

Centro do Porto, Porto, PORTUGAL 

Background: Adjuvant colon cancer treatment may include the oxaliplatin/ 

fluoropirimidine combination. This association has shown benefit on progression free 

survival (PFS) and overall survival (OS) compared to fluoropirimidine monotherapy 

in these patients. Adverse events are frequent and may cause delay on treatment 

delivery or drug dose reduction. The survival impact of oxaliplatin reduced dose 

intensity (RDI) is unknown. 

Objective: Evaluation of survival impact of oxaliplatin RDI in colon cancer 

patients treated with adjuvant mFOLFOX-6. Material and methods: A consecutive 

series of colon cancer patients treated with adjuvant mFOLFOX-6 at our 

institution between 09/2004 and 11/2009. The impact of Oxaliplatin < 75% 

(group A) and ≥ 75% (group B) on PFS and OS was estimated with a Cox 

Proportional Hazards model. 

Results: There were no differences in age, sex, ECOG, comorbidity, histologic grade 

and stage distribution between groups. Two hundred and seventy seven (277) 

patients were identified (53% in group A). Fifty nine percent (59%) of patients 

completed the 12 mFOLFOX-6 cycles and the median duration of adjuvant 

chemotherapy was 6,5 months. The mean oxaliplatin dose-intensity was 71% 

(median 74%). Adverse events led to dose reduction and drug suspension in 53% 

and 40% of patients, respectively. There were 3 deaths during treatment. The main 

causes to RDI were grade ≥ 3 hematologic toxicity (47%) and neuropathy (12%) – 

median cumulative oxaliplatin dose at first neurologic severe event was 1024 mg. 

There were no differences in PFS and OS between RDI groups, neither after stage 

stratification. 

Conclusion: In our cohort patient’s characteristics and toxicity profile were similar 

to published trials. FOLFOX conclusion rate was inferior than the described in 

MOSAIC trial (59% vs 74,7%). Despite the inferior accomplishment rate, there was 

no impact in PFS and OS in oxaliplatin RDI < 75% group. 



592P PHASE II TRIAL OF COMBINED CHEMOTHERAPY WITH 

IRINOTECAN, S-1, AND BEVACIZUMAB (IRIS/BEV) IN 

PATIENTS WITH METASTATIC COLORECTAL CANCER 

-UPDATED ANALYSIS-. HOKKAIDO GASTROINTESTINAL 

CANCER STUDY GROUP (HGCSG) TRIAL 

K. Hatanaka 1 , S. Yuki 2 , T. Miyagishima 3 ,T.Kato 4 , M. Nakamura 5 , M. Kudo 6 , 

M. Tateyama 7 , M. Asaka 8 , Y. Sakata 9 , Y. Komatsu 10 

1 Gastroenterology, Hakodate City Hospital, Hakodate, JAPAN, 

2 Gastroenterology, Hokkaido University Hospital, Sapporo, JAPAN, 3 Internal 

Medicine, Kushiro Rosai Hospital, Kushiro, JAPAN, 4 Gastoroenterology, 

Hokkaido Gastoroenterology Hospital, Sapporo, JAPAN, 5 Gastroenterology, 

Sapporo City General Hospital, Sapporo, JAPAN, 6 Gastroenterology, Sapporo 

Hokuyu Hospital, Sapporo, JAPAN, 7 Internal Medicine, Tomakomai Nisshou 

Hospital, Tomakomai, JAPAN, 8 Cancer Preventive Medicine, Hokkaido 

University, Sapporo, JAPAN, 9 Medical Oncology, Misawa City Hospital, Misawa, 

JAPAN, 10 Cancer Center, Hokkaido University Hospital, Sapporo, JAPAN 

Background: The FIRIS study (Muro K et al. Lancet Oncol 2010;11:853–860) 

previously demonstrated the non-inferiority of Irinotecan plus S-1(IRIS) to FOLFIRI 

for metastatic colorectal cancer(mCRC), with progression-free survival (PFS) as the 

primary endpoint. We previously reported that IRIS plus bevacizumab (IRIS/bev) is 

very effective as first-line treatment (Komatsu Y et al. ESMO 2010). We now report 

the updated results of this study. 

Methods: Eligible patients had to have mCRC with a confirmed diagnosis of 

adenocarcinoma, an age of >20 years, ECOG performance status (PS) of 0-1, and no 

history of prior chemotherapy. S-1 40-60 mg twice daily p.o. was given on days 1-14 

and irinotecan 100 mg/m 2 and bevacizumab 5 mg/kg i.v. were given on days 1 and 15 

of a 28-day cycle. The primary endpoint was safety. The secondary endpoints included 

overall response (OR), progression-free survival (PFS), and overall survival (OS). 

Results: The target number of 53 patients was enrolled as of March 2009. The results 

are reported for 52 patients with evaluable lesions. The clinical characteristics of the 

patients were as follows. The median age was 63.5 years (range, 48 to 82). The male: 

female ratio was 3:2. The performance status on the Eastern Cooperative Oncology 

Group scale was 0. In January 2012, on safety analysis, the incidence of grade 3 or 4 

neutropenia was 27%. The incidences of other grade 3 or 4 adverse reactions were as 

follows: diarrhea, 17%; anorexia, 4%; stomatitis, 2%; hypertension, 21%; and 

gastrointestinal perforation, 0%. The overall response rate was 63.5%. Three patients 

had complete response. Thirty patients had partial response, 16 had stable disease, 

none had progressive disease, and 3 were not evaluable. Median progression-free 

survival was 17.0 months and median survival time was 39.6 months. 

Conclusions: IRIS/Bev is a remarkably active and generally well-tolerated first-line 

treatment for patients with mCRC. Randomized control trial comparing this regimen 

with oxaliplatin containing regimen (XELOX or mFOLFOX6 plus bevacizumab: 

TRICOLORE study) is already started. 


593P CLINICAL OUTCOME OF SYSTEMIC CHEMOTHERAPY FOR 

COLORECTAL PERITONEAL CARCINOMATOSIS 

Y. Sasaki 1 , T. Hamaguchi 2 , Y. Yamada 3 , Y. Shimada 2 , K. Kato 2 , S. Iwasa 2 , 

Y. Honma 2 

1 Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, 

JAPAN, 2 Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, 

JAPAN, 3 Division of Gastrointestinal Oncology, National Cancer Center Hospital, 

Tokyo, JAPAN 

Background: Peritoneal carcinomatosis (PC) is the second leading cause of death in 

patients with metastatic colorectal cancer. Despite improved survival after 

cytoreduction and hyperthermic intraperitoneal chemotherapy, systemic 

chemotherapy is not typically considered. 

Purpose: This study investigated the characteristics and clinical outcomes of 

colorectal PC patients treated with systemic chemotherapy. 

Methods: This was a retrospective review of patients with colorectal PC presenting to 

the National Cancer Center Hospital from July 2004 to October 2009. Data collected 

included patient characteristics, sites of metastases, chemotherapy regimen, 

histopathological data, gene variations (KRAS and BRAF), and duration of survival. 

Results: PC was confirmed in 50 patients. The median overall survival (OS) of the 

PC patients were similar to those of the non-PC patients (n = 133) (23 vs. 25 

months, p = 0.94). In the PC group, 37 patients (74%) were treated with an 

oxaliplatin regimen and 9 patients (18%) were treated with an irinotecan regimen 

as first-line chemotherapy, among whom 15 patients (30%) also received 

bevacizumab combined with oxaliplatin or irinotecan. Although there was no 

statistically significant difference in progression-free survival (PFS) between 

oxaliplatin (10 months) and irinotecan (8 months) regimens (p = 0.58), addition of 

bevacizumab resulted in longer PFS (18 months) compared to those without 

bevacizumab (9 months) (p = 0.26). The median OS for patients with isolated PC 

was 32 months, compared with 20 months for PC patients with extraperitoneal 

metastases (p = 0.08). Of 50 patients, 33 patients (66%) had available gene status 


results. KRAS mutations were found in 36% of patients, while BRAF mutations were 

identified in 20%. The treatment effect on OS in the wild-type BRAF group was 

greater compared to the mutant group (32 vs. 18 months, p = 0.16). 

Conclusion: Colorectal PC versus non-PC derive the same benefits from systemic 

chemotherapy, and optimal regimens warrant further prospective study. 


594P CANADIAN ECONOMIC ANALYSIS OF BEVACIZUMAB, 

CETUXIMAB, AND PANITUMUMAB IN THE FIRST LINE 

TREATMENT OF KRAS WILD-TYPE METASTATIC 

COLORECTAL CANCER (MCRC) 

D. Lawrence 1 , M. Maschio 2 , S. Yunger 3 , J. Easaw 4 , N. Aucoin 5 , M. Weinstein 6 

1 Health Economics & Outcomes, Optum Insight, Burlington, ON, CANADA, 2 Life 

Sciences, Optum Insight, Burlington, ON, CANADA, 3 Public Affairs, Hoffmann La 

Roche, Mississiauga, ON, CANADA, 4 Medical Oncology, Tom Baker Cancer 

Centre, Calgary, AB, CANADA, 5 Medical Oncology, Cité-de-la-Santé Hospital, 

Laval, QC, CANADA, 6 Harvard School of Public Health, Harvard University, 


Background: CRC is the second leading cause of cancer death in Canada. 

Bevacizumab, a recombinant humanised monoclonal antibody that selectively binds 

to human vascular endothelial growth factor, is approved and funded for first line 

mCRC use in Canada. A substudy has also confirmed its effectiveness in KRAS 

wild-type patients. Recent evidence has also shown clinical benefit from 

anti-epidermal growth factor treatments panitumumab and cetuximab in these 

patients. Objective: We assessed cost-effectiveness of fluoropyrimidine-based 

chemotherapy (FBC) alone and in combination with bevacizumab, panitumumab or 

cetuximab for first line treatment of KRAS wild-type mCRC patients. 

Methods: Cost-effectiveness to the Canadian health care system was estimated using 

separately reported trial survival and adverse event results for each comparator. We 

used a Markov model calibrated to progression-free/overall survival, and calculated 

quality-adjusted life years (QALYs). Health-state resource utilization was derived 

from published data and Canadian oncologist input. Health state utilities and unit 

prices were obtained from published literature and standard Canadian sources. 

Results: Results per patient over a lifetime horizon, to a maximum 10 years with 5% 

discounting are presented below. Comparators are ordered by total cost, and the 

incremental cost-effectiveness ratio (ICER) of each is determined against the previous 

non-dominated therapy. 

Comparator Total Cost Total QALYs Δ Cost Δ QALYs ICER 

FBC $39,061 1.354 - - - 

Bevacizumab + FBC $104,054 1.848 $64,993 0.494 $131,631 

Panitumumab + FBC $151,776 1.806 $47,722 -0.041 Dominated 

Cetuximab + FBC $161,596 1.865 $57,542 0.017 $3,327,501 

Conclusion: For first line treatment of KRAS wild-type mCRC in Canada, 

bevacizumab + FBC is associated with substantially lower costs than panitumumab + 

FBC or cetuximab + FBC. All three biologics may be associated with similar QALYs, 

although; this conclusion was based on the limitation of modelling life expectancy 

from separate trials. Given these findings, bevacizumab seems likely to offer the best 

value for money for this patient population. 

Disclosure: D. Lawrence: Donna Lawrence is an employee of OptumInsight under 

contract with Roche. M. Maschio: Michael Maschio is an employee of OptumInsight 

under contract with Roche. S. Yunger: Simon Yunger is employee of Roche Canada. 

N. Aucoin: Dr. Aucoin has participated in advisory boards with Roche and Amgen. 

M. Weinstein: Dr. Weinstein is a consultant to OptumInsight for research under 

contract with Roche. All other authors have declared no conflicts of interest. 

595P THE INTERIM ANALYSIS OF NUTRITION AND IMMUNE 

RECOVERY AND STRESS RESPONSE AFTER LAPAROSCOPY 

OR OPEN SURGERY WITH FAST TRACK OR CONVENTIONAL 

TREATMENT (FTMDT TRIAL) IN RESECTABLE COLORECTAL 

CANCER 

K.F. Ding, D. Xu, J. Li, Y.M. Song, J.W. Wang, F.F. Sun, J.J. Zhou, J. Zhou, 

Y. Liu, S.Z. Zhang 

Department of Surgical Oncology, 2nd Affiliated Hospital of Zhejiang University, 

Hangzhou, CHINA 

Objective: To study the detailed effect of laparoscopy or open surgery with fast track 

or conventional treatment on patient’s postoperative nutrition and immune recovery 

and stress response. 

Methods: Patients with resectable colon cancer and high rectal cancer were 

randomized to 4 groups: (1) Laparoscopy with fast track treatment (LAFT); (2) Open 

surgery with fast track treatment (OSFT); (3) Laparoscopy with conventional 



treatment (LAC); (4) Open surgery with conventional treatment (OSC). Blood 

samples were collected preoperatively (baseline), and 12, 96 hours after surgery. 

Peripheral blood levels of albumin, prealbumin, Ig G, Ig A, Ig M and C-reactive 

protein (CRP) were analyzed. 

Results: 19 patients were randomized for LAFT group, 18 for OSFT, 17 for LAC, 

and 19 for OSC. The four groups were balanced with respect to patients’ 

characteristics. Mean albumin level (in percentage from baseline) was 94.35 in the 

LAFT group, 88.16 in the LAC group, 79.05 in the OSFT group, and 76.50 in the 

OSC group. Only in LAFT and LAC groups, the albumin level of 96 hours was 

higher than that of 12 hours, indicating the better potency of postoperative 

recovery of nutrition status. Similarly, postoperative Ig G levels were also highest in 

the LAFT group and showed the same rank with albumin levels in the 4 groups. 

Repeated-measures (2-way ANOVA) indicated the difference of albumin and Ig G 

can be attributed to surgery type and not perioperative treatment (P < 0.05). CRP 

levels were highest in the OSC group and lowest in the LAFT group. Further 

repeated-measures (2-way ANOVA) also indicated it can be attributed to surgery 

type (P < 0.05). No significant differences were seen between the 4 groups with 

respect to prealbumin, Ig A or Ig M. No differences in postoperative complication 

rates such as anastomotic leakage, ileus and wound infection were observed 

between the groups. 

Conclusions: Our FTMDT randomized trial indicats: 1. laparoscopic surgery 

shortens the period of postoperative nutrition and immune recovery while fast track 

treatment retards the decrease of postoperative nutrition and immune levels; 

2. Combined laparoscopic surgery with fast track treatment provides best 

postoperative recovery of nutrition and immune status and lowest stress response. 

This study was registered under NCT01080547 (ClinicalTrials.gov). 


596P ADVERSE EVENTS (AES) ASSOCIATED WITH BEVACIZUMAB 

(BV) IN OLDER PATIENTS (PTS) WITH METASTATIC 


V. Shankaran 1 , D. Mummy 1 , L. Koepl 1 , D. Blough 2 , Y.M. Yim 3 ,E.Yu 3 , 

S. Ramsey 1 

1 Cancer Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA, 

UNITED STATES OF AMERICA, 2 Pharmacy, University of Washington, Seattle, 

WA, UNITED STATES OF AMERICA, 3 Health Economics and Outcomes 

Research, Genentech, Inc., San Francisco, CA, UNITED STATES OF AMERICA 

Background: The relative safety of BV in older mCRC pts is understudied. The 

objectives of this analysis are to investigate treatment-related AE incidence and to 

determine factors associated with AEs in a population-based sample of older mCRC 

pts. 

Methods: Pts age ≥ 65 diagnosed (Dx) with mCRC in 2001-7 were identified from 

SEER-Medicare. First-line (1L) chemotherapy (CTx) was identified by claims 

within 3 months of Dx; pts were categorized as receiving no 1L CTx, 1L CTx 

alone, or 1L CTx + BV. Pts were also categorized by Dx period (2001-3 vs. 

2005-7); pts Dx in 2004 were excluded as BV use could not be reliably identified 

in that year. Preexisting conditions (PCs) identified in the year prior to Dx were 

grouped into 5 categories (cardiovascular (CV), cerebrovascular (CNS), 

gastrointestinal (GI), tissue integrity (TI), and pulmonary (Pulm). Claims for these 

conditions between start of 1L CTx and end of follow-up were identified as AEs. 

AE incidence rates were determined by Dx year and 1L CTx cohort. We used a 

competing risks regression model to compare time to 1st AE for pts who received 

1L CTx + BV in 2005-7 to pts who received 1L CTx alone in 2001-7. Similar 

models were constructed for specific serious AEs (stroke, DVT/PE, GI bleed, GI 

perforation). 

Results: 6,899 pts (median age 77) were identified. In 2001-3, 37% of pts received 

1L CTx alone; in 2005-7, 21% and 19% of pts received 1L CTx alone and 1L 

CTx + BV. AE incidence was similar between pts receiving 1L CTx alone in 

2001-3 (135 AEs / 100,000 person-days (PD)) and 1L CTx + BV in 2005-7 (140 

AEs / 100,000 PD). Time to 1st AE was not shorter in pts receiving 1L CTx + BV 

in 2005-7 compared with 1L CTx alone in 2001-7 (HR 0.99, p = 0.90). Similarly, 

receipt of 1L CTx + BV was not associated with a shorter time to specific AE. 

(Table) 

Conclusions: Older pts who received 1L CTx + BV had neither increased AE 

incidence nor decreased time to 1st AE compared with pts who received 1L CTx 

alone. BV utilization may not increase AE risk among elderly mCRC pts. 

Time to 1st AE: BV vs. 1L CTx alone 

AE Type HR 95% CI 

Any AE 0.99 0.90-1.10 

Stroke 1.04 0.95-1.15 

DVT/PE 1.03 0.94-1.14 

GI bleed 1.03 0.94-1.14 

GI perforation 1.05 0.95-1.15 

Models adjusted for: age, comorbidity, race, gender, CTx backbone, PC 

Disclosure: V. Shankaran: This research activity received industry funding from 

Genentech, Inc. D. Mummy: This research activity received industry funding from 

Genentech, Inc. L. Koepl: This research activity received industry funding from 

Genentech, Inc. D. Blough: This research activity received industry funding from 

Genentech, Inc. Y.M. Yim: Financial interests include employment at Genentech, Inc. 

as as health economist and ownership in Genentech stocks. E. Yu: Financial interests 

include employment at Genentech, Inc. as Associate Director and stock ownership in 

Roche. S. Ramsey: This research activity received industry funding from Genentech, 

Inc. 

597P OVERALL SURVIVAL IN METASTATIC COLORECTAL CANCER 

(MCRC) PATIENTS RECEIVING 2ND-LINE THERAPY: A 

SYSTEMATIC REVIEW 

A.L. Martin 1 ,Y.Xu 1 , K. Knopf 2 , S.U. Iqbal 3 , J. Jasso-Mosqueda 4 

1 Health Economics, United Biosource Corporation, Lexington, MA, UNITED 

STATES OF AMERICA, 2 Oncology, California Pacific Medical Center, 

San Francisco, CA, UNITED STATES OF AMERICA, 3 Global Evidence and Value 

Development, Sanofi, Cambridge, MA, UNITED STATES OF AMERICA, 4 Global 

Evidence & Value Development, Sanofi, Chilly-Mazarin, FRANCE 

Background: Currently, oxaliplatin or irinotecan-based regimens are the standard of 

care (SOC) in 1 st – and 2 nd -line therapy of mCRC, often combined with bevacizumab 

or an EGFR inhibitor. A systematic literature review was conducted to address gaps 

in the current evidence and gain an understanding of the clinical efficacy of 2 nd -line 

chemotherapy in patients with mCRC. 

Methods: Searches were conducted in EMBASE, PubMed, CENTRAL, and key 

congresses using keywords for CRC and chemotherapy to identify relevant 

randomized trials assessing 2 nd -line clinical efficacy, published between 1992 and 

April 2012. 

Results: Twenty-three primary trials evaluating 2 nd -line treatment of mCRC were 

identified for inclusion. Chemotherapeutic agents investigated included irinotecan 

monotherapy (k = 11), FOLFOX4 (k = 6), FOLFIRI (k = 4), IROX (k = 3), irinotecan/ 

5-FU/FA (k = 3) and IRIS (k = 1). FU-based regimens were the most common prior 

therapy, with 13 studies reporting that 100% of patients received FU as 1st-line 

therapy for metastatic disease. Eight studies excluded patients who previously 

received irinotecan. Of the included studies, the VELOUR trial, comparing 

aflibercept + FOLFIRI versus FOLFIRI, was the only trial evaluating the current SOC 

(FOLFIRI based regimens) in patients who received oxaliplatin-based chemotherapy 

as a 1st-line agent. Overall survival (OS) ranged from 6.4 to 18 mos across studies. 

The addition of specific targeted agents to chemotherapy regimens demonstrated 

significant incremental survival gains. Addition of bevacizumab to FOLFOX4 in the 

2 nd -line setting was associated with a median OS of 12.9 mos, compared with 10.8 

mos for FOLFOX4 alone. Similarly, the addition of panitumumab to FOLFIRI 

improved median OS from 12.5 mos to 14.5 mos in KRAS wild type patients and 

addition of aflibercept improved median OS from 12.1 mos to 13.5 mos. 

Conclusions: OS in 2 nd -line trials showed significant survival gains when targeted 

agents were added to chemotherapy regimens. However, variability in treatment 

choices, prior chemotherapy regimen, patient selection and study approaches may 

hamper efforts to conduct reliable pooled analyses on outcomes to examine 

comparative effectiveness. VELOUR was one of the few trials that investigated 

patients who had received the current SOC in their 1st-line therapy. 

Disclosure: A.L. Martin: I am an employee of United BioSource Corporation (UBC), 

which received funding from Sanofi to conduct the study on which this abstract is 

based. Y. Xu: I am an employee of United BioSource Corporation (UBC), which 

received funding from Sanofi to conduct the study on which this abstract is based. K. 

Knopf: I am a paid consultant of United BioSource Corporation (UBC), which 

received funding from Sanofi to conduct the study on which this abstract is based. S. 

U. Iqbal: I am a paid employee of Sanofi which provided funding to conduct the 

study on which this abstract is based. J. Jasso-Mosqueda: I am a paid employee of 

Sanofi which provided funding to conduct the study on which this abstract is based. 

598P A PROSPECTIVE MULTICENTER FEASIBILITY STUDY WITH 

SHORT-TIME INFUSION OF PANITUMUMAB (SHIP TRIAL) 

K. Akiyoshi 1 , T. Hamaguchi 1 , Y. Nagai 2 , H. Yasui 3 , G. Sakai 4 , S. Akatsuka 5 , 

A. Hosokawa 6 , S. Hirai 7 , K. Yoshimura 8 , Y. Shimada 1 


JAPAN, 2 Clinical Trial Support Office, National Cancer Center Hospital, Tokyo, 

JAPAN, 3 Medical Oncology, Kyoto Medical Center, Kyoto, JAPAN, 4 Division of 

Gastrointestinal Medicine, Saiseikai Utsunomiya Hospital, Utsunomiya, JAPAN, 

5 Division of Medical Oncology, Yokohama Rosai Hospital, Yokohama, JAPAN, 

6 Gastroenterology, Toyama University, Toyama, JAPAN, 7 Division of 

Gastrointestinal Medicine, Toyama Prefectural Central Hospital, Toyama, JAPAN, 

8 Dept. Clinical Trial Design & Management, Translational Research Center, Kyoto 

University Hospital, Kyoto, JAPAN 

Background: Panitumumab (Pmab) is now considered to be the standard treatment 

for metastatic colorectal cancer. Pmab infusions are normally administered over 60 


minutes. In a previous study, 30-minute infusions of panitumumab showed similar 

safety, pharmacokinetics, and frequency of infusion reaction to 60-minute infusions. 

Because Pmab consists of fully human monoclonal antibodies, infusion reactions 

occur less frequently than with cetuximab, chimeric monoclonal antibodies. 

Short-time infusion of Pmab has the potential to improve patient convenience and 

reduce costs. 

Purpose: We evaluated the safety of short-time infusion of panitumumab in a 

prospective multicenter study. 

Methods: Between January 2011 and December 2011, from 14 centers in Japan, a 

phase II study of Pmab + irinotecan (CPT-11) or Pmab monotherapy in KRAS 

wild-type metastatic colorectal cancer refractory to CPT-11, oxaliplatin, and 

fluoropyrimidines was performed. As an additional study, the initial dose of Pmab 

was administered over 60 minutes, followed by 30-minute infusion; then, all 

subsequent doses were to be administered over 15 minutes. 

Results: Forty-eight patients were enrolled. Their characteristics were median age of 

62 (32-75); male/female, 27/21; Performance Status 0/1/2, 23/24/1; primary lesion in 

colon/rectum, 21/27; and treatment regimen of CPT-11 + Pmab/Pmab monotherapy, 

43/5. The number of patients and doses with 60-/30-/15-minute administration were 

48/45/38 cases and 67/56/206 doses, respectively. In all cases with 60-/30-/15-minute 

infusion, infusion reaction was not encountered. Grade 3/4 toxicities included 

anorexia 8%, stomatitis 4%, diarrhea 6%, fatigue 4%, rash acneiform 6%, perionychia 

4%, leucopenia 8%, neutropenia 8%, anemia 15%, hyponatremia 4%, and 

hypomagnesemia 4%. This was similar to the results from previous clinical studies 

on panitumumab. 

Conclusion: In this study, no infusion reactions with 60-/30-/15-minute 

administration of panitumumab and no increase of frequency of adverse events were 

observed. This is the first prospective study describing the feasibility of short-time 

infusion of panitumumab. This study suggests that 15-minute infusions of 

panitumumab are feasible in patients who tolerate a 60- and then 30-minute infusion 

sequence. 


599P EARLY TUMOR SHRINKAGE (ETS) FOR THE PREDICTION OF 

EFFICACY IN METASTATIC COLORECTAL CANCER (MCRC): 

POST-HOC ANALYSIS FROM AN IRINOTECAN-BASED 

RANDOMIZED FIRST-LINE TRIAL 

C. Giessen 1 , R. Laubender 2 , S. Stintzing 1 , L. Fischer von Weikersthal 3 , 

D. Quietzsch 4 , U. Vehling-Kaiser 5 , D. Oruzio 6 , H. Lambertz 7 , A. Schalhorn 1 , 

V. Heinemann 1 

1 Department of Medical Oncology and Comprehensive Cancer Center, University 

of Munich, Munich, GERMANY, 2 University of Munich, Institute of Medical 

Informatics, Biostatistics, and Epidemiology, München, GERMANY, 3 Department 

of Medical Oncology, Klinikum St. Marien, Amberg, GERMANY, 4 Department of 

Medical Oncology, Klinikum Chemnitz, Chemnitz, GERMANY, 5 Onkologische 

Schwerpunktpraxis, Onkologisches und Palliativmedizinisches Netzwerk 

Landshut, Landshut, GERMANY, 6 II. Medizinische Klinik, Klinikum Augsburg, 

Augsburg, GERMANY, 7 Zentrum Fuer Innere Medizin - Onkologie, Klinikum 

Garmisch-Partenkirchen, Garmisch-Partenkirchen, GERMANY 

Background: Early tumor shrinkage (ETS) has been highlighted as a favorable 

prognostic factor related to progression-free survival (PFS) and overall survival (OS) 

in cytotoxic chemotherapy with or without cetuximab. We investigated ETS ≥20% 

and


did not modify CSS, irrespective of AC choice (interaction p for capecitabine and 

age = 0.26; interaction p for FOLFOX and age = 0.40). 

Conclusions: EPs with stage III CC frequently received either no adjuvant treatment 

or capecitabine monotherapy due to advanced age and comorbidities. The treatment 

effect of AC on CSS is similar across age groups, with comparable side effects and 

rates of discontinuation between EPs and YPs. AC should not be withheld from CC 

patients based on advanced age alone. 


602P COMPARATIVE BUDGET IMPACT ANALYSIS OF TREATMENT 

SEQUENCES IN METASTATIC COLORECTAL CANCER 

(MCRC): FROM FIRST (1ST) LINE TO THIRD (3RD) LINE 

THERAPIES 

J.A. Maroun 1 , T. Boucher 2 , K. Alloul 3 

1 Medical Oncology, The Ottawa Hospital Regional Cancer Centre, Ottawa, ON, 

CANADA, 2 Evidence Value and Access, Sanofi Canada, Montréal, QC, 

CANADA, 3 Health Economics and Health Outcomes, Sanofi Canada, Montreal, 

QC, CANADA 

Background: In the context of personalized cancer care, patients (pts) should receive 

the therapy that best meets their needs while optimizing the use of healthcare 

resources. A budget impact model was developed to compare each of the most 

commonly used mCRC treatment sequences – from 1 st line to 3rd line in a Canadian 

context. 

Methods: This Excel based model considers the price of each agent, the number of 

cycles per treatment course, the relative dose intensity of the regimens to determine the 

cost of the most commonly used mCRC therapies and calculates the costs per overall 

sequence from 1 st line to 3 rd line. It takes into account the percentage of pts who benefit 

from a R0 resection post 1 st line chemotherapy and who forego subsequent treatments. 

Factors such as different percentage use of 1 st line FOLFOX vs FOLFIRI and pts’ 

volumes per line of therapy are considered in this model. Users can choose the 

scenarios they would like to examine. Key variables can be extracted through expert 

opinion, the literature or, to assess real-world local practices, through chart reviews. 

Results: As scenarios considered, the budgetary impact of the 1 st line use of FOLFOX 

or FOLFIRI both given with bevacizumab (bev) on 1 st to 3 rd line therapy costs was 

assessed. The relative use of FOLFOX and FOLFIRI with bev was varied from 80% use 

of FOLFOX and 20% use of FOLFIRI to the opposite. As key variables, the model 

compares, as 1 st line therapy, 18 cycles of FOLFIRI and bev to 8 cycles of mFOLFOX6 

followed by 10 cycles of 5FU/LV given with 18 cycles of bev. Also 80% of 1 st line pts 

receive a second line chemotherapy. Assuming a cohort of a 100 pts, when FOLFOX’s 

1 st line use varies from 80% to 20%, the budget varies from $4.14M to $3.85M, with all 

pts undergoing a R0 resection varying from 11.8 to 8.2 pts. 

Conclusions: Focusing on drug costs only, this dynamic and flexible model goes 

beyond the comparison of upfront 1 st line mCRC costs and considers cascading costs 

on subsequent lines (2 nd and 3 rd line) and consequences. It can be used to assess 

variability in local and provincial practice patterns and their impact on overall budget 

costs and number of pts benefiting from a R0 resection. 

Disclosure: J.A. Maroun: Advisory board member for Roche and Sanofi. Involved in 

research projects with Roche and Sanofi. T. Boucher: Employee of Sanofi. K. Alloul: 

Employee of Sanofi Canada Inc. 

603P FREQUENCY OF SECOND AND THIRD LINE TREATMENT 

AMONG ELDERLY MEDICARE STAGE 4 COLON CANCER 

PATIENTS 

C.D. Mullins 1 , K. Bikov 2 , E. Onukwugha 2 , N. Hanna 3 , B. Seal 4 

1 PHSR, Univ of MD, Baltimore, MD, UNITED STATES OF AMERICA, 2 PHSR, 

Univ of MD, Baltimore, MD, UNITED STATES OF AMERICA, 3 Surgery, Univ of 

MD, Baltimore, MD, UNITED STATES OF AMERICA, 4 Health Economics and 

Outcomes Research, Bayer HealthCare, Wayne, NJ, UNITED STATES OF 

AMERICA 

Background: Stage 4 colon cancer (CC4) patients may receive multiple lines of 

chemotherapy and/or biologics as treatment (TX) to improve survival or quality of life. 

The tendency to use less aggressive treatment with elderly CC4 patients suggests that 

elderly CC4 patients may receive fewer TX lines than equivalent younger patients. 

Methods: Elderly (65+) SEER-Medicare patients diagnosed with CC4 in 2003-2007 

were followed through death or 2009 to examine variation across sub-groups in the 

number of TX lines. We examined NCCN treatments that included any combination 

of 5-fluorouracil and/or (levo) leucovorin (5FU/LV), irinotecan (IRI), oxaliplatin 

(OX), and bevacizumab, cetuximab, or panitumumab (collectively identified as 

BIOLOGICS). Certain non-NCCN treatments were also considered as possible last 

TX line. A hierarchy categorized treatments as: 1) IROX (IRI + OX); 2) IRI or OX; 3) 

5FU/LV; 4) BIOLOGICS without chemotherapy; and 5) other TX. Gaps in TX or 

changes from OX or IRI to 5FU/LV were not considered new lines. 

Results: Of 7,937 elderly CC4 patients, 3,263 (41%) received any TX, while 1,166 

(15% of all, 36% of TX) and 244 (3% of all, 7% of TX) received second and third 

line TX, respectively. Fewer than 1% of treated patients had a fourth TX line. Among 

the TX group, relatively younger (p < 0.01), married (48 vs. 39%, p < 0.01) and urban 

(45 vs. 39, p = 0.04) patients were more likely to go on to second line TX. Medicare 

buy-in coverage, which generally indicates dual Medicaid-Medicare coverage (40 vs. 

45%, p = 0.05), lowered the likelihood of second line TX. Having comorbidities 

impacted receipt of initial TX (CCI = 0: 44%, CCI = 1: 42%, CCI = 2: 28%; p < 0.01) 

and the likelihood of second (CCI = 0: 46%, CCI = 1: 42%, CCI = 2: 39%; p= 0.02) 

but not third TX (CCI = 0: 19%, CCI = 1: 21%, CCI = 2: 15%; p = 0.3) lines 

conditional upon receipt of prior line treatment. There was no significant association 

between second line TX and race/ethnicity or gender. There was no significant 

association between the examined characteristics and receipt of third line TX. 

Conclusions: One in three elderly CC4 patients who received initial TX received a 

second TX line. The likelihood of having a second TX line was associated with age, 

marital status, urbanicity, and comorbidity burden. Only one in fourteen elderly CC4 

patients had a third TX. 

Disclosure: C.D. Mullins: C. Daniel Mullins, PhD receives consulting income from 

Amgen, Bayer, BMS, Celgene, GSK, Mitsubishi, Novartis, Novo Nordisk, Novartis, 

and Pfizer. He also receives research funding from Bayer and Pfizer. E. Onukwugha: 

Ebere Onukwugha receives consulting income from Pfizer and grant support from 

Bayer, Novartis, and Pfizer. B. Seal: Brian Seal is an employee of Bayer HealthCare. 


604P PROGNOSTIC VALUE OF STEM CELL QUANTIFICATION IN 

STAGE II COLON CANCER 

M.A.V. Salgado 1 , J.C.M. Montero 2 , M. Devesa 1 , J.D. Trill 1 , V. Abraira 1 , 

A. Riquelme 3 , A. Carrato 1 

1 Medical Oncology, Hospital Universitario Ramon y Cajal, Madrid, SPAIN, 

2 Pathologist, Instituto Oftalmico/Hospital Universitario Gregorio Marañon, Madrid, 

SPAIN, 3 Medical Oncology, Hospital Infanta Cristina Parla, Madrid, SPAIN 

Background: Cancer stem cells (CSCs) are a subset of tumor cells with capacity to 

self-renew and generate the diverse cells that comprise the tumor. They are considered 

cancer (Ca) initiating cells responsible for tumor recurrence and maintenance. These 

cells express pluripotency markers (CD133 and NANOG) and do not express markers 

of differentiation as cytokeratin 20 (CK20). The potential prognostic value of CSCs in 

colorectal cancer has been studied with conflicting results. However some of these series 

were based on heterogeneous situations, involving rectal and colon cancer (CC) and 

different tumor stages (I-IV). The aim of this study is to evaluate the prognostic value of 

CSCs in a highly homogeneous population of stage II CC. 

Methods: One hundred stage II CC patients (pts) treated by the same surgical team 

at Ramon y Cajal University Hospital between 1977 and 2005 were retrospectively 

analyzed. None of the pts received adjuvant chemotherapy. Inmunohistochemistry 

expression of CD133, NANOG and CK20 was scored on paraffin sections using four 

levels: 50% positivity. Kaplan-Meier analysis and log 

rank test were used to compare survival. 

Results: Median age: 68 years (45-92). Median follow up: 5.8 years. Recurrent 

disease: 17 (17%). Expression of CD133 was shown in 60% of the tumors, in 95% for 

NANOG and 78% for CK20. No correlation was found among expression levels of 

CD133, NANOG or CK 20 and relapse-free survival (RFS) and overall survival (OS). 

Conclusions: Stem Cell quantification defined by CD133 and NANOG expression 

has no correlation with RFS or OS in this cohort of Stage II CC. Therefore, our 

results suggest that CSCs may not play a major role in early phases of CC. 


605P PHASE II TRIAL OF PANITUMUMAB IN COMBINATION WITH 

OXALIPLATIN AND CAPECITABINE CHEMOTHERAPY AS 1ST 

LINE THERAPY IN PATIENTS WITH COLORECTAL CANCER 

AND ADVANCED LIVER METASTASES: THE METAPAN STUDY 

F. Leone 1 , D. Marino 2 , S. Artale 3 , C. Cagnazzo 2 , S. Cascinu 4 , A.A. Martoni 5 , 

A. Sobrero 6 , M. Tampellini 7 , S. Siena 3 , M. Aglietta 8 

1 Oncological Sciences, Fondazione Piemontese per la Ricerca sul Cancro Onlus, 

Candiolo, ITALY, 2 Medical Oncology, Fondazione Piemontese per la Ricerca sul 

Cancro Onlus-IRCC Institute for Cancer Research and Treatment, Candiolo, 

ITALY, 3 Struttura Complessa di Oncologia Falck, A.O. Ospedale Niguarda Ca’ 

Granda, Milano, ITALY, 4 Clinica di Oncologia Medica, AOU Ospedali Riuniti 

Ancona Università Politecnica delle Marche, Ancona, ITALY, 5 Medical Oncology 

Unit, S. Orsola-Malpighi University Hospital, Bologna, ITALY, Bologna, ITALY, 

6 Oncologia Medica, Azienda Ospedaliera Universitaria S. Martino di Genova, 

Genova, ITALY, 7 Dipartimento di Oncologia Medica, Azienda Ospedaliera San 

Luigi, Orbassano, ITALY, 8 Div Oncologia ed Ematologia, Fondazione Piemontese 

per la Ricerca sul Cancro Onlus, Candiolo, ITALY 

Background: Preoperative chemotherapy improves outcome in potentially resectable 

colorectal cancer with liver metastases. We evaluated the activity of a neoadiuvant 

treatment with capecitabine–oxaliplatin (XELOX) associated with the anti-EGFR 

antibody Panitumumab in patients with unresectable, liver-only, metastatic colorectal 

cancer (CRC). 


Patients and methods: Chemotherapy-naïve patients with unresectable liver 

metastases of CRC and no other metastatic sites were enrolled. Criteria of 

unresectability were defined as: more than3livermetastasesincluding>50% 

hepatic involvement and requiring a major hepatectomy with controlateral 

wedge resection or any metastases requiring a resection that does not preserve 

two contiguous hepatic segments. Since November 2008 only patients bearing 

wild type KRAS were included. All patients received neoadjuvant XELOX plus 

panitumumab (P-XELOX) and were reevaluated for resectability every four 

cycles. Primary endpoint was radiological objective response rate (ORR). 

Secondary endpoints were overall survival (OS), progression free survival 

(PFS), percentage of patients whose disease became radically resectable, and 

safety. 

Results: Forty-nine patients were recruited, of which 35 were KRAS wild type, and 

14 (enrolled before study amendment), were unknown (9 patients) or mutated (5 

patients). Forty-six were evaluable for response. Following neoadjuvant P-XELOX, 

the ORR in the general population was 54%, with 3 CR, 22 PR, 14 SD. In wild type 

KRAS patients ORR reached 65% (3 CR, 18 PR, 7 SD), and this allowed 15 patients 

with initial unresectable liver metastasis to be converted to resectability. Survival 

analysis showed median PFS and OS of 8.5 months and 22.1 months, respectively. 

Resected patients had significantly better OS if compared to unresected (p = 

0.00014). The most common toxicities were cutaneous, gastrointestinal, and 

neurologic. 

Conclusion: Neoadjuvant P-XELOX yields high response rates for patients with 

metastatic CRC and extensive liver involvement, and leads to remarkable conversion 

to resectability of liver metastasis. 


606P BODY MASS INDEX AND IMPAIRED FASTING BLOOD 

GLUCOSE AS PREDICTIVE FACTORS OF EFFICACY IN 

CETUXIMAB-BASED COLORECTAL CANCER TREATMENT 

F.M. Guida1 , F. Pantano1 , E. Vasile2 , M. Rodriguez Garrote3 , E. Grande3 , 

N. Silvestris4 , B. Vincenzi1 , D. Santini1 , A. Falcone5 , G. Tonini1 1 2 

Medical Oncology, University Campus Bio-Medico, Rome, ITALY, Oncologia, 

Trapianti e Nuove Tecnologie in Medicina, Polo Oncologico - Azienda 

Ospedaliero-Universitaria Pisana - Istituto Toscano Tumori, Pisa, ITALY, 3 Medical 

Oncology, University Hospital, Madrid, Madrid, SPAIN, 4 Medical and 

Experimental Oncology Unit, Cancer Institute Giovanni Paolo II, Bari, ITALY, 

5 

Dept. of Oncology-Presidio Ospedaliero, Azienda Ospedaliero Univesitaria S. 

Chiara, Pisa, ITALY 

Introduction: Cetuximab is an anti-EGFR monoclonal antibody with antitumor 

efficacy in metastatic colorectal cancer harboring wild-type K-Ras gene. 

However, not all patients K-Ras wild-type benefit from Cetuximab, 

underscoring the need for additional markers to help in patient selection. 

Preclinical evidences suggest that the EGFR and Insulin-like Growth Factor-1 

Receptor (IGF-1R) pathways interact to drive tumor growth and survival. It’s 

well known that in hyperinsulinemic state, higher insulin levels upregulate 

IGF-1 production, leading this state a potential biomarker for Cetuximab 

efficacy. The aim of our study was to evaluate the feasibility to stratify patients 

more likely to benefit from Cetuximab treatment using two well known signs 

of hyperinsulinemic state such as the high Body Mass Index (BMI) and 

impaired Fasting Blood Glucose (FBG). 

Methods: We retrospectively collected 250 K-Ras wild-type metastatic colorectal 

cancer patients treated with Cetuximab containing regimens in first to fifth line 

setting. From this cohort we selected 76 patients treated with Cetuximab + 

CPT11 after failure of first line CPT11 based containing regimen. We divided 

this population into two groups according to the presence of both elevated BMI 

(cut-off 24.99 sec. WHO Criteria) and high FBG (cut-off 100 mg/dL sec 

American Diabetes Association) and we evaluated the Time To Progression 

(TTP) of these two groups. 

Results: We found a statistically significant lower TTP in patients with both elevated 

BMI and FBG compared to patients with presence of none or only one of the two 

parameters (median TTP 4.3 months, CI95%:2.5-5.4 vs 5.6 months, CI95%:2.5-5.8; 

P = 0.034). 

Conclusions: The statistically significant poorer outcome in patients with both 

BMI and FBG treated with Cetuximab + CPT11 after CPT11 failure could be 

explained by the reduction of Cetuximab efficacy due to the probable presence of 

upregulation of vicar pathways such as IGF-1R linked to hyperinsulinemic state. 

If confirmed in larger populations and in perspective studies the 

hyperinsulinemic state may represent a new predictive marker of efficacy in this 

type of population. 



607P EFFICACY AND SAFETY OF TWO NEOADJUVANT 

STRATEGIES WITH BEVACIZUMAB IN LOCALLY ADVANCED 

RESECTABLE RECTAL CANCER: INTERIM RESULTS OF A 

RANDOMIZED, NON-COMPARATIVE PHASE II STUDY 

J. Bosset 1 , G. Mantion 2 ,T.André 3 , F. Boudghène 4 , F. Piard 5 , F. Mornex 6 , 

P. Maingon 7 , A. Adenis 8 , M. Piutti 9 , C. Borg 10 

1 Radiotherapy, CHU Jean Minjoz, Besançon, FRANCE, 2 Service de Chirurgie 

Digestive Et Vasculaire, Hôpital Jean Minjoz, Besançon, FRANCE, 3 Medical 

Oncologie, Hôpital Saint Antoine, Paris, FRANCE, 4 Service Imagerie Médicale, 

Hôpital Tenon, Paris, FRANCE, 5 Service D’anatomo-pathologie, CHU de Dijon, 

Dijon, FRANCE, 6 Radiothérapie-oncologie, Centre Hospitalier Lyon-Sud, Lyon, 

FRANCE, 7 Radiothérapie, Centre Georges-François-Leclerc, Dijon, FRANCE, 

8 Medical Oncology, Centre Oscar Lambret, Lille Cedex, FRANCE, 9 Responsable 

Etudes Cliniques, Laboratoires Roche, Boulogne-Billancourt, FRANCE, 10 Medical 

Oncology, Hopital Minjoz, Besançon, FRANCE 

Background: Current therapy of locally advanced resectable rectal cancer 

(LARC) involves a combination of chemotherapy (CT), radiation therapy, (RT) 

and total mesorectal excision (TME) surgery. Two neoadjuvant strategies with 

bevacizumab (Bv) were assessed in a randomized, open-label, multicentre, phase 

II study. 

Method: Patients (pts) were treated with a sequential strategy including induction 

Bv/6 cycles (5mg/2weeks) + Folfox4, followed by CT-RT (Bv/6 cycles + 5-FU/5 

cycles) + RT(45Gy) then TME in Arm A and the same CT-RT, then TME in Arm 

B. Primary end-point was tumor sterilization rate (pCR) - at least 10% in each arm. 

Efficacy and safety were reviewed by an independent committee. Results at 8 weeks 

post-surgery are presented. 

Results: Pts characteristics in Arm A (n = 46) and in Arm B (n= 45) were: men 67%, 

age 60 ± 9 years, ECOG score 0 (85%), mid-rectum (60%), low-rectum (40%), MRI 

stage: T3N0M0/T3N1M0/T3N2M0 (20%/65%/15%). In Arm A, 94% pts completed 

induction and 91% had CT-RT and surgery; in Arm B 100% had CT-RT and 98% 

surgery. Resection was macroscopically complete in 91% pts. Median post-surgery 

hospitalization duration was 15 [0-84] days. In the ITT population, pCR (ypT0-N0) 

rate was 23.8% [12.1%-39.5%] in Arm A (p = 0.015) and 11.4% [3.8%-24.6%] in Arm 

B (p = 0.91), both compared to the 10% pCR initial hypothesis. Central review found 

similar results for pCR. At surgery and 4 weeks post-surgery grade 3/4 adverse events 

(AE) were reported in 10 (22%) of pts in both arms. At 8 weeks post-surgery, grade 

3/4 adverse events (AE) were reported in 59% of pts in Arm A and 36% in Arm 

B. Grade 3/4 AEs of special interest for bevacizumab were reported in 20% of pts in 

Arm A and 22% in Arm B. No death was reported at 8 weeks post-surgery follow-up. 

Conclusions: Interim results in patients with LARC treated with 2 neoadjuvant 

strategies showed that bevacizumab combination to neoadjuvant CT-RT did not 

significantly increase pCR in Arm B. The neoadjuvant strategy assessed in Arm A 

seems promising and deserves further investigation. Safety was comparable in Arms 

A and B at 8 weeks post-surgery. 

Disclosure: T. André: Consultant: Roche Honoraries: Amgen, Merck, Sanofi. F. 

Boudghène: Honoraries : Roche. M. Piutti: Employment: Roche. All other authors 


608P EXCITE: A PHASE II TRIAL OF PREOPERATIVE CETUXIMAB, 

IRINOTECAN AND CAPECITABINE PLUS RADIOTHERAPY (RT) 

IN MRI-DEFINED LOCALLY ADVANCED RECTAL CANCER 

(LARC) 

S. Gollins 1 , A.S. Myint 2 , M.P. Saunders 3 , S. Susnerwala 4 , D. Sebag-Montefiori 5 , 

S. Beare 6 , E. Williams 6 , N. West 7 , M. Jitlal 6 

1 Clinical Oncology, North Wales Cancer Treatment Centre, Rhyl, UNITED 

KINGDOM, 2 Clinical Oncology, Clatterbridge Cancer Centre, Liverpool, UNITED 

KINGDOM, 3 Clinical Oncology, The Christie Hospital NHS Foundation Trust, 

Manchester, UNITED KINGDOM, 4 Clinical Oncology, Royal Preston Hospital, 

Preston, UNITED KINGDOM, 5 Oncology, University of Leeds, Leeds, UNITED 

KINGDOM, 6 CR UK & UCL Cancer Trials Centre, University College London, 

London, UNITED KINGDOM, 7 Pathology & Tumour Biology, University of Leeds, 

Leeds, UNITED KINGDOM 

Introduction: This phase II trial examined combining cetuximab, irinotecan and 

capecitabine concurrently with RT in the preoperative downstaging of LARC. 

Methods: Patients (pts) had rectal adenocarcinoma with locally advanced/borderline 

unresectable disease on MRI. KRAS/BRAF was not assessed before treatment. Pts 

had pelvic RT to 45 Gy in 25 daily fractions over 5 weeks with concurrent oral 

capecitabine at 650 mg/m 2 twice daily 5 days/week. They also received intravenous 

(IV) cetuximab at 400 mg/m 2 one week before RT then weekly at 250 mg/m 2 weeks 

1-5 of RT plus IV irinotecan weekly at 60 mg/m 2 weeks 1-4 of RT. Surgical resection 



was stipulated at 8 weeks after chemoradiation (CRT) with primary end point 

histological circumferential resection margin (CRM) negative rate. 

Results: From Apr 2009-Oct 2011 82 pts were recruited. At baseline: male/female 61/ 

21, median age 62, WHO PS 0/1/missing 60/19/3. On MRI tumour was T2/3/4 in 6/ 

67/9 and N0/1/2 in 14/41/27 pts, mesorectal fascia or levator-sphincter complex was 

threatened (≤ 1mm gap) in 45 (55%), definitely involved in 21 (26%) and breached 

in 16 pts (20%). 2 pts did not commence RT and were withdrawn from trial 

treatment. The no. (%) of significant acute toxicities were diarrhoea grade (Gr)3 20 

(25%), acneiform rash Gr3 7 (9%), fatigue Gr3 6 (8%), thrombotic event Gr3 1 (1%) 

and Gr4 5 (6%) and febrile neutropenia Gr3 1 (1%) and Gr4 1 (1%). 75 pts had 

surgery (36 anterior resection, 37 abdominoperineal, 2 Hartmans). Post-resection 

histology showed a negative CRM (>1mm) in 67 (89%), a pathological complete 

response (pCR) (T0N0) in 14 (19%), T0/1/2/3/4 in 15/2/16/40/2 and N0/1/2 in 51/ 

15/9 pts. 38 of the 75 resected pts (51%) had their T and 49 of 63 (78%) their N1-2 

stage downstaged. 5 pts with a clinical CR (cCR) post CRT did not have surgery and 

were alive with no evidence of disease at 8, 12, 14, 24 and 26 m. 

Conclusion: EXCITE is the largest reported phase II trial of a triplet CRT regime 

including EGFR targeted therapy in LARC, showing acceptable toxicity and 

compliance. In MRI-defined locally advanced/borderline unresectable disease a 

combined pCR + cCR rate of 19/80 (24%) is promising. Data on KRAS and BRAF 

influence will be available by Aug 2012. 

Disclosure: S. Gollins: Research funding grants from Merck and Pfizer Honoraria 

from Roche (Advisory Boards). All other authors have declared no conflicts of 

interest. 

609P FIRST RESULTS FROM THE PHASE I DUAL RECTAL 

ANGIOGENESIS MEK INHIBITION RADIOTHERAPY 

(DREAMTHERAPY) TRIAL IN LOCALLY ADVANCED RECTAL 

CANCER 

F.E. Marti Marti 1 ,A.Backen 2 , A.G. Renehan 3 , A. Jackson 4 , P. Manoharan 5 , 

O. Ataman 6 , V. Misra 7 , G.C. Jayson 1 , C. Dive 2 , M.P. Saunders 7 

1 Medical Oncology, The Christie NHS Foundation Trust, Manchester, UNITED 

KINGDOM, 2 Clinical and Experimental Pharmacology, The Paterson Institue for 

Cancer Research, Manchester, UNITED KINGDOM, 3 Surgery, The Christie 

Hospital NHS Foundation Trust and Paterson Institute for Cancer Research, 

Manchester, UNITED KINGDOM, 4 Radiology, Wolfson Molecular Imaging Centre, 

Manchester, UNITED KINGDOM, 5 Radiology, The Christie Hospital NHS 

Foundation Trust, Manchester, UNITED KINGDOM, 6 Rockit, Astra Zeneca, 

Alderley Park, UNITED KINGDOM, 7 Clinical Oncology, The Christie Hospital NHS 

Foundation Trust, Manchester, UNITED KINGDOM 

Background: Less than 15% of patients (pts) receiving pre-operative chemoradiation 

(CRT) for rectal cancer have a complete pathological response (pCR). We tested the 

hypothesis that the addition of cediranib (a VEGFR TKI) or selumetinib (a MEK 

inhibitor), in combination with CRT, increases the proportion of complete 

responders. A translational protocol was also developed to study potential predictive 

biomarkers. 

Methods: This hypothesis was evaluated in a dual phase I design. The drugs are 

evaluated in parallel in an intertwined design: once a cohort of pts on cediranib 

completed treatment and during the toxicity assessment period, another cohort of 

pts was commenced on selumetinib at the next dose level. Alternating cohorts 

maximised the efficacy of their evaluation. The analysis here is for cediranib only. Pts 

received CRT (45Gy in 25#, capecitabine 825 mg/m 2 twice daily for 35 days) in three 

cohorts with cediranib: 15 mg, 20 mg and 30 mg/once daily (OD). Dose escalation 

was done upon fulfilment of the safety criteria outlined in the protocol. Cediranib 

was commenced 10 days prior to the start of CRT and continued throughout. Pts 

were followed up until and then after surgery. Safety, RECIST and pathological data 

were collected. In addition, blood, tissue and DCE-MRIs were obtained at baseline, 

post-monotherapy, throughout and post CRT for the study of candidate biomarkers. 

Results: 15 mg cohort: 3 pts were recruited. 2 pts had a pCR and the 3rd pt had a 

clinical complete response (cCR) not requiring surgery. 20 mg cohort: 3 pts were 

treated. 1 had a cCR and ypT3N0 on resection. The other 2 had partial responses on 

MRI with ypT3N0 and ypT3N2 pathologically. 30 mg cohort: 3 pts were recruited at 

this dose level. Two pts had a cCR and the other one is waiting restaging. There was 

one DLT in this cohort (Grade III lethargy). This cohort will be expanded to a 

maximum n = 6. As yet, all pts have had R0 resections and completed all planned 

treatment (except pt with DLT who did not complete capecitabine). cCR pts remain 

disease free and have not had surgery. 

Conclusions: The addition of cediranib to pre-operative CRT is a well tolerated 

regimen. All pts have responded with 5 out of 8 evaluable pts (62.5%) having either a 

pCR (n = 2) or cCR (n = 3). Updated clinical data, proposed optimal dose and 

translational data will be available for presentation at the meeting. 

Disclosure: F.E. Marti Marti: Dr Marti’s research fellowship is funded in equal parts 

by Cancer Research UK and Astra Zeneca. O. Ataman: Dr Ataman is an 

Astra Zeneca employee. G.C. Jayson: AZ advisory boards and research funding. M. 

P. Saunders: I have previously been a paid advisor on an AZ trial with 

AZD2171 (Horizon II). However, I have no conflicts on the use of this agent 

in the DREAMtherapy trial. All other authors have declared no conflicts 

of interest. 

610P UTILITY OF MAGNETIC RESONANCE IMAGING FOLLOWING 

LONG-COURSE PRE-OPERATIVE CHEMO-RADIOTHERAPY 

FOR LOCALLY ADVANCED RECTAL CANCER 

D.J. Lucey 1 , A. Murphy 2 , V. Curran 3 , M. McCourt 4 , E. Andrews 4 ,M.O’Riordain 3 , 

D.G. Power 5 ,S.O’Reilly 5 , P.J. Kelly 4 

1 Radiotherapy Department, Cork University Hospital, Cork, IRELAND, 2 Medical 

Oncology Department, Cork University Hospital, Cork, IRELAND, 3 Surgery, 

Mercy University Hospital, Cork, IRELAND, 4 Surgery, Cork University Hospital, 

Cork, IRELAND, 5 Medical Oncology, Cork University Hospital, Cork, IRELAND 

Aims/Rationale: Neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal 

cancer is associated with improved local control and results in tumour down-staging. 

The purpose of this study was to assess whether MRI performed following 

chemoradiotherapy alters surgical management. 

Methods: All patients with locally advanced (cT3-4 or cN+ by endorectal ultrasound, 

computed tomography, or magnetic resonance imaging) rectal adenocarcinoma 

diagnosed in 2010 and 2011 at Cork University Hospital/Mercy University Hospital 

and treated with long course preoperative CRT followed by radical resection were 

identified and their records were retrospectively reviewed from prospectively 

maintained institutional databases . Only patients who had MRI pre- and 

post-neoadjuvant therapy were eligible for inclusion. 

Results: Thirty patients had MRI pre- and post long course chemoradiotherapy. 

Male: Female was 3:2, the median age was 60 (range 36-77). Abdominoperineal 

resection was performed in 12 of these patients, and anterior resection in 18 patients. 

The median radiation dose was 50.4 Gy with concurrent 5FU-based chemotherapy. 

Median time from completion of CRT to post-treatment MRI was 30 days, and the 

median time to surgery from the 2 nd MRI was 23 days. Only 1 of the 30 patients 

(3.3%) showed disease progression on the repeat scan and R0 resection was achieved 

in this case. Three patients (10%) achieved pathologic complete remission and none 

of these had a radiographic CR on post-treatment MRI. Two patients (6.6%) had 

positive circumferential resection margins and neither was predicted by 

post-treatment MRI. 

Conclusions: MRI following neoadjuvant therapy prior to surgical resection did not 

alter clinical management in this small retrospective series. The utility of post CRT 

MRI prior to definitive resection is unclear and international guidelines do not 

recommend this approach. 


611P EFFECTS OF RADIOTHERAPY (RT) AND 

CHEMORADIOTHERAPY (CRT) ON LYMPH NODES (LNS) IN 

PATIENTS WITH RECTAL CANCER: EVALUATION OF 

NUMBERS OF RETRIEVED LNS AND LN SIZE 

K. Okada1 , S. Sadahiro2 , T. Suzuki1 , A. Tanaka1 , A. Kamijo1 1 

Gastrointestinal Surgery, Tokai University School of Medicine, Isehara, JAPAN, 

2 

Gastrointestinal Surgery, Tokai University School of Medicine Isehara Campus, 

Isehara, JAPAN 

Background: In patients with colorectal cancer, retrieval of 12 or more LNs has been 

reported to be associated with better outcomes. Preoperative RT or CRT reduces the 

number of retrieved LNs. The effects of RT and CRT on LNs may be different 

between LNs inside and LNs outside the radiation field. 

Methods: The study group comprised 368 patients with a cStage II/Stage III 

adenocarcinoma of the rectum between 1991 and 2010. 108 received surgery alone 

(S group), 158 received preoperative RT with 20 Gy in 10 frs. plus IORT with 15 Gy 

(RT20 group), and 102 received preoperative RT 40 or 45 Gy in 20 or 25 frs. plus 

concurrent chemotherapy with oral UFT or S-1 (RT45 group). The sizes of LNs 

(shortest axis, longest axis, and area) were measured on specimens stained with 

hematoxylin and eosin, using a computer digitizer. LNs were divided into 2 groups 

according to their distribution, inside the radiation field and outside. 

Results: The total number of retrieved LNs was 1718 in the S group, 2337 in the 

RT20 group, and 917 in the RT45 group. The total number of retrieved LNs was 

significantly lower in the RT45 group (9.0 ± 6.9) than in the S group (15.8 ± 10.6) 

and the RT20 group (14.8 ± 9.1). (p < 0.001, p < 0.001) The numbers of retrieved LNs 

within the radiation field were significantly lower in the RT20 group (4.6 ± 4.0) and 

the RT45 group (4.1 ± 4.0) than in the S group (6.4 ± 5.8). (p < 0.008,p < 0.001) The 

numbers of retrieved LNs outside the radiation field did not differ significantly 

among the groups. As compared with the S group (4.9 ± 3.1mm), LNs inside the 

radiation field were significantly smaller in the RT20 (4.4 ± 2.5mm) group and the 

RT45 group (4.1 ± 2.7mm). LNs outside the radiation field were also significantly 

smaller in the RT20 group and the RT45 group than in the S group although the 

numbers of LNS did not differ significantly. These findings were most likely caused 

by the effects of concurrent chemotherapy. 

Conclusions: Our results showed that the response of LNs to RT/CRT differed 

between inside and outside of the radiation field. The numbers of retrieved LNs 

should be separately assessed inside and outside the radiation field to ensure accurate 

disease staging. 



612P ARE PATIENTS WITH RESECTABLE RECTAL CANCER 

BETTER OFF IN THE ERA OF MULTIDISCIPLINARY CARE? 

V.T. Broadbridge, J. Hardingham, K. Pittman, A. Townsend, M. Colbeck, 

B. Hooper, T. Price 

Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville 

South, SA, AUSTRALIA 

Introduction: The management of rectal cancer (RC) has evolved with the 

introduction of Total Mesorectal Excision Surgery (TME), use of Magnetic 

Resonance Imaging (MRI) for staging, changes in chemotherapy and radiotherapy 

and multidisciplinary meetings (MDTs). The timing of therapy for T3/4 and/or node 

positive RC has also changed with neoadjuvant chemoradiotherapy (CRT) becoming 

standard based on lower local recurrence rates. Given these changes in management 

over time, we assessed disease free survival (DFS), overall survival (OS) and rates of 

local and distant recurrences of patients treated at The Queen Elizabeth Hospital 

(TQEH) between 1992 to 2006. 

Method: Demographic and outcome data of patients diagnosed with early stage RC 

from TQEH Cancer Registry from 2 different time cohorts 1992-99 (A) and 2000-06 

(B) were analysed. Survival analysis was by Kaplan-Meier method and prognostic 

factors were analysed using cox proportional hazards regression. 

Results: 423 patients were identified; 235 in A, 188 in B. Patient characteristics 

were generally similar. Median age A 68.1 yrs (range 32-94), B was 67.4 yrs 

(range 25-92). More patients had stage B in cohort A (47%) v B (39%). 56% of 

patients had surgery alone in cohort A compared to 47% in cohort B. Rates of 

any “adjuvant” therapy was similar (A = 41% v B = 46%), although there was a 

doubling in proportion of patients who received neoadjuvant CRT in the latter 

cohort (A= 7.2% v B= 16%). There was a significant improvement in rate of 5 

year local/distal recurrence; A 87%/71% v B 95%/81%, p < 0.0001. 5 year DFS 

improved over time; A 65.2% v B 73.3%, p = 0. 03. 5 year OS was A 66.1% v B = 

78.4% and median OS for A was 14.62 years and not reached for cohort B (p = 

0.007). Stage and cohort B were prognostic for OS while age, sex, preoperative RT 

and any chemotherapy were not. 

Conclusion: There has been significant improvement in DFS, OS and local and 

distant recurrence rates in patients diagnosed with early stage RC. The trend to 

greater use of neoadjuvant CRT in the latter cohort is consistent with changes in 

practice, and this may be a factor in improved local control, but does not appear to 

impact on survival. Other factors likely to have improved overall outcomes include: 

increased TME rates, improved preoperative staging including use of MRI and 

potentially the introduction of MDTs. 


613P PPPP1R13L VARIANT ASSOCIATED WITH PROGNOSIS FOR 

PATIENTS WITH RECTAL CANCER 

J.G. Kim, B.W. Kang, S.J. Lee, Y.J. Lee, Y.S. Chae 

Oncology/Hematology, Kyungpook National University Medical Center, Daegu, 

KOREA 

Backgroud: Genetic variants related to apoptosis and DNA repair pathways may 

play a meaningful role in cancer progression as well as carcinogenesis. Among 

them, ERCC1 and PPP1R13L polymorphisms was shown to synergistically affect 

these pathways. The aim of this study was to investigate the association between 

these genetic variants and prognosis of colorectal cancer (CRC) operated 

curatively. 

Methods: A total of 349 CRC patients underwent curative surgery were 

consecutively enrolled between March 2003 and August 2006. DNA was 

extracted from fresh frozen normal tissue and each polymorphism (ERCC1 

rs11615 and rs735482; PPP1R13L rs1005165 and rs967591) was genotyped by 

polymerase chain reaction-restriction fragment length polymorphism 

(PCR-RFLP). 

Results: No statistical significance between these 4 variants and survival in a 

multivariate analysis for all CRC patients. However, the CC genotype of the 

PPP1R13L rs1005165 was significantly associated with worse survival in 164 

patients with rectal cancer (HR = 2.10 and P = 0.037 for RFS; HR = 2.27 and P = 

0.039 for DSS, respectively) as a recessive model of the C allele in a multivariate 

analysis. Meanwhile, no statistical differences in clinicopathologic characteristics 

were observed according to the PPPIR13L rs1005165 genotype in patients with 

rectal cancer. 

Conclusions: Our results suggest that PPP1R13L rs1005165 variant is possible 

prognostic marker for patients with rectal cancer. 



614P NEOADJUVANT TREATMENT IN RECTAL CANCER: LONG- VS 

SHORT-COURSE RADIOTHERAPY 

J. Casalta-Lopes1 , I. Nobre-Góis1 , T. Teixeira1 , M. Borrego1 , P. Soares1 ,A.Sá2 1 2 

Radiation Oncology, CHUC, Coimbra, PORTUGAL, Medical Oncology, CHUC, 

Coimbra, PORTUGAL 

Introduction: Two schemes for pre-operative radiotherapy (RT) in locally advanced 

rectal carcinoma (RC) are possible: long-course irradiation (45 – 50.4 Gy / 25 – 28 

fr) with chemotherapy (CHT), followed by surgery after 6 to 8 weeks; and 

short-course irradiation (25 Gy / 5 fr), followed by surgery usually 1 week after. 

Some studies have shown a downstaging effect with delayed surgery in short-course 

irradiation Goal: Compare results of different irradiation schemes for neoadjuvant 

treatment of RC in a Radiation Oncology Department. 

Methods: Patients with RC treated pre-operatively between 2002 and 2012 were 

included. RT was performed according to 2 schemes: long-course scheme (GROUP 

1) using only RT (GROUP 1A), with oral CHT (GROUP 1B) or infusion CHT 

(GROUP 1C); and short-course scheme (GROUP 2). 

Results: 265 patients were included, 227 in GROUP 1. GROUP 1A were older than 

GROUP 1B and 1C (p < 0.001). Grade 3 and 4 toxicity was only observed in the 

groups treated with concomitant CHT. Median time to surgery was 7 weeks. 

Response to treatment was statistically different regarding node downstaging (58.3% 

vs 77.1% vs 55.8%; p = 0.015) and locoregional response (56.3 vs 82.6% vs 70.5%; 

p = 0.020). GROUP 2 patients were older than those from GROUP 1 (p < 0.001), had 

lower Karnofsky index (p = 0.004) and several comorbidities. 15.8% patients (vs 0%) 

were considered M1 and more tumours were further than 5 cm from the anal margin 

in GROUP 2 (68.4% vs 49.8%; p = 0.033). No acute toxicity was observed in GROUP 

2 and median time to surgery was 2 weeks, with 65.7% of locoregional response. 

Considering time to surgery (≤1 week vs >1 week) there were significant differences 

in locoregional response (28.6% vs 75.0%, p = 0.033), with 2 complete responses in 

those with greater time to surgery. 

Conclusions: These results are according to literature: long-course scheme with 

concomitant CHT provided better locoregional response, although with some acute 

toxicity; a higher time to surgery in short-course scheme appears to have better 

results, with no increase in surgical complications. Short-course irradiation with 

surgery delay appears to be a useful alternative to long-course radiochemotherapy, 

namely in patients with advanced age and associated comorbidities. 


1704P PROSPECTIVE FEASIBLE STUDY TO EVALUATE 

NEOADJUVANT-SYNCHRONUS S-1 + RT FOR LOCALLY 

ADVANCED RECTAL CANCER: A MULTICENTER PHASE-II 

TRIAL (UMIN ID03396) 

M. Inomata 

Department of Gastroenterological Surgery, Oita University Faculty of Medicine, 

Oita, JAPAN 

Background: Fluorouracil-based chemoradiotherapy (CRT) is regarded as a standard 

perioperative treatment in locally advanced rectal cancer. We investigated the efficacy 

and safety of substituting fluorouracil with the oral prodrug TS-1. 

Methods: A multi-institutional (17 specialized centers), interventional phase II trial, 

was conducted from April 2009 to August 2011.This study is registered with 

UMIN-CTR, number C003396. For inclusion, patients must fulfill the following 

requirements before neoadjuvant CRT: (i) histologically proven rectal carcinoma; (ii) 

tumor located in the rectum (upper,lower); (iii) cancer classified as T3-4, N0–3 and 

M0; Two cycles of neoadjuvant CRT with TS-1 (100 mg/m 2 on days 1-5, 8-12, 22-26, 

and 29-33) is administered, and irradiation (total 45Gy/25fr, 1.8Gy/day, on days 1-5, 

8-12, 15-19, 22-26, and 29-33) is performed. Total mesorectal excision with D3 

lymphadenectomy is performed during the 4th and 8th week after the end of the 

neoadjuvant CRT. The primary end-point is rate of complete treatment of 

neoadjuvant CRT. Secondary endpoints are response rate of neoadjuvant CRT, 

short-term clinical outcomes, rate of curative resection, and pathological response 

(grade2/3). 

Results: This trial included 37 patients. A complete treatment of neoadjuvant CRT 

was found in 83.3% of patients (95%CI;71.2 ∼ 95.5%), and an adverse event (grade 3/ 

4) occurred in 4 patients(11.1%). A rate of an overall downstaging (PR/CR;RECIST 

1.0) was 83.3% (95%CI; 71.2 ∼ 95.5%), and a pathologic response rate was 50.0% 

(95%CI; 33.7 ∼ 66.3%). 

Conclusion: Our prospective phase-II study demonstrated that a 

neoadjuvant-synchronus TS-1 + RT for locally advanced rectal cancer was feasible in 

terms of pathological response and adverse events. 




615 SINGLE NUCLEOTIDE POLYMORPHISMS (SNP’S) IN THE P53, 

SMAD7 AND TGFBR1 GENES ASSOCIATED WITH ADVANCED 

COLORECTAL CANCER IN CAUCASIAN PATIENTS COMPARED 

TO HEALTHY CONTROLS 

M. Pauly 1 , G. Mahon 1 , M.A. Dicato 2 , B. Metzger 1 , A. Menzel 3 

1 Laboratory, Foundation for Research on Cancer, Luxembourg, LUXEMBOURG, 

2 Hematology- Oncology, Centre Hospitalier de Luxembourg, Luxembourg, 

LUXEMBOURG, 3 Biology Moléculaire, Laboratoires Réunis, Junglinster, 

LUXEMBOURG 

Background: In order to evaluate various SNP’s in different genes and 

chromosomal locations in Caucasian patients as markers of the predisposition to 

the colorectal cancer (CRC) disease, we analyzed the frequency of different 

tumour-associated single-nucleotide polymorphisms in several genes including p53 

and SMAD7 of Caucasian CRC patients as compared to a healthy Caucasian 

control population. 

Method: Tumour samples were obtained from 188 CRC patients and from 

leukocytes of 98 healthy control individuals. After gDNA extraction, selected 

amplicons were amplified by PCR, followed by melting curve analysis. The statistical 

evaluation was carried out using the Chi-squared test. 

Results: Comparing the patients to the controls, a significant difference in the 

genotype distribution of the G429C SNP in the p53 gene was observed (P = 0.046). 

Similarly, a significant difference was found for rs4939827 C > T in the SMAD7 gene 

(P = 0.037), although no significant differences were found for rs4464148 T > C (P = 

0.585) or rs12953717 C > T (P = 0.197) also in SMAD7. Differences in genotype 

distribution for CHR9 C > A rs719725 and CHR8 G > A rs7014346 were almost 

significant (P = 0.050 and P = 0.054 respectively). Significant results previously 

reported for two other genes were confirmed:- PAI, 5G vs. 4G, rs1799899 (P = 0.047) 

and TGFBR1 A > G rs334348, G > A rs334349 and A > C rs1591 (P < 0.0001). No 

significant differences were found for SNP’s in 9 other genes. 

Conclusion: The results for p53, SMAD7, PAI, CHR8 and CHR9 are suggestive 

rather than conclusive and invite confirmation through further study. Concerning the 

association between the TGFBR1 SNP’s and colorectal cancer, the results are 

significant (p < 0.0001). For example, with the TGFBR1 SNP rs334348, the frequency 

of the GG genotype was as much as 43% for the CRC patients but 11% for the 

controls, while the frequency of the AA genotype was only 18% for the patients and 

43% for the controls. 


616 EARLY LYMPH NODE METASTASIS: ALTERED MICRORNA 

EXPRESSION IN COLON CANCER 

M. Rammer 1 , H. Rumpold 2 , H. Bösmüller 3 , R. Marschon 1 , T. Malli 1 , 

W. Kranewitter 1 , M. Erdel 1 , S. Deutschbauer 1 , A.L. Petzer 2 , G. Webersinke 1 

1 Laboratory for Molecular Biology and Tumor Cytogenetics, Barmherzige 

Schwestern Hospital, Linz, Linz, AUSTRIA, 2 Interne I:hematology and Oncology, 

Krankenhaus der Barmherzigen Schwestern, Linz, AUSTRIA, 3 Clinical Pathology, 

Barmherzige Schwestern Hospital, Linz, Linz, AUSTRIA 

Recently several studies confirmed the regulatory potential of microRNAs 

(miRNAs). Via incomplete complementarity, miRNAs bind to mRNA targets 

thereby causing translational inhibition or target decay. Alterations of miRNA 

expression can be associated with various tumors. Furthermore, different miRNA 

levels were found to be linked with distinct tumor stages and could have a 

predictive and prognostic value, even regarding treatment response. The aim of 

the study is evaluating miRNÀs that correlate with early lymph node metastasis. 

Therefore, we compare formalin fixed, paraffin-embedded primary tissue of stage 

T4 colon tumors without lymph node metastasis with stage T1/2 tumors 

exhibiting lymph node metastasis. In order to initially scan for differentially 

expressed miRNAs, miRNA arrays (n = 8) were performed. A selection of miRNAs 

(miR-1207-5p, miR-146b-5p, miR-15a, miR-21, miR-494) showing distinct 

expression was then validated in a patient collective via RT qPCR. MiR-191 and 

miR-720 were chosen as endogenous controls, since they showed consistent 

expression in the preliminary array analysis. According to our array results, eight 

miRNAs displayed an elevated expression in T4 tumors without lymph node 

metastasis compared to three miRNAs higher expressed in the second group 

investigated. The significantly elevated expression (≥2-fold) was confirmed via RT 

qPCR for two (miR-146b-5p, miR-21) and one miRNA (miR-494), respectively. 

Some of our miRNA expression data correlates with that presented in studies 

regarding metastasis in colon cancer and other malignancies. Nevertheless, several 

miRNAs diverge compared to studies from other groups, e.g. miR-21. This could 

be due to differences in the tumor stages examined in these studies. To our 

knowledge, miRNA expression in the colon cancer stages investigated here has not 

been compared so far. To validate our findings concerning miRNA expression 

patterns in colon tumors associated with early lymph node metastasis, we will 

investigate a larger cohort. This further enhances our understanding of disease 

progression. Moreover, it implies the possibility of distinguishing stage and 

metastatic potential in biopsy specimen for novel therapeutic strategies. 


617 WNT 5A EXPRESSION HAS ASSOCATION WITH VEGFR AND 

MMP-9 EXPRESSION IN PRIMARY OR METASTATIC TUMOR 

TISSUE IN COLORECTAL CANCER 

S.Y. You 1 , M.A. Lee 1 , S.T. Oh 2 , W.K. Kang 2 

1 Medical Oncology, Seoul St. Mary’s Hospital, of the Catholic University, Seoul, 

KOREA, 2 Surgery, Seoul St. Mary’s Hospital, Seoul, KOREA 

Background: It has been known that various molecular changes can develop as 

cancer progresses. However, it is difficult to confirm the progressive change in the 

human tissue because adequate tumor tissue cannot be obtained from metastatic site. 

Resection for metastatic lesion is commonly done in metastatic colorectal cancer in 

spite of palliative surgery. The Wnt, VEGFR, and MMP protein expression have been 

explored in advanced cancer due to its association with invasion and metastasis. We 

investigated these protein expressions in primary tumor and metastatic site to get the 

basic information of the role of these proteins in cancer progression. 

Method: Tissue specimens from 130 patients with metastatic colorectal cancer were 

analyzed. All patients took resection for primary tumor and metastatic lesion 

between Jan, 2000 and Aug, 2008 at Seoul St. Mary’s hospital, the Catholic 

University. We performed immunohistochemical staining using tissue microarray 

from the primary tumor tissue and metastatic site for Wnt 3a, Wnt 5a, VEGFR, and 

MMP-9. 

Result: Of the 100 patients, Male was 59, and female was 41. Colon cancer was 60 

and rectal cancer was 40. In primary tumor, Wnt 3 & 5 expression was 72% and 

70% respectively. VEGFR expression was 24% and MMP-9 was 39%. In metastatic 

site, Wnt 3 & 5 expression rate were slightly decreased to 66%. However, VEGFR 

expression rate was slightly increased to 30% and MMP-9 expression rate was same. 

In concordance rate between primary and metastatic site, Wnt 3a expression showed 

68% and 62% in Wnt 5a, 66% in VEGFR, 68% in MMP-9. There was no significant 

change of expression between primary and metastatic site. There was no association 

between Wnt 3a expression and VEGFR or MMP-9 expression both in primary 

tumor and metastatic site. However, Wnt 5a expression showed significantly 

correlation with negative VEGFR expression (p = 0.02 both in primary tumor and 

metastatic site. Wnt 5a expression was also associated with negative MMP-9 

expression in primary tumor tissue (p = 0.022). 

Conclusion: We could not find any significant change in protein expression between 

primary and metastatic site. However, there was a tendency of more VEGFR 

expression in metastatic site than primary tumor. The Wnt 5 expression was 

associated significantly negative expression of VEGFR and MMP-9. 


618 AN EXPLORATORY ANALYSIS OF AMPK AND ACC ACTIVATION 

IN COLORECTAL PRIMARY TUMORS AND THEIR 

CORRESPONDING METASTASIS 

F. Bergamo 1 , G. Griguolo 2 , E. Zulato 3 , G. Esposito 3 , M. Nardin 3 , C. Mescoli 4 , 

M. Rugge 5 , V. Zagonel 6 , S. Lonardi 1 , S. Indraccolo 3 

1 Medical Oncology Unit 1, Istituto Oncologico Veneto -IRCSS, Padua, ITALY, 

2 University of Padova - School of Medicine, University of Padova - School of 

medicine, Padova, ITALY, 3 Istituto Oncologico Veneto - Irccs, Istituto Oncologico 

Veneto - IRCCS, Padova, ITALY, 4 Istituto di Anatomia Patologica, University of 

Padova, Padova, ITALY, 5 Pathology and Cytopathology Unit, University of 

Padova, Padova, ITALY, 6 Medical Oncology Unit 1, Istituto Oncologico Veneto, 

Padua, ITALY 

Background: AMPK is a well known oncosuppresor, with prognostic significance in 

many neoplasms; it acts as a central metabolic sensor in cells, activated in 

energy-stress conditions. ACC is a central enzyme in cell metabolism activated 

through phosphorilation by AMPK. In pre-clinical models AMPK activation level 

correlates with necrotic response when tumors are treated with Bevacizumab. Our 

goal was 1) to evaluate the concordance of these markers’ activation in primary 

tumours and in the corresponding metastasis, 2) to investigate their correlation with 

clinical data, in particular radiological response to FOLFIRI plus Bevacizumab. 

Methods: This retrospective study analyzed histological pre-treatment material from 

32 patients with mCRC treated with FOLFIRI-Bevacizumab to evaluate AMPK and 

ACC activation in primary CRC and its metastasis using immunohistochemistry. The 

intensity was scored from 0 (negative) to 3 (intense), and then dichotomized in low 

(0-1) and high (2-3) activation categories. pAMPK and pACC intensity scores in 

primary tumors and metastasis were compared using Spearman’s correlation test. 

Radiological response has been going to be evaluated using both RECIST and 

morphologic criteria (Chun Criteria). 

Results: pAMPK was defined high in 20 (63%) primary and in 21 (66%) of the 

corresponding metastases while pACC in 23 (72%) primary tumors and 19 (59%) 

metastases. As attended from biological knowledge, AMPK and ACC activation 

correlated significatively in primary tumors (p = 0.0007). ACC activation in primary 

tumors correlated significatively with its activation in their metastasis (p = 0.04), 

while AMPK activation in primary tumors and in metastasis showed a correlation 

not reaching statistical significance (p = 0.13). Correlation between AMPK and ACC 

activation and radiological morphological response was still not possible at time of 

writing. 


Conclusions: AMPK and ACC activation showed a weak correlation in primary and 

metastastatic tumors, possibly due to the small number of patients and the higher 

heterogeneity of the metastatic tissue. The opportunity to use these biomarkers to 

predict a necrotic response to bevacizumab treatment is under investigation. 


619 DIFFERENTIAL ANTIGENIC EXPRESSION IN COLORECTAL 

CANCER, MUCOSA ADJACENT TO COLORECTAL CANCER, 

AND NORMAL COLORECTAL MUCOSA 

A. Zwenger 1 , G. Grosman 2 , S. Demichellis 3 , A. Segal-Eiras 3 , M.V. Croce 3 

1 Oncologia, Hospital Provincial Neuquen, Neuquen, ARGENTINA, 2 Patologia, 

Hospital Provincial Neuquen, Neuquen, ARGENTINA, 3 Centre for Basic and 

Applied Immunological Research, Faculty of Medical Sciences National University 

of La Plata, La Plata, ARGENTINA 

Introduction: Despite of an excellent oncologic surgery with broad normal tissue 

margins, the mucosa next to the bed anastomosed is a frequent place of tumoral 

recurrence on colorectal cancer. Objective: This study was performed to evaluate the 

expression of mucins and carbohydrates associated antigens in normal mucosa 

colorectal specimens (NMC), mucosa adjacent to colorectal cancer (MACCR) and 

malignant colorectal tumour samples (CCR). 

Methods: Ninety colorectal cancer tumour samples and their MACCR, and also 68 

NMC were included. Monoclonal antibodies (MAbs) against the following antigens 

were employed: anti-MUC1 (HMFG1), MUC2 (H-300) and MUC5AC (45M1), 

anti-Tn (HB-Tn1), Lex (KM380), sLex (KM93), Ley (C70) and sLea (1116-N5-19-9). 

An immunohistochemical approach following standard procedures was performed. 

Statistical analysis: an univariate statistical analysis with Chi2 was applied. 

Results: Malignant samples expressed MUC1 in 94% of cases, MUC2 in 52.4%, 

MUC5AC in 14.3%, Tn in 41%, Lex in 74.4%, sLex in 66.7%, Ley in 91.8% and sLea 

in 90.7%. Taking into account MUC2 and Ley expression, a positive correlation was 

found between MACCR and CCR: MUC2, P = .0006 and Ley, P = .0008. In 

malignant samples, MUC1 expression was increased compared to NMC (P = .04), 

also this mucin was 22.2% higher in MACCR than NMC. The expression of sLex 

and Ley was higher in CCR than NMC (179% and 33.6%, respectively). Expression 

of most antigens showed an increased tendency from NMC to MACCR and CCR: 

MUC1 (27.9%, 34.1% and 94%, respectively), Lex (60.9%, 30.5% and 74.4%, 

respectively), sLex (23.9%, 16.9% and 66.7%, respectively), Ley (68.7%, 78.3% and 

91.8%, respectively) and sLea (62.1%, 45.6% and 90.7%, respectively). On the other 

hand, MUC5AC expression decreased in the mentioned sequence (51.5%, 20.7% and 

14.3, respectively). 

Conclusion: Our results may support the hypothesis that the MACCR could be an 

intermediate point or “transitional zone” between NMC and CCR. Further studies 

are needed in order to correlate these findings with clinical outcomes. 


620 IMPACT OF THE INTERVAL BETWEEN SURGERY AND 

ADJUVANT MFOLFOX6 ON SURVIVAL OF COLON CANCER 

PATIENTS 

J. Godinho Bexiga, F. Carneiro, D.S. Marques, N. Sousa, C. Faustino, 

A. Raimundo, M. Machado, P. Ferreira, M. Fragoso 

Medical Oncology, Portuguese Institute of Oncology of Oporto, Oporto, 

PORTUGAL 

Background: Adjuvant chemotherapy with the association of Oxaliplatin and 

Fluoropyrimidines has shown to reduce recurrence risk and improve survival in stage 

III colon cancer patients in comparison to Fluoropyrimidines alone. The ideal timing 

for the start of adjuvant chemotherapy has not been defined. Our aim was to 

determine the impact of the interval between surgery and the start of adjuvant 

chemotherapy on survival of colon cancer patients. 

Material and methods: Retrospective cohort study, in a Portuguese cancer centre, of 

colon cancer (CC) patients treated with mFOLFOX6 in the adjuvant setting, from 

Table: 621 

Group 

5-year 

RFS HR [95% CI] 

September 2004 till November 2009. Two groups of patients were defined according 

to the timing of adjuvant chemotherapy (CT): ≤ 8weeks or >8 weeks after surgery. 

Efficacy was evaluated by overall survival (OS) and disease-free survival (DFS). 

Hazard ratios and 95% confidence intervals were calculated with the use of the Cox 

proportional hazards model. 

Results: Two hundred and seventy seven patients were treated with adjuvant 

mFOLFOX6 and followed for a median time of 45 months. Median age was 62 years 

(28-79); 57% were male and 77% had stage III CC. Median time to the start of CT 

was 8 weeks (P25 = 7, P75 = 10). The group of patients that started CT > 8 weeks 

after surgery was older (mean age: 62 vs 59 years, p = 0.001) and tended to 

accomplish lower relative dose-intensity of Oxaliplatin and 5-Fluorouracil (69,5% vs 

72% and 73% vs 76%, respectively; p > 0.05). There was a tendency to lower OS and 

DFS in the group that started CT >8 weeks after surgery. At 3 years, the probability 

of OS was 83% vs 90% (p = 0.118), and DFS: 75% vs 77% (p = 0.751). Multivariate 

analysis showed that the interval between surgery and the start of adjuvant CT had 

no impact in OS nor DFS. 

Conclusions: Our data point to a tendency to better survival when CT is started 

within 8 weeks of surgery, strengthening the need for a timely referral of 

patients to adjuvant treatment. The small sample size and the short follow-up 

might explain why we were unable to find statistical significance in this 

association. 


621 IS ADJUVANT CHEMOTHERAPY (CT) BENEFICIAL TO STAGE II 

COLON CANCER (CC) WITH ELASTIC LAMINANL INVASION 

(ELI)? 

M. Yokota 1 , M. Kojima 2 , S. Nomura 3 , A. Koyama 1 , M. Sugito 1 , M. Ito 1 , 

A. Kobayashi 1 , Y. Nishizawa 1 , A. Ochiai 2 , N. Saito 1 

1 Department of Gastrointestinal Oncology, Colorectal Surgery, National Cancer 

Center Hospital East, Kashiwa, JAPAN, 2 Research Center for Innovative 

Oncology, Pathology, National Cancer Center Hospital East, Kashiwa, JAPAN, 

3 Research Center for Innovative Oncology, Clinical Trial Section, National Cancer 

Center Hospital East, Kashiwa, JAPAN 

Background: The peritoneal elastic lamina (PEL) is situated just under the visceral 

peritoneum and invests intestine wall. We defined cases with tumor invasion beyond 

the PEL as positive for ELI (ELI (+)). We have reported that PEL can be a useful 

pathologic hallmark to classify the level of tumor invasion in CC, and represented as 

an independent risk factor for recurrence free survival (RFS) for stage II CC (Kojima 

et al. Am J Surg Pathol. 2010;34:1351-60). We evaluated the necessity of adjuvant CT 

for stage II CC with ELI (+). 

Methods: We screened a database of 436 patients (pts) who underwent curative 

resection for pT3 and pT4a CC in our hospital between 1996 and 2006, 

excluding 3 stage II pts who received adjuvant CT. RFS and overall survival 

(OS) were analyzed to assess the prognostic characteristics of stage II pts with 

ELI (+). Of 436 pts in the database, we performed Cox regression analysis. 

Covariates included age (


622 RANDOMIZED, OPEN-LABEL STUDY OF THE BIOLOGICAL 

EFFECTS OF BLP25 LIPOSOME (L-BLP25) IMMUNOTHERAPY 

IN RECTAL CANCER PATIENTS UNDERGOING NEOADJUVANT 

CHEMORADIOTHERAPY: SPRINT STUDY DESIGN 

T.J.M. Ruers 1 , D. Aust 2 , M. van den Eynde 3 , G. Folprecht 4 , J. Carrasco 5 , 

M. Fuchs 6 , J.M. Smit 7 , A. Victor 8 , S. Quaratino 9 

1 Department of Surgical Oncology, Nederlands Kanker Instituut - Antoni van 

Leeuwenhoek Ziekenhuis, Amsterdam, NETHERLANDS, 2 Institute of Pathology, 

Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, 

Dresden, GERMANY, 3 Medical Oncology, Cliniques universitaires St-Luc, 

Brussels, BELGIUM, 4 Department of Internal Medicine I, Universitätsklinikum Carl 

Gustav Carus an der Technischen Universität Dresden, Dresden, GERMANY, 

5 Medical Oncology, Grand Hopital de Charleroi, Charleroi, BELGIUM, 

6 Gastroenterology Clinic, Klinikum Bogenhausen, München, GERMANY, 7 Internal 

Medicine, Gelre Ziekenhuizen, Apeldoorn, NETHERLANDS, 8 Global Biostatistics/ 

oncology, Merck KGaA, Darmstadt, GERMANY, 9 Global Clinical Development, 

Merck KGaA, Darmstadt, GERMANY 

Background: Neoadjuvant chemoradiotherapy (NCR) followed by radical resection is 

the standard of care for patients with stage II-III rectal cancer. L-BLP25 (Stimuvax®) 

is an antigen-specific cancer immunotherapeutic agent targeting the mucin 1 

(MUC1) antigen. It may act by inducing the proliferation of interferon (IFN)-γ 

secreting MUC1-specific CD4+ T-cells and the generation of cytotoxic T 

lymphocytes capable of killing MUC1-expressing tumours. In the SPRINT 

(Stimuvax® [L-BLP25] in Rectal cancer In Neoadjuvant chemoradioTherapy) study, 

we will evaluate immune responses to L-BLP25 in patients with rectal cancer 

undergoing NCR. 

Study design: SPRINT is a phase II, multi-centre, open-label study in which patients 

(n = 24/arm) with resectable stage II-III rectal cancer are randomized to NCR 

(capecitabine 825 mg/m 2 twice-daily for 5–7 d/wk; 45–52 Gy in fractions of 1.8/2 Gy 

for ≥5 wk) alone, NCR + L-BLP25, or NCR + L-BLP25 + cyclophosphamide (CPA). 

L-BLP25 is administered as 8 consecutive weekly subcutaneous doses (930 µg) 

beginning on the first day of NCR, followed by a final injection 7–9 d before surgery. 

CPA (300 mg/m 2 ; maximum 600 mg) is given as a single intravenous infusion 3 d 

before the first L-BLP25 dose. Surgery will be performed 6–8 wk after the end of 

NCR. The primary objective is to assess L-BLP25-induced changes in immune 

response profile. The intra-tumoural response will be evaluated based on analysis of 

tumour-infiltrating lymphocytes (especially CD8+ and CD45RO+). Peripheral 

antigen-specific response will be assessed by measuring IFN-γ secretion by peripheral 

blood mononuclear cells (ELIspot assay) in response to MUC1 and 

carcinoembryonic antigen (CEA) as a test for ‘antigen spreading’. Secondary 

objectives include the assessment of additional immunological changes and 

correlation of intratumoural, peripheral and skin delayed-type hypersensitivity 

responses. Safety and pathological anti-tumour responses in resection specimens will 

be evaluated. 

Disclosure: A. Victor: Anja Victor is an employee of Merck KGaA Germany. 

S. Quaratino: Sonia Quaratino is an employee of Merck KGaA. All other authors 


623 EUROPEAN ORGANIZATION FOR RESEARCH AND 

TREATMENT OF CANCER QLQ-C30 AND FUNCTIONAL 

ASSESSMENT OF CANCER THERAPY-GENERAL FOR THE 

MEASUREMENT OF QUALITY OF LIFE IN COLORECTAL 

CANCER PATIENTS WHO RECEIVED ADJUVANT 

CHEMOTHERAPY: A COMPARISON 

A. Tsunoda 1 , Y. Tsunoda 2 

1 Surgery, Kameda Medical Center, Kamogawa City, JAPAN, 2 Breast Center, 

Kameda Medical Center, Kamogawa City, JAPAN 

Purpose: Quality of life (QOL) was measured using the European Organization for 

Research and Treatment of Cancer QLQ-C30 (QLQ-C30) and Functional 

Assessment of Cancer Therapy-General (FACT-G) in colorectal cancer patients who 

received adjuvant chemotherapy with oral uracil/tegafur plus leucovorin, and two 

QOL measurements were compared. 

Methods: QOL was assessed prospectively at baseline (pretreatment) and at 5-week 

intervals during treatment, using QLQ-C30 and FACT-G, and were compared with 

reference to the corresponding scales. 

Results: The study group comprised 58 men and 41 women, with a mean age of 65 

years (range, 30 to 80). The disease stage was stage II in 51 patients and stage III in 

48. The 99 patients had received a total of 444 treatment cycles (median, 5 cycles; 

range, 0.1 to 5 cycles). The most common type of toxicity was fatigue. However, the 

incidence of grade 3 or 4 fatigue was very low. The most common type of 

hematological toxicity was anemia, which was generally mild. Six patients had grade 

3 diarrhea and 6 had grade 3 anorexia. QOL was not evaluated either before or after 

treatment in 5 of the 99 enrolled patients; both baseline and post-treatment 

evaluations were available for the other 94 patients. Of 94 patients, the numbers of 

patients who completed the QOL questionnaires were 90 (96%) at baseline, and 87 

(93%), 85 (90%), 88 (94%), 84 (89%), and 81 (86%), consecutively. The mean 

number of evaluations per patient was 6.2 (range, 3-7). The post-treatment 

assessments changed significantly from the baseline values and favored 

post-treatment for all scales except social well-being of the FACT-G. All scales except 

social well-being in patients with Grade 0-1 toxicities were better than those with 

Grade 2-3 toxicities. Social well-being in patients with Grade 2-3 toxicities were 

worse than those with Grade 0-1. When corresponding scales between the two QOL 

questionnaires were compared, a high correlation for physical domain or emotional 

domain was found. However, no correlation was noticed for the social domain. 

Conclusion: The social domain of the two QOL questionnaires may evaluate 

different aspects of QOL each other. 


624 PATHOLOGICAL RESPONSE OF SYNCHRONOUS LIVER 

METASTASES FROM COLORECTAL CANCER TREATED WITH 

BEVACIZUMAB PLUS MFOLFOX6 IN AN ANALYSIS OF A PHASE 

II STUDY OF NEOADJUVANT CHEMOTHERAPY 

Y. Katayose 1 , J. Yamauchi 2 , M. Oikawa 3 , N. Sakurai 4 , H. Musya 5 , 

H. Shimamura 6 , K. Miura 7 , K. Nakagawa 1 , S. Egawa 7 , M. Unno 7 

1 Intergrated Surgery and Oncology, Tohoku University Graduate School of 

Medicine, Sendai, JAPAN, 2 Surgery, Sendai Kosei Hospital, Sendai, JAPAN, 

3 Surgery, Sendi city medical center, Sendai, JAPAN, 4 Surgery, Yamagata central 

hospital, Yamagata, JAPAN, 5 Surgery, Tohoku Rosai Hospital, Sendai, JAPAN, 

6 Surgery, Sendai Medical Center, Sendai, JAPAN, 7 Surgery, Tohoku University 

Graduate School of Medicine, Sendai, JAPAN 

Background: The prognosis of synchronous liver metastases (SLM) from colorectal 

cancer is poor. Therefore, we, the Miyagi Hepato-biliary pancreatic clinical oncology 

group (Miyagi-HBPCOG), conducted a phase II study of neoadjuvant chemotherapy 

for SLM to determine the appropriate initial treatment. Here, we assessed the 

radiologic and pathological responses. 

Patients and methods: Patients were enrolled after R0-resection of the primary 

colorectal cancer and received 8 courses of mFOLFOX6 with bevacizumab (the first 

and last courses were mFOLFOX6 alone). The main inclusion criteria were SLM 

within 10 nodules, histologically confirmed, measurable disease. The primary 

endpoint was the response rate (RR). 

Result: Between June 2008, and November 2008, 47 patients were enrolled from 17 

centers. The median age was 62 years (range 32-72 yrs). The median number of 

metastases was 2 nodules, and the maximum diameter of tumors was 12.9 cm. Three 

patients were excluded from the evaluation of RR because they did not receive any 

scheduled chemotherapy. The overall RR was 70.5% (2 complete responses and 29 

partial responses). Eleven patients (25%) showed stable disease and 1 patient (2.3%) 

had progressive disease. The liver resections rate was 90.9% (40/44) and the 

R0-resection rate was 86.3% (38/44). The pathological response was evaluated tumor 

regression grade (TRG1-5). Major response (TRG1 and 2) was 55%, partial response 

(TRG2) was 32.5%, and no response (TRG4 an 5) was 12.5%. This major response 

rate was high, so the progression-free survival and overall survival can be extended is 

expected. Necrosis was also graded as 1 to 4. Major necrosis of Grade 3 and 4 was 

52.5%, and Grade 2 was 17.5%, and Grades 0 and 1 of no necrosis were 30.0%. 

Although the necrosis rate slightly correlated with the pathological response, the 

radiological response did not correlate with it. 

Conclusion: Pathological and radiological response of liver metastases treated with 

bevacizumab plus mFOLFOX6 appeared favorable. Therefore, the progression-free 

survival and overall survival could be expected to be extended. (Trials Registry: 

UMIN000001568). 


625 FEASIBILITY REPORT OF A RANDOMIZED MULTICENTER 

CONTROLLED PHASE III TRIAL OF ADJUVANT UFT/LV 

THERAPY AFTER RESECTION FOR LIVER METASTASIS FROM 

COLORECTAL CARCINOMA 

J. Yamamoto 1 , K. Hatsuse 1 , N. Kokudo 2 , M. Oba 1 , T. Takayama 3 , S. Miyagawa 4 , 

Y. Bandai 5 , K. Hasegawa 2 , A. Saiura 6 , M. Makuuchi 7 

1 Surgery, National Defense Medical College, Tokorozawa, JAPAN, 2 Hepato– 

Biliary–Pancreatic Surgery Division, Department of Surgery, Graduate School of 

Medicine, University of Tokyo, Tokyo, Bunkyo-ku, JAPAN, 3 Department of 

Digestive Surgery, Nihon University School of Medicine, Tokyo, JAPAN, 4 First 

Department of Surgery, Shinshu University School of Medicine, Matsumoto, 

JAPAN, 5 Department of Surgery, Social Insurance Chuo General Hospital, 

Tokyo, JAPAN, 6 Department of Gastrointestinal Surgery, Cancer Institute 

Hospital, Japanese Foundation for Cancer Research, Ariake Hospital, Tokyo, 

JAPAN, 7 Department of Hepatobiliary Pancreatic Surgery, Japanese Red Cross 

Medical Center, Tokyo, JAPAN 

There is no established evidence yet to support the of postoperative adjuvant 

chemotherapy after resection of colorectal liver metastasis. A randomized multicenter 

controlled phase III trial was conducted and patients were recruited from 20 

hospitals to compare the efficacy of postoperative adjuvant UFT/LV therapy (UTF: 

300 mg/m 2 /day and LV: 75 mg/day, Day 1-28, once every 5 weeks, 5 cycles) with that 


of surgical monotherapy in patients with colorectal liver metastasis. A total of 180 

patients enrolled from January 2004 to December 2010 are currently under 

follow-up. The primary endpoint is recurrence-free survival time and the secondary 

endpoint is overall survival time, the results of which are awaited. It is expected that 

the patients who underwent liver resection in this study are different from the stage 

II or III colon cancer patients treated by surgery for primary diseases. We shall 

report the results of the interim analysis of compliance and safety in the 175 patients 

for whom the CRFs relevant to this study could be collected. Eighty-eight patients 

received surgical monotherapy and 87 received surgery plus UFT/LV therapy. There 

were no significant differences in the demographic or clinicopathological factors 

between the two groups. The rate of completion of UFT/LV therapy (5 courses) was 

53.8% (43/80), and the rates of completion up to 3 and 6 months were 71.3% (57/80) 

and 53.8% (43/80), respectively. The mean rate of dose intensity was 70.1%. Of the 

37 patients in whom the treatment was discontinued, the reason for the 

discontinuation was adverse events in 26 patients (in conflict with discontinuation 

criteria in 7 patients and no conflict in 19) and appearance of recurrence in 8 

patients. Adverse events of CTCAE grade 3 or higher observed in the UFT/LV Group 

included decrease in hemoglobin (3.8%), increase in AST/ATL (2.6%), febrile 

neutropenia (1.3%), hyperbilirubinemia (1.3%), diarrhea (5.0%), loss of appetite 

(2.5%), and nausea (2.5%). There were no treatment-related deaths. The incidence 

rates of these symptoms are not greatly different from those reported in relation to 

the safety profile after surgery for stage III colon cancer from the ACTS-CC study, 

which suggested that the tolerability of UFT/LV therapy was maintained even in 

stage IV colorectal cancer patients treated by hepatectomy. 


626 WHAT TO CHOOSE AS RADICAL LOCAL TREATMENT FOR 

LUNG METASTASES FROM COLO-RECTAL CANCER: 

SURGERY, RADIOFREQUENCY ABLATION OR STEREOTACTIC 

RADIOTHERAPY? 

R. Schlijper 1 , D. De Ruysscher 2 , J.P. Grutters 3 , R. Houben 4 , A.C. Dingemans 5 , 

J.E. Wildberger 6 , D.V. Raemdonck 7 , E. Van Cutsem 8 , G. Lammering 4 , 

P. Lambin 2 

1 Faculty of Health, Medicine and Life Sciences, School of Medicine, Maastricht 

University, Maastricht, NETHERLANDS, 2 Maastro Clinic, Maastricht University 

Medical Center (MUMC), Maastricht, NETHERLANDS, 3 Department of Health 

Service Research, School for Public Health and Primary Care (CAPHRI), 

Maastricht University, Maastricht, NETHERLANDS, 4 Department of Radiation 

Oncology, Maastro Clinic, Maastricht, NETHERLANDS, 5 Pulmonology, 

Maastricht University Medical Center (MUMC), Maastricht, NETHERLANDS, 

6 Department of Radiology, Maastricht University Medical Center, Maastricht, 

NETHERLANDS, 7 Department of Thoracic Surgery, University Hospital Leuven, 

Leuven, BELGIUM, 8 Digestive Oncology, University Hospital Leuven, Leuven, 

BELGIUM 

Background: Long-term survival can be obtained with local treatment of lung 

metastases from colorectal cancer. However, it is unclear as to what the optimal local 

therapy is: surgery, radiofrequency ablation (RFA) or stereotactic radiotherapy 

(SBRT). 

Methods: After a systematic review, 27 studies were included matching with the a 

priori selection criteria, the most important being at least 50 patients and a follow-up 

period of ≥ 24 months. However, no SBRT studies were eligible. The review was 

therefore conducted on 4 RFA and 23 surgical series. 

Results: Four of the surgical studies were prospective, all others were retrospective. 

No randomized trial was found. The reported data differed between the studies, 

which led to difficulties in the analyses. Treatment-related mortality rates for RFA 

and surgery were 0% and 1.4-2.4%, respectively, whereas morbidity rates were 

reported inconsequently but seemed the lowest for surgery. Weighted 2- and 5-year 

survival were 69.6% and 40.7% for RFA and 76.5% and 44.9% for surgery. 

Conclusion: Due to the lack of phase III trials, no firm conclusions can be drawn, 

although most evidence supports surgery. High-quality trials comparing currently 

used treatment modalities such as SBRT, RFA and surgery are needed. 


627 RESULTS OF ADJUVANT CHEMOTHERAPY AFTER HEPATIC 

AND/OR LUNG METASTASES RESECTION OF COLORECTAL 

CANCER 

E.I. Gutiérrez Damian 1 , A. Sancho Gutiérrez 1 , M. Arruti 1 , S. Carrera 2 , I. Rubio 1 , 

I. Marrodan 1 , A. Muñoz 1 , E. Azkona 1 , A. Buque 1 , G. Lopez-Vivanco 1 

1 Medical Oncology, Hospital of Cruces, Barakaldo, SPAIN, 2 Oncology, Hospital 

de Cruces, Barakaldo, Vizcaya, SPAIN 

Background: Adjuvant chemotherapy following metastases resection of colorectal 

cancer is recommended although the benefit has not been clearly demonstrated in 

clinical trials. 


Methods: We have performed a retrospective review of patients (pt) with hepatic 

and lung metastases treated with surgery and adjuvant chemotherapy in our 

institution, from January-96 to December-11. 

Results: One hundred ninety one patients were identified. Patient 

characteristics: median age 62 years (23-81). Sex: 114 male (60%) 77 female 

(40%). Primary tumour location: colon 129 (67.5%) rectal 62 (32.5%). 

Metastases location: hepatic 143 (75%), lung 46 (24%) lung and hepatic 2 

(1%). Primary tumour stage: I stage 2 (1%) II stage 50 (26%) III stage 87 

(46%) IV stage 52 (27%). Adjuvant chemotherapy: 5-Fluorouracil + Leucovorin 

70 (36.6%), Irinotecan-based 9 (4.7%) Oxaliplatin-based 112 (58.6%). 

Presurgical CEA: normal 146 pt (76%) increased 45 (24%). Number of 

metastases: one 87 pt (45%), two 65 (34%), three 18 pt (9%), more than 

three 21 pt (11%). Treatment compliance: 149 pt (78%) completed planned 

treatment; 42 pt (22%) did not complete it due to toxicity or progressive 

disease. Recurrence was diagnosed in 105 pt (55%). Surgery for relapsed 

disease was performed in 105 pt (38%). Median overall survival has not been 

reached, as only 77 pt have died. Estimated 5-years survival is 62%. Median 

progression free survival is 30 months. Significant factors for survival: sex 

(better female), node positive primary tumour, increased CEA, and more 

than 3 metastases. There were no differences between chemotherapy 

schedules. 

Conclusion: Surgery of hepatic and lung metastases from colorectal cancer has a 

curative goal. Adjuvant chemotherapy could achieve an improvement of survival 

by decreasing recurrence rate. We must emphasize that patients included in this 

analysis have good prognostic factors so results should be interpreted with 

caution. 


628 PROGNOSTIC ROLE OF ERCC1, BAX AND TP53 IN 

ADVANCED COLORECTAL CANCER (CRC) PTS RANDOMLY 

ASSIGNED TO FIRST-LINE UFT/LEUCOVORIN (LV) PLUS 

IRINOTECAN (TEGAFIRI) VERSUS UFT/LV PLUS 

OXALIPLATIN (TEGAFOX) 

F. Pietrantonio 1 , P. Biondani 1 , M. Milione 2 , F. Perrone 2 , F.G.M. De Braud 1 , 

G. Bertarelli 3 , L. Mariani 3 , F. Melotti 2 , G. Montemurro 2 , M. Di Bartolomeo 1 

1 Oncologia Medica 1, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, 

ITALY, 2 Pathology Department, Fondazione IRCCS - Istituto Nazionale dei 

Tumori, Milano, Milan, ITALY, 3 Medical Statistics, Biometry, and Bioinformatics, 

Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, Milan, ITALY 

Background: Currently, no validated biomarkers are available to tailor first-line 

chemotherapy in advanced CRC. In particular, Bax expression may be related 

to chemosensitivity, although Bax-negative CRC may display higher responses 

to irinotecan (Fallik et al, Cancer Res 2003). Candidate apoptosis-related 

biomarkers were assessed in patients enrolled into a multicenter, phase II, 

randomized trial of TEGAFIRI vs TEGAFOX (Bajetta et al, Br J Cancer 

2007). 

Methods: Tissue blocks were available for a subset of 49 pts who provided 

written consent and were enrolled from August 2002 to October 2004 at the 

coordinator center “Istituto Nazionale dei Tumori” of Milan. ERCC1, Bax and 

TP53 expression assessed by immunohistochemistry, with dicotomic 

discrimination. Association with RECIST response by logistic univariate regression 

and corrected Chi square test; interaction of significant biomarkers and treatment 

arm by logistic regression model. Progression-free (PFS) and overall survival (OS) 

curves were plotted by the Kaplan-Meier method and compared by log-rank test. 

Correlation with PFS and OS by univariate and multivariate Cox’s proportional 

hazard model. 

Results: Overall, 41% response rate (20/49, 4 CR/16 PR/19 SD/10 PD). ERCC1 

and TP53 failed to show any correlation with outcome. Responses significantly 

lower in Bax-positive vs Bax-negative (Odds Ratio [OR] = 0.26; p = 0.03 by logistic 

regression): 25% (6/24) vs 56% (14/25) (p = 0.05 by Chi square). No significant 

differences in terms of outcome in TEGAFOX-treated pts, while Bax-positive pts in 

TEGAFIRI subgroup had lower response rate as compared to Bax-negative (OR = 

0.11; p = 0.03 by logistic regression): 18% (8/12) vs 67% (2/11) (p = 0.05 by Chi 

square). In the overall population and both treatment subgroups, no significant 

differences in terms of PFS and OS according to selected biomarkers. Data on 

TP53 gene sequencing by means of polymerase-chain reaction will be presented at 

the Congress. 

Conclusion: Doublet UFT-based chemotherapy and, in particular, irinotecan-based 

treatment produced higher response rates in Bax-negative advanced CRC. Further 

prospective evaluation of Bax in patients undergoing triplet chemotherapy and 

anti-EGFR containing regimens is warranted. 




629 DIFFERENT CLINICAL OUTCOME OF METASTATIC 

COLORECTAL CANCER (MCRC) PATIENTS TREATED WITH 

INTENSIVE TRIPLET CHEMOTHERAPY PLUS BEVACIZUMAB 

(FIR-B/FOX) ACCORDING TO KRAS GENOTYPE AND DISEASE 

EXTENSION 

G. Bruera 1 , K. Cannita 1 , D. Di Giacomo 2 , A. Lamy 3 , A. Dal Mas 4 , T. Frebourg 5 ,J. 

C. Sabourin 6 , M. Tosi 5 , C. Ficorella 1 , E. Ricevuto 1 

1 Medical Oncology, S. Salvatore Hospital, University of L’Aquila, L’Aquila, ITALY, 

2 Department of Experimental Medicine, University of L’Aquila, L’Aquila, ITALY, 

3 Laboratory of Tumor Genetics, University Hospital, Rouen, Rouen, FRANCE, 

4 Pathology, S. Salvatore Hospital, L’Aquila, ITALY, 5 INSERM U614, University of 

Rouen, Rouen, FRANCE, 6 Department of Pathology, INSERM U614, Rouen 

University Hospital, Rouen, FRANCE 

Background: Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of 

first-line treatment of MCRC (Bruera G et al, BMC Cancer 2010, 10:567), 

particularly if integrated with secondary liver surgery in liver-limited (L-L) patients 

(pts) (Bruera G et al, Clin Colorectal Cancer 2012). Clinical outcome of FIr-B/FOx 

regimen was evaluated according to KRAS genotype in L-L and other MCRC pts. 

Methods: Tumoral and metastatic samples were screened for KRAS codon 12 and 

13, and BRAF mutations by SNaPshot and/or direct sequencing. MCRC pts were 

classified as L-L and other or multiple metastatic (O/MM). Activity and efficacy were 

evaluated and compared using log-rank test. 

Results: Fifty-nine pts were evaluated: 31 KRAS wild-type, 53%; 28 KRAS mutant, 

47%. At 21.5 months median follow-up, objective response rate (ORR), 

progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS 

wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. 

PFS and OS were, respectively: overall in 25 L-L compared to 32 O/MM evaluable 

pts, 17 and 12 months, 47 and 21 months, significantly different; in KRAS wild-type, 

12 L-L compared to 18 O/MM, 21 and 12 months, 47 and 28 months, significantly 

different; in KRAS mutant, 13 L-L compared to 14 O/MMS, 11 months equivalently, 

39 and 19 months, not significantly different. 

Conclusion: First line FIr-B/FOx regimen can increase activity and efficacy of KRAS 

wild-type and mutant MCRC pts; integration with secondary liver surgery 

significantly discriminates increased clinical outcome in KRAS wild-type L-L 

compared to O/MM pts while not in KRAS mutant pts. 


630 POTENTIAL BIOMARKERS FOR RESPONSE TO CETUXIMAB IN 

PATIENTS WITH METASTATIC COLORECTAL CANCER (MCRC). 

A HELLENIC COOPERATIVE ONCOLOGY GROUP STUDY 

E. Razis 1 , M. Bobos 1 , W. De Roock 2 , M. Bai 1 , A. Gousia 1 , I. Xanthakis 1 , 

E. Tsolaki 1 , P. Papakostas 1 , S. Tejpar 3 , G. Fountzilas 1 

1 Data Office, Hellenic Cooperative Oncology Group (HeCOG), Athens, GREECE, 

2 Human Genetics, Katholieke Universiteit Leuven, Leuven, BELGIUM, 3 Digestive 

Oncology Unit, University Hospital Gasthuisberg, Leuven, BELGIUM 

Background: Cetuximab has improved outcome of patients (pts) with mCRC. KRAS 

has emerged as a marker of resistance to monoclonal antibodies against EGFR, 

including cetuximab. Further biomarkers for response to cetuximab are being explored. 

Methods: In a heterogeneous cetuximab-treated population we retrospectively 

evaluated formalin-fixed paraffin-embedded tissue for EGFR and PTEN by 

Fluorescence In Situ Hybridization (FISH) and for PIK3CA and KRAS mutations by 

PCR and examined the association of these markers with patient outcome. 

Results: Two hundred twenty-three cetuximab-treated mCRC pts were identified, 

of which 38 were treated in first line, 107 in second and 78 in ≥ 3 rd line. 

Cetuximab was used with irinotecan-based therapy in 54.3% and with oxaliplatin 

in 26.9% of the cases. Two pts achieved a complete response, 53 a partial 

response and 65 stable disease for a clinical benefit rate of 63.2%. EGFR 

amplification was noted in 5 cases, PTEN deletion in 58 and PTEN gain in 

2. Finally, KRAS was mutated in 72 cases, and PIK3CA in 37. The mutations 

detected for KRAS were G12 (45 pts, 62.5%), G13 (16 pts, 22.2%), G61 (4 pts, 

5.6%) and A146 (7 pts, 9.7%) and for PIK3CA Exon9 (20 pts, 54.1%), Exon20 

(5 pts, 13.5%) and other (12 pts, 32.4%). No associations were found between 

these markers. PTEN deletion was associated with a higher overall response rate 

(ORR) (p = 0.031), while the other markers were not. Progression-free survival 

(PFS) and survival were calculated from initiation of cetuximab. PFS was 

numerically associated with EGFR gain but the numbers (5 gain vs. 138 normal) 

do not allow for a sound result. Additionally, given the different impact of 

diverse KRAS mutations on outcome, we evaluated the outcome in relation to 

the G12 mutations. The latter exhibited a trend for decreased survival (p = 

0.057). 

Conclusions: After a median follow up of 55.3 months (5.8-88.4 months), PTEN 

deletion was associated with improved ORR to cetuximab. Further examination of 

EGFR and PTEN by immunohistochemistry is in progress. 

Disclosure: E. Razis: Dr E. Razis received research grant from Merck S.A. and Roche 

(Hellas) S.A. All other authors have declared no conflicts of interest. 

631 BRAFV600E MUTATION ANALYSIS IN PATIENTS WITH 

METASTATIC COLORECTAL CANCER (MCRC) IN DAILY 

CLINICAL PRACTICE: CORRELATIONS WITH CLINICAL 

CHARACTERISTICS, PROGNOSTIC AND PREDICTIVE VALUES 

Z. Saridaki 1 , M. Tzardi 2 , M. Sfakianaki 3 , C. Papadaki 3 , K. Mpananis 3 , 

E. Tsakalaki 3 , M. Trypaki 3 , I. Messaritakis 3 , V. Georgoulias 4 , J. Souglakos 4 

1 Laboratory of Tumor Cell Biology, University of Crete, School of Medicine, 

Heraklion, GREECE, 2 Laboratory of Pathology, University of Crete, School of 

Medicine, Heraklion, GREECE, 3 Laboratory of Tumor Cell Biology, School of 

Medicine, University of Crete, Heraklion, GREECE, 4 Medical Oncology, University 

Hospital of Heraklion, Heraklion, GREECE 

Aim: To evaluate the usefulness of the BRAFV600E detection in the daily clinical 

practice, it’s clinical correlations and prognostic/predictive values in a prospective 

database of patients with mCRC. 

Patients and methods: 442 mCRC patients treated with systemic chemotherapy ± 

biologics at the Medical Oncology Department of the University Hospital of Heraklion 

from 1-07-07 were prospectively analyzed. The BRAF mutation was assessed by 

RT-qPCR using the allelic discrimination method. The laboratory findings were 

correlated with patients’ clinical-pathologic characteristics and the treatment outcome. 

Results: The median age was 68 years of age (21-89) while 37% of them were > 65 old; 

61% were male, in 71% of them the primary tumor was located in the colon and in 

29% in the rectum 48% of the tumors were low grade and 21% presented mucinous 

features. Salvage cetuximab or panitumumab therapy was administered to 228 patients 

with KRASwt tumors. The BRAF mutation was detected in 32 (7.5%) patients. 

Statistically significant higher incidence of the BRAF mutation was observed in patients 

with ECOG-PS 2 (p = 0.0001), > 65 years old (p = 0.001), primaries located in the right 

colon (p = 0.004), lowgrade tumors (p = 0.001) and in those with mucinous features 

(p = 0.021). Patients whose tumors harbored the BRAF mutation had a reduced 

progression-free survival (PFS) (4.1 months) compared with the wild-type (wt) (11.4 

months, p < 0.0001). The overall survival (OS) of the patients with BRAF mutation was 

statistically significantly shorter (13.5 months) compared with the wt ones (33.3 

months, p < 0.0001). In the multivariate analysis the BRAF mutation detection 

emerged as independent factor associated with reduced PFS (HR: 4.1, 95% CI 2.7-6.2, 

p < 0.0001) and OS (HR: 5.9, 95% CI 3.7-9.5, p < 0.0001). Among the patients treated 

with anti-EGFR moAbs salvage therapy, the BRAF mutation was correlated with 

reduced PFS (2.2 vs 6.0 months, p < 0.0001) and OS (4.3 vs 17.4 months, p < 0.0001). 

Conclusion: Our results document the unfavorable prognostic value of the 

BRAFV600E mutation and advocate in favor of its predictive value towards 

anti-EGFR moAbs therapy. 


632 EPIDEMIOLOGY PROJECTION TRENDS FOR METASTATIC 

COLORECTAL CANCER (MCRC) PATIENTS RECEIVING 

SECOND LINE (2L) THERAPY IN EU AND US 

O. Moulard 1 , J. Mehta 2 , S. Naoshy 2 , R. Olivares 1 , S.U. Iqbal 2 , I. Chau 3 

1 Evidence and Value Development, Sanofi, Chilly Mazarin, FRANCE, 2 Evidence 

and Value Development, Sanofi, Cambridge, MA, UNITED STATES OF 

AMERICA, 3 Medicine, Royal Marsden Hospital, Sutton, UNITED KINGDOM 

Background: Worldwide, CRC is the third most common cancer in men (663,000 

cases, 10% of the total) and second in women (571,000 cases, 9.4% of the total) 

(IARC 2008). Due to demographic expansion and an ageing population, the annual 

number of newly diagnosed and treated CRC cases is expected to increase in Western 

countries. Hence, epidemiology projection estimates by line of therapy are needed to 

support clinical, economic and resource planning. 

Methods: Epidemiological data was obtained using the CancerMPact® database 

(accessed Oct 2011), which includes line of therapy estimations through the US 

National Oncology Data Alliance and survey of a representative physician sample. 

Data was grouped by stage at diagnosis and stage IV refers to metastatic patients. 

Results: From 2010-2020, the distribution of mCRC patients receiving 2L differs by 

country in EU. The highest number of treated patients is in Germany, followed by 

Italy and UK. Among all treated mCRC patients, about 42% of patients in EU and 

45% of patients in US will go on to 2L. By 2020, the percentage of patients receiving 

1L and 2L will increase by about 15% across US and EU. Over a 10 year period, the 

number of treated patients for each line of therapy will increase by 19%, 11%, 15%, 

20%, and 14% for France, Germany, Italy, Spain and UK, respectively. The table 

below refers to the number of metastatic patients by line of therapy. 

Conclusions: Despite improvement in survival rates, approximately half of patients 

in US and EU who receive 1L go on to 2L. In addition to survey data, real world 

data and disease based registries can help validate these projection estimates. The 

projected increase in mCRC patients by 10-20% across the EU has implications for 

disease management and health resource planning in oncology. 

Disclosure: O. Moulard: I am an employee of Sanofi. J. Mehta: I am an employee of 

Sanofi. S. Naoshy: I am an employee of Sanofi. R. Olivares: I am an employee of 

Sanofi. S.U. Iqbal: I am an employee of Sanofi. All other authors have declared no 



Table: 632 

633 AFLIBERCEPT/FOLFIRI (AF) VS PLACEBO/FOLFIRI (PF) IN 

METASTATIC COLORECTAL CANCER (MCRC): POST-HOC 

ANALYSIS OF SURVIVAL EXCLUDING ADJUVANT (ADJ)-ONLY 

PATIENTS IN THE VELOUR TRIAL 

F. Joulain 1 , U. Iqbal 2 , F. Diamand 3 , E. Van Cutsem 4 , J. Tabernero 5 , C. Allegra 6 

1 Global Evidence and Value Development, Sanofi, Chilly Mazarin, FRANCE, 

2 Research and Development, Sanofi, Cambridge, MA, UNITED STATES OF 

AMERICA, 3 Evidence and Value Development, Keyrus Biopharma, 

Levallois-Perret, FRANCE, 4 Digestive Oncology Unit, University Hospital 

Gasthuisberg, Leuven, BELGIUM, 5 Oncology Department, Vall d’Hebron 

University HospitalMedical Oncology Service, Barcelona, SPAIN, 6 Oncology, 

University of Florida, Gainesville, FL, UNITED STATES OF AMERICA 

Background: A small proportion of poor prognosis CRC patients (pts) treated with 

ADJ therapy relapse within 6 months of treatment, and progress to mCRC (Sargent 

JCO 2007;25:4569). The VELOUR phase III trial evaluated the novel fusion protein 

aflibercept (VEGF Trap) plus FOLFIRI in mCRC pts previously treated with 

oxaliplatin. In this study 10% of pts directly progressed from ADJ setting to first-line. 

Median and mean overall survival (OS) was determined for VELOUR pts excluding 

those that progressed directly from the ADJ setting. 

Method: Baseline characteristics and efficacy were determined for the ITT pts 

excluding ADJ-only pts. Since some pts were alive at the time of final analysis, mean 

OS was estimated by extrapolating the trial Kaplan-Meier curve using a survival 

function. The goodness-of-fit of parametric distributions was evaluated by AIC, BIC 

criteria. Survival functions were fit to each treatment (TXT) arm separately or by 

combining the two arms and using TXT as a covariate to control for variation. 

Results: Of 1226 pts enrolled in VELOUR, 60 (9.8%) AF pts and 64 (10.4%) pF 

pts received oxaliplatin in ADJ setting only. Excluding these pts, baseline 

characteristics remained similar between the 2 arms. Median age was 61 years, 

60% of pts were male, 30% of pts were randomized in the prior bevacizumab 

stratum and very few pts had ECOG PS 2 (2.1%) as per IVRS. 43.6% of pts had 

1 or less metastatic site at baseline and 25.4% had liver metastasis only. Median 

OS was significantly improved with AF vs pF (13.8 vs 11.9 months; adjusted HR 

= 0.80 [95% CI: 0.69 to 0.92]). For mean OS, the loglogistic function provided the 

best fit of the VELOUR data for the ITT population excluding ADJ-only pts both 

with and without TXT as covariate. 

Conclusion: Excluding ADJ-only pts, the VELOUR trial increased median OS (1.9 vs 

1.4) and mean OS (5.1 vs 4.7) with AF compared to pF, thus reinforcing the 

therapeutic benefit of AF in clinically relevant patient populations. 

Disclosure: F. Joulain: I am an employee of Sanofi. U. Iqbal: I am an employee of 

Sanofi. F. Diamand: I am an employee of Sanofi. E. Van Cutsem: I have received 

research funding from Sanofi. J. Tabernero: I have an advisory relationship with 

Sanofi, Roche, and Regeneron. C. Allegra: I have an advisory relationship with 

Sanofi. 

Table: 633 


Year Line 

France Germany Italy Spain UK EU 5 US 

2010 1L 13705 25590 18171 9590 16646 83702 40484 

2L 8212 15378 10904 5746 9988 50228 27217 

3L 3117 5846 4125 2177 3792 19057 14602 

4L+ 695 1296 868 474 840 4173 5429 

Total stage IV* 19344 36313 25408 13432 23372 117869 60703 

2020 1L 16273 28410 20956 11533 19060 96232 47447 

2L 9755 17048 12592 6916 11434 57745 31672 

3L 3704 6476 4767 2622 4341 21910 16999 

4L+ 825 1439 1002 571 961 4798 6324 

Total stage IV* 22947 39931 29361 16194 26733 135166 69391 

* a patient may receive multiple lines of therapy in a given year Source: CancerMPact® Kantar Health (www.cancermpact.com) 

634 SECOND AND THIRD LINE CHEMOTHERAPY REGIMENS IN 

ELDERLY MEDICARE STAGE 4 COLON CANCER PATIENTS 

K. Bikov 1 , C.D. Mullins 2 , E. Onukwugha 2 , B. Seal 3 , N. Hanna 4 

1 Pharmaceutical and Health Services Research, University of Maryland, 

Baltimore, MD, UNITED STATES OF AMERICA, 2 Phsr, Univ of MD, Baltimore, 

MD, UNITED STATES OF AMERICA, 3 Health Economics and Outcomes 

Research, Bayer HealthCare, Wayne, NJ, UNITED STATES OF AMERICA, 

4 Surgery, Univ of MD, Baltimore, MD, UNITED STATES OF AMERICA 

Background: NCCN guidelines for stage 4 colon cancer (CC4) patients provide 

general guidance on which chemotherapies and targeted therapies improve survival 

or quality of life but do not provide specific treatment (TX) recommendations. The 

guidelines suggest that TX is highly individualized and no single treatment is right 

for everyone. This leads to variation in both the number and types of TX lines, 

especially for elderly patients where there are larger evidence gaps. 

Methods: Elderly (65+) SEER-Medicare patients diagnosed with CC4 in 2003-2007 

were followed through death or 2009 to examine variation across sub-groups in 

the number of TX lines. We examined NCCN treatments that included any 

combination of 5-fluorouracil and/or (levo) leucovorin (5FU/LV), irinotecan (IRI), 

oxaliplatin (OX), and bevacizumab, cetuximab, or panitumumab (collectively 

identified as BIOLOGICS). Certain non-NCCN treatments were also considered as 

possible last TX line. A hierarchy categorized treatments as: 1) IROX (IRI + OX); 

2) IRI or OX; 3) 5FU/LV; 4) BIOLOGICS without chemotherapy; and 5) other 

TX. Gaps in TX or changes from OX or IRI to 5FU/LV were not considered new 

lines. 

Results: Of 3,263 CC4 patients who received TX, 1,166 (36%) went on to second 

line TX. The most common sequences of TX lines were OX to IRI (49%), IRI to 

OX (14%), 5FU/LV to OX (12%) and 5FU/LV to IRI (12%). Approximately 6% 

switched from chemotherapy to BIOLOGICS alone only 3.6% ever used IROX. Of 

second line patients, 244 (21%) had a third line of treatment. The most frequent 

sequence for 3 TX lines were 5FU/LV to OX to IRI (26%), OX to IRI to 

MNCLA alone (25%); 5FU/LV to IRI to OX (14%); and IRI to OX to MNCLA 

alone (6%). 

Conclusions: The number of TX lines and the sequence of TX regimens vary 

considerably across elderly CC4 patients. OX to IRI for first and second line TX was 

the most common sequence. The choice of initial and subsequent treatment 

regimens impacts the total number of treatment lines receipt and survival. Further 

investigation is warranted to examine the relationship between patient and provider 

characteristics and choice of treatment. 

Disclosure: C.D. Mullins: C. Daniel Mullins, PhD receives consulting income from 

Amgen, Bayer, BMS, Celgene, GSK, Mitsubishi, Novartis, Novo Nordisk, Novartis, 

and Pfizer. He also receives research funding from Bayer and Pfizer. E. Onukwugha: 

Ebere Onukwugha receives consulting income from Pfizer and grant support from 

Bayer, Novartis, and Pfizer. B. Seal: Brian Seal is an employee of Bayer HealthCare. 


Median OS (months) Restricted Mean OS (months) over 15 years 

AF (N = 552) pF (N = 550) Δ 

Δ 

ITT Loglogistic AF pF Δ 


13.8 11.9 1.9 1.4 TXT group independently 22.7 17.6 5.1 4.7 

TXT group as covariate 21.5 18.5 3.0 2.5 

ix214 | Abstracts Volume 23 | Supplement 9 | September 2012 

Δ 

ITT


635 USE OF PALLIATIVE CHEMOTHERAPY AND TARGETED 

AGENTS IN ELDERLY PATIENTS WITH METASTATIC 


W.Y. Cheung, D. Renouf, H. Lim, H. Kennecke 

Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, CANADA 

Background: Elderly patients are increasingly diagnosed with advanced cancers, but 

they are consistently underrepresented in clinical trials, which may lead to 

undertreatment. Our aims were to 1) evaluate the impact of advanced age on 

patterns of first-line chemotherapy and bevacizumab use in mCRC, 2) examine the 

reasons for treatment choices and 3) compare adverse events and treatment 

discontinuations in elderly vs young patients. 

Methods: A random sample of mCRC patients diagnosed from 2006 to 2007 and 

referred to any 1 of 5 regional cancer centers in British Columbia, Canada was 

reviewed. Summary statistics were used to describe treatment patterns between the 

elderly (>/ = 70 years) and young (

factors play the determining role in a patient’s response to LCRT and this area 

requires further investigation to determine who may undergo a complete response. 

Group A (%) Group B (%) 

T stage T2 0 3 (6.7) 

T3 10 (77) 36 (80) 

T4 3 (23) 6 (13.3) 

N stage N0 4 (31) 7 (15) 

N1 4 (31) 12 (27) 

N2 5 (38) 26 (58) 

Sex Male 11 (85) 36 (78) 

Female 2 (15) 10 (22) 

Tumour height Low 11 (85) 30 (65) 

Mid 2 (15) 12 (26) 

Upper 0 4 (9) 


639 STUDY OF THE EFFECT OF RADICAL SURGERY COMBINED 

WITH PRE- OR POSTOPERATIVE RADIOTHERAPY IN 

TREATMENT OF RESECTABLE RECTAL CANCER 

E. Atif 1 , H. Sakr 2 , S. Teama 2 , D. Zayed 2 

1 Surgical Gastroenterology Center, Mansoura University, Egypt, Mansoura, 

EGYPT, 2 Clinical Oncology and Nuclear Medicine, Mansoura University, Egypt, 


Back ground: preoperative radiotherapy in resectable rectal cancer has a number of 

potential advantages, most importantly, preventing local recurrence, increasing 

survival and down-staging effect. 

Purpose: This study was done to compare between the effect of preoperative 

radiotherapy and postoperative radiotherapy in treatment of resectable rectal 

carcinoma. The primary endpoints are local recurrence rate, overall survival (OS) and 

disease free survival (DFS). The secondary endpoints are to evaluate down-staging, 

treatment toxicity, and ability to do sphincter preservation, aiming at choosing the 

optimal treatment modality. 

Patients and methods: This study included 100 patients with resectable rectal 

carcinoma who presented to Surgical Gastro Entrology Center and Clinical Oncology 

and Nuclear Medicine Department, Mansoura University during the period between 

January 2007 and September 2009. The included patients were randomized in two 

groups; group I: 50 patients received preoperative radiotherapy and group II: 50 

patients received postoperative radiotherapy. Concurrent 5-fluorouracil- based 

chemotherapy was given to all patients. Two major types of surgery were done: 

abdomino-perineal resection with a permanent colostomy and low anterior resection 

with colorectal or coloanal anastomosis. 

Results: Preoperative radiotherapy resulted in pathologic complete response in 3 

patients. T down-staging occurred in 18 out of 50 patients (36%) with statistically 

significant difference (p = 0.008). N down-staging occurred in 10 out of 24 patients. 

Sphincter preservation was more in group I. Delayed wound healing was the most 

common postoperative complication in group I with no significant difference. After a 

median follow up of 18 months, local recurrence rate and distant metastasis were 

higher in group II. The 2-years disease free survival was 72% and 60% in group I 

and II respectively with no statistically significant difference between both groups. 

Conclusion: This study concluded that preoperative radiotherapy is better than 

postoperative radiotherapy as regard local control, Sphincter preservation with higher 

disease free survival and overall survival. No difference in treatment toxicity between 

both groups. 


640 THE PREDICTIVE ROLE OF MTHFR AND ABCG2 SINGLE 

NUCLEOTIDE POLYMORPHISMS ON THE OUTCOME OF 

ADVANCED COLORECTAL CANCER TREATED WITH 

FIRST-LINE CHEMOTHERAPY 

J. Zhao, W. Zhang, W. Li, J. Li, W. Guo, S. Cai, M. Sun, Z. Zhang, D. Zhu, Q. Yu 

Department of Medical Oncology, Fudan University Shanghai Cancer Center, 


Objective: Chemotherapy with 5-fluorouracil and oxaliplatin (FOLFOX or XELOX) 

or irinotecan (FOLFIRI) has become the mainstay of treatment for advanced 

colorectal cancer. Since not all patients would benefit from the chemotherapy they 

received, exploring factors that would predict better effectiveness remains meaningful 

for understanding the concept of individual treatment. The purpose of this study is 

to confirm the predictive role of a serial of SNPs, MTHFR C677T, A1298C, ABCG2 

G34A and C421A, as well as the clinical features for the efficacy of first-line 

chemotherapy in advanced colorectal cancer. 


Methods: Patients with advanced colorectal cancer and treated with first-line 

standard FOLFOX/XELOX or FOLFIRI regimens between January 2009 and May 

2011 at Fudan University Shanghai Cancer Center were retrospectively studied. Gene 

polymorphisms of MTHFR and ABCG2 were detected using gene sequencing 

method, after DNA extraction from peripheral blood karyocytes and PCR 

amplification. 

Results: Of all 154 patients, patients with 3 ∼ 4 of the favorable genotypes (MTHFR 

677C/C, MTHFR 1298 A/A, ABCG2 G/A or A/A⍰ and ABCG2 421C/A or A/A) 

had a longer PFS than those with 0 ∼ 2 above genotypes (9.8m vs. 7.5m, P = 0.013; 

HR = 0.627, 95%CI: 0.427 ∼ 0.920, P = 0.017) The radical resection of primary lesion 

was also found as an independent factor for both PFS (HR = 0.524, 95%CI: 0.320 ∼ 

0.859, P = 0.010) and OS (HR = 0.291, 95%CI: 0.147 ∼ 0.575, P = 0.000). Interestingly, 

stratified univariate analysis revealed that patients with 2 ∼ 4 genotypes of MTHFR 

677C/C、MTHFR 1298 A/C or C/C、ABCG2 34G/G and ABCG2 421C/A or A/A 

would benefit more from FOLFOX/XELOX than FOLFIRI as first-line chemotherapy 

(FOLFIRI: HR = 1.722, 95%CI: 1.026 ∼ 2.892, P = 0.040, compared with FOLFOX/ 

XELOX). In contrast, patients with 0 or 1 above-mentioned genotype would have 

better outcomes if receiving FOLFIRI (FOLFIRI: HR = 0.422, 95%CI: 0.205 ∼ 0.870, 

P = 0.019, compared with FOLFOX/XELOX). 

Conclusions: SNPs detection may play a predictive role in selecting first-line 

chemotherapy for advanced colorectal cancer patients. Radical resection of primary 

lesion is an independent factor for both PFS and OS. 


641 PROGNOSTIC VALUE OF BRAF AND KRAS MUTATIONS IN 

COLORECTAL CANCER PATIENTS 

E.P. Murata1 , A. Stradella1 , D. Páez1 , M. Tobeña Puyal1 , A. Sebio Garcia1 , 

A. Gonzalez1 , E. Targarona1 , M. Baiget2 , A. Barnadas1 , M. Martín-Richard1 1 

Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, SPAIN, 

2 

Deparment of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, 

SPAIN 

Background: KRAS mutation has been established as a predictive marker of 

resistance to antiEGFR therapy in patients (pts) with colorectal cancer (CRC) but the 

role of BRAF is not yet clear. Both gene mutations have also been studied as 

prognostic factors but results are contradictory. AntiEGFR therapies impair 

evaluation of KRAS and BRAF as prognostic factors when overall survival is an 

endpoint. We hypothesized that if KRAS or BRAF were prognostic factors, they 

would influence time to relapse (TTR) after complete tumor resection. 

Methods: Patients who underwent surgery between 2007 and 2011 for stage II and 

III CRC were retrieved from our database. Codon 12 and 13 KRAS mutations and 

V600E BRAF mutation were analyzed. Clinical characteristics and mutation status 

were correlated with TTR. 

Results: We analyzed 170 pts with a median age of 66 (26 – 86) years. Tumors were 

located in the right colon in 27% of pts, in the transverse colon in 3%, in the left 

colon in 41%, and in the rectum in 29%. Most (55.3%) were stage III; 59% received 

adjuvant chemotherapy. KRAS and BRAF mutations were present in 66 (38.8%) and 

5 (2.9%) pts respectively, and both were mutually exclusive. The most frequent KRAS 

mutations were: G12D (39.3%), G12V (27.2%), G13D (15.1%). Median TTR was 71 

weeks (w) (13 – 520w). V600E BRAF mutation was the only factor associated with 

TTR. TTR was 42 w in tumors with the BRAF mutation and 74 w in wild-type 

tumors (p = 0.041). Among KRAS mutations, KRAS G12V conferred a significantly 

longer TTR (100w) than the other subtype mutations (69 w; p = 0.05). 

Conclusions: Our results suggest that V600E BRAF mutation is a negative prognostic 

factor in CRC, conferring a shorter time to relapse. Additionally, the KRAS G12V 

determines a different behavior among KRAS mutation tumors. 


642 NOTCH AND DLL4 EXPRESSION IN BEVACIZUMAB-TREATED 

COLON CANCER PATIENTS 

Abstract withdrawn in exceptional circumstances 




643 CETUXIMAB PLUS MFOLFOX-6 AS FIRST-LINE THERAPY FOR 

UNRESECTABLE LIVER METASTASIS FROM COLORECTAL 

CANCER: AN OPEN, NON-RANDOMIZED, MULTICENTER 

PHASE II CLINICAL TRIAL 

S. Cai 1 , W. Zhang 2 ,W.Li 2 ,Y.Xu 1 ,W.Gu 1 , Z. Guan 1 , J. Cai 3 , C. Song 4 ,J.Xu 5 , 

P. Chi 6 

1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 

Shanghai, CHINA, 2 Department of Medical Oncology, Fudan University Shanghai 

Cancer Center, Shanghai, CHINA, 3 Department of Abdominal Surgery, Cancer 

Hospital & Institute Chinese Academy of Medical Sciences Peking Union Medical 

College, Beijing, CHINA, 4 Department of Colorectal Surgery, Liaoning Cancer 

Hospital, Liaoning Province, CHINA, 5 Department of Colorectal Surgery, 

Zhongshan Hospital of Fudan University, Shanghai, CHINA, 6 Department of 

Colorectal Surgery, Fujian medical university Union hospital, Fujian Province, 

CHINA 

Background: This study is for KRAS wildtype patients with unresectable liver only 

metastasis of colorectal cancer, using cetuximab + modified FOLFOX-6 as first-line 

chemotherapy, to observe whether the addition of targeted drug further increases the 

curative resection rate and improves long-term survival for patients. 

Methods: Up to May 1st,a total of 82 KRAS wild-type patients enrolled and received 

cetuximab (500 mg/m 2 q2w)Plus mFOLFOX-6 including oxaliplatin 85 mg/m 2 plus 

CF 400 mg/m 2 and 5-FU as a 400 mg/m 2 bolus followed by 2400 mg/m 2 infusion 

over 46 hours on day 1, repeated every 2 weeks for maximum of nine cycles. The 

primary endpoint was R0 resection rate. 

Findings: The objective response rate (RR) was 81.82% ± 5.81% among 44 patients with 

efficacy assessment. Among 38 cases went through surgical evaluation (finished 

medication), 16 cases went through R0 resection and R0 resection rate was 42.11% ± 

8.01%, 4 cases went through R1 resection and R1 resection rate was 10.53% ± 4.98%, and 

4 cases went through R0 + RFA. There were AEs reported in 64 cases, mainly including 

rash and malaise. One SAE was reported and the subject was withdrawn due to allergy. 

Interpretation: Cetuximab + mFOLFOX-6 was well tolerated and provided good RR, 

R0 resection rates, which would be potentially used as a first-line treatment for 

patients with unresectable liver only metastasis of colorectal cancer. Funding: This 

study was supported by Fudan University Shanghai Cancer Center; Merck KGaA 

Darmstadt, Germany. 

Funding: This study was supported by Merck KGaA Darmstadt, Germany and 

Sanofi-aventis. 


644 OUTCOME OF PATIENTS WITH COLORECTAL LIVER 

METASTASIS: ANALYSIS OF 1613 CONSECUTIVE CASES 

J. Xu, D. Zhu, L. Ren, Y. Wei, H. Wu, Y. Zhong 



Objective: To evaluate the long-time outcome of patients with colorectal liver metastasis 

(CRLM) undergoing different types of therapy and identify prognosis factors. 

Methods: From 2000 to 2010, 1613 consecutive patients with CRLM were identified. 

Clinicopathological and outcome data were collected and analyzed by univariate and 

multivariate analyses. 

Results: Synchronous liver metastasis (SLM), female, grade III-IV, T4 and N positive of 

primary tumor, bilobar disease, number of liver metastases ≥ 4, size of largest liver 

metastases ≥ 5 cm, serum CEA level ≥5 ng/ml and CA19-9 level ≥ 37u/ml were the 

predictors of adverse outcome using univariate analysis. The median survival and 

five-year survival rate for patients after resection of liver metastases was 49.8 months 

and 47%, better than that for those after other therapy. In addition, patients without 

treatment had the poorest survival. Sixty-four initially unresectable patients underwent 

surgery after conversion therapy with a median survival of 36.9 months and a five-year 

survival of 30%. By multivariate analysis, SLM, poorly differentiated primary tumor, 

number of liver metastases ≥ 4, size of largest liver metastases ≥ 5 cm, and no surgical 

treatment of liver metastases were found to be independent predictors of poor survival. 

Conclusions: Patients with CRLM could get long-term survival benefit from different 

types of therapy, and resection of liver metastases was the optimal strategy. A 

predictive model using these above five factors may be of use in stratifying patients 

who may benefit from intensive surveillance and adjuvant therapy. 


645 THE PROGNOSTIC SIGNIFICANCE OF TYMIDINE KINASE 

ACTIVITY LEVELS IN METASTATIC COLORECTAL CANCER 

E.S. Seber 1 , T. Korkmaz 2 , K. Okutur 3 , F. Dane 4 , P.F. Yumuk 4 , B. Aktas 5 , 

M. Kanıtez 4 , G. Demir 3 , S.N. Turhal 1 

1 Medical Oncology, Marmara University Hospital, Istanbul, TURKEY, 2 Medical 

Oncology Department, Dr Lutfi Kirdar Kartal Research and Educational Hospital, 

Istanbul, TURKEY, 3 Medical Oncology Department, Bilim University, Istanbul, 

TURKEY, 4 Medical Oncology Department, Marmara University Hospital, Istanbul, 

TURKEY, 5 Internal Medicine Dpt, Medical Oncology Division, Marmara University 

Faculty of Medicine, Istanbul, TURKEY 

Aim and background: Serum thymidine kinase 1 (TK1) is a sensitive marker of tumor 

cell proliferation. It has been reported as a predictive factor for response rate and disease 

free survival for hematological and early stage solid organ tumors but its importance as 

a prognostic factor in metastatic solid organ malignancies is not well studied. In this 

study we aimed to investigate the prognostic significance of serum TK1 activity in 

metastatic colorectal cancer (MCRC) patients receiving palliative chemotherapy. 

Method: We prospectively measured serum TK1 activity immediately before the first 

and second cycle of the treatment in 46 consecutive metastatic MCRC patients. 10 

healthy volunteers were also included as a control group. TK1 activity was measured 

by means of high sensitive non-radioactive DIVITUM assay. The patients’ 

performance status, age, gender, weight loss, hematological and biochemical 

parameters, serum CEA and CA 19.9 levels and serum TK1 activity levels relation 

with survival were analyzed. 

Results: The mean TK1 level in the study group was significantly higher than the 

controls (162.1± 27.8 vs 32.97 ± 7.307; p < 0.03, respectively). In multivariate analysis 

adjusted for known clinicopathological risk factors, serum tumor markers, 

hemoglobin levels and trombosit count TK1 levels before chemotherapy and weight 

loss remained as independent prognostic factors ( p = 0.001; 0.018, respectively). 

Patients with TK1 activity level above 65 Du/L and 230 Du/L had a longer PFS (624 

vs. 231 days) and OS time respectively (p


647 PREDICTIVE MARKERS FOR OVERALL AND 

PROGRESSION-FREE SURVIVAL WITH CAPOX IN 

SECOND-LINE CHEMOTHERAPY OF METASTATIC 


M.D.P. Solís Hernández, P. Jimenez Fonseca, Q. Perez, C. Alvarez Fernandez, 

L. Ruiz, D. Rodríguez Rubí, W. Li, M.L. Sánchez, L. Faez, J.M. Viéitez 

Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, SPAIN 

Background: Age, sex, Karnofsky (KPS), number of metastatic sites (NMS), primary 

tumour localization, baseline CEA, CEA response, scan response and k-RAS status 

are focused on progression free survival (PFS) and overall survival (OS) as predictive 

factors in chemotherapy metastatic colorectal cancer (mCRC). This study aims to 

find which might generate impact on PFS and OS for a second line therapy. 

Patients and methods: 138 patients treated with capecitabine and oxaliplatin 

(CAPOX) in second-line from 2002 to 2010 were analyzed. Cox hazard model was 

employed to build univariante and multivariate analysis. 

Results: PFS and OS were 3.5 and 7.85 months, respectively. Among all evaluated 

factors, only KPS ≥70, CEA response and scan response were associated with better 

PFS and OS on univariate analysis with statistical significance. Age 2 sites, HR = 1.25, p = 0.0043) were predictive for worst PFS and OS, 

respectively. (See table 2) 

Conclusion: These findings suggest that scan response and good KPS may predict 

better PFS and OS in mCRC while primary tumour localization, CEA response and 

NMS should be further validated. 

Table 1 – PFS and OS univariate analyses 

N Median P-value 

PFS KPS


649 USE OF CETUXIMAB (CTX) IN 1ST-LINE THERAPY OF 

METASTATIC COLORECTAL CANCER (MCRC): PATIENT 

CHARACTERISTICS, SAFETY AND EFFECTIVENESS IN THE 

EREBUS COHORT 

D. Smith 1 , M. Rouyer 2 , E. Mitry 3 , E. Francois 4 , A. Monnereau 5 , A. Sa-Cunha 6 , 

J. Jove 2 , P. Noize 2 , N. Moore 2 , A. Fourrier-Réglat 2 

1 Oncologie Digestive, Hôpital Saint André, Bordeaux, FRANCE, 2 Pharmacology 

Department, University Hospital, Bordeaux, FRANCE, 3 Oncologie Médicale, 

Institut Curie, Paris, FRANCE, 4 Medical Oncology, Antoine Lacassagne Cancer 

Institute, Nice, FRANCE, 5 Statistic Department, Institut Bergonié, Bordeaux, 

FRANCE, 6 Digestive Surgery, Haut Lévêque Hospital, Pessac, FRANCE 

Background: CTX has demonstrated improved survival outcomes in mCRC but 

information in real-life is sparse. 

Methods: EREBUS is a French multicentre cohort with 92 centres. Patients initiating 

CTX 1 st -line therapy for unresectable mCRC in 2009 and 2010 were identified from 

dispensation registries and followed 12 months. Presented here is preliminary data 

for those included in 2009. 

Results: A total of 205 patients were included, all had wild-type (wt) KRAS gene. 

Median age: 64 yrs, 67.3% male, 65.8% ECOG = 0-1, 61% cardiovascular history, 

78.5% colon primary site, 55.6% primary tumor resection, 73.7% synchronous 

metastasis, single metastatic site: 52.7% (39% exclusively liver). A multidisciplinary 

team considered 1 st -line as palliative for 61.5% of pts, and 37.1% as potentially 

resectable. CTX was combined with oxaliplatin-based regimens: 37.6%, 

irinotecan-based regimens: 55.6%, and other regimens: 6.8%. For those receiving 

CTX + oxaliplatin (n = 77): median duration of CTX use was 3.6 months and 63.6% 

were treated every 2 weeks. For those receiving CTX + irinotecan (n = 114): it was 4.7 

months and 81.6% treated every 2 weeks. Response rate (CR + PR) according to 

physician evaluation was 48.6% for CTX + oxaliplatin and 46.8% for CTX + 

irinotecan. 1-yr OS was 59.9% (95%CI 47.6-70.2) and median PFS was 8.6 months 

(6.3-10.5) for CTX + oxaliplatin. 1-yr OS was 69.1% (59.6-76.7) and median PFS was 

9.3 months (7.4-10.5) for CTX + irinotecan. Incidence of any grade 3/4 event was 

58% for CTX + oxaliplatin and 57% for CTX + irinotecan: neutropenia (18.2% and 

19.3%, respectively), skin reaction (11.7% and 14%), asthenia (11.7% and 14.9%), 

hypokalaemia (13% and 4.4%), diarrhoea (6.5% and 10.5%) and infusion-related 

reactions (1.3% and 0.9%). Surgical evaluation was performed in 27.8%: 31.2% CTX 

+ oxaliplatin and 24.6% CTX + irinotecan. 

Conclusions: In France, CTX was frequently combined with irinotecan-based 

regimens in 1 st -line wt KRAS mCRC. These results indicate a high proportion of 

exclusive liver metastases, and a high proportion of patients undergoing surgery. 

Effectiveness and safety profile of CTX in real-life were in line with pivotal trials. 


650 PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF 

FLUOROURACIL IN CHINESE COLORECTAL CANCER 

PATIENTS 

Z. Wang, L. Zhao, F. Wang, Y. Lin, Y. Huang, F. Xu, C. Xue, H. Zhao, Z. Li 

Department of Medical Oncology, Cancer Center of Sun Yat-Sen University, 

Guangzhou, CHINA 

Background: Pharmacokinetic (PK) variability of 5-FU (fluorouracil) has been 

demonstrated for +30 years and a significant link between 5-FU exposure and 

therapeutic response has been identified. A maximum tolerated exposure (MTE) 

using area under curve (AUC) has been characterized for various regimens and 

therapeutic drug management (TDM) has been used to achieve effective dosing. 

In China the regimen most used to treat colorectal (CRC) cancer are FOLFOX 

or FOLFIRI. The objective of this study was to characterize the PK variability of 

5-FU in this population and examine the relationship between AUC and 

toxicity. 

Methods: Seventy-five treatment naïve colorectal cancer patients were treated with 

mFOLFOX6(Oxaliplatin 100 mg/m 2 ,d1; LV 400 mg/m 2 ,d1;5-FU 3g/m2,IV 46h, 

biweekly) or mFOLFIRI (Irrinotecan 180 mg/m 2 , d1;LV 400 mg/m 2 ,d1;5-FU 3g/m2, 

IV 46h,biweekly). Blood samples were collected at steady state 18 hrs after the start 

of 5-FU infusion. Plasma was analyzed by a 5-FU immunoassay and AUC was 

calculated. We examined the relationship between 5-FU AUC and 5-FU-related 

toxicities. 

Results: The patient AUC values varied widely, ranging from 6 to 57 mg • h/L. 44% 

of the patients were in the 20-30 mg• h/L target range of 29% were below and 27% 

were above. Toxicity was recorded for 75 patients. Severe mucositis or 

myelosuppression occurred in 9 of 20 patients with AUCs greater than the target 

range and in 3 of 55 patients in or below the target range (p = 0.00018). ROC 

analysis for 5-FU AUC and severe mucositis identified a cut-point of 39 mg• h/L, 

Area under the ROC curve = 0.870, efficiency = 88.0% (p < 0.001). 

Conclusions: Results of this observational study demonstrate wide PK-variability of 

5-FU exposure and a significant relationship between severe toxicity and AUC in 

colorectal cancer patients. The lower percentage of patients below the target range 

compared to European population suggests lower clearance of 5-FU in Asian 

population. The study confirms that the MTE in this population is similar to a 

European CRC population treated with mFOLFOX6 or FOLFIRI. TDM using the 

target range of 20-30 mg• h/L may have benefit in lowering toxicity in colorectal 



651 RETROSPECTIVE ANALYSIS OF PATHOLOGICAL RESPONSE IN 

COLORECTAL CANCER LIVER METASTASES FOLLOWING 

TREATMENT WITH BEVACIZUMAB: UPDATED FINDINGS 


652 PRIMARY RESISTANCE TO FIRST-LINE BEVACIZUMAB IN 

METASTATIC COLORECTAL CANCER: IMPLICATIONS ON 

PROGNOSIS 

E. Maccaroni 1 , R. Giampieri 1 , M. Scartozzi 1 , M. Del Prete 1 , A. Bittoni 2 , 

L. Faloppi 3 , M. Bianconi 3 , S. Cascinu 4 


Politecnica delle Marche, Ancona, ITALY, 2 Clinica di Oncologia Medica, Ospedali 

Riuniti di Ancona, Ancona, ITALY, 3 Clinica di Oncologia Medica, AOU Ospedali 

Riuniti Ancona Universit, Ancona, ITALY, 4 Dipartimento di Medicina Clinica E 

Biotecnologie A, University of Ancona, Ancona, ITALY 

A role of Bevacizumab after first-line failure is currently in study. We focused our 

analysis on patients who progressed directly under first-line Bevacizumab and 

assessed if lack of effect could be managed with second line chemotherapy. We 

conducted a retrospective analysis on metastatic colorectal cancer patients treated in 

the 2008-2011 period with first-line Bevacizumab. Stratification criteria were sex, age, 

performance status, metastatic sites, metachronous vs synchronous metastases, 

chemotherapy backbone, K-ras status. Chest-abdomen CT scan was performed every 

3 months. Response was scored according to RECIST criteria. Progression free 

survival and overall survival were defined as usual. 146 patients were eligible for 

analysis. 60 (41%) partial responses, 54 (37%) stable disease and 32 (22%) 

progressions were seen. Median overall survival was 18.5 months and median 

progression free survival was 8.2 months. No significant differences were seen in 

regards to stratification criteria for different response groups. Progression free 

survival for patients who achieved a partial response, a stable disease or progression 


were respectively 10.6 vs 8.5 vs 3.0 months (p < 0.0001). Overall survival for patients 

who achieved a partial response, a stable disease or progression were respectively 21.3 

vs 19.7 vs 9.1 months (p < 0.0001). All 32 patients who directly progressed under 

Bevacizumab based-treatment received a second line chemotherapy regimen and in 

16 (50%) it was anti-EGFR based (either Cetuximab or Panitumumab). Remaining 

16 patients received standard chemotherapy. Only a trend towards better overall 

survival for anti-EGFR based regimens (10 vs 7.78 months, p = 0.26) was seen. 

Monoclonal antibodies increased expected survival for metastatic colorectal cancer, 

reaching 20 months and more in historical series. In our analysis a dismal survival of 

9.1 months was seen for patients who directly progress under first-line Bevacizumab, 

regardless of the treatment received in second-line. It is thus suggested that, even if 

overall survival is the primary end-point of therapy, disease control rate should also 

be considered, because failure of first-line treatment may jeopardize global outcome. 


653 JAPANESE COHORT STUDY OF FIRST LINE CHEMOTHERAPY 

(CT) FOR METASTATIC COLORECTAL CANCER (MCRC) 

CONTAINING FLUOROPYRIMIDINE, OXALIPLATIN AND 

BEVACIZUMAB: EMERALD STUDY, FIRST REPORT 

K. Taku 1 , K. Ohata 1 , K. Yamazaki 2 , G. Nishikawa 1 , M. Watanabe 3 ,S.Sato 3 , 

T. Oshima 3 , H. Hirano 1 , T. Amano 4 , Y. Ohashi 5 

1 Division of Medical Oncology, Shizuoka General Hospital, Shizuoka, JAPAN, 

2 Gastrointestinal Oncology and Endoscop, Shizuoka Cancer Center, Shizuoka, 

JAPAN, 3 Division of Surgery, Shizuoka General Hospital, Shizuoka, JAPAN, 

4 Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, 

JAPAN, 5 Department of Biostatistics, School of Public Health, University of 

Tokyo, Tokyo, JAPAN 

Background: An observational cohort study plays a crucial role to understand the 

current status of clinical practice and can be utilized as database for multi-purpose 

outcome research. Such database is available in Europe and the United States based 

on several cohort studies especially in mCRC, while there is no database available 

including treatments for mCRC patients in Japan. 

Methods: According to the Japanese Ethical Guideline for Epidemiologic Study, we 

planned and conducted a large cohort study in Japan. Data from more than 1000 

patients were planned to be collected between October 2010 and September 2011 

with 2-year follow-up period. Enrollment criteria included documented mCRC and 

first line CT containing fluoropyrimidine, oxaliplatin and bevacizumab, started 

treatment in or after January 2010, tumor response image assessment available, safety 

assessment available and able to offer information outside of originally enrolled 

studies. The primary objectives are to evaluate overall survival, liver resection rate, R0 

liver resection rate; the secondary objectives are to evaluate response rate, 

progression-free survival, sub-group analysis by treatment regimens and by KRAS 

gene status, and safety. 

Results: From October 2010 to September 2011, 1270 patients were recruited from 

132 centers in Japan. The background of patients were as the following; male/female, 

766/504; median age of 65 (range, 21-89); ECOG PS 0/1/2/3, 1045/203/17/5; 

FOLFOX/ CapeOX/ others with bevacizumab, 563/667/40, KRAS gene status at 

baseline was wild/mutant/unknown, 286/223/761; CEA median of 13.8 (range, 0.0– 

90055.0 ng/ml) and comorbidity no/yes, 798/472. 

Conclusion: We have started the large Japanese cohort study which investigates first 

line CT containing fluoropyrimidine, oxaliplatin and bevacizumab for metastatic 

colorectal cancer. We performed a preplanned interim analysis. We present the first 

report of 6-month efficacy and safety data on 500 patients at the ESMO 2012 

Congress. The final results will be available in 2013. This study is sponsored by the 

Public Health Research Center Foundation CSPOR in Japan. 


654 ANTITUMOR AND ANTIANGIOGENIC ACTIVITY OF SORAFENIB 

ON COLORECTAL CANCER 

S. Kilickap 1 , A. Altun 2 , N.A. Babacan 1 , H. Ataseven 3 , T. Kaya 2 

1 Medical Oncology, Cumhuriyet University Faculty of Medicine, Sivas, TURKEY, 

2 Pharmacology, Cumhuriyet University Faculty of Medicine, Sivas, TURKEY, 

3 Gastroenterology, Cumhuriyet University Faculty of Medicine, Sivas, TURKEY 

Background: Addition to standard chemotherapy regimens of targeted biological 

agents such as bevacizumab and cetuximab has led to improved outcomes in 

colorectal cancer (CRC). We aimed to investigate antitumoral and antiangiogenic 

(AAG) effects of sorafenib (SRF) in CRC cells. 

Methods: The effect on proliferation of SRF was evaluated by using real-time cell 

analysis system (xCELLigence) in DLD-1 CRC cells. After the optimal seeding 

concentration for proliferation of the DLD-1 was determined, the cells were exposed 

to 10 µL of medium containing SRF 200 mg (500, 250, 125, 62.5, 31.25, 15.62, 7.81, 

3.9, 1.95, 0.97 and 0.48 nM/well). Controls received either medium only, or medium 

+ SRF with a final concentration of 500 nM. The effects of SRF on angiogenesis were 

studied with chorioallantoic membrane (CAM) model. Angiogenesis was evaluated 

by using Burgermeister’s scoring system. 


Results: We used the 40,000 cells/well concentration in the xCELLigence assay to 

examine the antiproliferative effect elicited by SRF, as the concentration displayed the 

lowest variation. SRF treated DLD-1 cells exhibited decreasing cell index values in a 

concentration-dependent manner. 500, 250, 125, 62.5 and 31.5 nM SRF caused 

statistically significant cytotoxic effect on DLD-1 cells. There was no a significantly 

difference between these concentrations. Also, 15.6 and 7.8 nM SRF led to cytotoxic 

effect, but these effects were significantly lower than the 500, 250, 125, 62.5 and 31.5 

nM SRF. The cytotoxic effect of SRF on DLD-1 cells gradually diminished with 

decreasing concentrations (p < 0,001). At 24-hours after treatment with SRF, an IC50 

value of (IC50) 1.26x10 −9 M was achieved. The eggs on which a 10 µl-agarose pellet 

with no drug was installed demonstrated no significant AAG effect (average AAG 

score = 0.1). The AAG effect of SRF compared with bevacizumab and negative control. 

The AAG effects of the drugs were similar and higher compared to the negative 

control (p < 0.05). AAG scores of SRF in 100, 10 and 1 nM concentrations were 1.05, 

0.75, and 0.55, respectively. The AAG effect on CAM of SRF was dose-dependent. The 

AAG score with the 100 nM was significantly higher than 1 nM (p = 0.043). 

Discussion: SRF has antitumor and AAG effects on human colorectal cancer cell 

line. These effects have positively correlated with its concentration. 


655 THE EFFICACY AND SAFETY OF BEVACIZUMAB BEYOND 

FIRST PROGRESSION IN JAPANESE PATIENTS TREATED WITH 

FIRST-LINE MFOLFOX6 FOLLOWED BY SECOND-LINE FOLFIRI 

IN ADVANCED COLORECTAL CANCER: A MULTICENTER, 

SINGLE-ARM PHASE II TRIAL (CCOG-0801); FINAL REPORT 

G. Nakayama 1 , K. Ishigure 2 , A. Ishiyama 3 , K. Uehara 4 , T. Fujii 1 , N. Hayashi 1 , 

Y. Ando 5 , Y. Kodera 1 

1 Department of Gastroenterological Surgery (Surgery II), Nagoya University 

Graduate School of Medicine, Nagoya, JAPAN, 2 Department of Surgery, Konan 

Kosei Hospital, Konan, JAPAN, 3 Department of Surgery, Okazaki City Hospital, 

Okazaki, JAPAN, 4 Department of Surgical Oncology, Nagoya University Graduate 

School of Medicin, Nagoya, JAPAN, 5 Department of Clinical Oncology and 

Chemotherapy, Nagoya University Hospital, Nagoya, JAPAN 

Purpose: The aim of this study was to evaluate the efficacy and safety of the planned 

continuation of bevacizumab beyond first progression in Japanese patients with 

metastatic colorectal cancer (mCRC). 

Methods: Previously untreated patients with assessable disease were treated with 

mFOLFOX6 plus bevacizumab until tumor progression, followed by FOLFIRI plus 

bevacizumab. The primary endpoint of the study was the second progression-free 

survival (2nd PFS), defined as duration from enrollment until progression after 

second-line therapy. Secondary endpoints of the study were overall survival (OS), 

survival beyond first progression (SBP), progression free survival (PFS), response rate 

(RR), disease control rate (DCR) and safety. 

Results: In the first-line setting, 47 patients treated with mFOLFOX6 plus bevacizumab 

achieved RR of 61.7%, DCR of 89.4% and median PFS of 13.1 months (95% CI, 8.7 to 

17.5 months). Thirty one patients went on to receive second-line therapy with FOLFIRI 

plus bevacizumab and achieved RR of 27.6%, DCR of 62.1% and median PFS of 7.5 

months (95% CI, 5.5 to 9.5 months). Median 2nd PFS, the primary endpoint, was 18.0 

months (95% CI, 13.7 to 22.3 months). The median OS was 30.8 months (95% CI, 27.7 

to 33.9 months), and median SBP was 19.6 months (95% CI, 14.3 to 24.9 months), after 

median follow up period of 35.9 months. No critical events associated with 

bevacizumab were observed during the second-line therapy. 

Concluson: The planned continuation of bevacizumab during second-line treatment 

is feasible for Japanese mCRC patients. A prospective randomized control study to 

confirm efficacy is warranted. 


656 SURVIVAL OUTCOMES IN METASTATIC COLORECTAL CANCER 

(CRC) WITH HIGH-LEVEL MICROSATELLITE INSTABILITY 

(MSI-H) 

M.J. Overman 1 , S. Kopetz 1 , S. Wong 2 , J. Tie 2 , S. Kosmider 2 , A. Jacob 1 , 

E. Vilar 3 , P. Gibbs 2 , J. Desai 2 ,B.Tran 2 

1 Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer 

Center, Houston, TX, UNITED STATES OF AMERICA, 2 Medical Oncology, Royal 

Melbourne Hospital, Melbourne, VIC, AUSTRALIA, 3 Clinical Cancer Prevention, 


OF AMERICA 

Background: The MSI-H phenotype is present in 15% of early stage CRC and 

confers good prognosis in this population. In metastatic CRC, MSI-H is rare and its 

impact on outcomes is unknown. We describe survival outcomes and responses to 

chemotherapy for the largest reported cohort of MSI-H metastatic CRC. 

Methods: A retrospective review of metastatic CRC patients (pts) with MSI-H 

(defined as ≥2 DNA microsatellite markers with instability by PCR) from two 

institutions was conducted. Pts from Royal Melbourne Hospital (Australia) were 

identified using a prospective CRC database. Pts from The University of Texas MD 



Anderson Cancer Center (United States) were identified from an institutional 

database. Statistical analyses utilized Kaplan-Meier method and Log-rank test. 

Results: 55 pts with metastatic MSI-H CRC were identified. Median age was 67 years 

(range: 20-90), 63% had poor differentiation, and 64% of primary tumors originated 

in the right colon. 25 (45%) pts had stage IV disease at presentation, while 30 (55%) 

pts presented with stage II/III disease (median time to development of metastases was 

9 months). 42 pts have died and median overall survival (OS) from the time of 

metastatic disease was 15.3 months. 14 pts underwent R0/R1 metastatectomies with 

median time to recurrence of 25.4 months and median OS from metastatectomy of 

33.7 months. 31 pts were evaluable for response to front-line systemic chemotherapy: 

single agent 5-FU in 7, oxaliplatin-based in 14, and irinotecan-based in 10. 

Radiographic response was seen in 11 pts (35%) and the median time to progression 

(TTP) and OS were 4.2 months and 11.6 months, respectively. No statistically 

significant differences in TTP or OS were seen between chemotherapy subtypes. BRAF 

mutation status was known in 47 pts: 14 pts had a BRAF V600E mutation, 33 pts were 

wildtype (wt). In comparison to BRAF wt pts, BRAF V600E pts demonstrated 

significantly worse median OS; 10.1 v 17.4 months, HR 2.6 (95%CI: 1.1-6.1), P =0.03. 

Conclusions: Compared to historical controls, pts with MSI-H metastatic CRC do 

not appear to have improved outcomes. BRAF V600E mutation is a poor prognostic 

factor in MSI-H metastatic CRC. 


657 ADJUVANT MFOLFOX6 IN THE TREATMENT OF ELDERLY 

COLON CANCER PATIENTS 

J. Godinho Bexiga, F. Carneiro, D.S. Marques, N. Sousa, A. Raimundo, 

M. Machado, P. Ferreira, C. Faustino, M. Fragoso 

Medical Oncology, Portuguese Institute of Oncology of Oporto, Oporto, 

PORTUGAL 

Background: In Europe, more than 60% of new cancer cases and more than 70% of 

cancer deaths occur in elderly patients. Approximately 50% of colorectal cancer cases 

occur in patients ≥ 70 years. Despite this, elderly patients are under-represented in 

clinical trials. Adjuvant chemotherapy with Fluoropyrimidines and Oxaliplatin is the 

recommended treatment for stage III colon cancer. Our aim was to determine the 

effectiveness of mFOLFOX6 in the adjuvant treatment of elderly colon cancer 

patients. 

Material and methods: Retrospective cohort study of colon cancer (CC) patients 

treated with adjuvant mFOLFOX6, in a Portuguese cancer centre, from September 2004 

till November 2009. Elderly patients were defined as having ≥ 70 years old. Toxicity was 

evaluated using Common terminology criteria for adverse events (CTCAE), v 

3. Comorbidity was assessed by Charlson’s Index. The primary efficacy variable was 

disease-free survival (DFS). Secondary endpoints were cancer-specific survival (CSS), 

overall survival (OS) and toxicity grade ≥ 3. Hazard ratios and 95% confidence intervals 

were calculated with the use of the Cox proportional hazards model. 

Results: In the study period, 277 patients were treated with adjuvant mFOLFOX6. Fifty 

three patients (19.1%) were ≥ 70 years and of these, 76.8% were male and 80% had stage 

III CC. Elderly patients were more likely to be male and have a higher comorbidity 

index than younger patients (p< 0.05). Patients older than 70 were more prone to 

grade ≥ 3 toxicity and a lower mean relative dose-intensity (Oxaliplatin: 66% vs 72%, p 

= 0.062; 5-Fluorouracil: 70% vs 76%, p = 0.01). With a median follow-up time of 45 

months, elderly patients had 3 year DFS, CSS and OS of 82%, 92% and 84%, 

respectively. Survival wasn’t significantly lower than that of patients aged < 70 (DFS: HR 

0.612, p = 0.243; CSS: HR 0.533, p = 0.166; OS: HR 1.226, p = 0.674). 

Conclusions: Adjuvant mFOLFOX6 is feasible in elderly patients and its benefit is 

similar to that of younger patients. Selection bias might explain the good results of 

this study and limit the external validity of our conclusions. 


658 USE OF COMPREHENSIVE GERIATRIC ASSESSMENT 

PARAMETERS TO PREDICT CHEMOTHERAPY TOXICITY IN 

ELDERLY PATIENTS WITH COLORECTAL CANCER: A 

PROSPECTIVE MONO-CENTER STUDY 

H. Djedi 1 , K. Bouzid 2 

1 Onco-Hematologie, CHU Annaba, Annaba, ALGERIA, 2 Medical Oncology, 

Centre Pierre et Marie Curie, Algiers, ALGERIA 

Background: Despite the younger age of Algerian population, Colorectal cancer that 

represent the second most common malignancy, occurred in Older patients (age ≥ 65 

y) in approximately one quarter of cases . Unfortunately, there is little studies 

including these geriatric population. 

Purpose: The aim of this study is to identify parameters of Comprehensive Geriatric 

Assessment “CGA“ that may represent risk factors for chemotherapy toxicity in older 

adults with colorectal cancer than to develop a predicting risk scoring for 

chemotherapy toxicity. 

Patients and methods: A prospective study in our department collected on 2 years 66 

patients age 65 years or older . Application of oncologic data and geriatric assessment 

variables (function, comorbidity, cognition, psychological state, social activity/support, 

and nutritional status) selected 49 patients illegible for chemotherapy. Mean age: 71 y 

(range 65-81 y), gender: 27 women, 22 men. Localization: colon: 36pts/ rectum: 12pts/ 

multifocal: 1pt. Balducci 1: 13 pts / Balducci 2 : 36 pts. All patients were evaluated for 

grade ¾ chemo-toxicity as defined by the version 4.0 of National Cancer Institute 

Common Terminology Criteria for Adverse Events. 

Results: After a total of 394 courses, 34 pts presents Grade ¾ toxicity. It 

occurred in 25,5% of cures and included neuropathy: 5%, diarrhea 5,6%, 

hand-foot syndrome 2,8%, neutropenia 0,8%, thrombocytopenia 0,8%, Anemia 

6% . According to univariate and multivariate analyses: age (≤ or ⍰ 70 y), 

Balducci groups, anemia and number of drugs used (mono vs 

poly-chemotherapy) were identified to be risk factors significantly associated with 

chemo-toxicity (p⍰0,05, IC95). A simple predictive model for grade ¾ 

chemo-toxicity was developed using regression coefficients from the multivariate 

model.The scoring system (range 0 to 13) stratification schema 3 groups : pts at 

low (0 to 3 points), intermediate (4 to 7 points), or high risk (8 to 13 points) of 

chemotherapy toxicity (p = 0,0112). 

Conclusions: Results of our study suggest that the incorporation of a mini- CGA in 

our daily practice can help physicians to establish a personalized therapeutic decision 

for elderly colorectal cancers based on chemo-toxicity risk stratification. 


659 BASELINE CEA SERUM LEVELS PREDICT THE EFFICACY OF 

BEVACIZUMAB-BASED TREATMENT IN ADVANCED 



660 BRAIN METASTASES IN GASTROINTESTINAL CANCERS 

D. Erdem 1 , I. Yücel 1 , B. Yilmaz 1 , G. Demirag 1 , E. Kut 1 , F. Cilingir 2 , Y. Kemal 1 , 

F. Teker 1 

1 Medical Oncology, Ondokuzmayis University, Samsun, TURKEY, 2 Internal 

Medicine, Ondokuzmayis University, Samsun, TURKEY 

Aim: Only 4% of cranial metastasis occur with gastrointestinal cancer. The aim of 

this study is to evaluate the characteristics of cranial metastasis derived from 

gastrointestinal system tumors. 

Material-method: 1863 patients diagnosed with gastrointestinal cancers between 

1997-2011 years were included. Among the patients; 51 esophageal cancer, 516 

gastric cancer, 5 small intestine tumor, 878 colorectal cancer, 11 gallbladder cancer, 

190 pancreas cancer, 119 hepatocellular cancer, 63 cholangiocarcinoma and 30 GIST 

were involved. SPSS 16 is used. 


Results: 20 gastrointestinal cancer patients with cranial metastases (1.07%) were 

included. The average age was 54.6 ± 1.1 years and 70% (n = 14) of the patients were 

male. 20 patients cancers were as follows: 4 gastric cancer (20%), 15 colorectal cancer 

( 75%) and 1 pancreas cancer (5%). 3 patients had no extracranial metastases (15%). 

Lung metastases was the most common extracranial metastatic site in general, but 

liver was the most solitary extracranial metastatic site. The median interval of 

diagnosis-recurrence/metastases was 20.6 months (range 0-89 months) and the 

median interval of diagnosis-cranial metastases was 30.1 months (range 0-138 

months). Mean OS was 36.6 months in 3 patients without extracranial metastases 

and 31.6 months in 17 patients with extracranial metastases. 

Discussion: The most common primary sites that intend to metastasize to brain are 

lung and breast. Gastrointestinal tumors rarely metastasize to cranium. Our results 

were similar with literature: 0.7% of cranial metastases in gastric cancer and 1.7% 

cranial metastases in colorectal cancer.The arguing site in our study were as follows: 

in the literature lung was the most common site of extracranial metastases; but in our 

study despite being general most common extracranial metastatic site, it was not the 

solitary site of metastases. In 10 metastatic patients at the diagnosis, 5 were solely 

had liver metastases without lung metastases. 

Conclusion: Cranial metastases is a rare and late sign of gastrointestinal cancers. By 

new approaches in diagnosis and therapy of cancer, cranial metastases is more 

common. All symptomatic patients and asymptomatic patients with liver or lung 

metastases may be suggested to be screened for brain. 


661 TUMORS OF THE APPENDIX: THE EXPERIENCE OF 

IPO-PORTO 

T. Malheiro Sarmento1 , M.H. Abreu1 , R. Fragoso2 , M. Machado1 , N. Sousa1 , 

C. Faustino1 , P. Ferreira1 1 

Medical Oncology, Portuguese Oncology Institute of Porto, Porto, PORTUGAL, 

2 

Medical Oncology, Instituto Portugues de Oncologia Centro do Porto, Porto, 

PORTUGAL 

Introduction: Malignant neoplasms of ileocecal appendix are rare, an clinical 

features are unspecific, often mimicking acute appendicitis. They are diagnosed in 

about 1% of appendicectomy specimens. The most common histologic types are 

mucinous adenocarcinoma, intestinal-type adenocarcinoma and carcinoid tumor. 

Methods: The authors reviewed the primary appendix carcinomas treated in Instituto 

Português de Oncologia Francisco Gentil-Porto (IPOFG-Porto) between January 

2000 and June 2011. 

Results: Fourty two patients were treated during this period: 30 women (71%) and 12 

men, aged between 20 and 90 years old (median age 58). Mucinous adenocarcinoma 

was the most common histologic subtype, with 27 cases (64%), followed by 

adenocarcinoma NOS (10 cases - 24%); carcinoids were 5 cases (12%). Fifteen percent 

presented as stage IV, 7% stage III, 24% stage II and 19% stage I. The primary treatment 

was surgery: 16 patients were submitted to appendicectomy, 6 patients to 

appendicectomy, ooforectomy and hysterectomy, 12 to hemicolectomy. Of patients 

submitted to appendicectomy, 11 (50%) had a second laparotomy in order to perform 

hemicolectomy. Five percent of the patients received adjuvant chemotherapy 

(mFOLFOX6). Hyperthermic Intraoperative Peritoneal Chemotherapy (HIPEC) was 

performed in 18 patients with stage IV disease (peritoneal carcinomatosis). The median 

follow-up was 35 months. Thirty three percent of the patients (n = 14) died because of 

disease progression and 62% (n = 26) were alive with no evidence of disease. 

Conclusion: Appendiceal carcinomas are rare tumours and there is limited evidence 

on the indications for right hemicolectomy. The role of adjuvant chemotherapy for 

adenocarcinoma of the appendix is unknown. Optimal treatment of patients with 

intraperitoneal dissemination of appendiceal adenocarcinoma (mucinous peritoneal 

carcinomatosis) is unclear. Selected patients treated with aggressive surgical 

cytoreduction and HIPEC may have a favorable outcome in long term, but patient 

selection and the experience of the treating team are critical. The benefit of systemic 

chemotherapy for advanced disease is unknown. 


662TiP PILOT STUDY OF TIGATUZUMAB (CS-1008) IN 

COMBINATION WITH FOLFIRI IN PATIENTS WITH 

METASTATIC COLORECTAL CANCER (CRC) 

G. Kim1 , M. Borad2 , H. Pitot3 , J. Rubin3 , J. Greenberg4 , P. McCroskery4 , 

R. Beckman4 , A. Grothey3 1 2 

GI Oncology, Mayo Clinic, Jacksonville, FL, UNITED STATES OF AMERICA, GI 

Oncology, Mayo Clinic, Scottsdale, AZ, UNITED STATES OF AMERICA, 3 GI 

Oncology, Mayo Clinic, Rochester, MN, UNITED STATES OF AMERICA, 

4 

Development, Daiichi Sankyo Pharma, Edison, NJ, UNITED STATES OF 

AMERICA 

Background: Tigatuzumab (T) is a humanized monoclonal antibody that acts as a 

death receptor 5 (DR5) agonist. Preclinical studies have shown that T monotherapy 

induces apoptosis in DR5-positive CRC cell lines and significantly inhibits growth in 


CRC xenograft models. T combined with FOLFIRI (folinic acid, 5-fluorouracil 

(5-FU), irinotecan) has demonstrated enhancement of preclinical antitumor activity. 

This pilot study assessed efficacy and safety of this combination therapy in patients 

(pts) with metastatic CRC. 

Methods: This was an open-label, single-arm, multicenter study of T plus FOLFIRI 

in pts with histologically-confirmed metastatic CRC, an ECOG (Eastern Cooperative 

Oncology Group) score ≤ 2, and adequate organ and bone marrow function. Pts were 

non-homozygous for UGT1A1*28 allele. T was initially administered intravenously 

(IV) at 6 mg/kg and thereafter at 2 mg/kg weekly with one treatment cycle = 4 weeks 

(wks). FOLFIRI was administered IV at wks 1 and 3: irinotecan 180mg/m 2 , folinic 

acid (leucovorin) 400mg/m 2 and 5-FU 400mg/m 2 bolus followed by 2400 mg/m 2 

over 46-48 hours. Radiographic assessments were performed every 8 wks. 

Results: Treated pts (n = 21) had a median of 3 prior therapies; 10 (48%) had prior 

FOLFIRI. All pts experienced ≥1 treatment-emergent adverse event (TEAE); the 

most common T-related TEAEs were fatigue (12 pts; 57%) and nausea (8 pts; 38%). 

17 pts (81%) experienced a ≥ grade 3 TEAE; the most common was neutropenia (9 

pts; 43%) which was partly attributed to T in 5 pts (24%). Serious AEs (SAEs) 

occurred in 15 pts (71%). The most common SAE was anemia (3 pts; 14%), all 

unrelated to T. There was 1 SAE of neutropenia related to T. Median progression-free 

survival (PFS) was 3.7 months. 2 pts had unconfirmed partial response; 9 pts had 

stable disease. The trial is ongoing. 

Conclusions: T displays acceptable safety and tolerability when combined with 

FOLFIRI. The observed median PFS compares favorably with historical results in 3 rd / 

4 th line treated pts, but study size and single arm design preclude formal conclusions. 

The SAEs reported were comparable to those reported for T in combination with 

other chemotherapies. 

Disclosure: J. Greenberg: Full-time employee of and stockholder in Daiichi Sankyo 

Pharmaceutical Development. P. McCroskery: Full-time employee of and stockholder 

in Daiichi Sankyo Pharmaceutical Development. Stockholder in Johnson & Johnson 

Corporation. R. Beckman: Full-time employee of and stockholder in Daiichi Sankyo 

Pharmaceutical Development. Stockholder in Johnson & Johnson Corporation. A. 

Grothey: Contracted researcher for Daiichi Sankyo Pharmaceutical Development. All 


663TiP AXE BEAM: ENCOURAGING EARLY RESULTS OF A 

NEO-ADJUVANT BEVACIZUMAB, CAPECITABINE +/- 

OXALIPLATIN AND RADIATION MULTIMODALITY REGIMEN 

FOR LOCALLY ADVANCED RECTAL CANCER 

G. Chiritescu 1 , K. Dumon 1 , P. Vergauwe 2 , J. Arts 3 ,A.D’Hoore 4 , A. Debucquoy 5 , 

M. Verstraete 5 , X. Sagaert 6 , K. Haustermans 5 , E. Van Cutsem 1 

1 Digestive Oncology, University Hospital Leuven, Leuven, BELGIUM, 

2 Gastroenterology, A.Z. Groeninge, Kortrijk, BELGIUM, 3 Gastroenterology, A.Z. 

Sint Lucas, Brugge, BELGIUM, 4 Abdominal Surgery, University Hospital Leuven, 

Leuven, BELGIUM, 5 Lab of Experimental Radiotherapy, Department of Radiation 

Oncology, University Hospital Leuven, Leuven, BELGIUM, 6 Pathology, University 

Hospital Leuven, Leuven, BELGIUM 

In an academic multicentric phase II study, patients (pts) with locally advanced 

rectal cancer are randomized to receive bevacizumab (5mg/kg), capecitabine 

(1650mg/m 2 /day) and radiotherapy (1.8Gy/day) with (Arm A) or without (Arm B) 

oxaliplatin (50mg/m 2 ). Chemoradiotherapy (CRT) starts at 2 weeks after 1 st infusion 

of bevacizumab and continues for 5 weeks. Total mesorectal excision is planned at 

6-8 weeks post CRT. Immunohistochemical staining to study the functionality of 

blood vessels and Luminex analyses to assess the changes in circulating VEGF 

ligands are performed on tissues and blood samples from consenting pts. 

Pathological complete response (pCR) rate, safety profile and identification of 

biomarkers for early response prediction are the main endpoints. 

Results: Sixty five pts with median age 60 have been enrolled to date. Fifty seven pts 

completed the full protocol scheme, with a relative dose intensity of 97% for 

bevacizumab, 95% for capecitabine and 93% for oxaliplatin. Preliminary safety data 

from 60 evaluable pts show that the regimen is generally well tolerated. Most severe 

adverse events were post-operative (wound infections, leaks) in 9 pts, equally 

distributed between arms. During CRT, grade 3 toxicities were more frequent in Arm 

A: fatigue (1), diarrhea (2), infection (2), febrile neutropenia (1), sensory neuropathy 

(1). Two pts deceased due to disease progression and one due to lung embolism 

post-surgery. Fifty two pts are evaluable for response. pCR was seen in 11 pts, 30% 

(8/26) in Arm A and 12% (3/26) in Arm B (p = 0.08). The rate of good responders 

(Dworak TRG 3,4) was higher in Arm A 18/26 versus Arm B 10/26 (p = 0.05). 

Changes in the pericyt coverage of the blood vessels, proliferation of the tumour cells 

and plasma concentrations of PDGF-AA, PDGF-BB and VEGF were observed and 

will be further assessed. 

Conclusions: Chemoradiotherapy in combination with bevacizumab showed an 

acceptable safety profile in this patient population. Adding oxaliplatin determined a 

slight increase of toxicity but might enhance the percentage of responders. PDGF 

may be a predictor of response in this setting. Further analyses are ongoing. 

Conducted with support from Roche and Sanofi Aventis. 

Disclosure: K. Haustermans: The author has received research funding from Roche. 

E. Van Cutsem: The author has received research funding by Roche and Sanofi 

Aventis. All other authors have declared no conflicts of interest. 



664TiP A PHASE I TRIAL OF IRINOTECAN (IRI) AND BKM120 IN 

PREVIOUSLY TREATED PATIENTS (PTS) WITH METASTIC 


J.C. Baranda 1 , G. Reed 2 , S. Williamson 1 , E. Dickman 1 , M. Stoltz 1 , R. Madan 3 , 

L. Wright 1 , K. Bhalla 1 , A. Godwin 3 

1 Hematology and Medical Oncology, University of Kansas Cancer Center, 

Westwood, KS, UNITED STATES OF AMERICA, 2 Pharmacology. Toxicology and 

Therapeutics, University of Kansas Medical Center, Kansas City, KS, UNITED 

STATES OF AMERICA, 3 Pathology and Laboratory Medicine, University of 

Kansas Medical Center, Kansas City, KS, UNITED STATES OF AMERICA 

Background: Reversal of Iri resistance may result with use of Iri plus anti-EGFR 

antibody in pts with kras wild-type mCRC. BKM120 is an oral pan-class PI3K 

inhibitor. The published results of a phase I trial of single agent BKM120 showed 

that BKM120 was well-tolerated and safe with favorable PK profile and promising 

anti-tumor effect. 

Methods: The primary objective of this phase I trial is to identify the maximum 

tolerated dose (MTD) for Iri and BKM120 combination in previously treated 

mCRC. The secondary objectives are to characterize the PK of Iri with or 

without BKM120 as well as PK of BKM120 when administered with Iri, to 

determine clinical response to the combination, and to correlate the expression 

of biomarkers associated with PI3K signaling pathway with clinical response to 

the combination of Iri plus BKM120. A traditional 3 + 3 dosing scheme is used 

for dose escalation. Iri is given intravenously every 14 days and BKM daily. Iri 

starts on cycle 1 day 1 while BKM120 starts after 24 hours after the first dose 

of Iri to allow us to monitor the PK of Iri both in the absence and presence of 

BKM120. The patients are assessed for safety and toxicities every cycle (q14 

days). 

Results: Eleven pts have been enrolled: six were evaluable for toxicity: 3 in 

cohort 0 (Iri 120 mg/m 2 + BKM120 50 mg/d) and 3 in cohort 1 (Iri 150 mg/m 2 

+ BKM 120 50 mg/d). The most common drug related adverse events were 

nausea and vomiting, diarrhea, fatigue, hyperglycemia, and elevation of 

transaminases. One dose limiting toxicity (DLT), genital mucositis, was observed 

in a male pt in Cohort 1. This resolved in less than 7 days but pt missed more 

than 7 days of BKM120. The MTD has not been reached. Of the 4 pts who 

have completed 4 cycles of therapy 3 had stable disease and one had progressive 

disease. The cycle 1 vs cycle 2 PK for cohort 0 showed SN-38 mean Cmax2/ 

Cmax1 was 0.89 + 0.16 and mean AUC2/AUC1 1.07 + 0.16. The Iri PKs for 

subsequent cohorts and BKM120 PKs as well as the molecular correlates will be 

presented. 

Conclusion: This is the first human trial of the combination of Iri and BKM120. No 

significant toxicities have been observed and the PK of Iri does not seem to be 

affected by BKM120. These preliminary data support continuing the effort to find 

the MTD for the combination of Iri and BKM120 for use in phase II trials and to 

identify potential biomarkers of response and toxicities. 

Disclosure: J.C. Baranda: Research Funds: Novartis, Roche. K. Bhalla: Novartis, 

Research Funding Novartis, honorarium, advisor. All other authors have declared no 


665TiP USE OF PANITUMUMAB IN PATIENTS WITH RECURRENT 

OR PROGRESSIVE COLORECTAL CANCER - AN INTERIM 

ANALYSIS OF THE VECTIS STUDY 

R. Lakomy 1 , W. Rogowski 2 , B. Pikó 3 , C. András 4 , E. Molnar 5 

1 Department of Clinical Oncology, Masaryk Memorial Cancer Institute, Brno, 

CZECH REPUBLIC, 2 Department of Oncology, ZOZ MSWiA z Warminsko 

Mazurskim Centrum Onkologii, Olsztyn, POLAND, 3 Dep. of Clinical Oncology, 

3Pándy Kálmán County Hospital, Center of Oncology, Gyula, Gyula, HUNGARY, 

4 Dpt. of Clinical Oncology, 4Medical University, Dpt. of Oncology, Debrecen, 

Debrecen, HUNGARY, 5 Medical, Amgen, Budapest, HUNGARY 

Registry Number: 20080618 

Background: Panitumumab (Pmab; Vectibix®) is a fully human monoclonal antibody, 

which binds specifically to the human epidermal growth factor receptor (EGFr). Skin 

toxicity (ST), a pharmacological effect observed with EGFr inhibitors, appears in 

almost all patients (pts) treated with Pmab and is usually mild to moderate in severity. 

The VECTIS study was designed to determine the safety and efficacy of Pmab as 

monotherapy in daily practice with special reference to ST and its management. 

Methods: This is an open-label, prospective, non-interventional study collecting data 

from pts from CEE countries, aged ≥18 years, who have EGFr expressing mCRC 

with wild type KRAS gene tumour status receiving Pmab monotherapy (6 mg/kg 

Q2W) after failure of chemotherapy regimens containing 5-FU, oxaliplatin and 

irinotecan. This interim analysis includes the data collected between 12/2008 and 06/ 

2011 from pts in Hungary, Poland, and the CzechRepublic. The observation period 

was limited to 18 cycles. 

Results: At the time of reporting, 177/205 (86.3%) enrolled pts have experienced a 

total of 266 ST events with an incidence rate (IR) (events per pt per year) of 3.47 

(95% confidence interval [CI] = 3.07, 3.91); 15 pts experienced Grade 3 ST with an 

IR of 0.20 (95% CI = 0.11, 0.32) and no pts had ST Grade ≥4. Of the recorded ST 

events, 25.9% have resolved; 3.4% have resolved with consequences; 19.9% continue 

but are improving; and 50.8% have not resolved. Overall, 69.8% of pts required 

therapeutic measures for ST. Four serious Adverse Drug Reactions (ADRs) were 

reported. Of 6 deaths that occurred, none was related to Pmab. Four pts have 

stopped Pmab therapy due to ADRs including ST or other toxicity. 

Overall 

(N = 205) % (95% CI) 

ST Grade ≥ 2 

(N = 112) % (95% CI) 

Tumor response 26.8 (20.9, 33.4) 30.4 (22.0, 39.8) 

Disease control rate 67.8 (60.9, 74.1) 70.5 (61.2, 78.8) 

Free from progression (18 cycles) 12.7 (8.5, 18.0) 13.4 (7.7, 21.1) 

A statistically significant positive correlation was observed between severity of ST and 

the best response (r = 0.13) as well as tumor response (r = 0.15). 

Conclusion: In clinical practice, Pmab monotherapy appears to be well tolerated and 

effective in pts who have heavily pre-treated mCRC with wild-type KRAS status. This 

study is sponsored by Amgen GmbH CEE Headquarters. 

Disclosure: R. Lakomy: Vectis study. W. Rogowski: Vectis study, Pegfilgrastim study. 

B. Pikó: Vectis study, Pegfilgrastim study. C. András: Vectis study, Pegfilgrastim 

study, Amgen sponsored scientific event speaker. E. Molnar: employment possition 

Amgen, stock 


abstracts 

gastrointestinal tumors, non-colorectal 

666O TH-302 + GEMCITABINE (G + T) VS GEMCITABINE (G) IN 

PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED 

PANCREATIC CANCER (PAC) 

M. Borad 1 , S. Reddy 2 , N. Bahary 3 , H. Uronis 4 , D.S. Sigal 5 , A.L. Cohn 6 , 

W. Schelman 7 , J. Stephenson 8 , C. Eng 9 , D.P. Ryan 10 

1 Oncology, Mayo Clinic Cancer Center - Arizona, Scottsdale, AZ, UNITED 

STATES OF AMERICA, 2 Oncology, Louisiana State University Health Sciences 

Center, Shreveport, LA, UNITED STATES OF AMERICA, 3 Oncology, University of 

Pittsburgh Medical Center, Pittsburgh, PA, UNITED STATES OF AMERICA, 

4 Oncology, Duke University, Durham, NC, UNITED STATES OF AMERICA, 

5 Oncology, Scripps Clinical Medical Group, La Jolla, CA, UNITED STATES OF 

AMERICA, 6 Oncology, Rocky Mountain Cancer Centers, Denver, CO, UNITED 

STATES OF AMERICA, 7 Oncology, University of Wisconsin, Madison, WI, 

UNITED STATES OF AMERICA, 8 Oncology, Institute for Translational Oncology 

Research, Greenville, SC, UNITED STATES OF AMERICA, 9 Clinical Operations, 

Threshold Pharmaceuticals, South San Francisco, CA, UNITED STATES OF 

AMERICA, 10 Oncology, Massachusetts General Hospital, Boston, MA, UNITED 


Background: TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 

2-nitroimidazole component designed to release the DNA alkylator, 

bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A 

randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of 

G + T to standard dose G as first-line therapy of PAC. 

Materials and methods: An open-label multi-center study of two dose levels of 

TH-302 (240 mg/m 2 or 340 mg/m 2 ) in combination with G versus G alone 

(randomized 1:1:1). G (1000 mg/m 2 ) and T were administered IV over 30-60 minutes 

on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after 

progression and be randomized to a G + T arm. The primary efficacy endpoint was a 

comparison of progression-free survival (PFS) between the combination arms and G 

alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). 

Summary PFS outcome has previously been reported; more detailed PFS as well as 

the initial overall survival (OS) data are presented. 

Results: 214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median 

age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or 

more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G 

vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer 

prognostic factors (older age, poorer performance status, reduced albumin) were 

associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G + 

T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G + 

T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340. 

A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G 

+ T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G + 

T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in 

combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G 

+ T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240 

and 59% G + T340. 

Conclusions: The combination of G plus TH-302 improved the efficacy of G. A 

TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity 

and myelosuppression were the most common TH-302 related AEs with no increase 

in treatment discontinuation. 




667PD A RANDOMISED MULTICENTRE TRIAL OF EPIRUBICIN, 

OXALIPLATIN AND CAPECITABINE (EOC) + PANITUMUMAB 

IN ADVANCED OESOPHAGO-GASTRIC CANCER (REAL3): 

UPDATED RESULTS 

T.S. Waddell 1 , J. Reis-Filho 2 , D. Gonzalez-De-Castro 3 , I. Chau 1 , 

A. Wotherspoon 4 , S. Gupta 5 , C. Saffery 1 , G. Middleton 6 , J. Wadsley 7 , 

D. Cunningham 1 

1 Department of Medicine, Royal Marsden Hospital, Sutton, UNITED KINGDOM, 

2 Department of Molecular Pathology, Institute for Cancer Research, London, 

UNITED KINGDOM, 3 Department of Molecular Diagnostics, Institute for Cancer 

Research, Sutton, UNITED KINGDOM, 4 Department of Histopathology, Royal 

Marsden Hospital, London, UNITED KINGDOM, 5 Statistics Department, Royal 

Marsden Hospital, London, UNITED KINGDOM, 6 St. Lukes Cancer Centre, 

Royal Surrey County Hospital, Guildford, UNITED KINGDOM, 7 Department of 

Oncology, Weston Park Hospital, Sheffield, UNITED KINGDOM 

Background: EGFR overexpression occurs in 30-90% of oesophago-gastric 

adenocarcinomas (OGA), and correlates with poor prognosis. The REAL-3 trial 

evaluated the addition of the anti-EGFR antibody panitumumab (P) to epirubicin, 

oxaliplatin and capecitabine (EOC) in advanced OGA. 

Methods: Patients with untreated, metastatic or locally advanced OGA were 

randomised to EOC (E 50mg/m 2 , O 130mg/m 2 , C 1250mg/m 2 /day) or mEOC + P (E 

50mg/m 2 , O 100mg/m 2 , C 1000mg/m 2 /day, P 9mg/kg). Primary endpoint was overall 

survival (OS); secondary endpoints were progression-free survival (PFS), response 

rate (RR), toxicity, and biomarker evaluation. Response was evaluated by RECIST 

after 4 and 8 cycles. 

Results: 553 patients were recruited (EOC 275, mEOC + P 278). Median OS was 11.3 

months with EOC compared to 8.8 months with mEOC + P (HR 1.37: 95% CI 

1.07-1.76, p = 0.013). Median PFS was 7.4 and 6.0 months respectively (HR 1.22: 

95% CI 0.98-1.52, p = 0.068), with RR being 42% compared to 46% (odds ratio 1.16: 

95% CI 0.81-1.57, p = 0.467). In the mEOC + P arm, OS was significantly improved 

in patients with G1-3 rash (77%, n = 209) on treatment compared to those without 

(23%, n = 63); median OS 10.2 vs 4.3 months (p < 0.001), with similar significant 

improvements seen in RR and PFS. Multivariate analysis demonstrated a negatively 

prognostic role for KRAS mutation (HR 2.1: 95% CI 1.10-4.05, p = 0.025) and 

PIK3CA mutation (HR 3.2: 95% CI 1.01-10.40, p = 0.048). The above information is 

being presented at ASCO 2012. Updated translational results will be available for 

presentation at ESMO Congress. This will include correlation of rash with toxicity 

endpoints and data relating to EGFR and KRAS amplification in this population. 

Disclosure: I. Chau: I have a compensated advisory role with Roche. I have also 

received honoraria and research funding from Roche. D. Cunningham: I have 

received research funding from Amgen, Roche, Merck-Serono. I have undertaken 

uncompensated advisory roles for Amgen and Roche. I have provided an 

uncompensated expert testimony for Amgen. All other authors have declared no 


668PD NON INFERIORITY ANALYSIS OF MULTICENTER PHASE III 

COMPARING CISPLATIN/S-1 (CS) WITH CISPLATIN/5-FU 

(CF) AS FIRST-LINE THERAPY IN PATIENTS WITH 

ADVANCED GASTRIC CANCER (FLAGS): METHODOLOGY 

AND RESULTS 

J.A. Ajani 1 , W. Rodriguez Pantigoso 2 , G. Bodoky 3 , V. Moiseyenko 4 , 

M. Lichinitser 5 , V.A. Gorbunova 5 , I. Vynnychenko 6 , I. Lang 3 , S. Falcon 1 

1 Gastrointestinal Medical Oncology, MD Anderson, Cancer Center, Houston, TX, 

UNITED STATES OF AMERICA, 2 Oncologia Y Radioterapia, Instituto de 

Oncologia Y RadioterapiaClinica Rica, Clinica Vesa, Lima, PERU, 3 Department of 

Oncology, St.László Hospital, Budapest, HUNGARY, 4 Medical Oncology, N.N. 

Petrov Research Inst. of Oncology, St. Petersburg, RUSSIAN FEDERATION, 

5 Department of Chemotherapy, N.N. Blokhin Russian Cancer Research Center, 

Moscow, RUSSIAN FEDERATION, 6 Medical Oncology, Sumy Regional Oncology 

Centre, Sumy, UKRAINE 

Background: S-1, a new generation of oral fluoropyrimidine, is active against Advanced 

Gastric Cancer (AGC). The primary analysis of FLAGS (JCO 2010; vol.28 p 1547-53) 

did not show any differences in overall survival (OS) between CS and CF. S-1 has been 

registered in Europe, with supportive analyses including non-inferiority (NI) analysis. 

Methods: 1,053 (1,029 treated; CS = 521/CF = 508) patients (non Asian 88 + %) with 

untreated, advanced gastric (83.1 %) / gastroesophageal (16.5%) adenocarcinoma 

were randomized to either S-1 (25 mg/m 2 bid, d 1-21)/cisplatin (75 mg/m 2 d1)q28 




d or 5-FU (1,000 mg/m 2 /d1-5 infusion)/cisplatin (100 mg/m 2 d 1) q 28 d. OS 

analyses for non-inferiority, by pre-specified stratifications, were performed. 

Results: OS for NI from CS (8.6 months) compared to CF (7.9 months) had a HR = 

0.92 (two-sided 95% CI, 0.80-1.05). HR = 1.05 being lower than HR = 1.10 non 

inferiority margin, derived from a literature meta-analysis, CS remains statistically 

significantly non-inferior (p = 0.0068) to CF. The 74% preserved control effect by CS 

is well above the suggested 50% by Rothmann et al. (Statist-Med2003; 22:239-264), 

based on which the 1.10 non-inferiority margin was derived. Moreover, statistically 

significant safety advantages for the CS arm were observed for the rates of G3/4 

neutropenia (18.6%, CS; 40.0%, CF), G3/4 febrile neutropenia (1.7%, CS; 6.9%, CF), 

G3/4 stomatitis (1.3%, CS; 13.6%, CF), renal adverse events (all grades: 18.8%, CS; 

33.5%, CF), and severe hypokalemia (3.6%, CS; 10.8%, CF). On the other safety 

items, no significant differences were noted between CS and CF, especially regarding 

Head and Foot Syndrome which was anecdotal and limited to grade 1/2. 

Treatment-related deaths were significantly reduced with CS compared to CF 

(respectively 2.5% and 4.9%). 

Conclusion: CS is non-inferior to CF while providing safety advantages for the 

patients and is a treatment alternative in advanced gastric carcinoma. 


669PD MET AS PROGNOSTIC FACTOR AND THERAPEUTIC TARGET 

IN PRETREATED HEPATOCELLULAR CARCINOMA (HCC): 

FINAL RESULTS OF A RANDOMIZED CONTROLLED PHASE 

2 TRIAL (RCT) WITH TIVANTINIB (ARQ 197) 

B. Daniele 1 , L. Rimassa 2 , C. Porta 3 , I. Borbath 4 , S. Salvagni 5 , J. van Laethem 6 , 

H. van Vlierberghe 7 , R. von Roemeling 8 , G. Abbadessa 9 , A. Santoro 10 

1 Clinical Oncology, G. Rummo Hospital, Benevento, ITALY, 2 Oncology 

Hematology, Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS, 

Rozzano, ITALY, 3 Oncologia Medica, Ospedale San Matteo, Pavia, ITALY, 

4 Gastro-Enterology, Cliniques Universitaires St. Luc, Brussels, BELGIUM, 

5 Oncology, Azienda Ospedaliera Parma, Parma, ITALY, 6 Gastroenterology, 

Erasme University Hospital, Brussels, BELGIUM, 7 Gastroenterology, Ghent 

University Hospital, Ghent, BELGIUM, 8 Clinical Development Oncology, Daiichi 

Sankyo Pharma Development, Edison, NJ, UNITED STATES OF AMERICA, 

9 Clinical Development, ArQule, Inc, Woburn, MA, UNITED STATES OF 

AMERICA, 10 Oncology Hematology, Humanitas Cancer Center, Istituto Clinico 

Humanitas, Rozzano, ITALY 

Background: Tivantinib (T), a selective, oral inhibitor of MET, the hepatocyte 

growth factor (HGF) receptor, was tolerated in HCC as monotherapy and with 

sorafenib. 

Methods: Multi center RCT; key selection criteria: unresectable HCC, 1 prior 

systemic therapy, PS

Day 8. A second identical course was administered after a 2-week break. If patients 

could not swallow the oral S-1 capsule, it was administered in powder form. In 

patients who showed an objective response to CRT, at least 2 courses of 

chemotherapy with S-1 and cisplatin were administered. 

Results: Eighty-three patients participated, 12 with Stage II and 71 with Stage III 

LAEC. Seventy-seven patients (92.7%) completed CRT. The most frequent adverse 

events were Grades 3 and 4 neutropenia (38.6%); thrombocytopenia (13.3%), and 

anemia (9.6%). One patient died on Day 20 from febrile bone marrow aplasia. 

Non-hematological adverse events were mild. The most common were Grade 2 

nausea (32.5%); esophageal pain and oral mucositis (16.9% each); and renal 

dysfunction (10.8%). Adverse events from the first course of CRT resolved during the 

2 weeks interval. Complete response rates in patients with Stage II and Stage III 

LAEC were 91.7% and 67.6%, respectively. No relapse occurred in patients with Stage 

II disease, and relapses occurred in 21 (43.8%) of 48 patients with Stage III disease 

who achieved CR. Median PFS for patients with Stage II and III patients was 6.6 and 

1.6 years, respectively. Median survival time was 7 years for Stage II and 2.6 years for 

Stage III LAEC. 

Conclusions: CRT combined with S-1 plus cisplatin showed promising safety and 

efficacy, as well as potential to become a standard treatment for LAEC. 


672P EFFECTS OF NEOADJUVANT CHEMORADIOTHERAPY ON 

POSTOPERATIVE MORBIDITY AND MORTALITY ASSOCIATED 

WITH ESOPHAGEAL CANCER 

Y. Hamai, J. Hihara, M. Emi, Y. Aoki, M. Okada 

Surgical Oncology, Research Institute for Radiation Biology and Medicine, 

Hiroshima University, Hiroshima, JAPAN 

Background: The results of clinical trials and meta-analyses suggest that neoadjuvant 

chemoradiotherapy (CRT) followed by esophagectomy confers a survival benefit 

upon patients with locally advanced esophageal cancer compared with 

esophagectomy alone. However, whether neoadjuvant CRT increases the risk of 

postoperative morbidity and mortality remains controversial. 

Methods: Data from 206 patients who underwent transthoracic esophagectomy with 

gastric tube reconstruction and cervical anastomosis between May 2003 and October 

2011 were reviewed. Neoadjuvant CRT comprised 40 Gy of radiation and concurrent 

chemotherapy with 5FU plus one of docetaxel, cisplatin or combined docetaxel/ 

cisplatin. We compared the surgical outcomes of 114 patients (55%) who underwent 

esophagectomy alone (group 1) and 92 (45%) who received neoadjuvant CRT followed 

by esophagectomy (group 2). We also assessed preoperative factors that influence 

postoperative major morbidity including anastomotic leak, graft necrosis, multilobar 

pneumonia, empyema, chylothorax and recurrent nerve palsy with tracheotomy. 

Results: The operative duration, blood loss and overall postoperative morbidity rates 

were 403 ± 79 and 421 ± 76 min (p = 0.10), 560 ± 407 and 589 ± 446 mL (p = 0.62) 

and 45% and 55% (p = 0.13) in groups 1 and 2, respectively. Rates of anastomotic 

leak (8.8 vs. 14.1%; p = 0.23), pneumonia (8.8 vs.13.0%; p = 0.32), recurrent nerve 

palsy (14.9 vs.9.8%; p = 0.27) and all other complications did not significantly differ 

between the groups. The 30-day mortality rate was 0% in each group and hospital 

mortality rates were 0.9 and 1.0% in groups 1 and 2, respectively (p = 0.88). 

Univariate analysis of preoperative factors indicated that advanced age, a history of 

cardiovascular disease, a high serum creatinine and advanced tumor stage were 

significantly associated with postoperative major morbidity, whereas neoadjuvant 

CRT was unrelated to the incidence of major morbidity. Multivariable analysis 

revealed cardiovascular disease (Odds ratio, 2.46; 95%CI, 1.27 - 4.78; p = 0.008) and 

advanced tumor stage (Odds ratio, 2.24; 95%CI, 1.15 - 4.35; p = 0.017) as 

independent covariates for major morbidity. 

Conclusion: Neoadjuvant CRT is safe and does not increase the incidence of 

postoperative morbidity and mortality compared with esophagectomy alone. 


673P INTERSTITIAL PULMONARY DISORDER IN PATIENTS WITH 

ESOPHAGEAL SQUAMOUS CELL CARCINOMA TREATED 

WITH DOCETAXEL AFTER CHEMORADIOTHERAPY 

Y. Ezoe 1 , M. Muto 2 , K. Ueda 2 , Y. Ozaki 2 , I. Aoyama 2 , T. Horimatsu 2 , S. Morita 2 , 

S. Miyamoto 2 , T. Chiba 2 

1 Department of Multidisciplinary Cancer Treatment, Kyoto University, Kyoto, 

JAPAN, 2 Department of Gastroenterology and Hepatology, Kyoto University, 

Kyoto, JAPAN 

Background and aims: Docetaxel (DOC) is a key drug in second-line chemotherapy 

after the failure of chemoradiotherapy (CRT) for esophageal cancer. Interstitial 

pulmonary disorder (IPD) is one of the fatal adverse effects of DOC, but its 

frequency and risk factors have not been clarified. The aim of this study was to 

determine the frequency of and risk factors for IPD in patients with esophageal 

squamous cell carcinoma (ESCC), who were treated with DOC after the failure of 

CRT. 


Patients and methods: We retrospectively reviewed the clinical data for 115 patients 

with ESCC who had been treated with CRT at Kyoto University Hospital from April 

2007 to March 2011. Thirty-seven of these patients had been treated with DOC after 

CRT (D group) and 78 had not been treated with DOC (non-D group). We 

compared the incidence of IPD in the two groups and also identified the risk factors 

for IPD. 

Results: The incidence of grade 3/4 IPD in the D and non-D groups was 10.8% 

(4/37) and 1.3% (1/78), respectively (P = 0.035). A median of 4 cycles of DOC 

was administered (range, 2–7). The median total radiation dose was 60 Gy. The 

mean value for V20 (% total lung volume receiving ≥20Gy) in patients with 

grade 3/4 IPD was greater than that in patients without IPD (20.0% vs 12.3%, 

respectively; P = 0.012). The V20 value was greater than 20% in 80% (4/5) of 

patients with grade 3/4 IPD. The mean lung dose (MLD) in patients with grade 

3/4 IPD was also greater than that in patients without IPD (11.1 Gy vs 6.6 Gy, 

respectively; P < 0.01). 

Conclusion: The incidence of grade 3/4 IPD was 10.8% in patients who received 

DOC after CRT. IPD must be considered when DOC is administered to patients who 

have already received radiotherapy with high V20 and MLD in their first-line CRT. 


674P PROGNOSIS IMPACT OF POSTOPERATIVE RADIATION IN 

PATIENTS WITH RADICAL ESOPHAGECTOMY AND 

PATHOLOGIC LYMPH NODES POSITIVE ESOPHAGEAL 

CANCER 

Y. Xu 1 ,W.Mao 1 , X.J. Sun 1 , Y.D. Zheng 1 , Y. Jiang 2 , J. Liu 2 

1 Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, 

CHINA, 2 Department of Surgery, Zhejiang Cancer Hospital, Hangzhou, CHINA 

Purpose: Though postoperative radiation for esophageal cancer is offered in selected 

cases, there is conflicting evidence as to whether it improves overall survival (OS). 

We performed a retrospective investigation to analyze the prognosis impact of 

adjuvant radiation in a large cohort of patients. 

Methods and materials: From 2002 to 2008, 545 patients underwent radical 

esophagectomy (R0) with or without postoperative radiation were eligible for 

retrospectively analysis. Patients were grouped to surgery only (n = 346) and surgery 

plus postoperative radiation therapy (PORT) (n = 199). Radiation dose was 50 Gy in 

25 fractions. Kaplan-Meier and Cox regression analysis were used to compare OS. 

Results: The use of PORT was associated with significantly improved OS (p =0.006). 

The median OS was 31 months in the group receiving PORT and 21 months in the 

group undergoing surgery alone. The addition of PORT improved OS at 3 years from 

38.3 to 45.8% compared with surgery alone. For American Joint Committee on 

Cancer (AJCC) stage III esophageal cancer (T1-2N2M0, T3N1-2M0, T4N1-3M0), 

there was significant improvement on OS (p < 0.001) in PORT group, for not only 

metastatic lymph-node ratio 0.25 (p = 0.013). However, for stages IIB disease (T1-2N1M0) there was no 

significant differences. 

Conclusions: This large population-based analysis supports the use of PORT for 

pathologic lymph nodes positive stage III esophageal cancer. Our results suggest 

that a subset of such patients may benefit from aggressive local therapy. As a 

retrospective study, our results do not have the same strength as a prospective 

study, however, it provides a basis for the design of future randomized, 

prospective clinical trials. 


675P A CLINICO-MOLECULAR RISK STRATIFICATION MODEL FOR 

RESECTED GASTRIC CANCER: PROGNOSTIC IMPACT OF 

HER2, FHIT AND APC EXPRESSION STATUS 

E. Bria 1 , G. De Manzoni 2 , S. Beghelli 3 , A. Tomezzoli 4 , S. Barbi 4 , M. Frizziero 1 , 

I. Sperduti 5 , S. Bersani 4 , G. Tortora 1 , A. Scarpa 4 

1 Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona-”Borgo 

Roma”, Verona, ITALY, 2 1st Division of General Surgery, University of Verona, 

Verona, ITALY, 3 Pathology, ARC-NET Applied Research on Cancer Center, 

Verona, ITALY, 4 Pathology and Diagnostics, University of Verona, Verona, ITALY, 

5 Biostatistics, Regina Elena Institute, Roma, ITALY 

Purpose: In order to complement the prognostic power of clinical parameters for 

resected gastric cancer, a stratification model to predict individual patient risk was 

developed taking into account 11 molecular factors. 

Methods: Clinicopathological and molecular data (expression of Cdx2, Apc, 

ß-Catenin, E-Cadherin, Fhit, p53, Her2; HER2 and TOPO2A gene copy number; 

PIK3CA mutations; microsatellite instability-MSI) were correlated to cancer-specific/ 

overall survival (CSS/OS) using a Cox model. A logistic equation including regression 

analysis coefficients was constructed to estimate individual patients’ probability (IPP) 

of death. Internal cross-validation (100 simulations, 80% of the dataset) was 

accomplished. Ratios from the multivariate model served to derive a prognostic 

continuous score to identify risk classes. 



Results: Two-hundred-eight patients were studied (median follow-up 20 months). At 

multivariate analysis, sex (HR 1.53, p = 0.04), stage (HR 5.40, p < 0.0001), margins 

(HR 2.69, p < 0.0001), localization (HR 1.64, p = 0.008), resected nodes (HR 1.55, p = 

0.02), APC (HR 1.91, p = 0.001), FHIT (HR 1.54, p = 0.05) and HER-2 (HR 1.92, p = 

0.08), were independent predictors for CSS; the same factors (plus age and except 

Fhit) predicted OS. Multivariate model predicted IPP with high prognostic accuracy 

(0.87 for CSS; 0.91 for OS). A 2-class risk stratification model, developed on the basis 

of the ROC generated cut-off prognostic score (AUC 0.87; Sensitivity 85.3%, 

Specificity 78.9%), significantly separated low and high risk patients for CSS (16.4% 

and 82.5%, p < 0.0001) and OS (15.6% and 79.7%, p < 0.0001), with a prognostic 

performance of 0.82 for CSS and 0.81 for OS. A further 3-class-model differentiated 

low, intermediate, and high-risk patients for CSS (7.3%, 37.3%, and 89.7%, p < 

0.0001) and OS (0%, 23.3%, and 84.8%, p < 0.0001). 

Conclusions: The concurrent evaluation of the expression of Apc, Fhit, Her2 proteins 

and clinicalpathological parameters (Stage, Resected Nodes, Margins, Location, Sex) 

may powerfully discriminate the prognosis of resected gastric cancer patients. 


676P THE PROGNOSTIC VALUE OF TUMOR-INFILTRATING 

NEUTROPHILS IN GASTRIC ADENOCARCINOMA AFTER 

RESECTION 

J. Xia 1 , J. Zhao 1 ,S.So 2 ,K.Pan 1 ,W.Wang 3 ,X.Li 4 , J. Chen 1 , D. Wang 1 

1 Biotherapy, Cancer Center, Sun Yat-sen University, Guangzhou, CHINA, 

2 Medical Corporation Zuiseikai, Tokyo, JAPAN, 3 Gastric and Pancreatic Surgery, 

Cancer Center, Sun Yat-sen University, Guangzhou, CHINA, 4 Thoracic 

Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, CHINA 

Background: Several pieces of evidence indicate that tumor-infiltrating neutrophils 

(TINs) are correlated to tumor progression. In the current study, we explore the 

relationship between TINs and clinicopathological features of gastric adenocarcinoma 

patients. Furthermore, we investigated the prognostic value of TINs. 

Patients and methods: The study was comprised of two groups, training group (115 

patients) and test group (97 patients). Biomarkers (intratumoral CD15+ neutrophils) 

were assessed by immunohistochemistry. The relationship between clinicopathological 

features and patient outcome were evaluated using Cox regression and Kaplan-Meier 

analysis. 

Results: Immunohistochemical detection showed that the tumor-infiltrating 

neutrophils (TINs) in the training group ranged from 0.00-115.70 cells/ 

high-power microscopic field (HPF) and the median number was 21.60 cells/ 

HPF. Based on the median number, the patients were divided into high and low 

TINs groups. Chi-square test analysis revealed that the density of CD15+ TINs 

was positively associated with lymph node metastasis (p = 0.024), distance 

metastasis (p = 0.004) and UICC (International Union Against Cancer) staging 

(p = 0.028). Kaplan-Meier analysis showed that patients with a lower density of 

TINs had a better prognosis than patients with a higher density of TINs (p = 

0.002). Multivariate Cox’s analysis showed that the density of CD15+ TINs was 

an independent prognostic factor for overall survival of gastric adenocarcinoma 

patients. Using another 97 patients as a test group and basing on the median 

number of TINs (21.60 cells/HPF) coming from the training group, 

Kaplan-Meier analysis also showed that patients with a lower density of TINs 

had a better prognosis than patients with a higher density of TINs (p = 0.032). 

The results verify that the number of CD15+ TINs can predict the survival of 

gastric adenocarcinoma surgical patients. 

Conclusions: The presence of CD15+ TINs is an independent and unfavorable factor 

in the prognosis of gastric adenocarcinoma patients. Targeting CD15+ TINs may be 

a potential intervenient therapy in the future. 


677P SURVIVAL IMPACT OF HER2 STATUS IN PATIENTS WITH 

GASTRIC CANCER: A MULTICENTER LARGE-SCALE STUDY 

IN JAPAN 

Y. Kurokawa 1 , N. Matsuura 2 , Y. Kimura 3 , R. Kawabata 4 , S. Adachi 5 , J. Fujita 6 , 

K. Nishikawa 7 , S. Takiguchi 1 , M. Mori 1 , Y. Doki 1 

1 Gastroenterological Surgery, Osaka University, Osaka, JAPAN, 2 Molecular 

Pathology, Osaka University, Osaka, JAPAN, 3 Surgery, NTT West Osaka 

Hospital, Osaka, JAPAN, 4 Surgery, Sakai City Hospital, Osaka, JAPAN, 

5 Surgery, Ikeda Municipal Hospital, Osaka, JAPAN, 6 Surgery, Toyonaka 

Municipal Hospital, Osaka, JAPAN, 7 Surgery, Osaka General Medical Center, 

Osaka, JAPAN 

Background: Although it has been proven in the ToGA study that HER2 expression is 

a predictive factor of trastuzumab treatment, the relation between HER2 status and 

prognosis in gastric cancer patients was still unknown. A multicenter large-scale study 

was conducted to evaluate the prognostic value of HER2 status in gastric cancer. 

Methods: A total of 1152 cases with gastric cancer which was surgically resected 

between 2000 and 2006 were registered to this study. The neoadjuvant treatment 

cases were excluded. Tumors were centrally tested for HER2 status with 

immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH). HER2 

expressions of resected tissues were evaluated according to the same criteria with the 

ToGA study. The relation between HER2 expression and clinicopathological factors 

was examined by Fisher’s exact test. The hazard ratio (HR) for death in 

HER2-positive cases was estimated, and overall survivals (OS) were compared 

between HER2-positive and HER2-negative cases using log-rank test. 

Results: The number of cases with IHC 0 / 1+ / 2+ / 3+ was 662 / 208 / 120 / 162, and 

eighteen of IHC 2+ cases showed FISH-positive. In total, the proportion of 

HER2-positive was 15.6% (180/1152). HER2-positive cases were more frequent in 

differentiated type tumors (P < 0.001), in upper body tumors (P = 0.065), and in T3-4b 

tumors (P = 0.074). OS in HER2-positive cases was clearly worse than in HER2-negative 

cases (HR 1.55 (95%CI, 1.21-1.97); P < 0.001). According to the tumor stage 

classification, the HR (95%CI) in HER2-positive cases and P values were as follows; 

Stage I: 2.05 (1.14-3.68), P = 0.015; Stage II: 1.87 (1.001-3.47), P = 0.046; Stage III: 1.46 

(0.95-2.27), P = 0.085; Stage IV: 1.41 (0.93-2.14), P = 0.101. There was no subgroup 

which showed interaction between HER2 status and any background factors. The Cox 

multivariate analysis with nine background factors revealed that HER2 expression was 

an independent prognostic factor (HR 1.55 (95%CI, 1.19-2.02); P = 0.001). 

Conclusions: HER2 expression is an independent factor of poor prognosis in 

resected gastric cancer, showing trends of higher HR in earlier stage. 


678P CLINICAL SIGNIFICANCE OF HER2 OVEREXPRESSION IN 

GASTRIC AND GASTROESOPHAGEAL JUNCTION CANCERS 

M. Baykara 1 , M. Benekli 2 , O. Ekinci 2 , U. Coskun 2 , E.P. Eser 2 , O. Polat 3 , 

U. Demirci 4 , A. Uner 2 , A. Ozet 2 , S. Buyukberber 2 

1 Medical Oncology, Gazi University Medical Faculty, Ankara, TURKEY, 2 Medical 

Oncology, Gazi University Faculty of Medicine, Ankara, TURKEY, 3 Internal 

Medicine, Gazi University Medical Faculty, Ankara, TURKEY, 4 Department of 

Medical Oncology, Ataturk Education and Research Hospital, Ankara, TURKEY 

Objectives: In this study, we investigated the rate of HER2 overexpression in gastric 

and gastroesophageal junction cancers (GC, GEJC), and the relationship with HER2 

expression and clinical, pathological parameters and prognosis. 

Materials and methods: Surgery or biopsy specimen of 285 (202 male, 83 female) 

patients with GC or GEJC, the presence of HER2 overexpression by 

immunohistochemistry (IHC) and silver insitu hybridization (SISH) were evaluated. 

The relationship between HER2 positivity and tumor size (TS), histopathology (H), 

grade (G), serosal invasion (SI), lenfovascular invasion (LVI), perineural invasion 

(PNI), Lauren and Borrmann type, tumor location (TL), TNM stage, local recurrence 

(LR) and metastasis (M) and survival (OS) were investigated. 

Results: HER2 IHC scores were; 194 (68.1%) IHC 0, 34 (11.9%) IHC +1, 30 (10.5%) 

IHC +2, 27 (9.5%) IHC +3. Twelve of 30 (4.2%) patients with IHC +2, SISH positive, 

and 18 patients SISH negative. The number of patients evaluated with IHC +3 or 

IHC +2 and SISH positive, HER2 positivity was 13.7%. There was no relationship 

between HER2 positivity and the age, gender, TNM stage, TS, TL, LR, M, LVI, PNI, 

and Borrmann type. HER2 positivity was higher in intestinal type tumors than in 

diffuse type (16.7% vs 6.9%, p = 0.075). HER2 positivity was significantly higher in 

well-moderately diferantiated tumors than poorly diferantiated tumors (24.3% and 

23.4% vs 7.3%, p = 0.001). HER2 positivity was higher in adenocarcinomas than the 

other histologic subtypes; 19.4% of adenocarcinomas, 4.2% of signet-ring cell 

carcinomas were HER2-positive (p = 0.013). HER2 pozitivity was no significant effect 

on median OS (22.7 vs 18.4 months, p = 0.81). But in the early stage median OS of 

HER2-positive patients was shorter than HER2-negative patients (54.9 months vs not 

reach, p = 0.022). However patients with advaced stage HER2-positive and –negative 

there was no significant difference between the median OS rates. 

Conclusion: HER2 positivity is associated with the degree of tumor differantiation 

and histopathology in GC and GEJC. Patients with early-stage, HER2 positivity is 

related to poor prognosis. 


679P IDENTIFICATION OF RISK FACTORS OF RELAPSE AFTER 

CURATIVE SURGICAL RESECTION IN STAGE I GASTRIC 

CANCER 

J. Park 1 , M.H. Ryu 2 , H.J. Kim 3 ,B.Ryoo 2 , I. Park 4 , Y.S. Park 5 , S.T. Oh 6 , 

J.H. Yook 6 , B.S. Kim 6 , Y. Kang 2 

1 Oncology, Internal Medicine, Asan Medical Center, Seoul, KOREA, 2 Division of 

Oncology, Dept of Internal Medicine, Asan Medical Center, Seoul, KOREA, 

3 Clinical Epidemiology and Biostatistics, Asan Medical Center, Seoul, KOREA, 

4 Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 

KOREA, 5 Department of Pathology, Asan Medical Center, Seoul, KOREA, 

6 Department of Surgery, Asan Medical Center, Seoul, KOREA 

Background: The therapeutic benefit of adjuvant chemotherapy is well established in 

stage (by AJCC 6th edition) II or III gastric cancer (GC). However, it has not been 


proven in stage I GC. The aim of this study was to identify risk factors of relapse in 

stage I GC, and to find out patients at high risk of relapse. 

Methods: We retrospectively reviewed the medical records of 2783 patients with 

pathologically confirmed stage I GC who underwent curative surgical resection 

alone in Asan Medical Center between 2003 and 2007. Clinicopathologic 

parameters of exploration included: age, sex, histologic differentiation, WHO 

classification, Lauren classification, size, location, multiplicity, stage, 

lymphovascular or perineural invasion, preoperative serum levels of tumor 

markers (CEA, CA 19-9, CA 72-4), and type of surgery. Then, we performed 

univariate and multivariate analysis to correlate each parameter with relapse-free 

survival (RFS) and overall survival (OS). 

Results: With a median follow-up of 54 months (range, 0-60), 213 (7.7 %) patients 

experienced recurrence or death, and 5-year RFS and OS was 90% and 94%, 

respectively. In univariate analysis, RFS was significantly related with age, sex, 

differentiation, WHO and Lauren classification, size, stage, lymphovascular invasion, 

perineural invasion, and serum levels of CEA and CA 19-9. The multiplicity of 

tumor instead of size was significantly related with OS. In multivariate analysis, 6 

factors (age over 65 years, male, stage Ib, lymphovascular invasion, perineural 

invasion, and elevated level of CEA) remained independent poor prognostic factors 

for RFS (p


2; 10 cases and grade 3; 14 cases, respectively. Surgery related morbidity was 13.0% 

and R0 resection rate was 98.1% (53/54). Grade 3/4 adverse events were acceptable 

such as leucopenia (8.9%), neutropenia (17.9%), febrile neutropenia (7.1%), anorexia 

(10.7%), and diarrhea (8.9%). There was no treatment related death and no major 

surgical complications except for one. 

Conclusions: Neoadjuvant DCS chemotherapy demonstrated a high histological 

response rate, acceptable feasibility and a sufficient R0 resection rate. This divided 

DCS regimen is attractive as NAC for pts with locally AGC. 


683P POSTOPERATIVE RADIOCHEMOTHERAPY WITH 

CAPECITABINE FOR GASTRIC ADENOCARCINOMA 

M. Skoblar Vidmar 

Radiotherapy, Institute of Oncology, Ljubljana, SLOVENIA 

Background: Complete removal of malignancy represents the treatment of choice in 

nonmetastatic gastric cancer. The Intergroup Study INT-0116 reported a significant 

improvment in survival with adjuvant radiochemotherapy. In Slovenia, the program 

of adjuvant radiochemotherapy with 5-fluorouracil and leucovorin was introduced 

into clinical practice in 2001. Capecitabine is an oral 5-FU prodrug and we assume 

that it can replace standard chemotherapy. 

Patients and methods: During 2006-2010, 101 patients with the mean age of 59 

years, were treated for gastric adenocarcinoma, stage Ib-IIIC, with post-operative 

radiochemotherapy with capecitabine. Radical (R0) and non-radical (R1) resection of 

the tumor was performed in 97 and 4 patients, respectively. Treatment was started 

with the first cycle of chemotherapy with oral capecitabine (1250 mg m 2 twice daily 

on day 1-14), radiotherapy with the total dose of 45 Gy was added after 3 weeks. 

Patients were irradiated on linear accelerator with 15MV photon beams for five days 

per week, at a daily dose of 1.8 Gy. During radiotherapy patients received 

capecitabine in lower dose (825 mg/m 2 twice daily, 7 days per week), but one dose 

was taken 1 hour before irradiation and the second twelve hours after. Three cycles 

of chemotherapy were added after the end of radiotherapy in 3-week intervals. 

Results: Postoperative ChT started 2.6–11.3 weeks after surgery (median 6 weeks). 

The treatment was completed according to the protocol in 59 patients. No death 

occurred due to the therapy. Stomatitis, dysphagia, nausea and vomiting, diarrhea, 

hand foot syndrome, stenocardia and alopecia of grade three occurred in 1, 0, 5, 2, 9, 

4 and 3 patients, respectively. Some 56 patients lost weight as measured with respect 

to the weight they had at the beginning of treatment. The maximum body weight 

loss was 18.9% (mean 6.2%). The median follow-up time of 66 survivors was 4 years 

(range 2.5-5.7 years). At 5 years, locoregional control (LRC), disease-free survival 

(DFS), disease-specific survival (DSS) and overall survival (OS) rates were 95%, 69%, 

74%, and 63%, respectively. 

Conclusion: In operable gastric carcinoma, postoperative radiochemotherapy with 

capecitabine is feasible and its toxicity is low. 


684P RESULTS OF TREATMENT OF LOCALLY ADVANCED GASTRIC 

CANCER IN THE ELDERLY PATIENTS 

D. Egamberdiev, M. Djuraev, S. Khudayorov, O. Nematov, A. Babaev, H. Tuyev 

Abdominal Oncology, National Cancer Center of Uzbekistan, Tashkent, 

UZBEKISTAN 

Background: Although the incidence of gastric cancer has declined in the general 

population, it is the second most frequent cancer in Uzbekistan with its incidence in 

the elderly increasing as a result of increased life expectancy. This present study tried 

to determine the role of age on outcomes of surgical treatment for gastric cancer in 

Uzbek population. 

Methods: The study reviewed 288 patients who underwent gasterectomy for locally 

advanced gastric cancer. The clinicopathological features of elderly patients (≥75 

years, n = 167) and younger patients (

Conclusions: Longer OS to FOLFOX was associated with low levels of both MMSET 

and 53BP1, while longer OS to second-line docetaxel was associated with high levels 

of both MMSET and BRCA1. MMSET, together with 53BP1 or BRCA1 can be useful 

for customizing chemotherapy in advanced gastric cancer p. 


687P UPDATED EFFICACY, BIOMARKER, AND 

EXPOSURE-RESPONSE DATA FROM A PHASE 2 STUDY OF 

RILOTUMUMAB (R) PLUS EPIRUBICIN, CISPLATIN, AND 

CAPECITABINE (ECX) IN GASTRIC (G) OR 

ESOPHAGOGASTRIC JUNCTION (EGJ) CANCER 

I. Davidenko 1 , T. Iveson 2 , R.C. Donehower 3 , S. Tjulandin 4 , A. Deptala 5 , Y. Jiang 6 , 

M. Zhu 7 , K.S. Oliner 8 , S. Dubey 9 , E. Loh 9 

1 Chemotherapy, Clinical Oncology Dispensary #1, Krasnodar, RUSSIAN 

FEDERATION, 2 Medical Oncology, Southampton General Hospital, 

Southampton, UNITED KINGDOM, 3 Cancer Center, Johns Hopkins, Baltimore, 

MD, UNITED STATES OF AMERICA, 4 Clinical Pharmacology and Chemotherapy, 

Russian Cancer Research Center, Moscow, Moscow, RUSSIAN FEDERATION, 

5 Department of Oncology and Hematology, Central Clinical Hospital 

MSWIA-WarsawMedical University of Warsaw, Warsaw, POLAND, 6 Global 

Biostatistical Science, Amgen Inc., Thousand Oaks, CA, UNITED STATES OF 

AMERICA, 7 Pharmacokinetics & Drug Metabolism, Amgen Inc., Thousand Oaks, 

CA, UNITED STATES OF AMERICA, 8 Molecular Sciences - Ivd, Amgen Inc., 

Thousand Oaks, CA, UNITED STATES OF AMERICA, 9 Oncology, Amgen Inc., 

South San Francisco, CA, UNITED STATES OF AMERICA 

Background: R (AMG 102) is an investigational, fully human monoclonal antibody 

to hepatocyte growth factor/scatter factor, the MET receptor ligand. Safety and 

efficacy of a placebo-controlled, double-blind, randomized phase 2 study of R + ECX 

in G/EGJ cancer from a 12.5-month (mo) follow up were previously reported (Iveson 

et al, Eur J Cancer. 2011; 47(suppl 1):S443. abstract 6.504). Updated data from a 

21.7-mo follow up are presented. 

Methods: Eligibility included unresectable, locally advanced or metastatic G/EGJ 

adenocarcinoma; ECOG PS ≤1; and no prior systemic therapy for this disease. 

Patients (pts) were randomized 1:1:1 to ECX (50 mg/m 2 IV day 1, 60 mg/m 2 IV day 

1, 625 mg/m 2 BID orally days 1–21, respectively) + R 15 mg/kg (Arm A); R 7.5 mg/ 

kg (Arm B); or placebo (Arm C) IV day 1 every 3 weeks. Overall survival (OS) and 

progression-free survival (PFS) were evaluated. MET protein was measured in 

archival tumor samples by IHC. R serum concentrations for all pts were measured. 

Individual R steady-state C minss were estimated with a population PK model. 

Results: 121 pts (Arms A/B/C: 40/42/39) were randomized Oct 2009 to June 2010. 

See table for data (Jan 16, 2012 cutoff). 

Conclusions: Within the context of a small, randomized phase 2 study, R + ECX 

improved outcomes in G/EGJ cancer pts. The treatment effect was strongest in pts 

with high MET tumors and high R exposure. Consistent with previously reported 

data, these results show continued separation of Arm A + B vs C beyond 16 mo. A 

planned phase 3 study will test the safety and efficacy of R + ECX in MET-positive 

G/EGJ cancer. 

Disclosure: T. Iveson: Dr. Iveson received research funding and travel payment 

from Amgen Inc. Y. Jiang: Dr. Jiang is an employee of and owns stock in Amgen 

Inc. M. Zhu: Dr. Zhu is an employee of and owns stock in Amgen Inc. K.S. 

Oliner: Dr. Oliner is an employee of and owns stock in Amgen Inc. S. Dubey: Dr. 

Dubey is an employee of and owns stock in Amgen Inc. E. Loh: Dr. Loh is an 

employee of and owns stock in Amgen Inc. All other authors have declared no 


Table: 687P 

688P A RANDOMISED PHASE III CLINICAL TRIAL OF COMBINED 

THERAPY WITH CPT-11/CDDP VERSUS CPT-11 ALONE IN 

PATIENTS WITH ADVANCED OR RECURRENT GASTRIC 

CANCER RESISTANT TO S-1(TRICS STUDY): SAFETY 

ANALYSIS 

H. Hasegawa 1 , K. Nishikawa 2 , H. Inagaki 3 , S. Akamaru 4 , S. Tokunaga 5 , 

M. Takagi 6 , S. Tamura 7 , S. Morita 8 , J. Sakamoto 9 , T. Tsujinaka 10 

1 Gastroenterology, National Hospital Organization Osaka National Hospital, 

Osaka, JAPAN, 2 Surgery, Osaka General Medical Center, Osaka, JAPAN, 

3 Surgery, GifuCentral Hospital, Gifu, JAPAN, 4 Surgery, Osaka Kose-Nenkin 

Hospital, Osaka, JAPAN, 5 Clinical Oncology, Osaka city General Hospital, Osaka, 

JAPAN, 6 Surgery, Shizuoka General Hospital, Shizuoka, JAPAN, 7 Surgery, 

Kansai Rosai Hospital, Amagasaki, JAPAN, 8 Biostatistics and Epidemiology, 

Yokohama City University Medical Center, Yokohama, JAPAN, 9 Social Life 

Science, Nagoya Universty, Nagoya, JAPAN, 10 Surgery, National Hospital 

Organization Osaka National Hospital, Osaka, JAPAN 

Background: There has been no established regimen as the second-line treatment for 

advanced gastric cancer (AGC), though CPT-11 showed survival benefit over BSC. 

Combination of CPT-11 with CDDP is one of the promising regimens as the 

second-line chemotherapy after S-1 mono-therapy. 

Methods: This study was designed as a randomized, multicenter phase III study 

comparing CPT-11 + CDDP vs. CPT-11 alone in patients with advanced or recurrent 

gastric cancer resistant to S-1 mono-therapy or prior adjuvant chemotherapy using 

S-1. Eligibility criteria include: histologically confirmed gastric adenocarcinoma, 

showing PD after receiving S-1 mono-therapy or recurrence within 6 months after or 

during S-1 adjuvant chemotherapy, age over 20 years old, PS:0-2, adequate organ 

functions and written informed consent. Patients received either CPT-11 150 mg/ 

m 2 day1 / q 2W (Arm A) or CPT-11 60mg/m 2 day1 +CDDP 30mg/m 2 day1/ q 2W 

(Arm B). Stratification was made according to PS, advanced or recurrence cases, 

institution and presence or absence of measurable target lesions. Primary endpoint is 

overall survival. Secondary endpoints are time to treatment failure (TTF), response 

rate, and safety (frequency and severity of adverse events). Calculated sample size 

was 160 assuming 74 events with alpha error 0.05 and beta error 0.2 to detect 

differences in survival. Planned number was 200 considering 40 for ineligibility or 

dropout. 

Results: 168 patients were enrolled between 2007 and 2011. Arm A (n = 84) and 

Arm B (n = 84) were well balanced for baseline factors.Median age was 67 years old 

and median number of treatment courses was 5 (range: 1-39).Relative dose intensity 

(RDI) in Arm A was 97.5% and RDI in Arm B was 98.9%. The most common grade 

3/4 toxicities in Arm A vs. Arm B were, neutropenia; 26.2 vs. 15.5%, anemia; 44.0 vs. 

27.3%, diarrhea; 0 vs. 11.9%, anorexia; 4.8 vs. 6.0%, nausea and vomiting; 3.5 vs. 

6.0%. 17.9% in Arm A and 10.7% in Arm B required dose modification for these 

toxicities. 

Conclusions: In this initial safety analysis, the incidence and severity of adverse 

events in both Arms were acceptable as second-line treatment. Final efficacy results 

will be performed at the end of this year. 


Median OS (80% CI), mo OS HR (95% CI) Median PFS (80% CI), mo PFS HR (95% CI) 

All pts Arm A + B n = 82 10.6 (9.5–12.0) 5.7 (5.1–6.9) 

Arm C n = 39 8.9 (5.7–10.6) 4.2 (3.7–4.6) 

Arm A + B vs C 0.70 (0.45–1.09) 0.60 (0.39–0.91) 

MET H * Arm A + B n = 27 11.5 (9.2–12.1) 6.9 (5.5–7.5) 

Arm C n = 11 5.7 (4.5–10.4) 4.6 (3.7–5.2) 

Arm A + B vs C 0.34 (0.15–0.78) 0.44 (0.20–0.96) 

MET H *, R H† 

Arm A + B n = 13 17.6 (13.3–21.0) 10.7 (6.9–15.3) 

Arm C n = 11 5.7 (4.5–10.4) 4.6 (3.7–5.2) 

Arm A + B vs C 0.18 (0.06–0.52) 0.19 (0.06–0.57) 

*Pts with >50% tumor cells MET positive, † Pts with R median C minss ≥ 94 µg/mL. 




689P DISEASE PROGRESSION CLINICALLY JUDGED WITHOUT 

CONFIRMATION BY IMAGE DIAGNOSIS IN A RANDOMIZED 

PHASE III TRIAL OF ADVANCED GASTRIC CANCER 

(JCOG9912) 

H. Kawai 1 , N. Boku 2 , Y. Yamada 3 , N. Fuse 4 , H. Yasui 5 , A. Sawaki 6 , W. Koizumi 7 , 

J. Mizusawa 8 , K. Nakamura 8 , A. Takashima 8 

1 Department of Endoscopy, Nagoya City West Medical Center, Nagoya, JAPAN, 

2 Department of Clinical Oncology, St. Marianna University School of Medicine, 

Kawasaki, JAPAN, 3 Medical Oncology, National Cancer Center Hospital, Tokyo, 

JAPAN, 4 Division of Gastrointestinal Oncology and Digestive Endoscopy, 

National Cancer Center Hospital East, Kashiwa, JAPAN, 5 Division of GI 

Oncology, Shizuoka Cancer Center, Shizuoka, JAPAN, 6 Department of Clinical 

Oncology, Nagoya Daini Red Cross Hospital, Nagoya, JAPAN, 7 Department of 

Gastroenterology/gastrointestinal Oncology, Kitasato University Schoool of 

Medicine, Sagamihara, JAPAN, 8 Japan Clinical Oncology Group Data Center, 

Multi-Institutional Clinical Trial Support Center, National Cancer Center, Tokyo, 

JAPAN 

Background: In advanced gastric cancer (AGC), some type of progression such as 

peritoneal metastasis are hardly detected by imaging, and progression was sometimes 

judged clinically (C-PD) apart from imaging-determined progression (I-PD). Thus, 

C-PD is regarded as a PFS event as well as I-PD in most cooperative group trials. 

However, it has rarely been reported how often C-PD is observed in the clinical trials 

of AGC. Objectives of this study are to evaluate the proportion of C-PD and to 

compare the backgrounds and outcomes between C-PD and I-PD. 

Methods: JCOG9912 is a large-scale randomized phase III trial comparing 5-FU 

continuous infusion (5-FUci), irinotecan plus cisplatin and S-1 in AGC. Among all 

randomized patients (n = 704), protocol treatments were terminated in 697 patients 

at the final analysis, and the reasons for off-treatment were prospectively classified as 

PD (n = 545), toxicities (n = 59), patient’s refusal (n = 73), death (n = 3) and others 

(n = 17). We retrospectively categorized patients with PD to I-PD and C-PD by 

reviewing the case report forms. 

Results: The proportion of C-PD was only 4.4% (I-PD: n = 520, C-PD: n = 24, 

unknown: n = 1) among those who terminated treatment due to PD. There were 

some differences in patient backgrounds between I-PD and C-PD; age (median 63, 

61.5 years old), diffuse type (51.0%, 70.8%), target lesion (+) (77.5%, 66.7%), sum of 

longest diameter of target lesions (median 9.3cm, 7.9cm), treatment arm of 5-FUci 

(36.2%, 45.8%), and second line chemotherapy (+) (83.1%, 70.8%). Median PFS in 

I-PD and C-PD were 3.7 months and 3.8 months (HR = 0.94 [0.63-1.42] in 

univariate analysis, HR = 0.93 [0.61-1.42] in multivariate analysis. Median OS in 

I-PD and C-PD were 11.1 months and 9.3 months (HR = 1.19 [0.78-1.80] in 

univariate analysis, HR = 1.25 [0.82-1.93] in multivariate analysis). 

Conclusions: The proportion of C-PD was far less than expected. Although the PFS 

in I-PD and C-PD were almost identical, there were some differences in patient 

background and clinical courses after PD. 

Disclosure: N. Fuse: I have research funding to disclose from Taiho Pharmaceutical 

and Yakult Honsha. All other authors have declared no conflicts of interest. 

690P A RANDOMIZED, CONTROLLED PHASE III TRIAL OF 

DOCETAXEL, CISPLATIN AND FLUOROURACIL (DCF) VERSUS 

CISPLATIN PLUS FLUOROURACIL (CF) AS FIRST-LINE 

THERAPY IN CHINESE ADVANCED GASTRIC CANCER 

L. Shen 1 ,R.Xu 2 , J. Wang 3 ,Y.Bai 4 , T. Liu 5 , S. Jiao 6 ,J.Xu 7 , Y. Liu 8 ,N.Fan 9 

1 GI Department of Oncology, Peking University Cancer Hospital, Beijing, CHINA, 

2 Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 

Guangzhou, CHINA, 3 Department of Oncology, Chinese Academy of Medical 

Sciences, Cancer Institute and Hospital, Beijing, CHINA, 4 Department of 

Oncology, Heilongjiang Cancer Hospital, Haerbin, CHINA, 5 Department of 

Oncology, Zhongshan Hospital Fudan University, Shanghai, CHINA, 

6 Department of Oncology, PLA General Hospital (301 Hospital), Beijing, CHINA, 

7 Department of Oncology, 307 Hospital of PLA, Beijing, CHINA, 8 Department of 

Oncology, The First Affiliated Hospital of China Medical University, Shenyang, 

CHINA, 9 Department of Onclogy, Fujian Provincial Tumor Hospital, Fuzhou, 

CHINA 

Background: Gastric cancer is the second prevalent cancer in China accounting for 

more than 200,000 deaths per year. Effective regimens are needed to improve the 

outcome for gastric cancer patients. TAX 325 study has demonstrated OS benefit and 

high toxicity of DCF regimen compared with CF in western population. Thus we 

investigated the effect of modified DCF (mDCF) regimen in Chinese patients with 

advanced gastric cancer in this prospective, multicenter, open-label, randomized and 

parallel-controlled phase III study. 

Methods: Eligible no prior palliative chemotherapy, advanced gastric cancer patients 

were randomized to either mDCF (Docetaxel 60mg/m 2 1-hour intravenous infusion 

(IV) and cisplatin 60mg/m 2 1-3-hour IV on day 1, followed by fluorouracil 600mg/ 

m 2 /d continuous IV for 5 days, every 3 weeks) or modified CF (mCF) (cisplatin 

75mg/m 2 1-3-hour IV on day 1, followed by fluorouracil 600mg/m 2 /d continuous IV 

for 5 days, every 3 weeks). Treatment continued until disease progression, 

unacceptable toxicity, death, or consent withdrawal. The primary end point was 

progression-free survival (PFS). 

Results: Between Nov 2008 and Dec 2010, a total of 241 patients were randomized, 

234 patients were treated and analyzed (mDCF = 119, mCF = 115) PFS was 

prolonged with mDCF vs mCF significantly (HR, 0.63; 95% CI, 0.48 to 0.85; P = 

0.0018; median PFS, 7.2 months vs.4.9 months), the trend of OS improvement was 

seen (HR, 0.78; 95% CI, 0.58 to 1.05; P = 0.099; median OS 10.2 months vs. 8.5 

months), Overall best response rate (ORR) was improved significantly with mDCF vs 

mCF (58% vs 39%, P = 0.0244). Treatment related grade 3/4 AEs occurred in 75.6% 

(DCF) vs 33.0% (CF), P < 0.0001. The most frequent 3/4 AEs included neutropenia 

(60.5% vs 8.7%), diarrhea (12.6% vs 0), vomiting (7.6% vs 11.3%) and febrile 

neutropenia (12.6% vs 0). 

Conclusion: mDCF regimen significantly improved PFS and ORR. The safety profile 

was consistent with previous report. mDCF should be considered as an option for 

untreated Chinese advanced gastric cancer patients. This study was funded by Sanofi, 

ClinicalTrials.gov identifier: NCT00811447. 


691P EVEROLIMUS (EVE) EXPOSURE IN PATIENTS (PTS) WITH 

PREVIOUSLY TREATED ADVANCED GASTRIC CANCER (AGC) 

S. Al-Batran 1 , N. Tebbutt 2 ,J.Xu 3 , G. Luppi 4 , H. Smith 5 , C. Costantini 6 , 

W. Cheung 5 , S. Rizvi 7 , T. Sahmoud 8 , L. Shen 9 

1 Medizinische Klinik Ii für Hämatologie und Onkologie, Institut für klinische 

Forschung (IKF) am Krankenhaus Nordwest - UCT, Universitäres Centrum für 

Tumorerkrankungen Frankfurt, Frankfurt, GERMANY, 2 Medical Oncology, Austin 

Hospital, Heidelberg, AUSTRALIA, 3 Gastrointestinal Oncology, 307 Hospital of 

PLA, Beijing, CHINA, 4 Oncology, Azienda-Ospedaliero Universitaria di Modena, 

Modena, ITALY, 5 Oncology, Novartis Pharmaceuticals Corporation, Florham 

Park, NJ, UNITED STATES OF AMERICA, 6 Oncology, Novartis Pharma AG, 

Basel, SWITZERLAND, 7 Oncology Clinical Research and Development, Novartis 

Pharmaceuticals, Florham Park, NJ, UNITED STATES OF AMERICA, 8 2W274, 

Novartis Pharmaceuticals, Florham Park, NJ, UNITED STATES OF AMERICA, 

9 Internal Medicine, Peking University Cancer Hospital, Beijing, CHINA 

Background: In GRANITE 1, EVE did not significantly improve overall survival 

(OS) over best supportive care (BSC) in previously treated AGC (median OS 5.4 mo 

with EVE vs 4.3 mo with BSC; HR, 0.90; P = .1244). Median progression-free survival 

(PFS) was 1.7 mo with EVE vs 1.4 mo with BSC (HR, 0.66; P < .0001). This analysis 

examined EVE exposure and its relationship with efficacy and safety. 

Methods: Pts with confirmed AGC who progressed after 1 or 2 chemotherapy lines 

were randomized 2:1 to EVE 10 mg/d + BSC or placebo + BSC. Primary endpoint was 

OS. EVE C min and C max were determined in whole blood from samples collected 

predose and 1 and 2 h postdose on day 1 of wk 5 using liquid chromatography/mass 

spectrometry (lower limit of quantification 0.3 ng/mL). Cox models adjusted for 

region (Asia/rest of world [ROW]) and gastrectomy (yes/no) were used to explore 

relationships between PFS and time-normalized (TN) EVE Cmin. A linear 

mixed-effects model was used to explore the relationship between change from 

baseline in target lesion size and TN C min. Kaplan-Meier curves for select adverse 

events (AEs) by TN C min categories were prepared. 

Results: 656 pts were enrolled from Jul 2009 to Dec 2010 and received EVE (n = 

439) or placebo (n = 217). Median age was 62 y, 74% were men, 55% were from Asia, 

and 50% had previous gastrectomy. Mean ± SD Cmin and Cmax were 16.1 ± 10.8 ng/ 

mL and 72.8 ± 36.5 ng/mL in pts receiving EVE 10 mg/d at sampling. EVE Cmin and 

C max were similar in pts from Asia and ROW and in pts with and without 

gastrectomy. No significant relationship between TN C min and PFS was observed 

(HR, 0.83; 95% CI, 0.65-1.06). A 2.72-fold increase in TN C min corresponded to a 

significant 7.6% reduction from baseline in target lesion volume. No differences in 

noninfectious pneumonitis, stomatitis/oral mucositis, or infection/infestation risk in 

pts with TN Cmin

692P PRELIMINARY SAFETY DATA FROM A RANDOMIZED PHASE 

II STUDY COMPARING DOSE-ESCALATED WEEKLY 

PACLITAXEL VERSUS STANDARD-DOSE WEEKLY 

PACLITAXEL FOR PATIENTS WITH PREVIOUSLY TREATED 

ADVANCED GASTRIC CANCER 

S. Yuki1 , K. Shitara2 , D. Takahari2 , M. Nakamura3 , C. Kondo2 , T. Tsuda4 ,T.Kii5 , 

Y. Tsuji6 , I. Oze7 , K. Muro2 1 

Department of Gastroenterology, Hokkaido University Hospital, Sapporo, 

JAPAN, 2 Department of Clinical Oncology, Aichi Cancer Center Hospital, 

Nagoya, JAPAN, 3 Department of Gastroenterology, Sapporo City General 

Hospital, Sapporo, JAPAN, 4 Department of Clinical Oncology, Saint Marianna 

University School of Medicine, Kawasaki, JAPAN, 5 Cancer Chemotherapy 

Center, Osaka Medical College, Osaka, JAPAN, 6 Department of Medical 

Oncology, KKR sapporo medical center Tonan hospital, Sapporo, JAPAN, 

7 

Division of Epidemiology and Prevention, Aichi Cancer Center Research 

Institute, Nagoya, JAPAN 

Background: Recently, we studied the effects of neutropenia occurring during 

second-line chemotherapy with weekly paclitaxel in a retrospective analysis of 242 

patients with advanced gastric cancer, and observed better survival among patients 

with neutropenia compared to patients without neutropenia (Shitara K, et al. Annals 

of Oncol. 2011). Therefore, we conducted a multi-institutional, open-label, 

randomized phase II trial comparing dose-escalated weekly paclitaxel with dose 

adjustments determined by degree of neutropenia versus standard-dose weekly 

paclitaxel for patients with previously treated advanced gastric cancer (protocol ID 

UMIN000004055). 

Patients and methods: Patients with advanced or recurrent gastric cancer that 

progressed during one or more previous chemotherapy regimens were included. 

Ninety patients were randomized to a standard dose of weekly paclitaxel (80 mg/m 2 , 

Arm A) or an escalated dose of weekly paclitaxel (80 mg/m 2 on day 1, 100 mg/m 2 on 

day 8, and 120 mg/m 2 on day 15 unless severe toxicity is observed, Arm B). The 

primary endpoint was overall survival. Secondary endpoints included objective 

response rate, disease control rate, progression-free survival, and adverse events. We 

present the preliminary safety data from the first 8 weeks. 

Results: From September 2010 to November 2011, a total of 90 patients were 

enrolled at 13 institutions. One patient in Arm B did not receive paclitaxel. The dose 

of paclitaxel was escalated to 100 mg/m 2 in 41 patients (91.1%) and then to 120 mg/ 

m 2 in 29 patients (64.4%) in Arm B. In the first 8 weeks, 25 (55.5%) patients in Arm 

A patients and 20 (46.7%) patients in Arm B required dose reduction or treatment 

delay. Frequencies of grade 1 or more neutropenia were 66.7% in Arm A and 86.4% 

in Arm B, and grade 3 or more neutropenia frequencies were 31.1% in Arm A and 

38.6% in Arm B. Grade 1 or more sensory neuropathy frequencies were 55.6% in 

Arm A and 68.1% in Arm B. Two patients in Arm A and one patient in Arm B 

experienced febrile neutropenia. No treatment-related deaths occurred. 

Conclusions: Preliminary safety data during the first 8 weeks of treatment indicate 

comparable compliance between the two arms, despite the substantial number of 

patients who underwent dose escalation. 


693P EFFICACY AND SAFETY OF DOSE-DENSE CHEMOTHERAPY 

WITH MODIFIED TCF REGIMEN (TCF-DD) IN ELDERLY 

PATIENTS WITH METASTATIC GASTRIC CANCER (MGC) 

G. Tomasello, W. Liguigli, S. Lazzarelli, R. Poli, F.M. Negri, L. Toppo, M. Ratti, 

M. Brighenti, F. Gerevini, R. Passalacqua 

Oncology Division, Istituti Ospitalieri di Cremona, Cremona, ITALY 

Background: GC is more common in elderly patients (pts). Most oncologists are 

reluctant to treat this pts population with the most active poli-chemotherapy 

combinations because of safety concerns. Subgroup analysis of elderly pts enrolled in 

European studies show limited and conflicting data. We previously reported on the 

feasibility and high activity of a dose-dense TCF regimen (TCF-dd) (Tomasello 

2010). This study aims to evaluate the efficacy and safety of this schema in the 

elderly pts subgroup (≥ 65 years). 

Methods: From 11/04 to 05/12, 111 consecutive pts with MGC (median age 65, 

range 31-81) were enrolled in a single-centre phase II study. Pts received Docetaxel 

70 mg/m 2 d1, CDDP 60 mg/m 2 d1, l-AF 100 mg/m 2 d1-2 followed by 5-FU 400 mg/ 

m 2 bolus d1-2, and then 600 mg/m 2 as a 22h c.i. d1-2, q2w, plus G-CSF d3. Pts ≥ 

65y (56) received the same schedule reduced by 30%. 

Results: 96 pts evaluable for response and all for toxicity. In pts ≥ 65y we observed 4 

CR (7%) 25 PR (45%) 10 SD (18%) 7 PD (13%); in younger pts: 2 CR (4%) 30 PR 

(55%) 9 SD (16%) 9 PD (17%); ORR by ITT 56% (95% IC 45-64). Median OS was 

11.9 months (9,4-14,8); in elderly and younger pts 11,2 (8,4-11,1) and 12,7 (9-16,5) 

respectively. Out of 48 evaluable pts ≥ 65y, 26 (54%) were treated at full doses 

without any delay. In the elderly most frequent G3-4 toxicities were neutropenia 

(14%) thrombocytopenia (15%) febrile neutropenia (7%) asthenia (27%) and 

hypokalemia (17%); in the younger: neutropenia (56%) thrombocytopenia (21%) 

febrile neutropenia (16%) asthenia (43%) hypokalemia (21%). 


Conclusions: This study shows that elderly pts can be treated with a TCF-dd 

regimen reduced by 30% achieving similar efficacy results of younger patients with 

lesser toxicity. 


694P PROGRESSION-FREE SURVIVAL AND POSTPROGRESSION 

SURVIVAL IN PATIENTS WITH ADVANCED GASTRIC CANCER 

TREATED WITH FIRST-LINE CHEMOTHERAPY 

K. Shitara 1 , K. Matsuo 2 , K. Muro 3 , A. Ohtsu 1 

1 Gastroenterology & Gastrointestinal Oncology, National Cancer Center Hospital 

East, Kashiwa, JAPAN, 2 Aichi Cancer Center Research Institute, Aichi Cancer 

Center, Nagoya, JAPAN, 3 Clinical Oncology, Aichi Cancer Center Hospital, 

Nagoya, JAPAN 

Background: Progression-free survival (PFS) has been reported to be moderately 

correlated to overall survival (OS) in patients with advanced gastric cancer (AGC) who 

received first-line chemotherapy (Shitara, K et al. Invest New Drug 2011; Shitara K 

and Burzykowski T. On behalf of GASTRIC. ASCO 2011). Impact of post progression 

survival (PPS) on OS of patients with AGC has not yet been reported in detail. 

Methods: We retrospectively analyzed AGC patients who received first-line 

chemotherapy including fluoropyrimidine plus platinum with confirmed disease 

progression. We partitioned OS into PFS and PPS and analyzed the correlation 

between OS and either PFS or PPS by Spearman rank correlation coefficient (r). 

Subgroup analyses were performed according to treatment setting (clinical trial or 

practice) and presence of measurable lesion. Multivariate analysis was also conducted 

to evaluate prognostic factors for PPS. 

Results: Between April 2005 to May 2011, 291 AGC patients met inclusion criteria. 

One-hundred five patients (36%) included in clinical trials and 246 patients (85%) 

received second-line chemotherapy. Median PFS, PPS, and OS were 5.3 months, 8.1 

months. 14.8 months, respectively. PFS and OS showed a correlation with r of 0.75 (95% 

CI, 0.69- 0.81). PPS and OS also showed a correlation with r of 0.87 (95% CI, 0.84- 0.91). 

Correlations tend to be higher between PSS and OS than that of PFS and OS in subset of 

patients in clinical trials (r = 0.84 vs. r = 0.72) or patients with measurable lesion (r = 0.87 

vs. r = 0.72). According to the multivariate analysis, performance status at progression and 

second-line chemotherapy were significantly associated with length of PPS. 

Conclusion: Our results indicate that both PFS and PSS is correlated with OS in 

first-line chemotherapy for advanced AGC, thus suggest the importance of reporting 

detailed patients characteristic and treatment course after disease progression in 

clinical trials of first-line chemotherapy for AGC. 


695P QUALITY OF LIFE IN FLAGS TRIAL A RANDOMIZED, 

COMPARATIVE, OPEN LABEL, MULTICENTER, PHASE 3 OF 

S-1 + CISPLATIN (CS) COMPARED TO 5-FU + CISPLATIN (CF) 

IN UNTREATED ADVANCED GASTRIC CANCER (AGC) 

PATIENTS 

G. Bodoky 1 , A. Carrato 2 , A. Ravaioli 3 , J.A. Ajani 4 

1 Dept of Medical Oncology, Szent Laszlo Korhaz, Budapest, HUNGARY, 

2 Medical Oncology, Hospital Ramon y Cajal, Madrid, SPAIN, 3 Primario 

Oncologia Medica, Ospedale “Infermi” di Rimini, Rimini, ITALY, 4 Gastrointestinal 

Medical Oncology, MD Anderson, Cancer center, Houston, TX, UNITED STATES 

OF AMERICA 

Background: FLAGS’ primary objective was overall survival. We report below the 

Patient-Reported Outcomes (PRO) (i.e., Quality-of-Life [QoL]) which was one of the 

secondary objectives. 

Methods: All patients who completed at least one PRO assessment were eligible for 

analysis. The primary PRO endpoint was the Trial Outcome Index (TOI) of the 

Functional Assessment of Cancer Therapy – Gastric (FACT-Ga). Patients completed 

the FACT-Ga at the beginning of Cycles 1, 2, 3, 4, 6 and then every 3 cycles prior to 

treatment administration. All individual subscales in the FACT-Ga were also 

evaluated as secondary endpoints. The Chemotherapy Convenience and Satisfaction 

Questionnaire (CCSQ) was administered at the beginning of the first 4 cycles. 

Results: Of the 508 patients dosed at cycle 1 in the CF arm, and the 521 in the CS 

arm, 456 and 498 respectively completed at least one question on the FACT-Ga and 

445 and 486 respectively completed at least 37 items. Compliance to questionnaire 

fulfillment was more than 80% through Cycle 9. Although there were no overall 

difference in FACT-Ga scores between the treatment arms and minimal changes over 

time, an advantage for CS relative to CF was observed for Physical Well-Being 

(PWB) (51.7% versus 45.1%, p = 0.044). CS treated patients experienced significantly 

longer time to worsening in PWB scores, with a median time of 4.5 months (95% 

CI: 3.0 – 5.1) compared to 3.0 months (2.8 – 4.6) with CF (p = 0.014).Patients 

receiving CS reported higher best and worst score of PWB, Chemotherapy 

Convenience and Chemotherapy Concerns scores. 

Conclusions: Even if there is little evidence to indicate any difference in FACT-Ga 

scores, some advantage to CS relative to CF was observed for PWB, one of the 



secondary PRO endpoints. This advantage was generally consistent across analysis 

method: time to worsening, best post-baseline score, and worst post-baseline score. 

CS treated patients did report significantly better Chemotherapy Convenience and 

Concerns scores, the difference was approximately one-half of a standard deviation 

generally considered to be a meaningful difference. 


696P A MULTI-CENTER PHASE II STUDY AND PREDICTIVE 

BIOMARKER ANALYSIS OF COMBINED CETUXIMAB AND 

MODIFIED FOLFIRI AS SECOND-LINE TREATMENT IN 

PATIENTS WITH METASTATIC GASTRIC CANCER 

L. Jin 

Medical Oncolgy, Fudan University Cancer Center, Shanghai, CHINA 

Background: This study was conducted to explore potential biomarkers for 

predicting clinical outcome of cetuximab in combination with modified FOLFIRI 

(mFOLFIRI) and to analyze safety of this regimen as a second-line treatment in 

metastatic gastric cancer patients. 

Methods: A total of 61 patients received an initial intravenous (IV) dose of 

cetuximab (400 mg/m 2 ) and weekly doses (250 mg/m 2 ) thereafter. On day 2 of each 

14-day period, patients received IV irinotecan (180 mg/m 2 ), leucovorin (200 mg/m 2 ), 

and an IV bolus dose of 5-FU (400 mg/m 2 ) followed by a continuous infusion of 

5-FU (2400 mg/m 2 ) for 46 hours. The primary endpoint was time-to-progression 

(TTP). 

Findings: The response rate (RR) was 33.3% among 54 evaluable patients. In the 

intention-to-treat (ITT) analysis, median TTP was 4.6 months (95% confidential 

interval [CI]: 3.6-5.6 months) and median overall survival (OS) was 8.6 months (95% 

CI: 7.3-9.9 months). It was demonstrated that plasma vascular endothelial growth 

factor (VEGF) levels could be a predictive factor for the treatment prognosis. In 

patients with low (≤12.6 pg/ml) and high (>12.6 pg/ml) baseline plasma VEGF 

levels, RR values were 55.0% and 5.3%, respectively (P = 0.001); median TTP values 

were 6.9 months and 2.8 months, respectively (P = 0.0005); and median OS values 

were 12 months and 5 months, respectively (P < 0.0001). None of these patients 

exhibited KRAS, BRAF, or PIK3CA mutations. 

Interpretation: Low baseline plasma VEGF levels were identified as a potential 

predictive biomarker of prognosis. Combination therapy comprising cetuximab and 

mFOLFIRI was well tolerated, which would be potentially used as a second-line 

treatment for patients with advanced gastric cancer. 

Funding: This study was supported by Fudan University Shanghai Cancer Center; 

Merck KGaA Darmstadt, Germany, and National “Eleventh Five-year plan” new 

drug discovery major projects of P. R. China. 


697P FINAL ANALYSIS OF RANDOMIZED PHASE III STUDY 

WJOG4007 COMPARING IRINOTECAN (CPT-11) WITH 

WEEKLY PACLITAXEL (WPTX) IN ADVANCED GASTRIC 

CANCER (AGC) REFRACTORY TO CHEMOTHERAPY (CT) OF 

FLUOROPYRIMIDINE PLUS PLATINUM (FP) 

T. Nishina 1 , S. Hironaka 2 , A. Tsuji 3 , K. Suzuki 4 , T. Otsuji 5 , T. Shibata 6 , S. Morita 7 , 

I. Okamoto 8 , N. Boku 9 , I. Hyodo 10 

1 Gastrointestinal Oncology, National Hospital Organization Shikoku Cancer 

Center, Matsuyama, JAPAN, 2 Clinical Trial Promotion Centre, Chiba Cancer 

Center Hospital, Chiba, JAPAN, 3 Department of Medical Oncology, Kochi Health 

Sciences Center, Kochi City, JAPAN, 4 Gastrointestinal Oncology, Kushiro City 

General Hospital, Kushiro, JAPAN, 5 Gastrointestinal Oncology, Dongo Hospital, 

Yamatotakata, JAPAN, 6 Gastrointestinal Oncology, Fujita Health University, 

Toyoake, JAPAN, 7 Biostatistics and Epidemiology, Yokohama City University 

Medical Center, Yokohama, JAPAN, 8 Medical Oncology, Kinki University School 

of Medicine, Osakasayama, JAPAN, 9 Department of Clinical Oncology, 

St. Marianna University School of Medicine, Kawasaki, JAPAN, 10 Gastrointestinal 

Oncology, University of Tsukuba, Tsukuba, JAPAN 

Background: We previously reported the primary results of WJOG4007 trial 

comparing wPTX with CPT-11 for AGC refractory to combination CT of FP (Ueda 

et al. ASCO 2012). This trial failed to demonstrate the superiority of CPT-11 to 

wPTX in OS. Here, we report the results of subgroup analysis, cross-over effect and 

patients’ general conditions at the time of discontinuation of protocol treatments. 

Methods: The main inclusion criteria were; 1) refractory to combination CT of FP, 

2) no prior CPT-11 or taxane, 3) no severe peritoneal metastasis. Pts with AGC 

refractory to the 1st-line FP regimen were randomized 1:1 to either CPT-11 (150 mg/ 

m 2 , days1, 15, q4w) or wPTX (80 mg/m 2 , days 1, 8, 15, q4w). Cross-over treatment 

between PTX and CPT-11 was recommended for the third line chemotherapy. 

Results: Between Aug 2007 and Aug 2010, 223 pts were enrolled and 219 were 

eligible; 108 pts were randomized to wPTX and 111 pts to CPT-11. Median OS for 

wPTX and CPT-11 was 9.5 and 8.4 months (HR 1.13; 95% CI, 0.86-1.49; p = 0.38). 

Subgroup analysis in OS revealed slightly favorable tendency of wPTX for almost all 

factors such as age, gender, PS, prior gastrectomy, histological type, presence of 

target lesion, peritoneal metastasis, number of metastatic sites. At the treatment 

discontinuation, 85 pts (80%) with wPTX and 77 with CPT-11 (70%) maintained PS 

0-1 (p = 0.12), and 2 (2%) and 13 pts (12%) were complicated with infection (p = 

0.006), respectively. Thereafter, proportion of pts receiving third line CT was higher 

in wPTX (89%) than CPT-11 (71%) (p = 0.04). As for the cross-over effect, among 

86 pts (80%) in the wPTX group who received CPT-11 containing regimens in the 

subsequent chemotherapy and 74 pts (67%) in the CPT-11 group who received 

taxane containing regimens, survival curves were quite similar (10.1months, HR 0.96; 

95%CI, 0.69-1.32). 

Conclusions: In this trial, while patients in the wPTX group showed better condition 

at the time of treatment discontinuation, a higher rate of subsequent CT and 

cross-over CT, quite similar survival curves were observed in pts of both arms who 

received cross-over treatments. It is speculated that the better condition at the end of 

the second line chemotherapy resulting in higher proportion of the third line 

chemotherapy might contribute to more favorable overall survival with wPTX than 

CPT-11. 

Disclosure: T. Nishina: Honoralia from Yakult Honsha, Daiichi Sankyo. I. Hyodo: 

Honoralia from Yakult Honsha and Daiichi-Sankyo. All other authors have declared 


698P PHASE II STUDY OF INTRAVENOUS AND INTRAPERITONEAL 

PACLITAXEL COMBINED WITH S-1 FOR GASTRIC CANCER 

WITH METASTASES TO THE DISTANT PERITONEUM 

H. Ishigami 1 , J. Kitayama 2 , H. Yamaguchi 2 , S. Emoto 2 , T. Watanabe 2 

1 Department of Outpatient Chemotherapy, The University of Tokyo, Tokyo, 

JAPAN, 2 Department of Surgical Oncology, The University of Tokyo, Tokyo, 

JAPAN 

Background: Intraperitoneal (i.p.) chemotherapy is a promising treatment option for 

gastric cancer with peritoneal metastasis. We previously carried out phase I and phase 

II studies of intravenous (i.v.) and i.p. paclitaxel (PTX) combined with S-1, and 

verified the safety and efficacy in gastric cancer with macroscopic peritoneal metastasis 

and/or cancer cells on peritoneal cytology (Oncology 2009, Ann Oncol 2010). This 

regimen was approved as an advanced medical treatment by the Ministry of Health, 

Labour and Welfare of Japan, and further clinical studies were required for approval of 

coverage by the Japanese Health Insurance System. Therefore, we carried out another 

phase II study in gastric cancer patients with macroscopic peritoneal metastasis. 

Patients and methods: Gastric cancer patients with macroscopic peritoneal 

metastasis confirmed by staging laparoscopy were enrolled. PTX was administered i. 

v. at 50 mg/m 2 and i.p. at 20 mg/m 2 on days 1 and 8. S-1 was administered orally 

twice daily at 80 mg/m 2 /day for 14 consecutive days followed by 7 days rest. The 

primary endpoint was the 1-year overall survival rate. Secondary endpoints were the 

response rate, efficacy against malignant ascites and safety. 

Results: Thirty-five patients were enrolled. All patients had several to numerous 

metastases to the distant peritoneum. The median number of courses was 11 (range 

2-29). The 1-year overall survival rate was 77% (95% CI, 63-91%). The overall response 

rate was 71% in 7 patients with target lesions. Malignant ascites disappeared or decreased 

in 6 of 9 (67%) patients with massive ascites. Cancer cells ceased to be detected by 

peritoneal cytology in 28 of 29 (97%) patients. The incidences of grade 3/4 hematological 

and non-hematological toxicities were 34% and 9%, respectively, all of which were 

manageable and reversible. The frequent grade 3/4 toxicities included neutropenia (34%), 

leukopenia (23%) and anemia (9%). There were no treatment-related deaths. 

Conclusion: Combination chemotherapy of weekly i.v. and i.p. PTX combined with 

S-1 is well tolerated and active in gastric cancer patients with macroscopic peritoneal 

metastasis. 


699P HER2 STATUS IN ADVANCED GASTRIC CARCINOMA 

PATIENTS TREATED WITH TRASTUZUMAB 

C. Gomez-Martin 1 , J.C. Plaza 2 , E. Del Valle 3 , F. Pons Valladares 4 ,P. 

Jimenez Fonseca 5 , A. Salud 6 , A. Leon 7 , F. Rivera 8 , E. Garralda 1 , F. Lopez-Rios 2 

1 Clinical Research Programme, Spanish National Cancer Research Center, 

Madrid, SPAIN, 2 Laboratorio Dianas Terapeuticas, Hospital Universitario 

Madrid-Norte Sanchinarro, Madrid, SPAIN, 3 Pathology Department, Hospital 

Universitario Miguel Servet, Zaragoza, SPAIN, 4 Medical Oncology, Hospital del 

Mar, Barcelona, SPAIN, 5 Medical Oncology, Hospital Universitario Central de 

Asturias, Oviedo, SPAIN, 6 Medical Oncology, Hospital Universitario Arnau de 

Vilanova, Lerida, SPAIN, 7 Medical Oncology, Fundacion Jimenez Diaz, Madrid, 

SPAIN, 8 Medical Oncology, Hospital Universitario Marques de Valdecilla, 

Santander, SPAIN 

Background: Trastuzumab (T) added to standard chemotherapy increases overall 

survival for HER2 positive advanced gastric carcinoma (AGC) patients. The approval 

of T by the EMA in AGC was linked to the determination of the HER2-status by 

immunohistochemistry (IHC), and hybridization was only permitted in the 2+ 


subgroup. Taking into consideration the previous highs and lows in breast carcinoma 

HER2 testing, we sought to evaluate the use of Dual Colour Silver-staining in situ 

Hybridization (dc-SISH) for selecting patients with AGC as candidates to anti-HER2 

therapies. 

Material and methods: Sixty-nine AGC patients meeting a previously set of specific 

inclusion criteria were included: previous treatment with Trastuzumab-based 

chemotherapy, adequate follow-up, available pathology data and suitable sample for 

molecular analyses. IHC results were determined by the Pathway anti HER2/neu 

(4B5) antibody in the fully automated platform BenchMark ULTRA® (Ventana 

Medical Systems, Inc, Tucson, AZ). Automated dc-SISH was performed on Ventana 

Benchmark XT (Ventana Medical Systems, Tucson, AZ). INFORM HER2 DNA 

Probe and INFORM Chromosome 17 Probe was visualized on the same slide 

following the manufacturer’s protocols. Gene to CEN-17 ratio was calculated using 

the cut-off value of HER2/CEN-17 ratio ≥2 as amplified. IHC evaluation was 

performed according to published guidelines. 

Results: All cases were amplified. Low polisomy was present in 4 cases. Heterogeneity 

was observed in 24 (34.78%) cases. A statistically significant relationship was found 

between IHC and dc-SISH results (p < 0.0001), with 94% of IHC 3+ expressing dc-SISH 

ratio >4. Median OS was 19.8 months (95% CI: 13.4 – 23.9 months) for the entire 

population. Mean OS was significantly longer in the group of patients with amplification 

ratio >4 (21.4 vs. 8.0 months, HR 0.41; p = 0.0087; CI95% 0.2126 – 0.8180). No 

differences were observed in OS according to IHC results when stratified in two groups 

(3+ vs 0/1 + 2+) (21.0 vs 10.9 months, HR 0.5288, CI95% 0.2469 – 1.1325, p = 0.0955). 

Conclusions: Dc-SISH amplification ratio >4 predicts OS benefit in AGC patients 

treated with trastuzumab in this study. Characterization in a larger cohort of patients 

is ongoing. 


700P A PHASE I DOSE-FINDING STUDY OF VORINOSTAT (V) 

COMBINED WITH CAPECITABINE (X) AND CISPLATIN (P) AS 

FIRST-LINE THERAPY IN PATIENTS WITH ADVANCED 

GASTRIC CANCER 

C. Yoo, M.H. Ryu, B. Ryoo, D.H. Koo, I. Park, Y. Kang 

Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 

KOREA 

Background: The purpose of this trial is to determine the recommended dose (RD) of 

vorinostat (V), a histone deacetylase inhibitor, in combination with capecitabine (X) and 

cisplatin (P) and to explore feasibility of V-XP at the RD in advanced gastric cancer. 

Patients and methods: The standard 3 + 3 method was used to determine the RD of 

3-weekly V-XP during the first cycle. The doses of X (days 1-14, p.o.), P (day 1, i.v.), 

and V (days 1-14, p.o.) were escalated as following scheme; X 1,600 mg/m 2 /day, P 

60 mg/m 2 , V 300 mg/day in level 1; X 1,600 mg/m 2 /day, P 60 mg/m 2 , V 400 mg/day 

in level 2A; X 2,000 mg/m 2 /day, P 60 mg/m 2 , V 300 mg/day in level 2B; X 2,000 mg/ 

m 2 /day, P 60 mg/m 2 , V 400 mg/day in level 3; X 2,000 mg/m 2 /day, P 80 mg/m 2 ,V 

400 mg/day in level 4. 

Results: A total of 24 patients were enrolled. Median age was 50 years (range, 25-66), 

and 11 (46%) were male. Dose limiting toxicity (DLT) was noted in 1 of 6 in level 1 

(Grade 4 thrombocytopenia), 0 of 3 in level 2A, 1 of 6 in level 2B (Grade 3 fatigue), 1 

of 6 in level 3 (Grade 3 stomatitis) and 2 of 3 in level 4 (Grade 4 thrombocytopenia, 

and discontinuation of X or V more than 25% of prescribed dosage due to Grade 3 

anorexia and Grade 3 fatigue). Level 4 was maximal tolerated dose, and RD was 

determined as level 3. Six additional patients were enrolled at level 3 to confirm the 

feasibility, and DLT was not occurred. In 12 patients who received dose level 3, median 

6 cycles (range, 3-10) of chemotherapy were given and most frequent Gr 3/4 toxicities 

were neutropenia (n = 5, 42%) and anorexia (n = 3, 25%). In overall, the objective 

responses were confirmed in 9 (47%) out of 19 patients with measurable lesions. With 

a median follow-up of 9 months, median progression-free survival was 7 months (95% 

confidence interval, 4 to 10 months), and median overall survival was not reached. 

Conclusion: Major DLTs of V-XP were thrombocytopenia, fatigue, anorexia and 

stomatitis. The 3-weekly schedule of X (2,000 mg/m 2 /day on day 1-14), P (60 mg/m 2 

on day 1), and V (400 mg/day on day 1-14) is recommended for further 

development of this regimen in patients with advanced gastric cancer. 

Disclosure: Y. Kang: Research fund from MSD. All other authors have declared no 


701P BIMONTHLY REGIMEN OF HIGH DOSE LEUCOVORIN, 

INFUSIONAL 5-FLUOROURACIL, DOCETAXEL AND CISPLATIN 

(MODIFIED DCF) IN ADVANCED GASTRIC ADENOCARCINOMA 

I.T. Unek 1 , T. Akman 1 , I. Oztop 2 , O.U. Unal 1 , T. Salman 1 , A.U. Yilmaz 1 

1 Medical Oncology, Dokuz Eylul University Faculty of Medicine, Izmir, TURKEY, 

2 Medical Oncology, Oncology Institute, Izmir, TURKEY 

The combination of docetaxel, cisplatin and 5-fluorouracil (DCF) is an effective but 

highly toxic regimen for the treatment of advanced gastric cancer. In the palliative 

chemotherapy of tumors, it is necessary to improve the drug safety while 

ensuring efficacy. We developed a modified DCF regimen with goal to minimize 

toxicity without compromising efficacy. In our study, seventy patients with 

advanced gastric cancer were treated. Each 2-week cycle consisted of docetaxel 

(60 mg/m 2 ), cisplatin (50 mg/m 2 ), 5-fluorouracil (400 mg/m 2 )IVbolusand 

5-fluorouracil (2400 mg/m 2 ) IV over 46 hours plus leucovorin (400 mg/m 2 )IV 

over 2 hours. The median progression-free survival and overall survival were 9.0 

months (95% CI, 7.1-10.9) and 10.8 months (95% CI, 7.4-14.2), respectively; 

the 1-year and 2-year survival rates were 46.3% and 18.4%, respectively. 

Twenty-nine (41.4%) partial responses, 19 (27.1%) stable disease, and 22 

(31.4%) progression of disease were observed. Grade 3-4 toxicities included 

neutropenia (37.1%), febrile neutropenia (15.7%), thrombocytopenia (10.0%), 

anemia (8.6%), nausea and vomiting (10.0%), stomatitis (5.7%), infection 

(8.6%), diarrhea (2.9%). In summary, our results show that a modified DCF 

regimen may have tolerable toxicities and be an effective and convenient 

palliative treatment of advanced gastric cancer. 


702P INTRAPERITONEAL INFUSION OF DOCETAXEL COMBINED 

WITH ORAL S-1 FOR METASTATIC OR RECURRENT GASTRIC 

CANCER PATIENTS WITH PERITONEAL METASTASIS 

H. Yabusaki, N. Atsushi, A. Matsuki, M. Aizawa 

Surgery, Niigata Cancer Center Hospital, Niigata, JAPAN 

Introduction: Though many modalities of chemotherapy have been tried for 

metastatic or recurrent gastric cancer (GC) patients (pts) with peritoneal 

dissemination, it remains uncontrollable yet. Docetaxel (DOC) and S-1 have different 

mechanisms of anti-tumor activity and they are effective against advanced GC. 

Recently, intraperitoneal administration (IP) of DOC has proved to be effective for 

peritoneal dissemination. 

Material and methods: Eligibility included metastatic or recurrent GC with 

peritoneal dissemination, capability of oral intake, adequate organ function, and good 

PS (0-2). IP catheters were placed for all patients after histological confirmation of 

peritoneal dissemination by laparoscopy or laparotomy. The treatment of oral S-1 

(80 mg/m 2 daily day 1-14, q4w) and DOC (35 ∼ 45 mg/m 2 ip day 1 and 15, q4w) 

was repeated every 4 weeks until disease progression or unacceptable toxicities. 

Results: Between Aug. 2001 and Mar. 2012, 52 pts (P3; 25, P2; 4, P0CY1; 23) 

including 27 males and 25 females, with a median age of 59 (21-80) were enrolled. 

Total No. of cycle was 334, the median No. of cycle was 6 (2-15), reduced courses 

were 109, delayed courses (>7 days) were 46. Reductive gastrectomy was performed 

for 7 cases. The grade 3/4 toxicities were neutropenia (5.8%), anemia (7.7%), 

anorexia (13.5%), fatigue (9.6%), and diarrhea (9.6%), respectively. However febrile 

neutropenia, grade 4 non-hematological toxicities and TRD were not observed. The 

incidence of cancer cell positive cytology (CY1) changed to negative (CY0) was 

61.0% (25/41), but no obvious peritoneal metastasis (P1-P3) disappeared. The MST 

was 11.1 months and l-, 2- and 3-year survival rate was 48.1%, 23.1 and 9.6%, 

respectively. 

Conclusions: With respect to low toxicity and high feasibility, IP infusion of DOC 

with oral S-1 is an alternate treatment for metastatic or recurrent GC with peritoneal 

dissemination. 


703P SMALL BOWEL ADENOCARCINOMA PHENOTYPE 

ACCORDING TO THE PRIMARY LOCALISATION 


T. Aparicio 1 , M. Svrcek 2 , A. Laforest 3 , A. Zaanan 4 , P. Afchain 5 , E. Mitry 6 , 

J. Taieb 4 , F. Di Fiore 7 , J. Gornet 8 , P. Laurent-Puig 3 

1 Gastroenterology, Hopital Avicenne, Bobigny Cedex, FRANCE, 2 Pathology, 

Hôpital Saint Antoine, AP-HP, Paris, FRANCE, 3 Umr-s775, Université Paris 

Descartes, Paris, FRANCE, 4 Gastroenterology, Hôpital Européen Georges 

Pompidou, APHP, Paris, FRANCE, 5 Oncology, Hôpital Saint Antoine, AP-HP, 

Paris, FRANCE, 6 Oncology, Institut Curie, Paris, FRANCE, 7 Digestive Oncology 

Unit, C.H.U. Charles Nicolle, Rouen, FRANCE, 8 Gastroenterology, Hôpital Saint 

Louis, Paris, FRANCE 

Background: Small bowel adenocarcinoma (SBA) is a rare tumor with poor 

prognosis. Data about molecular biology on SBA carcinogenesis are lacking. 

Methods: We characterised a number of candidate oncogenic pathways and the 

immunophenotype according to the primary localisation of patients with SBA treated 

in 11 centers between 1996 and 2008. Tissue microarrays were constructed from 

tumour samples and DNAs were extracted from formalin fixed paraffin embedded 

samples. HER2, b catenin, TP53 and mismatch repair (MMR) protein expression 

were assessed by immunohistochemistry. Overexpression of TP53 was defined as 

more than 50% of cells with nuclear staining. Abnormal expression of b catenin was 

defined as a nuclear staining. KRAS mutation was investigated. Patients were enrolled 

in the study at all stage of the disease. 



Results: Samples from 63 patients were obtained, ampullary tumours were excluded. 

The median age was 58 years. Tumour stages were I-II n = 19 (30%), III n = 22 (35%), 

IV n = 20 (32%) and undefined n = 2 (3%). A HER2 surexpression (3+) was observed 

in 2/51 (3.9%) cases both in ileum. Overexpression of TP53 was observed in 23/53 

(43%). Abnormal expression of b catenin was observed in 11/52 (21%) cases. A loss of 

MMR proteins occurred in 7/55 (13%) cases (3 MLH1, 2 MSH2, 2 MSH6), none was 

stage IV. A KRAS mutation was observed in 19/48 (40%) cases that involved codon 12 

in 13 (68%) cases or G > A transition in 16 (84%). Tumours with KRAS mutation were 

stage IV in 31% of the cases. Survival analysis will be available at the meeting. 

Conclusion: This large study suggests that molecular phenotype of SBA is close to 

colon phenotype with low level of HER 2 surexpression and high level of KRAS 

mutation. Ileum tumours seem to have a different phenotype than proximal tumours. 

Duodenum n = 32 

(51%) 

Jejunum n = 18 

(28%) 

Ileum n = 13 

(21%) 

Stage IV n = 20 9 (45%) 6 (30%) 5 (25%) 

HER2 surexpression n = 2 0 (0%) 0 (0%) 2 (100%) 

TP53 overexpression n = 23 12 (52%) 6 (26%) 5 (22%) 

Abnormal b catenin n = 11 4 (36%) 2 (18%) 5 (45%) 

Abnormal MMR n = 7 3 (43%) 4 (57%) 0 (0%) 

KRAS mutation n = 19 11 (58%) 6 (32%) 2 (10%) 


704P COST-EFFECTIVENESS OF THREE-YEARS OF ADJUVANT 

IMATINIB IN GASTROINTESTINAL STROMAL TUMORS (GIST) 

IN CANADA 

A. Parthan 1 , M. Sanon 1 , J. Coombs 2 , K. El Ouagari 3 

1 Health Economics and Outcomes Research, OptumInsight, Medford, MA, 

UNITED STATES OF AMERICA, 2 Health Economics, Novartis Pharmaceuticals, 

Florham Park, NJ, UNITED STATES OF AMERICA, 3 Health Economics, Novartis 

Pharmaceuticals Canada Inc, Quebec, QC, CANADA 

Background: Recent clinical trial data have demonstrated that 3 years (yrs) of 

adjuvant imatinib therapy for patients with surgically resected GIST leads to a 

significant improvement in recurrence free survival & overall survival vs. 1 yr of 

therapy. The objective of this study is to assess cost-effectiveness of treating with 3 

yrs vs. 1 yr of adjuvant imatinib in Canada from a payer’s perspective. 

Methods: A Markov model was developed to predict GIST recurrence, treatment 

(txt) costs, & quality-adjusted survival over a lifetime horizon. Patients transitioned 

between 3 health states: free of GIST recurrence, GIST recurrence, & death. Monthly 

recurrence & mortality rates for 3 yr & 1 yr imatinib were derived from SSGXVIII/ 

AIO clinical trial. The 5 yr recurrence rate observed in the trial was extrapolated for 

the remaining duration of the model horizon. First recurrence after active txt was 

treated with imatinib 400 mg daily and recurrence during active txt was treated with 

800mg daily. For subsequent disease progression, patients were treated with imatinib 

800mg, sunitinib or best supportive care. After 5 years, txt specific mortality rate was 

applied for patients with recurrence. Costs & utilities were derived from published 

literature. Expected costs & quality-adjusted life years (QALYs) were estimated for 

each txt strategy. Costs & QALYs were discounted at 5% per yr. Extensive sensitivity 

analyses were conducted. 

Results: Patients on 3 yrs of imatinib had higher QALYs (7.70 vs 6.54) vs. 1yr of 

imatinib. Total lifetime cost per patient was $182,000 with 3 yrs vs. $134,500 for 1 yr 

of imatinib therapy. Incremental cost effectiveness ratio of 3 yrs of imatinib vs 1 yr of 

imatinib was $40,877/QALY. Model results were sensitive to rate of GIST recurrence 

beyond 5 yrs. At a threshold of $100,000 or $50,000/QALY, 3yr imatinib therapy was 

cost-effective in 100% of simulations vs. 1 yr of imatinib. 

Conclusions: Model results suggest that treating patients with 3 yrs of imatinib is 

cost-effective vs. 1 yr of imatinib below the commonly used threshold in Canada. 

Both clinical & economic results suggest treating surgically resected GIST patients 

with 3 yrs of imatinib would result in improved quality-adjusted & overall 

survival. 

Disclosure: A. Parthan: Study was sponsored by Novartis and I have consulting 

relationship with Novartis. M. Sanon: The study was sponsored by Novartis and I 

had consultancy relationship with Novartis at the time of the study. J. Coombs: 

Employed at Novartis and holds Stock for Novartis. K. El Ouagari: employed at 

Novartis and owns stocks for Novartis 

705P PHASE I TRIAL OF SUNITINIB PLUS IMATINIB IN PATIENTS 

WITH METASTATIC OR UNRESECTABLE GASTROINTESTINAL 

STROMAL TUMORS (GIST) 

A. Lopez Pousa 1 , L. Paz-Ares 2 , C. Pericay 3 , X. Garcia Del Muro 4 , M.J. Flor 5 

1 Medical Oncology, Hospital de la Sta. Creu i St. Pau, Barcelona, SPAIN, 

2 Oncology Service, Hospital Virgen del Roc, Seville, SPAIN, 3 Medical Oncology, 

Corporació Sanitària Parc Taulí Institut Universitari, Sabadell, SPAIN, 4 Medical 

Oncology, Institut Catala d’oncologia, L’Hospitalet de Llobregat, SPAIN, 

5 Oncology Service, Hospital Virgen del Rocio, Seville, SPAIN 

Background: Patients (Pts) with GIST harboring mutations in KIT exon 9 or wild 

type tumors showed better responses to sunitinib along with longer median 

progression-free survival (PFS) rates compared with exon 11 mutant tumors pts. We 

have hypothesized that the combination of S plus I in unresectable GIST would be 

synergistic and associated to a tolerable side effect profile. 

Methods: This is a phase I, dose-escalation study to determine the 

maximum-tolerated dose (MTD), safety and antitumor activity measured by response 

rate of S plus I in naive patients with metastatic or unresectable GIST. Pts with 

adequate organ function, performance status (ECOG) 0-1, age >18 years, were 

eligible. Treatment consisted on oral S 25mg/day d1-28 combined with oral I 300mg/ 

day d1-28 (level I) or oral I 400mg/day d1-28 (level II). 

Results: 3 pts were enrolled on Level I. No DLTs were observed. At level II 7 pts 

were enrolled and 1 DLT was observed (posterior reversible encephalopathy 

syndrome on day19). Although 1DLT was observed in 7 pts, decision was not to 

increase the S dose to 37.5 mg due to toxicity. Other non-DLTs adverse events 

were G4 hyperbilirubinemia in cycle 2 and G4 intratumoral haemorrhage in cycle 

3.TheMTDwasdeterminedasI400mg/dayandS25mg/day.Othertoxicities 

were neutropenia, diarrhoea, vomiting, asthenia, musculoskeletal pain, anaemia 

and bacteraemia. Median time on treatment with the combination was 16 weeks 

(range 12-152) on level I and 20 weeks (range 3-88) on level II. 66% of patients 

completed 20 weeks of treatment. Serious Adverse Events were reported in 4 pts; 3 

deaths were reported, one due to disease progression, another due to reversible 

encephalopathy syndrome and the last one due to septic shock. A partial response 

was achieved in 6 (60%) pts; complete response in 2 (1 wild-type) (20%) and 

stable disease in 1 (10%). 

Conclusions: Sunitinib 25mg/day plus Imatinib 400mg/day is the MTD and a safe 

and well tolerated combination in pts with metastatic or unresectable GIST. Response 

rates seems to be higher than those expected and previously observed with S or I 

monotherapy. This study was supported by an Independent Investigator Research 

grant from Pfizer, Inc 


706P COST-EFFECTIVENESS ANALYSIS OF THREE YEAR VERSUS 

ONE YEAR IMATINIB FOR THE TREATMENT OF PATIENTS AT 

HIGH RISK OF DISEASE RECURRENCE FOLLOWING 

SURGICAL RESECTION OF KIT (CD117) POSITIVE 

GASTROINTESTINAL STROMAL TUMOURS (GIST) 

B. Nagy 1 ,L.Gray 2 , S.E. Ward 1 

1 Health Economics and Decision Science, University of Sheffield, Sheffield, 

UNITED KINGDOM, 2 Health Economics & Research Outcome, Novartis 

Pharmaceuticals UK Ltd, Frimley, UNITED KINGDOM 

Background: Imatinib is licensed for the adjuvant treatment of adult patients who 

are at significant risk of disease recurrence following resection of KIT (CD117) 

positive GIST. The SSG Phase III trial has shown significant survival benefits for 

patients who received three years of treatment with Glivec® (imatinib) after surgery to 

remove KIT (CD117)-positive GIST (KIT+ GIST) compared to one year of 

treatment. Aim: To evaluate the cost-effectiveness of three years’ imatinib adjuvant 

therapy in comparison with one year therapy for adult patients at high risk of disease 

recurrence following surgical resection of KIT (CD117) positive GIST in Scotland. 

Methods: The economic model predicts long-term survival for patients on three 

years of adjuvant imatinib compared with those on one year of therapy. A Markov 

state-transition model was used to simulate patient pathways over a lifetime horizon. 

Patients were grouped into three primary health states: (1) free of recurrent GIST; (2) 

recurrent GIST; and (3) death (from GIST or other causes). Efficacy data were 

derived from a retrospective review of the SSG study to identify high risk patients, as 

defined by the Miettinen risk criteria. Costs (drug costs, hospital appointments for 

administration and monitoring, and treatment for adverse events) and health related 

quality of life values were assigned to each health state. Cost-effectiveness was 

expressed in terms of incremental cost per quality-adjusted life-years (QALYs) 

gained. 


Results: Three years of adjuvant imatinib therapy for patients at high risk of 

recurrence was predicted to achieve an additional 1.58 QALYS compared with one 

year of treatment. These health benefits are gained at an estimated incremental cost 

per QALY of £14,108. These results were robust to changes in key model parameters. 

Conclusions: The analysis suggests that, for patients at high risk of recurrence 

following surgical resection of localised GIST, three years of adjuvant imatinib 

treatment leads to improved long term quality-adjusted survival compared with one 

year’s therapy. Extended adjuvant treatment with imatinib represents good value for 

money according to currently accepted standards of cost-effectiveness in Scotland. 

Disclosure: L. Gray: I am an employee of Novartis Pharmaceuticals UK Ltd, 

manufacturer of imatinib. All other authors have declared no conflicts of interest. 

707P A COST-EFFECTIVENESS ANALYSIS OF THREE YEARS OF 

ADJUVANT IMATINIB IN KIT+ GASTROINTESTINAL STROMAL 

TUMORS (GIST) IN GREECE 

M. Raikou 1 , I. Boukovinas 1 , M. Geitona 2 

1 Social Policy, London School of Economics & Political Sciences, London, 

UNITED KINGDOM, 2 Social Policy, University of Peloponnese, Athens, GREECE 

Background and objective: Clinical studies have demonstrated the clinical benefit of 

adjuvant imatinib for patients who undergo complete gross resection for KIT+ GIST 

both in terms of overall and recurrence-free survival. The aim of this study is to 

assess the cost-effectiveness of the following treatment options a) 3 yr adjuvant 

imatinib (IM) vs 1yr IM, b) 3yr IM vs. surgical resection only c) lifetime IM vs. 1 yr 

IM as adjuvant therapy in patients with KIT GIST, from the perspective of the Greek 

National Health Service (NHS). 

Methods: A Markov transition state model was developed and populated with data 

from published literature and expert opinion. All patients enter the model free of 

recurrence and over subsequent cycles, a patient may remain free of GIST, may enter 

a state of recurrent GIST or may die of GIST or other causes. The mean starting 

patient age was 58 years old and the discount rate 3% per year. Resource utilization 

reflects Greek disease management. Pharmaceutical and adverse events cost was 

based on 2012 prices. Extensive sensitivity analysis was also undertaken. 

Results: Mean total cost per patient was estimated at €72,899 for 1 yr of adjuvant IM 

versus €112,910 for 3yr IM. Effectiveness was estimated to be 10.80 and 12.76 

life-years and 7.63 and 9.19 QALYs respectively for 1yr vs. 3yr. The incremental 

cost-effectiveness was thus €20,387 per life-year gained and €25,700 per QALY 

gained over a patient’s lifetime. These results were most sensitive to the rate of GIST 

recurrence beyond 5 years. The incremental cost of 3 years of IM versus surgical 

resection alone was €14,649 per life-year gained and €18,448 per QALY gained and 

€65,943 per life-year gained and €82,851 per QALY gained over a patient’s lifetime 

for lifetime IM treatment versus 1 year of imatinib. These results were most sensitive 

to the monthly cost of IM. 

Conclusions: This analysis has shown that 3yr adjuvant IM therapy is considered 

highly cost-effective for the Greek NHS when compared to either 1yr adjuvant IM or 

surgical resection alone. Lifetime vs. 1y adjuvant IM is associated with a moderate 

incremental cost-effectiveness ratio that is far below the acceptable threshold of 

€100.000 for life-threatening diseases. 

Disclosure: M. Raikou: This study was sponsored by Novartis Hellas S.A. All other 


708P REAL-LIFE MANAGEMENT OF ADVANCED 

GASTROINTESTINAL STROMAL TUMORS (GIST) TREATED 

WITH IMATINIB IN FRANCE 

O. Bouché 1 , A. Le Cesne 2 , M. Rios 3 , L. Chaigneau 4 , B. Bui 5 , P. Xavier 6 , J. Blay 7 

1 Hepatology-gastroenterology, Hopital Robert Debré, Reims, FRANCE, 2 Dept. 

Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 3 Oncologie, Centre 

Alexis Vautrin, Vandoeuvre-lès-Nancy, FRANCE, 4 Oncologie, Hopital Jean 

Minjoz, Besancon, FRANCE, 5 Oncology, Institute Bergoni, Bordeaux Cedex, 

FRANCE, 6 Oncology, Novartis, Rueil Malmaison, FRANCE, 7 University Claude 

Bernard Lyon I, Centre L, Lyon Cedex, FRANCE 

Introduction: GISTs are rare tumors of the gastrointestinal tract. Imatinib has been 

approved for the treatment of Kit+ unresectable or metastatic GIST since 2002. 

However, information is lacking in the real-life, non-trial setting on the efficacy, use, 

and safety of imatinib, and the quality of life of imatinib-treated patients. The 

EPIGIST study was set up in 2006 in France to obtain this information. 


Method: EPIGIST is a multicenter, observational, longitudinal follow-up cohort 

study conducted in France on patients diagnosed with a Kit + unresectable or 

metastatic GIST, treated with imatinib for the first time, between its market 

introduction and 2011. Sites were selected at random from a national file of 

oncologists, gastroenterology surgeons, and gastroenterologists. The intended 

follow-up period was 3 years. A clinical case report form was completed at 

enrollment and at each visit. 

Results: 31 sites enrolled at least one patient. A total of 164 patients were enrolled, 

151 were analyzed. Median age at diagnosis was 60 years (range: 21–86 years), sex 

ratio was predominantly male (58%). The commonest locations of the primary GIST 

at diagnosis were stomach (46%) and small intestine (37%). 85 (56%) analyzed 

patients had localized disease at diagnosis, and 42 (49%) were at high risk of relapse 

according to Miettinen’s classification; 60 (70%) had developed metastatic disease by 

the time imatinib therapy was instituted (median 13 months after diagnosis; range 0– 

135 months). The starting dose of imatinib for 148 (98%) patients was 400 mg/day. 

The estimated 4-year overall survival was 60.7% (95% CI: [51.4%; 68.8%]), with a 

median follow-up of 4 years. Adverse events disorders were gastrointestinal (70%), 

general disorders and administration site conditions (70%), eye (38%), 

musculoskeletal and connective tissue (35%), and skin and subcutaneous tissue 

(34%). 

Conclusion: The EPIGIST observational study confirms that the results of the 

clinical studies are maintained in the real-life setting. The indications for imatinib 

have been recently extended to include the adjuvant treatment of patients at 

significant risk of relapse following resection of Kit+ GIST. This population is not 

described in this study. 

Disclosure: O. Bouché: Consulting fees from Novartis and Pfizer. A. Le Cesne: 

Honorary Grants from Novartis, Pfizer, Pharmamar. P. Xavier: Employment full time 

Novartis. J. Blay: Research grants: Novartis, Roche, GSK, Pfizer, Pharmamar 

Consulting fees: Novartis, Roche, GSK, Pfizer, Pharmamar. All other authors have 


709P THE HENT1 IMMUNOHISTOCHEMISTRY DIAGNOSTIC TEST 

IS PREDICTIVE OF GEMCITABINE OUTCOME IN PANCREATIC 

DUCTAL ADENOCARCINOMA 

M. Raponi 1 , J. Isaacson 1 , H. Hahn 2 , M. Bartosiewicz 1 , A. Magnusson 2 , K. Lin 1 , 

L. Rolfe 3 , A. Allen 1 , V. Picozzi 2 

1 Clovis Oncology, Clovis Oncology, San Francisco, CA, UNITED STATES OF 

AMERICA, 2 Pathology, Virginia Mason Medical Center, Seattle, WA, UNITED 

STATES OF AMERICA, 3 Sheraton House, Clovis Oncology UK Ltd, Cambridge, 


Human equilibrative nucleoside transporter 1 (hENT1) is the primary membrane 

channel through which gemcitabine (GEM) enters pancreatic tumor cells. Patients 

(pts) whose resected pancreatic ductal adenocarcinoma (PDAC) express low levels of 

hENT1 may derive little benefit from GEM therapy. Recently, a validated diagnostic 

immunohistochemistry (IHC) test has been developed. Here, we prospectively test 

this diagnostic in a series of 204 retrospectively collected formalin-fixed 

paraffin-embedded (FFPE) PDAC tissues. 134 primary and 70 metastatic PDAC 

pre-treatment specimens were dichotomized into high versus low hENT1 tumor 

expression. Overall, 39% of primary and 23% of metastatic cases had high levels of 

tumoral hENT1. In the primary tumor set 90/134 pts went on to receive GEM-based 

therapy; pts with high hENT1 tumor levels had a median overall survival (OS) of 35 

months compared to 15 months in those with low levels of tumoral hENT1 (HR = 

0.48). In 44 non-GEM treated pts there was no association between hENT1 tumor 

expression and overall survival (median OS of 26 versus 28 months in pts with 

hENT1 high and low, respectively; HR = 0.8). In 63/70 metastatic specimens from 

patients treated with GEM the median OS was 25 versus 10 months (HR = 0.64) for 

high versus low hENT1 tumors respectively. In conclusion, we have prospectively 

tested the utility of the hENT1 IHC diagnostic in predicting clinical outcome in an 

institutional series of FFPE tumors from PDAC pts. The assay was effective in 

identifying GEM-treated pts with a poorer OS outcome using both primary and 

metastatic FFPE tumor tissues. This diagnostic is being prospectively tested in a 

global pivotal trial of CO-101 (CP-4126; a lipid drug conjugate of GEM designed to 

enter tumor cells independently of hENT1) versus GEM alone in metastatic PDAC 

(“LEAP“, NCT01124786). 

Disclosure: M. Raponi: Employee and stock holder of Clovis Oncology. J. Isaacson: 

Employee and stock holder of Clovis Oncology. M. Bartosiewicz: Employee and stock 

holder of Clovis Oncology. K. Lin: Employee and stock holder of Clovis Oncology. L. 

Rolfe: Employee and stock holder of Clovis Oncology. A. Allen: Employee and stock 

holder of Clovis Oncology. All other authors have declared no conflicts of interest. 



710P FIRGEM, A SEQUENTIAL FOLFIRI.3 (CPT-11 PLUS FOLINIC 

ACID PLUS 5-FU) FOLLOWED BY GEMCITABINE OR 

GEMCITABINE ALONE IN PATIENTS WITH PREVIOUSLY 

UNTREATED METASTATIC PANCREATIC ADENOCARCINOMA: 

RESULTS OF A RANDOMIZED MULTICENTER AGEO PHASE II 

TRIAL 

I. Trouilloud 1 , A.C. Dupont-Gossard 2 , P. Artru 3 , T. Lecomte 4 , M. Gauthier 5 , 

T. Aparicio 6 , A. Thirot-Bidault 7 , D. Malka 8 , F. Bonnetain 9 , J. Taieb 1 

1 Oncologie Digestive, Hopital Europeen Georges Pompidou, Paris, FRANCE, 

2 Hepato-Gastro-Enterologie, CHU Jean Minjoz, Besancon, FRANCE, 3 Oncologie 

Digestive, Hopital Prive Jean Mermoz, Lyon, FRANCE, 

4 Hepato-Gastro-Enterologie, Hopital Trousseau, Tours, FRANCE, 5 Biostatistic 

Unit, Georges-François Leclerc Cancer Center, Dijon, FRANCE, 

6 Hepato-Gastro-Enterologie, Hopital Avicenne, Bobigny, FRANCE, 

7 Hepato-Gastro-Enterologie, Bicetre Hospital, Kremlin-Bicetre, FRANCE, 

8 Oncologic Medicine, Institut Gustave Roussy, Villejuif, FRANCE, 9 Biostatistic and 

Epidemiological Unit (ea 4184), Centre Georges François Leclerc, Dijon, 

FRANCE 

Background: CPT-11 showed modest activity and tolerability in metastaic pancreatic 

cancer (MPA). We developed a new strategy to improve efficacy and tolerability of 

CPT-11 based regimen in MPA patients (pts). 

Methods: Chemotherapy-naive pts with histologically proven MPA, bilirubin levels < 

1.5 ULN and performance status (PS) 0-1 were randomized in a phase II trial to 

receive either FOLFIRI.3 (CPT-11 90 mg/m 2 as a 60-min infusion on day (D) 1, 

leucovorin 400 mg/m 2 as a 2-hr infusion on day 1, followed by 5-FU 2000 mg/m 2 as 

a 46-hr infusion and CPT-11 90 mg/m 2 , repeated on D3, at the end of the 5-FU 

infusion, every 2 weeks) for 2 months alternarting with Gemcitabine (G) (1000 mg/ 

m 2 at a fixed dose rate of 10 mg/m 2 /min on D1, D8, D15, D29, D36 and D43) for 2 

months (arm A) or G alone (arm B). Using Fleming design the primary end point 

was rate of progression free survival (PFS) at 6 months from (H0) 25% over (H1) 

45% needing to include 49 pts/arm. 

Results: Between 2007 and 2011, 98 pts were enrolled (males: 59, median age: 62 

years, PS 0: 32%). Median follow-up was 23 months. Grade 3-4 toxicities per pts (%) 

in arm A/B were diarrhea 13/0, nausea-vomiting 11/4, neutropenia 51/25 and febrile 

neutropenia 4/0. No toxic death occurred. Response rate were 40 and 11% as disease 

control rate (CR + PR + SD) were 73 and 52% in arm A and B, respectively. The 

primary endpoint of the trial was met with rate of PFS at 6 months of 48% (95% CI: 

33-63) in arm A while in arm B PFS was 30% (95% CI: 17 - 44). One year PFS was 

23% (95%CI: 11.5-36) and 11% (95%CI: 4-21), respectively. 

Conclusions: FIRGEM strategy is feasible and efficient with a manageable toxicity 

profile in good condition pts with MPA. A phase III trial comparing this strategy 

with the FOLFIRINOX triplet therapy focusing on quality of life should now be 

performed. 


711P DOES FDG-PET-CT BASED RE-STAGING INFLUENCES 

INITIAL MANAGEMENT DECISION AND CLINICAL OUTCOME 

IN PATIENTS WITH LOCALLY ADVANCED PANCREATIC 

CARCINOMA PLANNED TO UNDERGO 

CHEMORADIOTHERAPY? 

C. Parlak 1 , O.C. Guler 1 , U. Selek 2 , O. Ozyilkan 3 , E. Topkan 1 

1 Department of Radiation Oncology, Baskent University Adana Medical Faculty, 

Adana, TURKEY, 2 Department of Radiation Oncology, American Hospital- 

University of Texas M.D. Anderson Radiation Oncology Center, Istanbul, 

TURKEY, 3 Medical Oncology, Baskent University Faculty of MedicineAdana 

Uygulama Ve Arastirma Mer., Adana, TURKEY 

Background: Impact of re-staging with 18F-fluoro-deoxy-glucose positron emission 

tomography (PET-CT) on management decision and clinical outcomes in patients 

with locally-advanced pancreatic carcinoma (LAPC) initially planned to undergo 

concurrent chemoradiotherapy (CRT) was investigated. 

Materials and methods: Seventy-one consecutive patients with conventionally staged 

LAPC were re-staged with PET-CT before CRT. Patients were categorized into 

non-metastatic (M0) and metastatic (M1) groups according to PET-CT findings. 

M0patients underwent 50.4 Gy (1.8 Gy/fr) of radiotherapy and concurrent 5-FU 

followed by maintenance gemcitabine. 

Results: Re-staging PET-CT revealed conventional imaging occult distant metastases 

in 19 cases (26.8%). Of 52 patients with LAPC confirmed by PET-CT, additional 

regional lymph nodes were identified to be involved in 7 (13.4%), mandating 

enlargement of radiation field. Taken together, PET-CT results changed or revised 

initial management decision in 37.2% patients. Median follow-up times for the 

whole, M 0 and M 1 cohorts were 11.3, 14.5, and 6.2 months, respectively. Median 

overall, locoregional progression-free, and progression-free survivals for the same 

cohorts were 11.4, 7.8, and 5.1 months,16.1, 9.9, and 7.4 months, and 6.2, 3.4, and 

2.5 months, respectively. Survival differences between M0 and M1 cohorts were 

statistically significant (p < 0.05, for each). 

Conclusions: Current results demonstrated the importance of PET-CT based 

re-staging of LAPC in selection of suitable patients for CRT, prevention of useless 

aggressive treatment in metastatic cases, and precise estimation of survival outcomes 

of LAPC patients following radical CRT. 


712P MISTLETOE EXTRACT THERAPY VERSUS NO 

ANTINEOPLASTIC THERAPY IN PATIENTS WITH LOCALLY 

ADVANCED OR METASTATIC PANCREATIC CANCER: A 

RANDOMIZED CLINICAL PHASE III TRIAL ON OVERALL 

SURVIVAL 

D. Galun 1 , W. Tröger 2 , M. Reif 3 , A. Schumann 4 , N. Stanković 5 , M. Milićević 1 

1 HPB Surgical Department, First Surgical Clinic of the Clinical Centre of Serbia, 

Belgrade, SERBIA, 2 Directorship, CRDT, Freiburg, GERMANY, 3 Directorship, 

Institute for Clinical Research, Berlin, GERMANY, 4 Biometry, Institute for Clinical 

Research, Berlin, GERMANY, 5 Data Management, Clinicoboss, Niš, SERBIA 

Purpose: To compare the overall survival (OS) and quality of life (QoL) of advanced 

pancreatic cancer patients receiving mistletoe extract (ME) therapy or no 

antineoplastic therapy. 

Patients and methods: In this prospective, parallel, open label, monocenter, 

group-sequential, randomized phase III study patients with locally advanced or 

metastatic adenocarcinoma of the pancreas were stratified according to their prognosis 

index, a binary composite of age, tumor stage and performance status, and were evenly 

randomized to s.c. injections of ME (Iscador® Qu special) in a dose-escalating manner 

from 0.01 mg up to 10 mg three times per week, or no antineoplastic therapy 

(control). All patients received best supportive care. The primary endpoint was 

12-month OS to be repeatedly assessed in three subsequent group-sequential analyses. 

Secondary efficacy parameters were the QoL dimensions of the core questionnaire of 

the European Organisation for Research and Treatment of Cancer. 

Results: This first interim analysis includes data from 220 patients. Baseline 

characteristics were well balanced between the ME and control groups. Median OS for 

ME versus control patients was 4.8 vs. 2.7 months (prognosis-group adjusted hazard 

ratio, HR = 0.49; p < 0.0001); within the ‘good’ prognosis subgroup 6.6 vs. 3.2 months 

(HR = 0.43; p < 0.0001); within the ‘poor’ prognosis subgroup 3.4 vs. 2.0 months (HR 

= 0.55; p = 0.0031). Thirteen of the 15 QoL dimensions significantly favored ME. The 

‘Global Health Status/QoL’ was sig-nificantly higher for ME versus control patients by 

23.5 points (average patients’ post-baseline median: 54.2 ± 8.17 vs. 30.7 ± 8.46; p < 

0.0001). No ME-related serious or non-serious adverse events were observed. 

Conclusion: In this analysis ME therapy showed a significant and clinically relevant 

increase of OS and quality of life. The independent data monitoring committee 

recommended the termination of the trial due to proven efficacy. ME may provide an 

effective second-line therapy for patients with locally advanced or metastatic 

pancreatic cancer after failure of, or ineligibility for, first-line therapies. 

Disclosure: D. Galun: Danijel Galun has received financial compensation for the 

conduct of the submitted study by the Society of Cancer Research, Arlesheim. 

Otherwise, no payments were received. W. Tröger: Wilfried Tröger has received 

financial compensation for the conduct of the submitted study and another clinical 

trial in breast cancer by the Society of Cancer Research, Arlesheim. Otherwise, no 

payments were received. M. Reif: The non-profit organization Society for Clinical 

Research receives donations from different institutions including the sponsor of the 

submitted study, the Society of Cancer Research, Arlesheim. A. Schumann: The 

non-profit organization Society for Clinical Research receives donations from 

different institutions including the sponsor of the submitted study, the Society of 

Cancer Research, Arlesheim. N. Stanković: Nikola Stanković has received financial 

compensation for the conduct of the submitted study by the Society of Cancer 

Research, Arlesheim. Otherwise, no payments were received. M. Milićević: Miroslav 

Milićević has received financial compensation for the conduct of the submitted study 

by the Society of Cancer Research, Arlesheim. Otherwise, no payments were received. 

713P NEOADJUVANT GEMOX FOLLOWED BY GEM-BASED 

CHEMORADIATION FOR LOCALLY ADVANCED 

UNRESECTABLE PANCREATIC CANCER 

V. Vaccaro 1 , I. Sperduti 2 , E. Bria 3 , B. Saracino 1 , M.S. Pino 4 , G. Grazi 5 , 

A. Gelibter 1 , G. Vallati 6 , F. Cognetti 1 , M. Milella 1 

1 Medical Oncology, Regina Elena National Cancer Institute, Roma, ITALY, 

2 Biostatistics, Regina Elena Institute, Roma, ITALY, 3 Medical Oncology, Azienda 

Ospedaliera Universitaria Integrata Verona-”Borgo Roma”, Verona, ITALY, 

4 Medical Oncology, USL 10 Firenze, Firenze, ITALY, 5 Surgical Oncology, Regina 

Elena National Cancer Institute, Roma, ITALY, 6 Radiology, Regina Elena National 

Cancer Institute, Roma, ITALY 

Purpose: To asses activity, safety and secondary resectability in unresectable locally 

advanced pancreatic cancer (LAPC) patients (pts). 

Methods: Unresectable LAPC pts were eligible for this phase II study. Primary 

endpoint was clinical benefit (CB = CR + PR + SD). A sample size of 37 pts was 


considered sufficient to give an 80% probability of rejecting a baseline clinical benefit 

rate of 55%, with an exact 5% one-sided significance test when the true disease 

control rate was 75%. The drug regimen would have been considered interest if at 

least 26 patients showed clinical benefit. Neoadjuvant induction chemotherapy 

(CHT) encompassed gemcitabine (GEM) 1000 mg/m 2 (100-min infusion on d1) and 

oxaliplatin 100 mg/m 2 (2-hr infusion on d2) every 2 wks, for 6 cycles. After CHT pts 

were restaged for surgery and/or chemoradiation (CRT) consolidation (EBRT up to a 

total dose of 50.4 Gy plus concomitant GEM 300 mg/m 2 /week). After CRT 

completion, pts were restaged to evaluate secondary surgery. 

Results: From January 2005 to January 2012, 35 pts (M/F: 17/18; median age: 68 yrs, 

range: 46-78; ECOG PS 0-1/2: 28/7) entered the study. A median of 5 (range 1-7) 

CHT induction cycles were delivered. Toxicity was mild, with G3-4 neutropenia in 2 

pts (6%), G3 thrombocytopenia in 1 pt (3%), G3 transaminase elevation in 5 pts 

(14%), and G3 diarrhea in 2 pts (6%). CHT dose was reduced or delayed in 8 and 7 

pts, respectively. Nine confirmed PR and 17 SD were observed for a CB of 74% (95% 

confidence interval [CI], 56.7-87.5%). A decrease in serum CA 19.9 ≥50% of the 

baseline was observed in 14 of 23 evaluable pts. Nine-teen pts completed CRT, 

including 5 pts who subsequently underwent surgery; 1 pt underwent surgery 

without CRT. Toxicity for the CRT phase was mild, with G3 thrombocytopenia in 1 

pt (3%) and G3 neutropenia in 3 pts (8%). Median overall survival (OS) and 

progression free survival (PFS) for all 35 patients were 10 (95% CI, 8-12) and 9 mos 

(95% CI, 6-12), respectively. One-yr OS and PFS rates were 26% and 30%, 

respectively. 

Conclusions: The regimen under study is active and well tolerated. Although an 

encouraging response rate was reported, OS remains poor, calling for a better 

selection strategy for LAPC pts who are candidates to neoadjuvant treatment. 


714P MODIFIED FOLFOXIRI IN ADVANCED PANCREATIC CANCER 

L. Ginocchi, E. Vasile, S. Caponi, M. Lucchesi, C. Caparello, V. Da Prat, 

M. Baretti, M. Lencioni, S. Ricci, A. Falcone 

Oncologia, Trapianti e Nuove Tecnologie in Medicina, Polo Oncologico - Azienda 

Ospedaliero-Universitaria Pisana - Istituto Toscano Tumori, Pisa, ITALY 

Background: The combination regimen of 5-fluorouracil/folinic acid, oxaliplatin and 

irinotecan named FOLFIRINOX has been proposed as a new standard of care for 

metastatic pancreatic cancer patients. However, FOLFIRINOX was associated with 

high incidence of grade 3 and 4 toxicities (neutropenia in 45.7% of patients with 

G-CSF use in 42.5% of patients; febrile neutropenia in 5.4%; diarrhea in 12.7%). Our 

group had developed a very similar schedule in colorectal cancer named FOLFOXIRI 

which contains no bolus 5-fluorouracil and a slight lower dose of irinotecan. 

Methods: The objective of this study was to prospectively evaluate the tolerability 

and activity of a modified (m) FOLFOXIRI regimen in metastatic or locally advanced 

pancreatic cancer patients. The regimen included a lower dose of irinotecan 

(administered at 150 mg/sqm on day 1 every 14 days) and of infusional 

5-fluorouracil (2800 mg/sqm administered as a 48-hour continuous infusion on days 

1 to 3 every 14 days). Folinic acid and oxaliplatin remained unchanged. 

Results: Thirty-nine patients with cytological or histological diagnosis of pancreatic 

adenocarcinoma have been treated with mFOLFOXIRI from august 2010 onwards; 17 

had metastatic disease while 22 had locally advanced disease. A total of 260 cycles 

have been administered so far. The grade 3-4 toxicities reported are: neutropenia in 

35.9% of patients; thrombocytopenia 2.6%; diarrhea 5.1%; stomatitis 7.7%; nausea/ 

vomiting 5.1%; fatigue 2.6%; liver toxicity 5.1%; sensory neuropathy 5.1%. No toxic 

deaths and no febrile neutropenia have been occurred. G-CSF has been used in seven 

patients (18%). A delay in the administration of chemotherapy was required in 12 

patients (31%) and a reduction of doses in 7 cases (18%). Among 30 evaluable 

patients 11 partial responses (36.7%) and 14 stable disease (46.7%) have been 

observed. Median progression-free survival (PFS) was 11.5 months and median 

overall survival (OS) 25.5 months. For metastatic patients only, response rate resulted 

33% with a PFS and OS of 8.4 and 14.8 months, respectively. 

Conclusions: The mFOLFOXIRI regimen as we used resulted feasible and quite well 

tolerated and it maintained its good activity in metastatic pancreatic cancer. 


715P TIMING AND PATTERNS OF DISEASE PROGRESSION 

FOLLOWING CONCURRENT RADIOCHEMOTHERAPY IN 

PATIENTS WITH UNRESECTABLE LOCALLY-ADVANCED 

PANCREAS CANCER 

C. Parlak 1 , O.C. Guler 1 , O. Ozyilkan 2 , E. Topkan 1 


Adana, TURKEY, 2 Medical Oncology, Baskent University Faculty of 

MedicineAdana Uygulama Ve Arastirma Mer., Adana, TURKEY 

Background: Timing and patterns of disease progression in patients with 

unresectable locally-advanced pancreas carcinoma (LAPC) treated with definitive 

concurrent radiochemotherapy (C-RCT) was analyzed. 


Materials and method: Fifty-two patients with histologic proof of LAPC underwent 

50.4 Gy (1.8 Gy per fraction) of C-RCT with 5-FU followed by maintenance 

gemcitabine. Disease was considered to be unresectable if contrast-enhanced CT or 

staging laparoscopy/laparotomy revealed a low likelihood of complete resection and/ 

or any of the following: involvement of superior mesenteric artery/cealiac trunk, 

encasement of 180 degrees or more of the circumference of superior mesenteric/ 

portal vein, and/or evidence of narrowing of or thrombus within the superior 

mesenteric/portal vein. Elective nodal irradiation was not adopted. Primary aim was 

to assess timing and patterns of disease progression. 

Results: Treatment was well tolerated and all patients were able to receive intended 

C-RCT regimen. At median 17.4 months of follow-up 38 (73.1%) were dead. Median, 

1- and 2-year overall- and progression-free survival estimates were 16.1 months, 

61.2% and 22.6%, and 7.4 months, 27% and 12.3% respectively. Analysis for timing 

of disease progression revealed that 7 (13.5%), 15 (28.8%), 20 (38.5%), and 22 

(42.3%) patients experienced disease progression at 3, 4, 5, and 6 months, 

respectively, since initiation of R-RCT. Interestingly, although there were no isolated 

local or regional failures during this early follow-up period, all failures were 

presented as distant metastases with/without local/regional disease progression. 

Conclusion: Results of this study demonstrated that, despite aggressive staging and 

treatment strategies, early distant disease progression are common source of 

treatment failures in unresectable LAPC. Present findings impact the urgent need for 

more efficacious chemotherapeutic agents for control of distant metastatatic tumor 

deposits and better treatment strategies, such as induction chemotherapy followed by 

C-RCT, to eliminate early treatment failures and unnecessary and futile C-RCT in 

metastatic disease state. 


716P FOLFIRINOX FOR LOCALLY ADVANCED PANCREATIC 

ADENOCARCINOMA. RESULTS OF AN AGEO MULTICENTRIC 

PROSPECTIVE STUDY 

L. Marthey 1 , A. Sa-Cunha 2 , J.F. Blanc 3 , A. Cueff 4 , E. Francois 5 , I. Trouilloud 6 , 

D. Malka 7 , J. Bachet 8 , R. Coriat 9 , J. Taieb 10 

1 Gastroenterology, Bicêtre Hospital, Kremlin Bicêtre, FRANCE, 2 Digestive 

Surgery, Haut Lévêque Hospital, Pessac, FRANCE, 3 Digestive Oncology, Saint 

André Hospital, Bordeaux, FRANCE, 4 Biostatistics and Epidemiology, Georges 

Leclerc Cancer Institute, Dijon, FRANCE, 5 Medical Oncology, Antoine 

Lacassagne Cancer Institute, Nice, FRANCE, 6 Digestive Oncology, European 

Georges Pompidou Hospital, Paris, FRANCE, 7 Medical Oncology, Gustave 

Roussy Cancer Institute, Villejuif, FRANCE, 8 Gastroenterology, Pitié-Salpêtrière 

Hospital, Paris, FRANCE, 9 Digestive Oncology, Cochin Hospital, Paris, FRANCE, 

10 Oncologie Digestive, Hopital Europeen Georges Pompidou, Paris, FRANCE 

Background: The FOLFIRINOX regimen improves survival when compared to 

gemcitabine as first line treatment for patients (pts) with metastatic pancreatic 

cancer (1). There is no such data in non resecable, non metastatic, locally advanced 

pancreatic adenocarcinoma (LAPA). The aim of this study was to evaluate the safety 

and efficacy of FOLFIRINOX in this setting. 

Methods: From February 2010 to February 2012, all pts from eleven French 

hospitals, who started FOLFIRINOX for a pathologically proven LAPA were included 

in a prospective database. Non resectability was determined by each local 

multidisciplinary staff. The absence of metastases was assessed by TAP CT-scans. 

FOLFIRINOX was administered every 2 weeks (oxaliplatin 85 mg/m 2 ; irinotecan 180 

mg/m 2 ; leucovorin 400 mg/m 2 ; fluorouracil 400 mg/m 2 as bolus and 2400 mg/m 2 as 

46-hour continuous infusion). 

Results: Seventy seven pts were enrolled. We report the preliminary analysis of the 

first 53 pts as data collection is still ongoing. Patients characteristics were M/F: 30/23; 

median age 63 (46-79); PS 0/1/2 : 24/28/1. twenty one pts had a bilary stent before 

starting treatment. The median number of cycles administered was 5 (1-30). There 

were no treatment-related deaths and 8% of pts stopped treatment because of 

toxicity. Grade 3-4 toxicities were neutropenia (15%), nausea (13%), diarrhea (8%), 

anemia (2%), and thrombopenia (2%). Grade 2-3 sensitive neuropathy occured in 

19% of pts. Dose reduction was necessary in 28% and prophylactic GCSF was used 

in 86% of pts. Partial response rate was 30% [95 CI% 17%-43%], and 53% of pts 

showed stable disease [95% CI 39%-67%], resulting in a disease control rate of 83% 

[95% CI 73%-93%]. Closure external radiotherapy was performed in 62% of pts and 

32% underwent surgical resection of their tumour. With a median follow up of 8.5 

months [95% CI 7-11], median overall and progression free survivals have not been 

reached. One year overall and progression free survival rates were 80% [95% CI 

57%-92%] and 54% [95% CI 29%-74%], respectively. 

Conclusion: FOLFIRINOX in LAPA seems efficient with a manageable toxicity 

profile and led to secondary potentially curative surgery in approximately one third 

of the pts. These promising results are encouraging to test this regimen in a phase 3 

trial. (1) Conroy et al. NEJM 2011; 364: 1817 




717P GEMCITABINE COMBINED WITH THE MTOR INHIBITOR 

TEMSIROLIMUS(CCI-779) IN PATIENTS WITH INOPERABLE 

OR METASTATIC PANCREATIC CANCER (HE 3/07). A PHASE I 

STUDY BY THE HELLENIC COOPERATIVE ONCOLOGY GROUP 

V. Karavasilis, G. Pentheroudakis, J. Sgouros, S.T. Dimoudis, I. Varthalitis, 

E. Samantas, G. Fountzilas 

Data Office, Hellenic Cooperative Oncology Group, Athens, GREECE 

Aim: To investigate the feasibility of the gemcitabine (G) and mTOR inhibitor 

temsirolimus (T) combination and define the maximum tolerated dose (MTD) in 

patients with inoperable or metastatic pancreatic cancer (MPC). 

Methods: Eligible patients with histologically confirmed inoperable or MPC were 

entered into the trial. Available biopsy material for subsequent translational research 

analysis was mandatory for inclusion in the study. G was given bi-weekly and T was 

administered on a weekly basis. Each cycle consisted of four consecutive weeks of 

treatment. First dose level was set at G 800 mg/m 2 and T 10 mg. G was escalated in 

increments of 200 mg/m 2 and T in increments of 5 mg. 

Results: A total of 30 patients [16M/14F, median age: 63y, PS: 1 (63%)] were 

enrolled for the pre-planned six dose levels. Up to date, 80 complete cycles of 

treatment were delivered. Four patients did not complete the first cycle due to rapid 

disease progression and were therefore replaced. Another patient was found ineligible 

and was replaced, as well. Ten patients received four or more cycles of treatment. 

MTD was not achieved and the study was terminated at the sixth dose level of G 

1000 mg/m 2 and T 25 mg. Dose-limiting toxicity (DLT) was thrombocytopenia of 

grade 4, which occurred at the first dose level. Non-DLT grade III toxicities were 

neutropenia (9 patients), abnormal liver biochemistry (8 patients) and fatigue (1 

patient). Toxicities below the grade III level were mild, the most predominant being 

anemia, neutropenia, raised liver function tests and fatigue. Two patients at the final 

level of G 1000 mg/m 2 and T 25 mg are still on treatment. This dose is the 

recommended dose for phase II evaluation. With regard to response, two partial 

responses were documented and 11 patients had stable disease. 

Conclusion: Combination of G and T is feasible in patients with inoperable or MPC 

with manageable side effects. The activity of this combination is currently 

investigated in a recently initiated phase II study. 


718P A THREE-STEP STRATEGY OF INDUCTION CHEMOTHERAPY, 

CHEMO-RADIOTHERAPY AND SURGERY IN LOCALLY 

ADVANCED PANCREATIC CANCER (LAPC). A SINGLE 

INSTITUTIONAL EXPERIENCE 

O.E. Carranza Rua 1 , E. Arevalo 1 , J.P. Fusco 1 , E. Castanon Alvarez 1 , L. Zubiri 1 ,J. 

A. Gonzalez 2 , L. Arbea 3 , F. Pardo 4 , S. Martin Algarra 1 , J. Rodriguez 5 

1 Medical Oncology, Clinica Universitaria de Navarra, Pamplona, SPAIN, 

2 Radiation Oncologist, Clinica Universidad de Navarra, Pamplona, SPAIN, 

3 Radiation Oncology, Clinica Universidad de Navarra, Pamplona, SPAIN, 

4 Surgical Oncology, Clinica Universidad De Navarra, Pamplona, SPAIN, 5 Medical 

Oncology, Clinica Universidad de Navarra, Pamplona, SPAIN 

Background: Pancreatic cancer is one of the most highly fatal cancers. A growing 

evidence suggests that even potentially resectable patients (pts) benefit from a 

multidisciplinary approach aimed to improve resectability and reduce recurrence. We 

report our experience after a long-term follow-up. 

Methods: From December 2005 to July 2011, 69 histologically confirmed LAPC, 

endoscopic ultrasound (EUS) staged T3/T4, N0/N1 were scheduled to receive 

induction gemcitabine-oxaliplatin-based chemotherapy followed by 

chemo-radiotherapy with weekly oxaliplatin and capecitabine (mean radiotherapy 

dose of 50.4 Gys) and salvage surgery when feasible. Adjuvant chemotherapy was 

considered depending on results of the pathologic report. 

Results: The median age was 63 years (range 35-83 years). Male to female ratio was 

37/32. Forty-one pts (59%) completed the whole program (group A), whereas 26 

(37%) received chemo and chemo-radiotherapy but were not eligible for surgery 

(group B). Two patients (3%) progressed after induction chemotherapy (group C). 

Endoscopic stent placement was performed in thirty-four pts (49%). Toxicity profile 

was mild, with no grade 4 toxicity being documented. Grade 3 toxicity included: 

leucopenia (7%), neutropenia (11%), asthenia (13%) and nausea, diarrhea and 

anorexia (1% each). On an intent to treat basis, the R0 resection rate was 55% (38/ 

69). Among resected patients, local and distant failure rates were 5 and 55% 

respectively. After a median follow up of 43 months (range 9 to 88), median PFS was 

17, 9 and 1 month in groups A, B and C respectively. Median overall-survival (mOS) 

was 13 and 4 months in groups B and C. In group A mOS has not been reached. 

The 2 and 3-year actuarial overall survival in this group are 71% and 45% 

respectively. 

Conclusions: Our data suggest that this three-step strategy is feasible and active in 

LAPC patients Correlative molecular analysis seem warranted to rule out the subset 

of pts most likely to benefit from this approach. 


719P DENDRITIC CELL VACCINATION IN COMBINATION WITH 

OK432, GEMCITABINE AND/OR S-1 IN PATIENTS WITH 

ADVANCED PANCREATIC OR BILIARY TRACT CANCER 

M. Ogasawara, S. Ota 

Internal Medicine, Sapporo Hokuyu Hospital, Sapporo, JAPAN 

Background: Although dendritic cells (DCs) are potent antigen presenting cells that 

can generate T cells specific to tumor antigens, efficacy of immunotherapy using DCs 

is so far limited. To improve the efficacy of this modality, we conducted a clinical 

trial of DC vaccination in combination with gemcitabine (GEM) and/or S-1 for 

patients with advanced pancreatic or biliary tract cancer. The advantages of using 

these drugs are immunomodulatory functions including the inhibition of regulatory 

T cells (Tregs). OK432, a toll like receptor (TLR) 4 agonist, was employed to enhance 

activation of DCs both in vitro and in vivo. 

Methods: 31 patients (17 males, 14 females; aged 27-81 years, median 61 years) with 

advanced pancreatic (24) or biliary tract (7) cancer refractory to standard treatment 

were treated with DC vaccination in combination with OK432 and GEM and/or S-1 

from 2009 to 2011. Autologous DCs were generated from adherent mononuclear 

cells using standard protocols. Wilms’ tumor 1 (WT1) and/or MUC1 peptide-loaded 

mature DCs were administered intradermally every 2 weeks for 7 times. Induction of 

vaccine-induced T cell responses was monitored using HLA-tetramer assays. 

Results: The treatment was well tolerated and none of the patients experienced more 

than grade 3 adverse events during the treatment period. Of 31 patients, 5 patients had 

partial response (PR), 14 had stable disease (SD), 2 had mixed response and 10 had 

progressive disease following one course of the treatment. Median overall survival was 

289 days for all patients, which was longer than that of the patients treated with GEM 

and/or S-1.Survival of patients achieving PR or SD (responder) after one course of DC 

vaccination was longer than those who did not respond to the treatment (p < 0.01). 

Increased numbers of cancer antigen-specific cytotoxic T cells and decreased numbers 

of Tregs was observed in responders after one course of treatment. 

Conclusions: DC vaccine-based immunotherapy combined with a TLR agonist and 

chemotherapy was demonstrated to be safe and more effective in patients with 

advanced pancreatic or biliary tract cancer compared with chemotherapy alone. 


720P PANCREATIC DUCTAL ADENOCARCINOMA: A 

HOMOGENEOUS MORPHOLOGICALLY BUT MOLECULARLY 

HETEROGENEOUS TUMOR. IMPLICATIONS FOR ITS 

MANAGEMENT 

L. Faloppi 1 , A. Mandolesi 2 , M. Scartozzi 1 , C. Loretelli 1 , M. Bianconi 1 , A. Bittoni 1 , 

R. Giampieri 1 , M. Del Prete 1 , I. Bearzi 2 , S. Cascinu 1 


Politecnica delle Marche, Ancona, ITALY, 2 Anatomia Patologica, AOU Ospedali 

Riuniti Ancona Università Politecnica delle Marche, Ancona, ITALY 

Pancreatic cancer has not achieved significant improvements in therapeutic results, 

probably due to a poor comprehension of the underlying molecular mechanisms. 

The aim of our study was to classify pancreatic tumors in categories from a 

molecular point of view, in order to better identify the main pathogenetic molecular 

alterations potentially useful as targets for new drugs. In 110 histological samples of 

pancreatic ductal adenocarcinoma were performed immunohistochemical evaluations 

of K-ras, stromal IL-6 (IL-6s), tumoral IL-6 (IL-6t), Cox-2, EGFR, Her2, Her3, 

MLH1, MSH2, MSH3 and molecular biology assessment of CD24, MUC6, HGF, 

MET, SMAD4, CDKN2A, PGF, VEGF-A/B, VEGFR-1/2, PDGFRB, WNT1, BMP4, 

stemness (ALCAM, PROM1, OCT3/4, CD44, LGR5,), Hedgehog (SHH, DHH, IHH, 

SMO, PTCH1, PTCH2), SPARC, NOTCH1, BRCA1, BRCA2. A preliminary analysis 

showed that the positivity of the inflammation mediators stromal IL-6, tumoral IL-6, 

Cox-2 allowed to differentiate two categories of pancreatic tumors: inflammatory 

tumors, associated with an intense desmoplastic reaction and alteration of EGFR and 

MLH1, and on the contrary tumors not associated with inflammation. Within these 

two groups statistical significant differences were found for EGFR and MLH1. An 

overexpression of EGFR was found in triple (97%) and double (88%) positive 

tumors, compared to negative or single positive (52%) (p0.0002). An higher rate of 

loss of MLH1 expression was found in triple positive tumors (69%), compared to 

double positive (40%) and negative or single positive (27%) (p0.02). Inflammation 

has been identified as a significant factor in the development of other malignancies. 

Mediators of the inflammatory pathway have been shown to be involved in 

proliferation, loss of tumor suppressor function, oncogene overexpression, all of 

which may lead to malignancy. Although definitive results concerning all the 

molecular factors analyzed will be presented during the ESMO 2012 congress, 

inflammation and its related molecular alterations may be specific targets for novel 

agents potentially useful for the treatment of these malignancies. 



721P FIRST-LINE TREATMENT WITH FOLFIRINOX IN ADVANCED, 

INOPERABLE PANCREATIC CANCER (APDAC) PATIENTS 

(PTS): SUPPORTIVE MEASURES OPTIMIZATION FOR A SAFE 

ADMINISTRATION IN ROUTINE CLINICAL PRACTICE 

V. Vaccaro 1 , E. Bria 2 , I. Sperduti 3 , F. Massari 2 , M.S. Pino 4 , E. Lucchini 2 , 

A. Gelibter 1 , F. Cognetti 5 , G. Tortora 2 , M. Milella 1 

1 Medical Oncology, Regina Elena National Cancer Institute, Roma, ITALY, 

2 Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona-”Borgo 

Roma”, Verona, ITALY, 3 Biostatistics, Regina Elena Institute, Roma, ITALY, 

4 Medical Oncology, USL 10 Firenze, Firenze, ITALY, 5 Division Medical Oncology 

A, Istituto Regina Elena, Roma, ITALY 

Purpose: Although FOLFIRINOX has become one of the standard option for the 

treatment of aPDAC, tolerability and safety issues, with particular regard to 

hematologic toxicity and increased risk of AE in pts carrying biliary stents, may 

represent a barrier for the routinely adoption in clinical practice. 

Methods: The clinical reports of 36 aPDAC pts undergone 1st-line FOLFIRINOX in 

2 different institutions were reviewed. Toxicities, activity and efficacy were 

determined according to 1) primary G-CSF prophylaxis (dd 7-9-11; yes/no 21/15 

pts), and 2) presence/absence biliary stent. 

Results: Pts characteristics: N°: 36; cycles: 241, M/F: 22/14; median age: 57 yrs [range 

37-70]; ECOG PS 0/1: 33/3; stage III/IV: 10/26. G3/4 toxicity occurred in 50% reduction in CA19.9. 

Conclusions: These data indicate that FOLFIRINOX seems to be well tolerated and 

easily manageable in young (50%, no PD after 6 months of CT were randomized to O (arm A) or MS at 37.5 mg 

daily until PD or a maximum of 6 months (arm B). Functional polymorphisms of 6 

genes involved in sunitinib activity, metabolism and transport (VEGFA, VEGFR-2, 

CYP3A5, CYP1A1, ABCB1, ABCG2) were studied in genomic DNA from baseline 

blood samples, using PCR Taqman®-probes-based assays. Associations of genotypes 

with overall survival (OS) and progression-free survival (PFS) were evaluated by 

Log-rank test. Genotyping was successfully performed in all the DNA samples of 43 

consenting pts of 55 enrolled in the trial (78%; arm A/B: 83%/73%; p = 0.39). 

Significantly longer OS was observed in 7 pts harbouring the ABCB1 3435TT 

genotype (group-1; median OS 20 months) as compared to 36 pts with 3435CC/CT 

genotype (group-2; median OS 7 months; p = 0.027). Median OS was 26 months in 4 

group-1 arm B pts, 7 months in 15 group-2 arm B pts (p = 0.12); 16 months in 3 

group-1 arm A pts and 9 months in 21 group-2 arm A pts (p = 0.67). No OS 

difference was observed in 28 pts harbouring the VEGFA -634GC-CC genotype 



(group-3; median OS 10 months) as compared to 15 pts with -634GG genotype 

(group-4; median OS 8 months; p = 0.15). However, median OS was 13 months in 

13 group-3 arm B pts, 6 months in 6 group-4 arm B pts (p = 0.016); 9 months in 

15 group 3 arm A pts and 11 months in 9 group 4 arm A pts (p = 0.67). These 

results suggest that polymorphisms of genes involved in expression of the main 

ligand for VEGFR2 (VEGFA 634G > C) and of efflux transporters (ABCB1 3435C > 

T) are promising candidates as predictive marker for selecting pts with MPA who 

may benefit of MS. Given the small sample size of these analyses, a larger 

confirmatory trial is necessary and appears worthwhile. 


725P PATHOLOGICAL PROOF AND SURVIVAL FOR PATIENTS WITH 

BILIARY-TRACT OR PANCREATIC TUMOR 

C. Desauw 1 , F. El Hajbi 2 , K. Ligier 3 , A. Duhamel 4 , F. Richard 4 , C. Rose 2 

1 Medical Oncology, C.H.U. Claude Huriez, Lille, FRANCE, 2 Hôpital St Vincent De 

Paul. Service D’Onco-Hématologie, Université Catholique de Lille, Lille, FRANCE, 

3 Registre Général Des Cancers De Lille Et De Sa Région, Centre de Référence 

Régional en Cancérologie, Lille, FRANCE, 4 Unité de Biostatistiques, EA2694, 

Univ Lille Nord de France, Lille, FRANCE 

As recommended by ESMO, a final pathological diagnosis (PD) has to be obtained 

before any chemotherapy, radiotherapy or other non-surgical oncological therapy for 

pancreatic or biliary tract cancer. PD is also required for inclusion in a clinical trial. 

In practice, it is sometimes difficult to obtain this pathological proof because of 

difficult access or poor performance status. Treatment decision is then collegial, 

based on a clinical, radiological and biological suspicion. We studied patient survival 

based on availability of PD from the cancer registry of Lille and its region (800 000 

inh. - North France). We reviewed patients records over 15 years old diagnosed in 

2005 or 2008 for a pancreatic or biliary tract cancer (neuroendocrine excluded). The 

point was made on 01/12/2011. Patients were divided into 5 groups: PD and surgery 

(PD-Surg), PD and radiotherapy or chemotherapy (PD-RC), PD and untreat 

(PD-Un), no PD and radiotherapy or chemotherapy (noPD-RC), no PD and untreat 

(noPD-Un). Observed survival analysis was obtained from Kaplan-Meier method 

and statistical significance from log-rank test. Males accounted for 45.8% of 260 

patients. The average age was 71.8 years (+/- 12.1). 59.6% were diagnosed as pancreas 

cancer. PD was not obtained in 54.2% (60% in pancreas and 45.7% in biliary tract 

respectively). Seven patients were lost of follow-up. 

PD-Surg PD-RC noPD-RC PD-Un noPD-Un 

n (%) 45 (17.3) 44 (16.9%) 37 (14.2%) 30 (11.5%) 104 (40%) 

Median 

survival (days) 

709 198 203 76 60 

2 years 

survival 

p > 0.2 p > 0.9 

46.7% 6.8% 2.9% 0% 2.1% 

27 patients were alive beyond 24 month: 21 in PD-Surg group, 3 in PD-RC, 1 in 

noPD-RC and 2 in noPD-Un. In conclusion, the absence of PD is common in 

clinical practice, without apparent impact on survival. 14.2% of patient were treated 

without PD. These patients are not take account in current recommendations. 

Centralized monitoring of this condition would be required. In the absence of 

treatment plan, PD is not essential. 


726P NEOADJUVANT MODIFIED FOLFOXIRI IN LOCALLY 

ADVANCED PANCREATIC CANCER 

E. Vasile 1 , N. De Lio 2 , C. Cappelli 3 , L. Ginocchi 1 , S. Caponi 1 , A. Sainato 4 , 

C. Greco 4 , F. Mosca 5 , A. Falcone 1 , U. Boggi 2 

1 Oncologia, Trapianti e Nuove Tecnologie in Medicina, Polo Oncologico - 

Azienda Ospedaliero-Universitaria Pisana - Istituto Toscano Tumori, Pisa, ITALY, 

2 Dipartimento di Oncologia, dei Trapianti e delle Nuove Tecnologie In Medicina, 

U.O. Chirurgia Generale e Trapianti - Azienda Ospedaliero-Universitaria Pisana, 

Pisa, ITALY, 3 Dipartimento Di Radiodiagnostica e Radiologia Interventistica, 

Azienda Ospedaliero-Universitaria Pisana, Pisa, ITALY, 4 Dipartimento di 

Oncologia, dei Trapianti e delle Nuove Tecnologie In Medicina, U.O. Radioterapia 

- Azienda Ospedaliero-Universitaria Pisana, Pisa, ITALY, 5 Dipartimento di 

Oncologia, dei Trapianti e delle Nuove Tecnologie In Medicina, U.O. Chirurgia 

Generale 1 Universitaria - Azienda Ospedaliero-Universitaria Pisana, Pisa, ITALY 

Background: FOLFIRINOX has shown high activity in metastatic pancreatic cancer 

patients. Considering its activity, the regimen could be of interest also for patients 

with inoperable locally advanced disease. Our group had developed a very similar 

schedule in colorectal cancer named FOLFOXIRI which contains no bolus 

5-fluorouracil and a slight lower dose of irinotecan with good tolerance and activity. 

Methods: We have performed a phase II trial in order to prospectively evaluate the 

activity of a modified (m)FOLFOXIRI regimen in locally advanced pancreatic cancer. 

mFOLFOXIRI consisted of: oxaliplatin 85 mg/sqm, irinotecan 150 mg/sqm and 

folinic acid 200 mg/sqm on day 1, plus infusional 5-fluorouracil 2800 mg/sqm 

administered in 48 hours on days 1 to 3, with cycle repeated every 14 days. The 

study enrolled patients with cytological or histological diagnosis of pancreatic 

adenocarcinoma, stage III locally advanced disease without evidence of metastatic 

disease, ECOG performance status (PS) 0 or 1, age 18-75. The primary end-point of 

the study was the percent of patients who can achieve radical surgical resection after 

chemotherapy; the trial was designed with a percentage of low activity of 30% and a 

percentage of interest of 50% with an α and β error of 0.05 and 0.20. 

Results: Twenty-two patients have been so far enrolled; 8 men and 14 women; PS 

was 0 in 10 patients. Median age was 60 years (range 44-75). Celiac axis was involved 

in 7 patients, superior mesenteric artery in 10 cases, both arteries in 5 patients. 

Among the 15 patients so far evaluated, 6 partial responses (40%) and 9 stable 

disease (60%) have been observed. A local treatment after chemotherapy was received 

by 9 patients until now: 5 (55.5%) underwent to radical surgery; 1 underwent an 

explorative laparotomy with evidence of liver metastases; 3 received concomitant 

chemo-radiotherapy with gemcitabine. Median progression-free survival was 24.5 

months and median overall survival was 30.1 months. 

Conclusions: Chemotherapy with mFOLFOXIRI seems active in locally advanced 

pancreatic cancer patients and may allow to obtain a downstaging of disease leading 

some patient to achieve a curative surgical resection. Longer follow up is needed to 

better evaluate long-term outcome of this strategy. 


727P COMPARISON IN 1323 PATIENTS OF PREOPERATIVE 

IMAGING STAGING AND PATHOLOGICAL EXAMINATION OF 

RESECTED PANCREATIC HEAD ADENOCARCINOMA: SERIES 

OF THE ASSOCIATION FRANçAISE DE CHIRURGIE 

M. Gilabert 1 , J.M. Boher 2 , J.L. Raoul 3 , O. Turrini 3 ,F.Paye 4 , P. Bachellier 5 , 

J. Delpero 6 , G. Afc 7 

1 Medical Oncology, Institut Paoli Calmettes, Marseille Cedex, FRANCE, 

2 Bioinformatics, Institut Paoli-Calmettes, marseille, FRANCE, 3 Oncology, Institut 

Paoli-Calmettes, Marseille, FRANCE, 4 Surgery, Hopital Saint Antoine, Paris, 

FRANCE, 5 Surgery, Hopital de Hautepierre, Strasbourg, FRANCE, 6 Surgical 

Oncology, Institut Paoli-Calmettes, Marseille, FRANCE, 7 France, Association 

Francaise de Chirurgie, France, FRANCE 

Resection is possible in less than 15% of pancreatic ductal adenocarcinoma (PDAC) 

patients. Prognosis is dismal and particularly related to arterial, venous or lymph 

node invasion. In this retrospective analysis were compared imaging preoperative 

data and pathological reports on arterial, venous and lymph node invasion in a large 

series of PDAC benefiting from pancreaticoduodenectomy. Retrospective series of 

1323 patients resected for a PDAC of the head of pancreas in 35 French and 2 Swiss 

centers, data analyzed by the Association Française de Chirurgie; 142 with (95 

chemoradiotherapy, 47 chemotherapy; given to a borderline tumor in 65% and 

systematically in 35%) and 1181 without preoperative treatment. Preoperative 

imaging consisted in: ceCTscan (97%), ceMRI (45%), US (65%) and endoscopic US 

(59%). Were calculated concordance, Sensibility, Specificity, PPV and NPV of 

preoperative data compared to pathological conclusions. Artery-Artery + Vein-Vein+ 

LN- LN+ Imaging negative 1047 16 788 137 246 613 positive 17 9 40 130 38 157 

Concordance 97% 84% 38% Se 36% 49% 20% Spe 98% 95% 87% PPV 35% 76% 80% 

NPV 98% 85% 29%. In conclusion, in this biased series of patients who were 

operated on from a PDAC, the value of preoperative imaging “in the real life” is not 

optimal, particularly regarding arterial and lymph node involvement 


728P RANDOMIZED PHASE II TRIAL OF S-1 VERSUS S-1 PLUS 

OXALIPLATIN (SOX) IN PATIENTS WITH GEMCITABINE 

REFRACTORY PANCREATIC CANCER 

T. Okusaka 1 , S. Ohkawa 2 , H. Isayama 3 , A. Fukutomi 4 , K. Yamaguchi 5 , M. Ikeda 6 , 

A. Funakoshi 7 , M. Nagase 8 , S. Nakamori 9 , Y. Hamamoto 10 

1 Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center 

Hospital, Tokyo, JAPAN, 2 Department of Gastroenterology, Kanagawa Cancer 

Center Hospital, Kanagawa, JAPAN, 3 Department of Gastroenterology, Graduate 

School of Medicine The University of Tokyo, Tokyo, JAPAN, 4 Division of 

Gastrointestinal, Shizuoka Cancer Center, Shizuoka, JAPAN, 5 Division of 

Gastroenterology, Saitama Cancer Center, Saitama, JAPAN, 6 Division of 

Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 

Chiba, JAPAN, 7 Department of Gastroenterology, National Kyushu Cancer 

Center, Fukuoka, JAPAN, 8 Department of Medical Oncology, Jichi Medical 

University Hospital, Tochigi, JAPAN, 9 Department of Surgery, Osaka National 

Hospital, Osaka, JAPAN, 10 Tochigi, Department of Clinical Oncology, Tochigi 

Cancer Center, Tochigi, JAPAN 

Background: Gemcitabine (Gem) monotherapy or Gem-based combination therapy 

is used as standard first-line therapy for advanced pancreatic cancer (PC). There is 

no consensus on second-line therapy in patients (pts) with disease progression (PD) 


after Gem-based therapy. The addition of oxaliplatin (L-OHP) to 5-FU/LV, however, 

yielded a significant improvement in overall survival (OS) and progression-free 

survival (PFS) in a second-line setting in the CONKO 003 trial. As S-1, an oral 

fluoropyrimidine derivative, is commonly used to treat advanced PC rather than 

5-FU/LV in Japan, we conducted a randomized phase II trial to evaluate the efficacy 

and safety of S-1 plus L-OHP (SOX) compared with S-1 alone in a second-line 

setting. 

Material and methods: The inclusion criteria were as follows: 1) histologically or 

cytologically proven pancreatic adenocarcinoma or adenosquamous carcinoma; 2) 

confirmed PD after Gem treatment; 3) ECOG PS, 0-1; 4) measurable metastatic 

lesion based on RECIST criteria; 5) age ≥ 20 years. Patients were randomized to 

receive either S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w; Arm A) or 

SOX (L-OHP 100 mg/m 2 , iv, d1 plus S-1 80/100/120 mg/day based on BSA, po, 

d1-14, q3w; Arm B). The primary endpoint was PFS to detect the superiority of Arm 

B over Arm A. 

Results: Of a total of 271 pts enrolled between January 2009 and July 2010, 264 were 

eligible (130 randomized to Arm A and 134 to Arm B). Median PFS in Arm A and 

B was 2.8 and 3.0 months, respectively (HR= 0.838; 95% CI, 0.649-1.082; P = 0.1795) 

with a median follow-up time of 12.6 months. Median OS in Arm A and B was 7.0 

and 7.5 months, respectively (HR = 1.031; 95% CI, 0.791-1.344; P = 0.8235) with a 

median follow-up time of 13.8 months. Response rate (RR) was 11.5% in Arm A (15/ 

130; 95% CI, 6.6-18.3) and 20.9% in Arm B (28/134; 95% CI, 14.4-28.8)(P = 0.0395). 

The incidences of grade 3/4 toxicities were as follows: neutropenia (11.4% and 

14.0%), thrombocytopenia (3.8% and 9.8%), anorexia (11.4% and 12.5%), diarrhea 

(4.5% and 5.1%) and nausea (3.0% and 9.8%) in Arm A and B, respectively. Both 

regimens were tolerable. 

Conclusions: Although SOX showed an advantage in RR, it provided no significant 

improvement in PFS or OS compared with S-1 alone. 

Disclosure: T. Okusaka: The study detailed in the abstract was funded by a 

pharmaceutical company. S. Ohkawa: The study detailed in the abstract was funded 

by a pharmaceutical company. H. Isayama: The study detailed in the abstract was 

funded by a pharmaceutical company. A. Fukutomi: The study detailed in the 

abstract was funded by a pharmaceutical company. K. Yamaguchi: The study detailed 

in the abstract was funded by a pharmaceutical company. M. Ikeda: The study 

detailed in the abstract was funded by a pharmaceutical company. A. Funakoshi: The 

study detailed in the abstract was funded by a pharmaceutical company. M. Nagase: 

The study detailed in the abstract was funded by a pharmaceutical company. S. 

Nakamori: The study detailed in the abstract was funded by a pharmaceutical 

company. Y. Hamamoto: The study detailed in the abstract was funded by a 

pharmaceutical company. 

729P PROFILE OF DOSES TO ORGANS AT RISK USING 3-D 

CONFORMAL RADIOTHERAPY (3-DCRT) VERSUS INTENSITY 

MODULATED RADIOTHERAPY (IMRT) IN POSTOPERATIVE 

RADIOTHERAPY OF PERIAMPULLARY CANCERS: 

IMPLICATIONS FOR RADIATION DOSE ESCALATION 

A. Bahl 1 , R. Kapoor 2 , P. Tomar 1 , A.O. Singh 1 , R. Gupta 3 , S.C. Sharma 1 

1 Department of Radiotherapy, Post Graduate Institute of Medical Education and 

Research (PGIMER), Chandigarh, INDIA, 2 Radiation Oncology, PGIMER, 

Chandigarh, INDIA, 3 General Surgery, PGIMER, Chandigarh, INDIA 

Introduction: Periampullary cancers are treated with Whipple’s surgery in 

combination with radiotherapy & chemotherapy. The common cause of treatment 

failure in these patients is recurrence in the tumor bed & regional lymph nodes. A 

treatment approach aiming to increase the local control rate, by escalating radiation 

dose is likely to translate into a better survival.The purpose of the present study was 

to do a dosimetric analysis of the doses to organs at risk in postoperative 

radiotherapy using a dose of 45Gy/25 fractions and to assess the feasibility of 

radiation dose escalation. 

Material & methods: Ten patients of periampullary cancers in head of pancreas were 

selected. All patients had undergone Whipple’s surgery. IMRT and 3DCRT plans 

were generated for each patient. IMRT contouring was done as per RTOG guidelines. 

3DCRT planning was done using one anterior and two lateral fields. A dose of 45Gy/ 

25 fractions was prescribed to the Planning Target volume. Dosimetric evaluation of 

doses to liver, kidneys, stomach, bowel bag, spinal cord was done using ‘QUANTAC’ 

parameters. For statistical analysis the data was arranged in SPSSv18. ‘t’ test was used 

to compare the mean doses. A ‘p’ value of < 0.05 was considered significant. 

Results: Dose to the bowel bag was less using IMRT versus 3-DCRT with a V45 of 

80.91 ± 57.40 cc (Mean volume ± Standard deviation) versus 212.28 ± 159.04cc (p = 

0.03).The mean doses to liver, stomach, spinal cord, Rt kidney & Lt. kidney using 

3-DCRT were 24.59± 3.90 Gy (Mean Dose ± Standard deviation), 21.90 ± 6.73 Gy, 

26.50 ± 14.72 Gy, 14.14 ± 3.90 Gy, 13.71 ± 3.83 Gy respectively. With IMRT the doses 

to the above structures were 22.91 ± 3.14Gy (p = 0.32), 20.71 ± 5.78 Gy (p = 0.69), 

24.77 ± 7.93Gy (p = 0.76), 11.55 ± 4.12 Gy (p = 0.19), 13.72 ± 2.44 Gy (p = 0.99) 

respectively. 

Conclusions: With a prescription of 45Gy/25# the dose to bowel bag is significantly 

reduced using IMRT compared to 3-DCRT. The doses received by other organs are 

lower with IMRT compared to 3-DCRT though not statistically significant. The 


profile of doses received by organs at risk leaves ample scope of dose escalation using 

IMRT. 


730P MULTICENTRIC PHASE II RANDOMIZED TRIAL COMPARING 

CHEMORADIATION (CHRT) WITH 5-FLUOROURACIL, 

CISPLATIN (CDDP) AND 50 GY VERSUS CHEMOTHERAPY 

ALONE (CH) WITH GEMCITABINE (G) PLUS OXALIPLATIN (O) 

FOR LOCALLY ADVANCED BILIARY TRACT CANCER 

(FFCD9902) 

J.M. Phelip 1 , V. Vendrely 2 , J. Jouve 3 , F. Subtil 4 , M. Gasmi 5 , P. Michel 6 , 

D. Smith 7 , J. Seitz 8 , L. Bedenne 9 , B. Chauffert 10 

1 Gastroenterologie and Digestive Oncology, University Jean Monnet, Saint 

Etienne, FRANCE, 2 Service d’Oncologie Médicale et Radiothérapie, Hôpital Saint 

André, Bordeaux Cedex, FRANCE, 3 Hepatogastrolentorology Department, CHU 

le Bocage, Dijon Cedex, FRANCE, 4 Data Center, FFCD, Dijon Cedex, FRANCE, 

5 Hepatogastroenterology Department, Hôpital Nord, Marseille Cedex, FRANCE, 

6 Gastroenterology and Digestive Oncology, CHU de Rouen, Rouen, FRANCE, 

7 Oncologie Digestive, Hôpital Saint André, Bordeaux, FRANCE, 8 Oncologie 

Digestive, Hôpital de la Timone, Marseille, FRANCE, 9 Hepatogastroenterology 

Department, University Hospital, Dijon Cedex, FRANCE, 10 Medical Oncology, 

University Hospital, Amiens Cedex, FRANCE 

Background: No study is available to determine the best strategy for inoperable 

locally advanced biliary tract cancer. CHRT has shown its efficacy in small series to 

control the local evolution. However CHRT results were not compared to palliative 

CH. 

Methods: This prospective multicentric phase II trial randomized patients with hilar 

or extrahepatic non metastatic and locally advanced biliary tract cancer between 

CHRT (50 Gy plus 5FU infusion 300 mg/m 2 /D, D1 to D33 and CDDP 20 mg/m 2 /D 

D1 to D4 and D29 to D32 or CDDP 80 mg/m 2 D1 and D29) and CH (G 1000 mg/ 

m 2 D1 + O 100mg/m 2 D1; D1 = D15, 6 months). Main inclusion criteria required 

WHO performance status


(NEJM 2010; 362:1273). No second line regimen is established although small 

retrospective series suggest that chemotherapy may be active in selected patients. We 

present results of a large retrospective series of patients undergoing second-line 

chemotherapy at institutions across the UK that use the ABC-02 standard of 

Cisplatin and Gemcitabine (CisGem) as first-line treatment. 

Methods: Patients with ABC, previously treated with CisGem and who went on to 

receive second-line chemotherapy, were identified from institutional databases. 

Demographic data, response and survival outcome measures were collected according 

to an agreed proforma. 

Results: Sixty-three eligible patients (median age: 61.6 years (range: 39.8 – 78.3 

years)) were identified between Feb 2007 and Feb 2011, from 9 centres. Patients were 

treated mostly with a platinum based regimen (n = 42), either a re-challenge of 

CisGem (n = 17), an oxaliplatin/ infused 5-FU regimen (mFOLFOX, n = 17) or 

oxaliplatin with capecitabine (n = 4). Most patients had a performance status of 

0 or 1. A median PFS of 4.0 months (95% CI: 3.3 – 5.6 months) and an OS of 8.1 

months (95% CI: 5.3 – 11.4 months) following second line therapy were 

demonstrated. Patients had an overall OS of 19.5 months (95% CI: 17.0 – 25.2 

months) from the start of first-line therapy; this compares with a median OS of 11.7 

months from the ABC-02 study. 

Conclusions: Use of second-line chemotherapy in advanced BTC is of potential 

benefit. These data, although retrospective, suggests there is a population suitable for 

second-line, prospective randomised studies with chemotherapy or targeted agents 

and provide baseline outcome data with which to statistically design such studies. 

Updated data will be shown. 


732P FINAL RESULTS OF A RANDOMIZED PHASE II STUDY OF 

TSU-68 AFTER TRANSARTERIAL CHEMOEMBOLISATION IN 

JAPANESE PATIENTS WITH UNRESECTABLE 

HEPATOCELLULAR CARCINOMA.CHEMOEMBOLIZATION 

S. Kaneko 1 , Y. Inaba 2 , F. Kanai 3 , T. Aramaki 4 , T. Yamamoto 5 , T. Tanaka 6 , 

K. Yamakado 7 , M. Kudo 8 , K. Imanaka 9 ,Y.Arai 10 

1 Department of Gastroenterology, Kanazawa University Hospital, Ishikawa, 

JAPAN, 2 Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, 

Aichi, JAPAN, 3 Gastroenterology, Chiba University Hospital, Chiba, JAPAN, 

4 Diagnostic Radiology, Shizuoka Cancer Center Hospital, Shizuoka, JAPAN, 

5 Diagnostic Imaging, Tochigi Cancer Center, Tochigi, JAPAN, 6 Radiology, Nara 

Medical University Hospital, Nara, JAPAN, 7 Radiology, Mie University Hospital, 

Mie, JAPAN, 8 Gastroenterology and Hepatology, Kinki University Hospital, 

Osaka, JAPAN, 9 Hepatobiliary and Pancreatic Oncology, Osaka Medical Center 

for Cancer and Cardiovascular Diseases, Osaka, JAPAN, 10 Diagnostic 

Radiology, National Cancer Center Hospital, Tokyo, JAPAN 

Purpose: TSU-68 is an antitumor drug that acts by inhibiting angiogenesis. We 

evaluated the efficacy and safety of TSU-68 in combination with transcatheter arterial 

chemoembolization (TACE) in patients with intermediate-stage hepatocellular 

carcinoma (HCC). 

Methods: In this multicenter, open-label phase II study, we randomly assigned 

patients with HCC who had been treated by TACE to receive either 200 mg TSU-68 

twice daily or no medication. TACE was performed according to the standard 

technique using anticancer drugs, lipiodol, and gelatin sponge. TACE was completed 

for all patients within the 2 weeks prior to randomization. The primary endpoint was 

progression-free survival (PFS) and the secondary endpoints were safety and 

biomarker assessments. 

Results: In total, 103 patients were enrolled. Median PFS was 5.2 months in the 

TSU-68 group and 4.0 months in the control group (HR in the TSU-68 group, 

0.699; p = 0.054, log-rank test with a 2.5% one-sided significance level). Fatigue, 

elevated aspartate aminotransferase (AST), elevated alkaline phosphatase, edema, 

and anorexia were more frequent in the TSU-68 group than in the control group. 

The most frequent grade 3/4 adverse events were AST elevation (46% of patients 

in the TSU-68 group and 12% of controls) and alanine aminotransferase elevation 

(26% of patients in the TSU-68 group and 8% of controls). Subgroup analyses 

suggested that treatment with TSU-68 may extend PFS for patients with Child– 

Pugh A liver function and those with hepatitis C. Among patients with baseline 

t-PA concentrations below the median value, the PFS of the TSU-68 group was 

longer than that of the control group. TSU-68 treatment may also improve PFS 

among patients with VCAM-1, ELAM-1, IL-8, or PDGF-BB levels above the 

median values. 

Conclusion: TSU-68 was well tolerated, and may provide longer PFS after TACE 

than was observed for controls. This result suggests that TSU-68 combined with 

sequential and repeated TACE sessions may provide additional clinical benefits to 

patients, including prolongation of overall survival. A randomized placebo-controlled 

phase III global study was initiated in 2010 to evaluate the survival benefit of TSU-68 

in combination with repeated TACE. 


733P 3-MONTHS POSTRESECTION ALPHA-FETOPROTEIN: AN 

INDEPENDENT PROGNOSTIC TOOL IN PATIENTS WITH 

HEPATOCELLULAR CARCINOMA ON CIRRHOSIS 

M. Allard, A. Sa-Cunha, E. Vibert, B. Paule, G. Pelletier, M. Sebagh, C. Guettier, 

D. Castaing, R. Adam 

Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, Villejuif, FRANCE 

Background: Alpha Fetoprotein (AFP) is a major tumor marker in patients with 

hepatocellular carcinoma (HCC). Our aim was to assess the prognostic value of AFP 

measured within the 3-months following partial hepatectomy for HCC on cirrhosis. 

Methods: All patients treated for HCC on cirrhosis by partial hepatectomy with 

intention to treat between January 1990 and December 2010 and presenting an 

elevation of AFP (>15ng/ml) at diagnosis were included in the study. The AFP value 

within the 90 postoperative days was retrospectively collected and analyzed as a 

dichotomized variable (normalization or absence of normalization). Performed on 

the whole study population, Cox proportional hazards models were utilized to assess 

the impact of postresection AFP normalization on overall survival (OS). 

Results: Among 271 patients treated for HCC on cirrhosis by liver resection, 145 

(53%) patients presented an elevation of AFP level (>15ng/ml). The AFP value was 

available within the 90 postoperative days in 96 patients (66%). Missing data were 

related to the 7 post-operative deaths, the 22 patients lost from follow up, and the 20 

patients for which the first post-operative AFP measurement was performed beyond 

the 90 postoperative days. 5 years-OS after liver resection and median survival were 

45% and 54 months in the group with post-resection AFP normalization versus 24% 

and 23 months in the group without postresection AFP normalization, respectively 

(P = 0,02). There was a significant decline of disease-free survival in the group 

without postresection AFP normalization experiencing median survival of 6 months 

versus 19 months (P < 0,001). At multivariate analysis, postresection AFP 

normalization within the 90 post-operative days (OR: 2,38; CI: 1,32-4,28; P = 0,004) 

and microvascular invasion (OR: 4; CI: 2,1-7,6; P < 0,001) were two independent 

predictors of OS. Interestingly, among patients without AFP normalization, 13 had 

no vascular invasion but all of them developed further recurrence. 

Conclusion: This study emphasizes the role of AFP in the 3-months period 

following HCC resection on cirrhotic livers, which should be considered more 

systematically to help postresection management. 


734P THE ROLE OF TUMOUR VASCULAR ENDOTHELIAL GROWTH 

FACTOR (VEGF) AND VASCULAR ENDOTHELIAL GROWTH 

FACTOR RECEPTORS (VEGFR) POLYMORPHISMS IN THE 

PREDICTION OF CLINICAL OUTCOME FOR ADVANCED 

HEPATOCELLULAR CARCINOMA RECEIVING SORAFENIB 

L. Faloppi 1 , M. Scartozzi 1 , G. Svegliati Baroni 2 , C. Loretelli 1 , S. De Minicis 3 , 

A. Mandolesi 4 , M. Bianconi 1 , I. Bearzi 1 , A. Benedetti 2 , S. Cascinu 1 


Politecnica delle Marche, Ancona, ITALY, 2 Clinica di Gastroenterologia, UNIVPM, 

Ancona, ITALY, 3 Clinica di Gatroenterologia, Università Politecnica delle Marche, 

Ancona, ITALY, 4 Anatomia Patologica, AOU Ospedali Riuniti Ancona Università 

Politecnica delle Marche, Ancona, ITALY 

Hepatocellular carcinoma (HCC) still represents a medical challenge in cancer therapy. In 

recent years the introduction of new targeted therapies has radically changed the 

approach to the disease and patients outcome. Currently the therapeutic stronghold is a 

TKIs directed against the VEGF family sorafenib. Polymorphisms of VEGF and its 

receptor genes are involved in regulating angiogenesis and lymphangiogenesis and thus 

in growth tumor control. The aim of our study is to evaluate the potential predictive and 

prognostic role of VEGF and VEGFR polymorphisms in determining the clinical 

outcome of HCC patients receiving sorafenib. 41 histologic samples (biopsies and 

surgical specimens) of HCC patients receiving sorafenib were tested for VEGF-A, 

VEGF-C and VEGFR-1,2,3 singlenucleotide polymorphisms (SNPs). Patients time to 

progression (TTP) and overall survival (OS) were analysed. VEGF-AI rs25648 C > T 

polymorphism was statistically significant in OS (15.0 months for C vs 9.4 months for T; 

p = 0.025). VEGF-AII rs10434 G > A was statistically significant for TTP (4.1 months for 

G vs 1.2 months for A; p = 0.0076) and OS (14.2 months for G vs 1.7 for A; p < 0.0001). 

VEGF-CII rs7664413 C > T was significant in TTP (13.4 months for C vs 2.0 for T; p = 

0.0125) and OS (14.7 months for C vs 5.6 for T; p = 0.0007). VEGR2-I rs1870377 A > T 

was significant in TTP (19.9 months for A vs 3.0 for T; p = 0.0271) and OS (29.6 months 

for A vs 11.9 for T; p = 0.0096). In our analysis patients with G polymorphism at rs10434, 

C polymorphism at rs7664413 and A polymorphism at rs1870377 have a better response 

(PFS and OS) during treatment with sorafenib. Patients with C polymorphism of 

rs7664413 and A polymorphism of rs1870377 show a favourable impact in this setting. 

Notably, VEGFR polymorphism result closely related to the treatment response and the 

specific signalling of sorafenib. Thus analysis of VEGF and its receptor genes 

polymorphisms represents a clinical tool to identify patients with favourable response to 

sorafenib presumably related to a more efficient control of tumor growth. 



735P RADIOGRAPHIC PARAMETERS IN PREDICTING OUTCOME 

OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) 

TREATED WITH YTTRIUM-90 MICROSPHERE 

RADIOEMBOLIZATION (SIRT) 

M. Salem 1 , N. Jain 1 , S. Taylor 1 , G. Dyson 1 , J. Beebe-Dimmer 1 , I.P. Le 2 , 

M. Choi 1 , A.F. Shields 1 , J.J. Critchfield 1 , P.A. Philip 1 

1 Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI, 

UNITED STATES OF AMERICA, 2 Department of Internal Medicine, Wayne State 

University, Detroit, MI, UNITED STATES OF AMERICA 

Background: The predictive role of radiographic parameters in HCC pts undergoing 

transarterial hepatic selective internal radiotherapy (SIRT) is not fully characterized. 

The objective of this retrospective study was to determine whether radiographic 

parameters at baseline and/or radiographic changes following SIRT predict outcome 

in HCC pts treated with Yttrium-90 glass microsphere radioembolization. 

Methods: Baseline and post-SIRT CT images (median of 6 weeks) were analyzed. 

Various features such as tumor size; attenuation; margins; enhancement; and amount 

of tumor necrosis were examined. Selected radiographic parameters were evaluated & 

correlated with PFS & OS. Objective response was assessed by RECIST 1.1 and 

Morphology, Attenuation, Size, and Structure (MASS) criteria (favorable (FR) vs. 

non favorable). Differences were analyzed using Wilcoxon Signed Rank Test and 

Fisher’s Exact Test. Kaplan-Meier methods were used to estimate survival curves. 

Cox regression was used in uni- and multivariable survival analyses 

Results: Twenty-four pts (79% M; median age 63 y) received a median radiation dose of 

1.965 GBq. On post-SIRT CT, 65% of tumors had decreased longest diameter (median 

decrease 8%, p = 0.27); 64% had decreased attenuation (median decrease 18 HU, p = 

0.067), and 45% demonstrated increased tumor necrosis (p < 0.001). RECIST-defined 

partial response was seen in 10% of pts, stable disease in 80% and 10% had disease 

progression. Median PFS and OS were 4.4 and 11.6 months, respectively. Of the 9 pts 

who were response evaluable by MASS criteria, FR was a predictor of PFS (p = 0.03) 

with median time to progression not being reached vs. 5.5 months for the non-FR 

group. In univariate analyses, well-defined tumor margins, lower hepato-pulmonary 

shunt fraction and peripheral hypervascularity were associated with prolonged PFS. On 

multivariate analysis, tumor margins and shunt fraction were correlated with PFS 

whereas extrahepatic disease and liver cirrhosis were independent predictors of OS. 

Conclusions: In pts with HCC, pre-treatment tumor margins and shunt fraction 

may be developed as biomarkers to identify pts who are unlikely to benefit from 

SIRT. In addition, response evaluation by MASS criteria may provide better and 

earlier determination of lack of benefit from SIRT and the need for further therapy. 


736P THE USE OF SECOX (SORAFENIB, OXALIPLATIN, 

CAPCITABINE) AS THE TREATMENT OF ADVANCED 

HEPATOCELLULAR CARCINOMA (HCC) – A SINGLE CENTER 


J. Chiu 1 ,V.Tang 1 , P. Chan 2 , R. Leung 1 , H. Wong 1 , R. Poon 3 , S.T. Fan 3 ,T.Yau 1 

1 Medicine, Queen Mary Hospital, The University of Hong Kong, HONG KONG, 

2 Medicine, Ruttonjee Hospital, HONG KONG, 3 Surgery, Queen Mary Hospital, 

The University of Hong Kong, HONG KONG 

Background: Combining sorafenib with chemotherapy can potentially provide a new 

regime with enhanced benefit. Phase II study has demonstrated promising activity in 

combining sorafenib, oxaliplatin and capecitabine (SECOX) in treating advanced 

HCC. We reported our experience in using this regime in our centre. 

Methods: This retrospective study included all consecutive advanced HCC patients 

treated in our centre with SECOX regimen: daily oral sorafenib 400 mg B.D., oxaliplatin 

85 mg/m 2 infusion on D1, and oral capecitabine 850 mg/m 2 B.D. from D1-7 every 2 

weeks. Univariate and multivariate analyses were employed to explore the potential 

predictive factors for overall survival benefits treated with this combination. 

Results: 89 patients were included in the analysis with 29 patients previously enrolled 

in the phase II trial and 60 patients treated outside the clinical trial in our centre. Of 

89 patients received SECOX (male, 85%; median age, 53 year; hepatitis B carrier, 

91%), 72 (81%) patients had CP A and 17 (29%) patients had CP B. Moreover, 

42.7% patients had ECOG performance status (PS) 0, 53.9 % patients had PS 1 and 

3.4% patients had PS 2. The most common grade 3 or 4 drug-related toxicities were 

hand-foot syndrome (10.5%), diarrhea (5.8%), and hypertension (5.8%). G3/4 

thrombocytopenia was found in 18.1% and neutropenia was present in 6.0%. The 

overall response rate was 14.6%, with one (1.1%) patient had complete response and 

12 (13.5%) patients achieved partial response. Moreover, 30 (33.7%) patients had 

stable disease. Overall, 48.3% patients derived benefits from SECOX. The 

progression-free survival (PFS) was 4.1 months (95% C.I. 3.6-4.6) and median overall 

survival (OS) was 11.0 months (95% C.I. 8.2-12.3). Patients with CP A cirrhosis had 

better PFS (4.2 vs 2.9 months, p = 0.027) and OS (11.8 vs 5.0 months, p = 0.003) 

than CP B patients. Multivariate analysis revealed that both ECOG 1-2 (p = 0.005) 

and vascular involvement (p = 0.048) were associated with worse overall survival. 

Conclusions: The SECOX regime had promising activity in advanced HCC with 

good tolerability, especially in Child-Pugh A patients with good performance status. 


Disclosure: R. Poon: Advisory board with Bayer. T. Yau: Advisory board with Bayer. 


737P PHASE I/II TRIAL OF LENVATINIB (E7080), A 

MULTI-TARGETED TYROSINE KINASE INHIBITOR, IN 

PATIENTS (PTS) WITH ADVANCED HEPATOCELLULAR 

CARCINOMA (HCC) 

K. Ikeda 1 , H. Kumada 2 , M. Kudo 3 , S. Kawazoe 4 , Y. Osaki 5 , M. Ikeda 6 , 

T. Okusaka 7 , T. Suzuki 8 , J.P. O’Brien 9 , K. Okita 10 

1 Department of Hepatology, Toranomon Hospital, Tokyo, JAPAN, 2 Department 

of Hepatology, Toranomon Hospital Kajigaya, Kanagawa, JAPAN, 3 Department 

of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, 

JAPAN, 4 Department of Internal Medicine, Saga prefectural Hospital Koseikan, 

Saga, JAPAN, 5 Department of Gastroenterology and Hepatology, Osaka Red 

Cross Hospital, Osaka, JAPAN, 6 Division of Hepatobiliary and Pancreatic 

Oncology, National Cancer Center Hospital East, Chiba, JAPAN, 7 Division of 

Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, 

JAPAN, 8 Oncology Clinical Development, Eisai, Tokyo, JAPAN, 9 Oncology, Eisai 

Inc., Woodcliff Lake, NJ, UNITED STATES OF AMERICA, 10 Department of 

Gastroenterology and Hepatology, Shimonoseki Kohsei Hospital, Yamaguchi, 

JAPAN 

Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, 

FGFR1-4, RET, KIT and PDGFRβ. The inherent vascularity of HCC makes it a target for 

VEGF inhibitors and other molecular mediators of angiogenesis like FGFR and PDGFR. 

The current study established a MTD of lenvatinib for HCC patients with Child-Pugh A 

of 12 mg qd. The current presentation is a report on the efficacy and safety of lenvatinib. 

Methods: Between July 9, 2010 and June 22, 2011, 46 pts with advanced HCC and 

Child-Pugh A status were enrolled in Japan (n = 43) and Korea (n = 3). Pts may have 

received up to one prior treatment regimen including sorafenib. Pts were treated with a 

starting dose of lenvatinib 12 mg once daily in 28 day cycles until disease progression 

or development of unmanageable toxicities. Response was assessed by RECIST 1.1 

(modified to evaluate viable lesions) by independent radiologist review (IRR). 

Results: 46 pts were enrolled (med age: 67; M: 72%) and were evaluable for response. 

76% of pts required dose adjustments for management of toxicity. The most common 

adverse events were hypertension 76% (Gr3: 54%), palmar-plantar erythrodysaesthesia 

syndrome 65% (Gr3: 9%), anorexia 59% (Gr3: 2.2%), proteinuria 54% (Gr3: 17%), 

fatigue 54% (Gr3: 0%), and thrombocytopenia 52% (Gr3: 33%). A higher level of 

toxicity was observed in pts weighing < 60 kg compared to pts ≥ 60 kg correlating with 

differences in drug exposure. ORR based on IRR is (PR = 32.6%, SD = 45.7%). Median 

Time to progression (TTP) is 7.49 mo (95% CI: 5.45 - 9.43)(based on minimum 6 mo. 

f/u, with 56.5% progression events) based on IRR. Median overall survival (OS) is 13.9 

mo (95% CI: 11.8 -) (based on minimum 8 mo. f/u, with 46% death events). OS data 

has not yet matured and will be reported in the future. 

Conclusions: In this Phase I/II study, lenvatinib administered to patients with 

advanced HCC was not associated with any new toxicities associated with TKI class 

and was managed by dose adjustments. A weight-based starting dose (


advanced HCC, tivantinib monotherapy improved time to progression by 56%. 

However, in that study at the standard phase 2 dose of 360 mg twice daily (BID), 

tivantinib exposure was increased, and the absolute incidence of severe neutropenia 

increased approximately 6% compared to pts with solid tumors from previous 

studies. An exposure-response analysis was conducted to explore the relationship 

between neutropenia and tivantinib pharmacokinetics (PK). 

Methods: Tivantinib plasma concentration and incidence of grade ≥ 2 neutropenia 

were pooled from phase 1/1b and 2 studies. A population PK model (NONMEM 

v.7.1.0) was used to predict tivantinib exposure in HCC. The relationship between 

tivantinib exposure and neutropenia was evaluated by logistic regression analysis 

(S plus v8.0). 

Results: Data were available from 289 cancer pts, including 73 pts with HCC and 

mild-to-moderate hepatic impairment. Cases of grade ≥ 3 (n = 28) and grade ≥ 2 

(n = 40) neutropenia were included in the analysis. Based on the population PK 

analysis, tivantinib clearance was reduced approximately 67% in HCC pts, resulting 

in approximately 3 times higher exposure compared with other cancer pts. There was 

a significant (P < .001) relationship between tivantinib exposure and incidence of 

grade ≥ 2/3 neutropenia. By reducing the tivantinib starting dose from 360 to 240 mg 

BID, the incidence of grade ≥ 3 neutropenia is modeled to decrease from 28% to 16% 

in HCC pts. Further reduction in the risk of neutropenia (∼6%) was achieved with 

intensive clinical monitoring and an aggressive dose-reduction schema. 

Conclusions: Based on the current analysis, the increased incidence of neutropenia 

in HCC pts compared to pts with other solid tumors resulted from increased 

tivantinib exposure due to hepatic impairment. Consistent with the model, the risk of 

neutropenia was successfully managed in HCC pts by implementing dose reduction 

and tighter clinical monitoring without compromising efficacy. 

Disclosure: H. Zahir: H Zahir is an employee of Daiichi Sankyo, Inc. H. Kastrissios: 

H Kastrissios is an employee of Pharsight Corporation and was retained by Daiichi 

Sankyo to provide scientific consulting services on tivantinib. M. Jansen: M Jansen is 

an employee of Daiichi Sankyo, Inc. R. Savage: R Savage is currently an employee of 

ArQule. I participate in the ESPP employee stock purchase plan and receive stock 

options as part of my compensation package as an employee of ArQule. 

G. Abbadessa: G Abbadessa is an employee of ArQule, Inc. and owns Arqule stock 

options. F. Chai: F Chai is an employee of ArQule, Inc., the sponsor of the studies. 

F Chai holds ArQule stock. B. Schwartz: B Schwartz is currently an employee (Chief 

Medical officer) of ArQule and own stock in the company. R. Miller: R Miller is a 

full time employee of Daiichi Sankyo Pharma Development. T. Tokui: T Tokui is an 

employee of Daiichi Sankyo Co., Ltd. All other authors have declared no conflicts of 

interest. 

739P PHASE 1 EXPERIENCE OF TIVANTINIB IN PATIENTS WITH 

HEPATOCELLULAR CARCINOMA (HCC) OR BILIARY TRACT 

CANCER (BTC) 

F. Chai 1 , G. Abbadessa 2 , R. Savage 3 , H. Zahir 4 , Y. Chen 2 , M. Lamar 5 , 

J. Kazakin 6 , D. Ferrari 2 , R. von Roemeling 7 , B. Schwartz 2 

1 Medical Administration, ArQule, Inc., Woburn, MA, UNITED STATES OF 

AMERICA, 2 Clinical Development, ArQule, Inc., Woburn, MA, UNITED STATES 

OF AMERICA, 3 Preclinical Development and Clinical Pharmacology, ArQule, Inc., 

Woburn, MA, UNITED STATES OF AMERICA, 4 Clinical Pharmacology, Daiichi 

Sankyo, Inc., Edison, NJ, UNITED STATES OF AMERICA, 5 Clinical Operations, 

ArQule, Inc., Woburn, MA, UNITED STATES OF AMERICA, 6 Arqule, Inc., ArQule, 

Inc., Woburn, MA, UNITED STATES OF AMERICA, 7 Clinical Development 

Oncology, Daiichi Sankyo Pharma Development, Edison, MA, UNITED STATES 

OF AMERICA 

Background: Tivantinib is a selective MET inhibitor that is extensively metabolized 

by the liver. Since 2006, > 700 cancer patients (pts) have been treated with tivantinib. 

Herein we summarize safety, pharmacokinetic (PK), and efficacy data for pts with 

HCC or BTC treated with tivantinib in phase 1 clinical trials. 

Methods: Adverse events (AEs) were assessed using Common Terminology Criteria 

for Adverse Events (CTCAE) version 3.0. Tumor responses were assessed via 

Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PK parameters 

were calculated using blood samples collected on day 1 and on day 2 or day 15 of 

cycle 1. 

Results: 53 pts (median age, 63 y) with HCC (n = 42; 79%), cholangiocarcinoma 

(n = 10; 19%), or gallbladder adenocarcinoma (n = 1; 2%) were included. Of these, 23 

pts (43%) received tivantinib monotherapy, and 30 pts (57%) received tivantinib in 

combination with sorafenib (n = 20; 38%), gemcitabine (n = 8; 15%), or erlotinib 

(n = 2; 4%). Starting tivantinib BID doses were < 240 mg in 3 (6%), 240 mg in 11 

(21%), and 360 mg in 39 (74%) pts. Common treatment-emergent AEs (≥ 15% of 

pts) were fatigue and anemia (45% each); diarrhea (40%); neutropenia and anorexia 

(38% each); asthenia (30%); thrombocytopenia, peripheral edema, pyrexia, and 

nausea (25% each); hyperbilirubinemia (23%); vomiting and alopecia (21% each); 

rash (19%); leukopenia (17%); and palmar-plantar erythrodysesthesia syndrome, 

dyspnea, and ascites (15% each). Tivantinib PK analysis indicated peak plasma levels 

2 h after oral administration (range, 1-6 h). Tivantinib exposure was higher in pts 

with HCC vs pts with BTC (12,385 vs 5,992 ng·h/mL). Best responses were complete 

response in 1 pt (2%), partial response in 2 pts (4%), and stable disease (SD) in 30 

pts (57%). Response rate and disease control rate were 6% and 62%, respectively. 

Conclusions: Tivantinib demonstrated a manageable safety profile and was well 

tolerated at doses up to 360 mg BID in pts with BTC and up to 240 mg BID in pts 

with HCC. Only pts with HCC had increased exposure, presumably due to 

disease-specific hepatic impairment. Encouraging clinical activity (primarily SD) was 

observed in this pt population. 

Disclosure: F. Chai: F Chai is an employee of ArQule, Inc., the sponsor of the 

studies and holds ArQule stock. G. Abbadessa: G Abbadessa is an employee of 

ArQule, Inc. and owns ArQule stock options. R. Savage: R Savage is currently an 

employee of ArQule and participates in the ESPP employee stock purchase plan and 

receives stock options as part of his compensation package as an employee of 

ArQule. H. Zahir: H Zahir is an employee of Daiichi Sankyo, Inc. Y. Chen: Y Chen 

is an ArQule employee and own ArQule stocks. M. Lamar: M Lamar is an employee 

of ArQule, Inc. J. Kazakin: J Kazakin is an employee of ArQule, Inc. and has 

ArQule’s stock options. D. Ferrari: D Ferrari is an ArQule Inc. employee and 

currently owns ArQule stock. R. von Roemeling: R von Roemeling is an employee of 

Daiichi Sankyo Pharma Development. B. Schwartz: B Schwartz is currently an 

employee of ArQule Inc. and own stock in the company. 

740P PHASE I STUDY OF NINTEDANIB (BIBF 1120) IN EUROPEAN 

PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA 

D. Palmer 1 , A.B. Loembé 2 , M. Studeny 2 , J. Hocke 3 ,T.Meyer 4 

1 Liverpool Cancer Research Uk Centre, University of Liverpool, Liverpool, 

UNITED KINGDOM, 2 Oncology, Boehringer Ingelheim RCV GmbH & Co KG, 

Vienna, AUSTRIA, 3 Oncology, Boehringer Ingelheim Pharma GmbH & Co.KG, 

Biberach an der Riss, GERMANY, 4 UCL Cancer Institute, University College 

London, London, UNITED KINGDOM 

Background: Caucasian and Asian patients (pts) with hepatocellular carcinoma 

(HCC) tolerate anticancer drugs differently. This open-label, multicentre, phase I/ 

randomised phase II study (NCT01004003; phase II in progress) evaluated the 

efficacy, safety and pharmacokinetics of nintedanib (a triple angiokinase inhibitor 

targeting VEGFRs, PDGFRs and FGFRs) versus sorafenib in pts with advanced HCC 

from Europe. Initial phase I results are reported. 

Methods: Pts (ECOG performance status ≤2, Child-Pugh [CP] score ≤7) with 

histologically/cytologically confirmed HCC and no prior systemic therapy were 

enrolled in the phase I trial and stratified into two groups: (I) AST and ALT ≤2 x 

upper limit of normal (ULN), and CP 5–6; (II) AST or ALT >2 to ≤5 x ULN, or CP 

7. Utilising a 3 + 3 design, cohorts received oral nintedanib continuously in 28-day 

courses, starting at 50mg bid (group II) or 100mg bid (group I) and escalating up to 

200mg bid in 50mg bid intervals. Therapy was continued until no clinical benefit or 

undue toxicity. The phase I primary endpoint was the maximum tolerated dose 

(MTD) of nintedanib in Course 1. 

Results: A total of 28 pts (71% Caucasian) have been treated: 13 in group I (median 

[range] days: 345 [2–757]; 100/150/200mg bid, n = 6/3/4) and 15 in group II (median 

[range] days: 74 [17–428]; 50/100/150/200mg bid, n = 3/4/4/4). No dose-limiting 

toxicities (DLTs) were seen in group I or II during Course 1 at doses up to 200mg 

bid, which was the MTD of nintedanib. After the dose-escalation phase and 

determination of MTD, seven pts reported DLTs at various dose levels (CTCAE 

Grade [G]3 bilirubin increase, G3 AST increase, G4 amylase increase, G3 

hypertension/ALP increase, G3 amylase increase, G5 multi-organ failure, G3 

bilirubin increase). The most frequent adverse events (AEs) in both groups, by 

system organ class, were gastrointestinal (89%) and general/administration site (39%) 

disorders. Class-related AEs (any grade) were uncommon (hypertension [n = 2], rash 

[n = 3]). Hepatic enzyme data will be presented. 

Conclusions: Nintedanib has an acceptable safety profile in pts with advanced HCC 

at the same dose used in other cancers (200 mg bid). 

Disclosure: D. Palmer: Daniel Palmer: research funding from Boehringer Ingelheim. 

A.B. Loembé: Arsene-Bienvenu Loembé: employee of Boehringer Ingelheim. M. 

Studeny: Matus Studeny: employee of Boehringer Ingelheim. J. Hocke: Julia Hocke: 

employee of Boehringer Ingelheim. T. Meyer: Tim Meyer: research funding from 

Boehringer Ingelheim 

741P VALIDATION OF PROGNOSTIC VALUE OF AJCC 7TH STAGING 

SYSTEM IN PATIENTS WITH RESECTED HEPATOCELLULAR 


S.F. Ang1 ,H.Li2 , S. Choo1 , I.B. Tan1 , M.H. Tan1 , H.C. Toh1 1 

Medical Onocology, National Cancer Center Singapore, SINGAPORE, 

2 

Department of Clinical Research, Singapore General Hospital, Singapore, 

SINGAPORE 

Background: Accurate cancer staging is essential to determine prognosis and 

appropriate treatment. The American Joint Committee on Cancer (AJCC) Staging 

Manual 7th edition for HCC released in 2010 subdivided stage III HCC to IIIA 

(multiple tumors of which any are greater than five centimeters, but lack major 

vessel invasion, T3A) and IIIB (invasion of major vessels, T3B). Both were previously 

classified as stage IIIA in the AJCC 6th. T4N0M0 and patients with node-positive 

disease (N1) are upstaged to stage IIIC and IVA respectively. The aim of our study is 


validate the revised AJCC 7th staging system based on outcomes of patients 

undergoing liver resection for HCC from a single institution. 

Methods: Records for all patients undergoing potentially curative surgery for 

localized HCC between 1992 – 2007 were retrospectively reviewed. Pathological 

staging were determined post-operatively. Survival curves were plotted with the 

Kaplan–Meier method and were compared by using a log-rank test for various 

disease stages based on AJCC 7th staging system. 

Results: 543 patients were included (439 male) and 80% were Chinese ethnicity. 303 

patients were chronic hepatitis B carriers. The median follow up was 1.78 years with 

282 relapsed patients (51.9%) and 189 deaths (34.8%). Median survival (MS) and 

time-to-relapse (TTR) were 4.83 years and 2.00 years respectively. MS for AJCC 7 

stage I, II, III and IV were 6.35, 4.44, 2.41 and 0.49 years respectively (p


Methods: Phase I pts had histologically, cytologically or clinically confirmed HCC, 

ECOG performance status ≤2, Child-Pugh (CP) score ≤7, and ≤1 line of prior 

systemic therapy. Using a 3 + 3 design, pts were stratified into two groups by liver 

function and CP score: (I) AST and ALT ≤2 x upper limit of normal (ULN), and CP 

5–6; (II) AST or ALT >2 x to ≤5 x ULN, or CP 7. Nintedanib (given continuously in 

28-day courses) was started at 50mg bid (group II) or 100mg bid (group I) and 

increased in 50mg bid increments up to 200mg bid. Therapy was continued until no 

clinical benefit or undue toxicity. The phase I primary endpoint was the 

maximum-tolerated dose (MTD) of nintedanib. 

Results: Overall, 35 pts have received nintedanib: 11 in group I(100/150/200 mg 

bid, n = 4/3/4; median [range] duration: 140 [10–337] days) and 24 in group II 

(50/100/150/200 mg bid, n = 3/7/3/11; median [range] duration: 81 [2–587] days). 

In group I, no dose-limiting toxicities (DLTs) were seen at any dose during the 

first course. In group II, one pt experienced a DLT (CTCAE Grade [G] 3 AST 

increase) at 100 mg bid in Course 1 (dose-escalation phase). The MTD of 

nintedanib was thus 200 mg bid in both groups. DLTs seen after MTD 

assessment were G4 gastrointestinal (GI) haemorrhage/anaemia (50 mg bid), G3 

ALT increase (150 mg bid), G3 GI haemorrhage (150 mg bid), G3 hypertension 

(200 mg bid; n = 2) and G4 gastric ulcer (200 mg bid). The most common 

adverse events, by system organ class, were GI (83%) and general/administration 

site disorders (51%), and investigations (51%). Hypertension and rash (any 

grade) occurred in 6 and 8 pts, respectively. 

Conclusions: Nintedanib has an acceptable safety profile in this Asian HCC 

population. As in other cancer types and European HCC pts, the MTD of nintedanib 

was 200 mg bid. 

Disclosure: C. Yen: Chia-Jui Yen: research funding from Boehringer Ingelheim. Y. 

Shen: Ying-Chun Shen: research funding from Boehringer Ingelheim. H. Shiah: 

Her-Shyong Shiah: research funding from Boehringer Ingelheim. J. Chen: Jo-Pai 

Chen: research funding from Boehringer Ingelheim. C. Hsu: Chiun Hsu: research 

funding from Boehringer Ingelheim. C. Hsu: Chih-Hung Hsu: research funding from 

Boehringer Ingelheim. D.C. Huang: Dennis Chin-Lun Huang: employee of 

Boehringer Ingelheim. J. Hocke: Julia Hocke: employee of Boehringer Ingelheim. W. 

Su: Wu-Chou Su: research funding from Boehringer Ingelheim. A. Cheng: Ann-Lii 

Cheng: research funding from Boehringer Ingelheim. 

745P PACLITAXEL AND CISPLATIN COMBINED WITH 

INTENSITY-MODULATED RADIOTHERAPY FOR UPPER 

ESOPHAGEAL CARCINOMA 

L. Tu 1,2 , L. Sun 1,2 , Y. Gong 1,2 , Y. Liu 1 , L. Zhou 1,2 , X. Zhou 1 ,Y.Xu 1 , J. Wang 1 , 

M. Hou 1 ,Y.Lu 1,2 

1 Department of Thoracic Oncology, Cancer Center, West China Hospital, 

Sichuan University, CHINA, 2 State Key Laboratory of Biotherapy, West China 

Hospital, Sichuan University, Chengdu, CHINA 

Purpose: Concurrent radio-chemotherapy has been recommended as a standard 

therapy in patients with upper esophageal carcinoma which is not suitable for 

surgery. Although INT 0123 trial indicated that the 5-fluorouracil (5-FU) plus 

cisplatin (DDP) combined with radiotherapy was the initial strategy, the optimal 

management of upper esophageal carcinoma remains undetermined. This study was 

conducted to evaluate the effectiveness and safety of intensity-modulated 

radiotherapy (IMRT) and concurrent paclitaxel plus cisplatin (TP regimen) for upper 

esophageal carcinoma. 

Materials and methods: 36 patients of upper esophageal carcinoma were 

retrospectively analyzed. Patients were treated with IMRT (median 60 Gy) combined 

with concurrent TP regimen chemotherapy. The Kaplan-Meier analysis was 

performed in statistical analysis. Toxicities were recorded according to the NCI CTC 

version 3.0. 

Results: 36 patients aged 43-73 years (median 57 years). The median follow-up 

period was 14.0 months. The 1-year and 2-year survival rates were 83.3% and 42.8%, 

respectively. The median progression-free survival (PFS) time and overall survival 

(OS) time were 12.0 (95% CI 8.6-15.4 months) and 18.0 months (95% CI 14.2-21.8 

months), respectively. Grade 3 neutropenia, radiation-induced esophagitis and 

radiodermatitis were observed in 5 (13.9%), 3 (8.3%) and 8 (22.2%) patients, 

respectively. There were two treatment-related deaths due to esophageal perforation 

and hemorrhea. 

Conclusions: For those patients with upper esophageal carcinoma, IMRT combined 

with concurrent TP regimen chemotherapy was an effective treatment. However, 

special attention should be paid to the occurrence of perforation and hemorrhea. 


746P PHASE I/II STUDY OF NC-6004, A NOVEL MICELLAR 

FORMULATION OF CISPLATIN, IN COMBINATION WITH 

GEMCITABINE IN PATIENTS WITH PANCREATIC CANCER 

IN ASIA – RESULTS OF PHASE I 

W. Su 1 , L. Chen 1 ,C.Li 2 , J. Chen 3 ,Y.Lin 4 , S. Choo 5 , Y. Matsumura 6 

1 Internal Medicine, National Cheng Kung University Hospital, Tainan, TAIWAN, 

2 Merdicine, Taipei Veterans General Hospital, Taipei, TAIWAN, 3 Internal Medicine, 

Chang Gung Memorial Hospital, Taipei, TAIWAN, 4 Oncology, National Taiwan 

University Hospital, Taipei, TAIWAN, 5 Medical Oncology, National Cancer Center 

Singapore, SINGAPORE, 6 Innovative Oncology, National Cancer Center Hospital 

East, Kashiwa, JAPAN 

Introduction: NC-6004 is a cisplatin-incorporated polymeric micelle with a size of 

30 nm in diameter composed of polyethylene glycol-polyglutamic acid block 

co-polymer via polymer-metal complex formation. A phase I study of NC-6004 

monotherapy in patients with advanced solid tumours confirmed that NC-6004 

exhibits delayed and sustained release of cisplatin characterized by lower Cmax and 

higher AUC compared to an equivalent dose of cisplatin, resulting in the reduction 

of cisplatin-related toxicity, and 2 out of 17 patients with pancreatic cancer 

demonstrated the evidence of disease stabilization. Preclinical studies demonstrated 

that NC-6004 in combination with gemcitabine (GEM) was effective against 

pancreatic cancer. On the basis of these results, phase I part of a phase I/II study of 

NC-6004 in combination with GEM in patients with pancreatic cancer has been 

conducted at 4 sites in Taiwan and 1 site in Singapore. The objectives of the study 

were to determine the MTD and RD of NC-6004 in combination with GEM in the 

treatment of pancreatic cancer for the following phase II study. 

Methods: A total of 19 patients with pancreatic cancer were treated with NC-6004 at 

a dose of 30, 60, 90 and 120 mg/m 2 once every 3 weeks, and GEM at 1000 mg/m 2 

twice every 3 weeks on Day 1 and 8. The 2-dose oral steroid regimen was 

implemented to reduce the risk of hypersensitivity. 

Results: Two DLTs occurred at 120 mg/m 2 , which led to the conclusion that the 

MTD and the RD of NC-6004 in combination with GEM are 120 mg/m 2 and 

approximately 90 mg/m 2 , respectively. In the interim analysis of ITT population for 

efficacy evaluation (17 patients), no patient had CR based on RECIST criteria, 

however best overall response (BOR) of PR was found in 1 (5.9%) and 10 (58.8%) 

had a BOR of SD, resulting in the disease control ratio of 64.7%. Because of the 

stringent prophylactic steroid regimen, eight out of 19 (42.1%) completed the 

per-protocol period (8 cycles; 24 weeks), and 1 of them reached cycles up to 20. 

Conclusion: Treatment with NC-6004 in combination with GEM was relatively well 

tolerated, and exhibited modest efficacy in patients with pancreatic cancer. 


747P PREVALENCE, CLINICAL FEATURES AND PROGNOSIS OF 

DIFFUSE MALIGNANT PERITONEAL MESOTHELIOMA 

(DMPM): DO PATIENTS IN CLINICAL TRIALS REFLECT THE 

REAL WORLD? 

F. Grosso 1 , D. Degiovanni 2 , A. Roveta 1 , S. Barbero 3 , R. Libener 1 , F. Musante 4 , 

O. Testori 5 , D. Mirabelli 6 , P.G. Betta 7 , M. Botta 8 

1 Oncology, SS Antonio e Biagio General Hospital, Alessandria, ITALY, 2 Palliative 

Care, S Spirito General Hospital, Casale Monferrato, ITALY, 3 Radiology, S Spirito 

General Hospital, Casale Monferrato, ITALY, 4 Radiology, SS Antonio e Biagio 

General Hospital, Alessandria, ITALY, 5 Nuclear Medicine, SS Antonio e Biagio 

General Hospital, Alessandria, ITALY, 6 Epidemiology Cancer Unit, University of 

Tumor, Turin, ITALY, 7 LILT, SS Antonio e Biagio General Hospital, Alessandria, 

ITALY, 8 Oncology, S Spirito General Hospital, Casale Monferrato, ITALY 

Background: Peritoneum is the second most frequent site of origin of malignant 

mesothelioma (MM). DMPM is the most frequent primary peritoneal malignancy in 

developed countries. Highly specialized centres have reported improved outcomes 

following an aggressive loco-regional approach, including cytoreductive surgery 

(CRS) and perioperative intraperitoneal chemotherapy (PIC), with median overall 

survival (OS) approaching 50 months and almost 50% relapse-free patients at 5 

years. Conversely, in population based studies prognosis still remains very poor with 

OS in the range of 5.7-10. To describe clinical features and prognosis in unselected 

consecutive patients, we report on the clinical outcome of a series of DMPM treated 

at a single Oncological Department, in a highly asbestos-polluted area in Piedmont. 

Patients and methods: By using our database (MesoDB), we retrieved DMPM 

patients diagnosed between November 1993 and September 2011 at Alessandria and 

CasaleMonferratoHospitals. All cases were confirmed by the same expert 

pathologists. 


Results: Among 862 MM we identified 35 patients, 9 F and 26 M. Median age at 

diagnosis was 67 years, IQR 61-73, range 30-83. Occupational asbestos exposure was 

definite in 23 and probable in 2 patients, whereas environmental in 10. The histological 

diagnosis followed a laparoscopic/laparotomic procedure in 25 patients, the other 10 had 

only US-guided, fine-needle aspiration biopsy. Only 1 patient in the series underwent 

CRS and PIC. The others were deemed unsuitable for surgery. Ten patients had systemic 

chemotherapy, 6 pemetrexed and 2 raltritrexed-based. The other 25 received only best 

supportive care and among these 3 received also subcutaneous IFNbeta or IL2 and 1 

intraperitoneal IFNbeta. PFS of the 12 patients receiving systemic therapy was 3.9 

months (range 1-7,7). Median OS was 6.1 months (95%CI 2-8,7). 

Conclusions: DMPM accounts for 5% of MMs in our mesoDB, a percentage lower 

than reported in the literature. Outcomes in our patients were more disappointing 

compared to those reported by referral centres, but similar to population-based 

studies. These differences emphasize the strict selection of patients enrolled into 

aggressive loco-regional treatment programs and the need for new therapeutic 

approaches suitable for the real clinical practice setting. 


748 EXPRESSION AND CLINICAL SIGNIFICANCE OF NPRA 

IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA 

J. Wang 1 , Z. Zhao 1 , H. Fang 2 , E. Tangsakar 1 , J. Zhang 1 

1 Department of Surgical Oncology, First Affiliated Hospital, Medical School, Xi’an 

Jiaotong University, Xi’an, CHINA, 2 Department of Thoracic Surgery, Second 

Hospital of Yulin, Yulin, CHINA 

Background and objective: Esophageal cancer is a main reason of cancer related 

mortality, and the tumer targeted therapy is a new and effective treatment. NPRA 

(natriuretic peptide receptor A), as a new oncogene, that promotes tumorigenesis in 

several cancer types, might represent a novel therapeutic target in esophageal cancer. 

In this study we suggested that the expression and clinical significance of NPRA in 

esophageal squamous cell carcinoma (ESCC). 

Methods: The expression of NPRA in 45 cases of ESCC tissues, 40 cases of adjacent 

tissues, 30 positive Lymph node tissues and 24 negative Lymph node tissues were 

assessed by SP immunohistochemical method. No patients received preoperative 

chemotherapy, radiation therapy, and immune therapy and all of patients were 

confirmed for ESCC by pathologist at Department of Thoracic Oncosurgery, the First 

Affiliated Hospital of Xi , an Jiaotong University. 

Results: In esophageal squamous cells, the expression of NPRA was strongly detected 

in cytoplasm, while undetectable or very weak in nuclear. The positive rates of 

NPRA in the cancer tissues was 71.1%, while that in the adjacent tissues group was 

17.5%, and showed 63.32% and 24.3% in the positive Lymph node tissues and 

negative Lymph node tissues respectively, there was a significant difference between 

the two groups ( P>0.05). Clinicopathological analyses revealed that increased 

cytoplasmic NPRA expression correlated with differentiation and TNM stage, while 

showed no statistically significant among the association of age, gender, and lymph 

node metastasis. 

Conclusion: Our findings demonstrate that the NPRA has high expression in ESCC 

tissues, and the positive rate is closely correlated with the differentiation and TNM 

stage, and suggest that NPRA represents a potential therapeutic target. 


749 A PHASE II TRIAL OF NEOADJUVANT CONCURRENT 

CHEMO-RADIOPTHERAPY CONTAINING CISPLATIN AND 5-FU 

FOLLOWED BY RESECTION FOR ESOPHAGEAL CARCINOMA 

K. Anvari, S.A. Aledavood, M. Seilanian Tousi, F. Nosrati 

Cancer Research Center, Omid Hospital, Faculty of Medicine, Mashhad 

University of Medical Sciences, Mashhad, IRAN 

Introduction: Combined modality treatments have been adopted to improve survival 

in patients with esophageal carcinoma. In this trial, we evaluated the efficacy and 

toxicity of a preoperative concurrent chemoradiotherapy protocol in patients with 

locally advanced esophageal carcinoma. 

Method and material: Between 2006 and 2011, eligible patients with locally 

advanced esophageal carcinoma underwent concurrent radiotherapy (40 Gy/20 

fractions) and chemotherapy (cisplatin 20 mg/m 2 for 4 days plus 5-FU 700 mg/m 2 

24-hour infusion for 4 days on the first and the last week of radiation therapy). In 

patients with unsuitable hematological or general condition only one cycle of 

chemotherapy was prescribed. The patients underwent esophagectomy 3 to 4 weeks 

following radiation therapy. Pathologic response, overall survival rate, toxicity and 

feasibility were evaluated. 

Results: 197 patients with a median age of 59 (range; 27-70) with a female to male 

ratio of 100/97 entered the protocol. 194 cases (98.5%) had esophageal SCC. Grades 

3-4 of toxicity were as follows: neutropenia in 41 (21%) and esophagitis in 5 (2.5%) 

cases. There were 11 (5.6%) early death probably due to treatment related toxicities. 

The other reasons for not completing the protocol were as follows: toxicity in 6 (3%), 

refusing surgery in 35 (17.8%), improper general condition for surgery in 18 cases 

(9.1%). 127 cases (64.5%) completed the protocol among which 60 cases received 2 

courses of chemotherapy. For patients who underwent surgery, the complete 

pathological response was shown in 38 cases (29.9%) with a 5-year overall survival 

rates of 47.2 % and median overall survival of 33 months. There were no significant 

difference in overall survival rates in patients receiving one or two cycles of 

chemotherapy (log-rank p = 0.64). 

Conclusion: The pathological response rate and the overall survival rate are 

promising in patients who completed the protocol as receiving at least one cycle of 

chemotherapy. However, the toxicity rates were relatively high. prescribing two cycles 

of chemotherapy resulted in no significant improvement in survival rate as compared 

with those receiving one cycle. 


750 HER2 STATUS IN OESOPHAGOGASTRIC JUNCTION AND 

GASTRIC CANCER – THE IRISH LANDSCAPE 

A. Jayaram 1 , J.E. Battley 2 , M.Y. Teo 3 , R. Abdul Rahman 4 , R. Bambury 2 , 

M.W. Bennett 5 , M. Margaret Sheehan 6 , R. McDermott 3 , D.G. Power 7 , 

G. Leonard 8 

1 MA, Galway University Hospital, Galway, IRELAND, 2 Medical Oncology, Cork 

University Hospital, Cork, IRELAND, 3 Dept. of Medical Oncology, AMNCH 

Adelaide and Meath Hospital, Dublin, IRELAND, 4 Medical Oncology, AMNCH 

Adelaide and Meath Hospital, Dublin, IRELAND, 5 Pathology, Cork University 

Hospital, Cork, IRELAND, 6 Pathology, Galway University Hospital, Galway, 

IRELAND, 7 Medical Oncology, Mercy University Hospital, Cork, IRELAND, 

8 Medical Oncology, University College Hospital Galway, Galway, IRELAND 

HER2 is overexpressed in ∼ 7-34% of gastroesophageal (GE) adenocarcinomas. The 

ToGA study, established the benefit of trastuzumab in combination with 

chemotherapy in HER2(+) metastatic GE tumours. In this study, 22% of patients 

were HER2(+) {immunohistochemistry (IHC)3+ or fluorescence insitu hybridization 

(FISH)(+)}. We report a multi-center Irish experience by examining HER2 status by 

IHC and FISH in GE tumours. 

Methods: Database from three regional cancer centres were examined to identify pts 

with junctional or gastric adenocarcinoma. HER2 testing was performed on biopsy 

or resection specimens of patients with early stage and metastatic GE tumors 

between 2008–2011. We defined HER2 positive as IHC3+ or FISH(+) 

{HER2:17ch ≥ 2}. In addition, age, gender, histology, stage of disease, were recorded. 

Clinicopathologic characteristics were extracted and compared with t-test or Fisher’s 

exact as appropriate. 

Results: Between 2008 and 2011, 177 pts were identified. Median age was 68 years 

(range: 25 – 96), 36% were male. Gastric tumours were identified in 51%, while 53% 

were metastatic at diagnosis. Median number of metastatic sites was 1 (0 – 4). IHC 

and FISH were performed on 170 pts (96%) and 131 (74%) of patients. Distribution 

of IHC score of 0, 1, 2 and 3 were 38%, 32%, 19% and 11%, respectively. With 

respect to tumour heterogeneity of HER2 amplification, in IHC3 + , 50% were 

FISH(+), IHC2 + , 21.1% were FISH(+) and IHC1 + , 3.7% were FISH(+). Overall 

HER2(+) rate for the cohort was 16.4% (n = 29). Comparing patients with HER2(+) 

and HER2(-)disease, gender (males, 38 vs 38%, p = .84), age(69 vs 68, p = .79) and 

site distribution gastric, (45 vs 52%, p = .54) were identical .The rate of metastasis at 

diagnosis were similar, at 54 vs 53%. Presence of metastases in the liver (69 vs 48%, 

p = .22), peritoneum (38 vs 49%, p = .55), brain (8 vs 3%, p = .44) were comparable 

in both patient cohorts. 

Conclusions: HER2(+) GE adenocarcinomas in the analyzed cohort displays similar 

pattern of heterogeneity in IHC staining and FISH positivity but with lower 

incidence (16.4%) of HER2 amplification than was reported in the ToGA study. 

Further analysis did not identify differences in clincopathologic characteristics in 

HER2 + ve patients. 


751 CLINICOPATHOLOGICAL SIGNIFICANCE OF 

HYPOXIA-INDUCIBLE FACTOR-1 ALPHA (HIF-1α) 

EXPRESSION IN GASTRIC CANCER 


T. Isobe, K. Aoyagi, K. Hashimoto, J. Kizaki, M. Miyagi, K. Koufuji, T. Sasatomi, 

K. Shirouzu 

Department of Surgery, Kurume University School of Medicine, Kurume, 

Fukuoka, JAPAN 

Background: Hypoxia is a common feature of rapidly growing solid tumors. 

Therefore, cellular adaptation to hypoxia and altered glucose metabolism are 

fundamental to the biology of cancer cells. Hypoxia-inducible factor-1α (HIF-1α) is 

a transcription factor for over 60 genes recognized to control the delivery of oxygen 

and nutrients through the induction of angiogenesis and glycolysis under hypoxic 

condition. Therefore, Inhibition of expression of HIF-1α will be expected to the 

tumor specific molecular target-based therapy. In this study, we evaluated the 

significance of HIF-1α expression in relation to the clinicopatholgical factors, the 



prognosis, VEGF expression, and microvessel density (MVD) expressed as the mean 

count of CD34 immunostained vessels in gastric cancer. 

Methods: Paraffin-embedded tumor specimens from 128 patients who underwent 

gastrectomy at the Kurume University from 2004 to 2005 were used to assess the 

clinical significance of HIF-1α expression. We used ABC method to perform an 

immunohistochemical analysis of HIF-1α, VEGF expression, and MVD. 

Results: 84(65.6%) of gastric cancer specimens were positive for HIF-1α expression. 

The multivariate analysis showed that the histology, depth of invasion, VEGF 

expression, and MVD were significantly associated with the HIF-1α expression. On 

relapse-free and overall survival curves, the HIF-1α negative group was significantly 

higher than the HIF-1α positive group. The HIF-1α expression was identified as 

significant predictor of relapse-free survival and overall survival by Multivariate Cox’s 

proportional hazard analyses. 

Conclusion: Overexpression of HIF-1α was found to be a poor prognostic factor for 

patients with gastric cancer and correlated with histology, depth of invasion, and VEGF. 


752 CLINICOPATHOLOGIC SIGNIFICANCE OF EXPRESSION OF 

NUCLEAR FACTOR KAPPA B AND VASCULAR ENDOTHELIAL 

GROWTH FACTOR IN GASTRIC CANCER PATIENTS 

H. Kwon 1 , K.W. Park 2 , S. Kim 3 

1 Internal Medicine, Dong-A University Medical Center, Busan, KOREA, 2 Internal 

Medicine, Dankook University, Cheonan, KOREA, 3 Pathology, Dong-A University 

Medical Center, Busan, KOREA 

Aim: Nuclear factor-κB (NF-κB) and vascular endothelial growth factor (VEGF) are 

involved in cell proliferation, invasion, angiogenesis and metastases. The principal 

objective of this study was to assess the prognostic significance of NF-κB and VEGF 

expression in gastric cancer. 

Methods: The tumor tissues of 154 patients with gastric cancer, all of whom 

underwent potentially curative resection, were immunohistochemically evaluated 

using monoclonal antibodies against NF-κB and VEGF. 

Results: Positivity rates of NF-κB and VEGF were 44.2% and 39.6%, respectively. 

NF-κB expression in tumor tissues was correlated significantly with VEGF expression 

(p < 0.001). VEGF expression was related to Lauren’s classification (p = 0.002), 

differentiation (p = 0.043), depth of invasion (p = 0.005), carcinoembryonic antigen 

(p = 0.032), and stage (p = 0.026). However, NF-κB expression was not related to any 

of these parameters. Univariate analysis demonstrated that NF-κB expression was 

significantly related with both 5-year disease free survival (65.2% vs. 46.4%, p = 

0.007), and 5-year overall survival (60.0% vs. 42.5%, p = 0.014). Multivariate analysis 

verified that NF-κB was independently associated with disease free survival (hazard 

ratio: 2.082, p = 0.005), and overall survival (hazard ratio: 1.841, p = 0.008). However, 

VEGF did not appear to be related to adverse clinical outcome. 

Conclusion: NF-κB expression in tumor tissue is associated with poor survival in 

gastric cancer patients. 


753 DOCETAXEL, CISPLATIN AND FLUOROURACIL AS 

PERIOPERATIVE CHEMOTHERAPY IN RESECTABLE 

GASTROESOPHAGEAL CARCINOMA: A RETROSPECTIVE 

ANALYSIS 

F. Fiteni 1 , Z. Lakkis 2 , T. Nguyen 1 , C. Borg 1 , B. Benzidane 1 , V. Nerich 3 ,B.Heyd 2 , 

X. Pivot 1 , C.H.S. Kim 1 

1 Medical Oncology, Hopital Minjoz, Besançon, FRANCE, 2 Digestive Surgery, 

Hopital Minjoz, Besançon, FRANCE,, 3 Pharmacy, Hopital Minjoz, Besançon, 

FRANCE 

Introduction: Perioperative chemotherapy has demonstrated a survival benefit versus 

surgery alone in resectable gastroesophageal adenocarcinoma (RGC). The association 

Docetaxel, cisplatin, and fluorouracil (DCF) is superior to cisplatin and fluorouracil 

in advanced gastric cancer. The efficacy and safety of perioperative DCF regimen in 

patients with RGC was retrospectively analyzed. 

Patients and methods: All patients with RGC assigned by the staff to receive 

perioperative DCF regimen were included in the analysis. Chemotherapy consisted of 

three preoperative cycles of intravenous docetaxel 75 mg/m 2 and cisplatin 75 mg/m 2 

(day 1) plus fluorouracil 750 mg/m 2 (days 1 to 5) every 3 weeks followed by 3 

postoperative cycles of this regimen. 

Results: Forty-nine patients with gastric cancer were analysed (38 adenocarcinoma 

subtype and 11 Signet Ring Cell (SRC)). A total of 37 patients (76%) completed the 

3 preoperative planned cycles of DCF, and 45 (92%) undergone to surgery. Then 16 

patients (33%) underwent postoperative chemotherapy based on DCF nevertheless 5 

patients only (10%) completed 3 cycles. Among patients with adenocarcinoma, 

pathological complete response (pCR) rate was 8% and 45 % had a partial response 

(PR) above 50% (grade 1a/1b/2 according to Becker’s classification). Among patients 

with SRC, no pCR and 9% of PR were observed. Histological complete resection rate 

was 89% among patients with adenocarcinoma and 55% among patients with SRC. 

Median overall survival and progression-free survival were 58 months (95% CI, 

58-non achieved) and 43 months (95% CI, 16-non achieved) respectivelly. 

Conclusion: In patients with RGC, DCF perioperative regimen is feasible and 

significantly active. Prospective assessment is justified. One could consider to exclude 

SRC taking into account the poor activity observed. 


754 A PHASE I TRIAL OF BORTEZOMIB IN COMBINATION WITH 

EPIRUBICIN, CARBOPLATIN AND CAPECITABINE (ECARBOX) 

IN ADVANCED GASTRIC AND GASTRO-OESOPHAGEAL 

JUNCTION (GOJ) ADENOCARCINOMA 

R.C. Turkington, C. Purcell, R.H. Wilson, M.M. Eatock 

Northern Ireland Cancer Centre, Belfast City Hospital, Belfast, UNITED 

KINGDOM 

Background: Combination chemotherapy is the treatment of choice for patients with 

advanced oesophago-gastric cancer and efforts to incorporate novel agents into 

chemotherapy regimens have been problematic. Bortezomib (Velcade®) attenuates the 

action of the transcription factor NF-κB, and has shown preclinical activity alone 

and in combination with chemotherapy in oesophago-gastric cell lines. 

Design: A Phase I dose-escalation study using a 3 + 3 design was performed with 

Bortezomib (Velcade®) in combination with Epirubicin 50 mg/m 2 day1, Carboplatin 

AUC 5 day 1 and Capecitabine 625 mg/m 2 BD days 1-21 every 21 days, in advanced 

or metastatic gastro-oesophageal adenocarcinoma. Bortezomib was administered at 

four dose levels of 0.7, 1.0, 1.3 and 1.6 mg/m 2 on days 1 + 8. Due to myelotoxicity 

the dose of capecitabine was reduced to 500 mg/m 2 after the first patient cohort. The 

primary end point was to define the maximum tolerated dose (MTD) of Bortezomib 

when combined with ECarboX with secondary end points of radiological response 

rate (RR) and toxicity. 

Results: 20 patients, 18 evaluable for response, were enrolled (6 gastric, 9 GOJ and 3 

oesophageal), 2 were Stage III and 16 Stage IV. The overall RR was 33.3% with 6 

patients achieving a partial response. An additional 7 patients had stable disease for 

an overall Disease Control Rate (DCR) of 61.1%. Common grade 3/4 adverse events 

included nausea, fatigue, anaemia, neutropenia and thrombocytopenia. The first 3 

patients developed grade 4 neutropenia and pyrexia resulting in a protocol 

amendment reducing the Capecitabine dose to 500 mg/m 2 BD. Bortezomib-induced 

pulmonary infiltrates occurred in one patient treated at dose level 2, requiring 

discontinuation of Bortezomib and withdrawal from the study. Recruitment is 

ongoing at dose level 4 and the MTD is yet to be defined. 

Conclusions: The addition of Bortezomib to amended combination chemotherapy 

for locally advanced or metastatic gastro-oesophageal adenocarcinoma has not been 

previously investigated and is well tolerated. Response rates are comparable with 

standard chemotherapy and updated data will be presented. 


755 OXALIPLATIN, IRINOTECAN, BEVACIZUMAB FOLLOWED BY 

DOCETAXEL, BEVACIZUMAB IN INOPERABLE GASTRIC 

CANCER. A MULTICENTER PHASE II TRIAL (AGMT GASTRIC-3) 

OF THE ARBEITSGEMEINSCHAFT MEDIKAMENTöSE 

TUMORTHERAPIE (AGMT) 

E. Wöll 1 , F. Keil 2 , J. Thaler 3 , B. Gruenberger 4 , M. Hejna 5 , W. Eisterer 6 , 

M.A. Fridrik 7 , F. Romeder 8 ,R.Greil 8 

1 Internal Medicine, St. Vinzenz Krankenhaus Zams, Zams, AUSTRIA, 2 Internal 

Medicine, Hanusch Krankenhaus, Vienna, AUSTRIA, 3 Internal Medicine, Klinikum 

Wels Grieskirchen, Wels, AUSTRIA, 4 1 Medical Oncoloy, Krankenhaus der 

Barmherzigen Br, Vienna, AUSTRIA, 5 Internal Medicine, Medical University 

Vienna, Vienna, AUSTRIA, 6 Department of Internal Medicine, University Hospital 

Innsbruck, Innsbruck, AUSTRIA, 7 Internal Medicine 3, Allgemeines Krankenhaus 

Linz, Linz, AUSTRIA, 8 Internal Medicine III, University Hospital Salzburg, 

Salzburg, AUSTRIA 

Background: In previous phase II trials (AGMT-Gastric-1 and AGMT Gastric-2) we 

could show efficacy of oxaliplatin and irinotecan as well as oxaliplatin, irinotecan and 

cetuximab in advanced gastric cancer. Time to progression however was short suggesting 

acquired chemotherapy resistance. To address this problem sequential chemotherapy 

combined with bevacizumab is investigated in the presented Gastric-3 trial. 

Methods: Oxaliplatin 85 mg/m 2 biweekly (q2w) and irinotecan 125 mg/m 2 q2w are 

administered for the first three months followed by docetaxel 50mg/m 2 q2w for 

subsequent three months. Chemotherapy is combined with bevacizumab 5 mg/kg 

q2w which is administered until progression. For this abstract 36 pt. with 

histologically proven unresectable and/or metastatic gastric adenocarcinoma treated 

in a first line setting have been evaluated. Median age: 62.5 years (range 26-80 years), 

PS 0: 25 patients, PS 1: 10 patients, missing: 1 patients, single metastatic site: 24 

patients, multiple metastases: 10 patients, missing: 2. 


Results: Frequently reported adverse events (more than 20% of pts.) were 

predominantly grade 1 or 2 and included diarrhea (25/36, 69%), polyneuropathy 

(17/36, 47%), nausea (17/36, 47%), fatigue (15/36, 42%), neutropenia (13/36, 36%), 

abdominal pain (11/36, 31%), hypokalemia (9/36, 25%). Grade 3 and 4 toxicities 

included neutropenia (6/36, 17%), diarrhea (3/36, 8%), hypokalemia (3/36, 8%), 

anemia in (2/36, 6%), leucopenia (2/36, 6%), thrombocytopenia (1/36, 3%), nausea in 

(1/36, 3%). Weight loss Grade 1 was initially documented in 1/36 pts., (3%). 

Objective response rate after 3 cycles was available in 25 patients: CR 1/25 (4%), PR 

14/25 (56%), SD 8/25 (32%), PD 2/25 (8%). After 6 cycles there were 12 evaluable 

patients with CR 2/12 (16.7%), PR 5/12 (41.7%), SD 4/12 (33.3%) and PD 1/12 

(8.3%). Median time to progression was 24 weeks, median overall survival was 48 

weeks. Progression total was 12/36 (33%). 

Conclusions: The combination of oxaliplatin and irinotecan with bevacizumab followed 

by docetaxel with bevacizumab is feasible and active in advanced gastric cancer. 


756 CLINICAL OUTCOME OF ADVANCED GASTRIC CANCER (GC) 

PATIENTS RECEIVING FIRST-LINE CHEMOTHERAPY 

ACCORDING TO TUMOUR HISTOLOGY AND LOCATION 

A. Bittoni 1 , M. Scartozzi 1 , R. Giampieri 1 , L. Faloppi 1 , M. Bianconi 1 , 

A. Mandolesi 2 , M. Del Prete 1 , M. Pistelli 2 , I. Bearzi 2 , S. Cascinu 1 



Riuniti Ancona Università Politecnica delle Marche, Ancona, ITALY 

Background: In the daily clinical practice GC is considered as a single disease. 

However, preliminary data identified distinct subtypes characterized by relevant 

differences in epidemiology, carcinogenesis and gene expression profiles. Recently, 

a new classification has been proposed, based on Lauren’s histology and on anatomic 

tumour location, identifying three subtypes: type 1 (proximal non diffuse GC), type 

2 (diffuse GC) and type 3 (distal non diffuse GC). Aim of our analysis was to 

compare clinical outcome (in terms of response rate, RR, progression-free survival, 

PFS, and overall survival, OS) according to different GC subtypes (1,2,3) in patients 

(pts) receiving first-line chemotherapy. 

Patients and methods: Advanced GC pts treated with a first-line combination 

chemotherapy were included in our analysis. Pts were divided in three subgroups 

(type 1, type 2 and type 3) as previously defined. 

Results: A total of 202 advanced GC pts were included: most of pts belonged to type 

2 (50.5%) and type 3 (40.6%); type 1 included 18 pts (8.9%). The majority of pts 

(62%) received a three-drugs chemotherapy combinations including a platinum 

derivate, a fluoropyrimidine with the addition of an anthracycline, a taxane or 

mytomicin C; the remaining patients received a platinum and fluoropyrimidine 

combination. The three pts subgroups resulted comparable for relevant clinical 

factors such as ECOG PS, tumour stage, number of metastatic sites, previous surgical 

resection, first-line combination and use of second-line treatments; as expected 

peritoneal carcinosis was more common in type 2 pts. RR was found to be higher in 

type 3 pts (RR = 45.1%) than in type 1 (27.8%) and type 2 (25.5%) (p = 0.017). Type 

2 pts presented a shorter PFS (median PFS 5.7 months) compared to type 1, median 

PFS = 6.9 months, and type 3, median PFS = 7.8 months (p = 0.0069). These 

differences did not translate in statistically significant differences in OS. 

Conclusions: Our results suggest that GC subtypes may be important predictors of 

benefit from chemotherapy in advanced GC patients. Future clinical trials should 

take in account these differences for a better stratification of patients. 


757 A RANDOMIZED, SINGLE CENTER PHASE II TRIAL OF 

CAPECITABINE PLUS CISPLATIN VERSUS TS-1 PLUS 

CISPLATIN AS FIRST LINE TREATMENT IN PATIENTS WITH 

ADVANCED OR METASTATIC GASTRIC CANCER 

J. Lee 1 , S.Y. Roh 2 , E. Jeon 1 , S.H. Hong 2 , Y.H. Ko 1 , H.S. Won 1 , H.J. An 1 , 

K.W. Park 3 , J.H. Kim 1 , Y.S. Hong 1 

1 Division of Oncology, Department of Internal Medicine, Seoul St. Mary’s 

Hospital, Seoul, KOREA, 2 Medical Oncology, Catholic Medical Center, Seoul, 

KOREA, 3 Medical Oncology, Fatima Hospital, Daegu, KOREA 

Background: Platinum agents and oral fluoropyrimidines are widely used in the 

treatment of advanced gastric cancer. This study was aimed to evaluate the efficacy 

and safety of two combination regimens (capecitabine plus cisplatin [XP] vs S-1 plus 

cisplatin [SP]) in patients with untreated recurrent or metastatic gastric cancer. 

Methods: Patients diagnosed as untreated recurrent or metastatic gastric cancer were 

randomly assigned to either capecitabine (2500 mg/BSA/day; day 1-14) plus cisplatin 

(60 mg/BSA/day; day 1), every 3 weeks or TS-1 (80-120 mg/day; day 1-14) plus 

cisplatin (60 mg/BSA/day; day 1), every 3 weeks. Primary end point was overall 

response rate (ORR), accessed by RECIST criteria (ver. 1.0). The secondary end point 

was progression free survival (PFS), overall survival (OS), and toxicities. 

Results: 86 patients were anticipated to be enrolled, but 51 patients were randomized 

to XP (25 patients) arm or SP (26 patients) arm because enrollment was slower than 


expected. ORR of XP and SP was 52% (13 of 25 assessable patients) vs. 44% (15 of 

25 assessable patients), and no significant differences were found (P = 0.778). OS of 

XP vs. SP was 10.3 months (95% CI; 4.8-15.8) vs. 12 months (95% CI; 9.5-14.5), 

with no differences (P = 0.785). PFS was 4.6 months (95% CI; 4.6-5.2), 4.4 months 

(95% CI; 2.2-6.6) each (P = 0.68). The incidence of grade 3-4 neutropenia of XP vs. 

SP was 40% vs. 43.2%. There were no febrile neutropenia in XP arm, but 7.7% in SP 

arm. Grade 3-4 thrombocytopenia was 12%, 3.8% each. Other grade 3-4 toxicities 

were; Nausea (4% vs. 0%), Stomatitis (12% vs. 3.8%), Hand-foot syndrome (16% vs. 

0%), Diarrhea (0% vs. 3.8%). Median relative dose intensity of capecitabine vs. TS-1 

was 78.7% (range 51.9-116.7%), 87.5% (range 57.1-166.7%). 

Conclusion: There were no significant differences in ORR, OS, and PFS between XP 

vs. SP arm. The incidence of grade 3-4 neutropenia was similar in both arms, but 

thrombocytopenia was relatively more common in XP arm. SP was more tolerable 

than XP in non-hematologic toxicities. Considering the usual dosage of capecitabine 

in monotherapy is 2500 mg/BSA/day, capecitabine 2500 mg/BSA/day combined with 

cisplatin 60 mg/BSA may be overdosed, and higher rate of non-hematologic toxicity 

can be explained. Dosage of capecitabine when combined with cisplatin, needs to be 

further adjusted for routine use. 


758 FEASIBILITY OF ORAL ADMINISTRATION OF S-1 FOR 

ADJUVANT CHEMOTHERAPY OF GASTRIC CANCER; 4-WEEK 

S-1 ADMINISTRATION FOLLOWED BY 2-WEEK REST VS. 

2-WEEK ADMINISTRATION FOLLOWED BY 1-WEEK REST 

T. Yamatsuji 1 , Y. Fujiwara 2 , H. Matsumoto 3 ,S.Hato 4 , T. Namikawa 5 , 

K. Hanazaki 5 , M. Ninomiya 2 , T. Fujiwara 6 , T. Hirai 3 , Y. Naomoto 1 

1 Department of General Surgery, Kawasaki Hospital, Kawasaki Medical School, 

Okayama, JAPAN, 2 Department of Surgery, Hiroshima City Hospital, Hiroshima, 

JAPAN, 3 Digestive Surgery, Kawasaki Medical School, Kurashiki, JAPAN, 

4 Depatment of Surgery, Shikoku Cancer Center, Matsuyama, JAPAN, 

5 Department of Surgery, Kochi Medical School, Nankoku, JAPAN, 6 Department 

of Gastroenterological Surgery, Okayama University Graduate School of 

Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JAPAN 

Background: In 2006, ACTS-GC study revealed that S-1 is an effective adjuvant 

therapy of gastric cancer. Following the study, S-1 is used as the standard treatment 

for adjuvant therapy for gastric cancer in Japan. S-1 therapy with 4-week 

administration followed by 2-week rest was continued for 6 months in 78%, and 12 

months in 66% of the patients. The compliance is the critical problems of the 

therapy. Tukuda et al. reported a randomized study of S-1 for adjuvant 

chemotherapy of advanced head and neck cancer, showing that the feasibility of 

4-week administration followed by 2-week rest for 6 months was 29%, and 2-week 

administration followed by 1-week rest was 40%. They claimed that the 2-week 

administration followed by 1-week rest seems to be more feasible in adjuvant therapy 

of squamous cell carcinoma of the head and neck. There is no study of the feasibility 

for S-1 in adjuvant chemotherapy of gastric cancer. Here we conducted a study to 

evaluate the feasibility, safety and efficacy of S-1 in adjuvant chemotherapy of gastric 

cancer. 

Method: The criteria for eligibility were histologically proven gastric cancer of stage 

II (excluding T1), IIIA or B with D2 lymph-node dissection. Patients were randomly 

assigned to either arm A; S-1 administration for 4 weeks followed by a 2-week rest or 

arm B; S-1 administration for 2 weeks followed by a 1-week rest. In each arm, the 

therapy was continued for 12 months unless there was any recurrence or severe 

adverse event. The primary end point was feasibility. The secondary were the safety 

of S-1, relapse-free and overall survival. 

Results: We randomly assigned 46 patients to the arm A or B between May 2008 

and February 2010. The first interim analysis showed the feasibility of the arm A and 

B, those were 83% and 100% in 6 months, 49% and 89% in 12 months respectively. 

S-1 administration for 2 weeks followed by a 1-week rest was more feasible in 

adjuvant chemotherapy of gastric cancer (P = 0.0046). Adverse events of grade 3 in 

the arm A were anorexia (8.0%), nausea (4.0%). There is no event of grade 3 in the 

arm B, and no event of grade 4 in both arms. Efficacy of the therapies; relapse-free 

survival and overall survival will be reported in the few years. 

Conclusion: The schedule of 2-week administration followed by 1-week rest is more 

feasible for oral administration of S-1 in adjuvant chemotherapy of gastric cancer. 


760 DOCETAXEL, CISPLATIN, 5-FLUOROURACIL AND 

LEUCOVORIN AS FIRST-LINE THERAPY IN ADVANCED 

GASTRIC CANCER (AGC) 

E. Trusilova, N. Besova, V.A. Gorbunova 

Chemotherapy, N.N. Blokhin Russian Cancer Research Center, Moscow, 


Purpose: AGC is relatively chemosensitive, but a standard chemotherapy (CT) 

regimen has yet to emerge, and responses are of short duration. Docetaxel-containing 

combinations are new option for pts with AGC. The V325 trial demonstrated the 



efficacy benefit of adding docetaxel to CF (cisplatim + 5-fluorouracil) (DCF). DCF is 

associated with significant toxicity, making it less tolerable to pts. We modified the 

original DCF regimen to reduce its toxicity without decreasing efficacy. 

Patients and methods: AGC pts received docetaxel 75 mg/m 2 and cisplatin 75 mg/ 

m 2 in day2 with leucovorin 50 mg and 5-fluorouracil 500 mg/m 2 (3-hour infusion) in 

day 1-3 every 3w (TPF) instead of original DCF (docetaxel 75 mg/m 2 , cisplatin 75 

mg/m 2 in day 1 and fluorouracil 750 mg/m 2 in day 1-5 continuous infusion). 

Results: 39 CT-naïve pts with AGC were included in our study from Feb2008 to 

Dec2010 (20 female, 19 male). ECOG 0/1/2 were10/80/10% pts. ORR was 40% (16/39), 

SD – 40% (16/39), PD – 20% (7/39). Median PFS and median OS were evaluated in 

38pts and were 5,4m and 9,5m, respectively. Toxicity was moderate. Grade 3 and 4 

toxicities included leucopenia – 32,5 and 7,5%, neutropenia – 25 and 40%, 

thrombocytopenia – 2,5 and 0% pts, febrile neutropenia -1pt (2,5%); asthenia – 2,5 and 

0%, stomatitis – 2,5 and 0%, diarrhea – 12,5 and 0%, vomiting – 0 and 2,5% pts. We 

didn’t use G-CSF prophylaxis. There were no deaths and treatment discontinuation due 

to toxicity. At present 5 pts are still alive, in three of them distant mts disappeared and 

operation became possible. Their survival is 28,5m (without PD), 32.9m with PD over 

10m after surgery and 42m with PD over 12m after surgery. 

Conclusion: Our data suggest that TPF regimen has the similar efficacy and better 

tolerability than the standard DCF. TPF regimen can be safely given in an ambulant 

setting. 


761 SECOND-LINE DOCETAXEL (D) IN METASTATIC GASTRIC 

CANCER (MGC) 

C. Caparello 1 , M. Lencioni 1 , E. Vasile 1 , S. Caponi 1 , S. Santi 2 , M.G. Fabrini 3 , 

L. Ginocchi 1 , M. Lucchesi 1 , S. Ricci 1 , A. Falcone 1 



2 Department of Gastroenterology, Esophageal Surgery Unit, Tuscany Regional 

Referral Center for the Diagnosis and Treatment of Esophageal Disease, Pisa, 

Italy, Pisa, ITALY, 3 Division of Radiation Oncology, S. Chiara Pisa Hospital, Pisa, 

Italy, Pisa, ITALY 

Background: Although second-line chemotherapy with irinotecan or docetaxel 

seemed to confer an improvement in overall survival over best supportive care, at 

today no standard second-line chemotherapy regimen is approved in MGC. 

Methods: The objective of our retrospective analysis was to evaluate the activity of a 

second-line taxane-based treatment in MGC patients (pts). 

Results: A total of forty-eight pts (M/F 40/8; ECOG PS at second-line treatment 0/1/ 

2: 23/22/3) were included in the study; median age 67 years (range 38-86). All pts 

received a first-line fluoropyrimidine-based chemotherapy; 42 in combination with 

platinum compounds (9 received a triplet with anthracyclines and 2 with Herceptin) 

and 6 in monochemotherapy. 46 pts were evaluable for analysis: 37 pts received a 

docetaxel monochemotherapy (16 weekly, 5 biweekly and 16 three-weekly schedule), 

10 a combination of docetaxel with fluorouracil, 1 with cisplatin. Grade 3 or 4 

toxicities included: anemia 3 pts, neutropenia 6 pts, diarrhea 1 patient, fatigue, 

vomiting and neurotoxicity 1 patient each, stomatitis 2 pts; 13 pts needed a delay of 

treatment and 5 a reduction of doses. Among 46 evaluable pts 7 (15.2%) experienced 

a partial response, 13(28.3%) a stable disease, 26(56.5%) a progression of disease. 24 

pts received a third-line chemotherapy, 21 of these an irinotecan-based treatment. 

Median progression-free survival was 4.3 months and median overall survival was 8.6 

months from the start of second-line treatment. No significant differences were 

found in mPFS, RR and toxicity profile between different treatment schedules. mPFS 

seemed to be longer in patients with PS 0 than in patients with PS 1 or 2 (5.4 

months versus 2.1 and 0.95 respectively; p = 0.046). No difference in mPFS was 

detected according to RR at first-line therapy. 

Conclusions: Docetaxel in MGC second-line setting seems to have an encouraging 

activity with an acceptable toxicity profile. 


762 THIRD-LINE FOLFIRI IN METASTATIC GASTRIC CANCER 

PATIENTS 

C. Caparello 1 , E. Vasile 1 , M. Lencioni 1 , M.G. Fabrini 2 , M. Lucchesi 1 , L. Ginocchi 1 , 

S. Caponi 1 , S. Santi 3 , S. Ricci 1 , A. Falcone 1 



2 Division of Radiation Oncology, S. Chiara Pisa Hospital, Pisa, Italy, Pisa, ITALY, 

3 Department of Gastroenterology, Esophageal Surgery Unit, Tuscany Regional 

Referral Center for the Diagnosis and Treatment of Esophageal Disease, Pisa, 

Italy, Pisa, ITALY 

Background: The use of systemic chemotherapy increased median survival of advanced 

gastric cancer patients. Besides fluoropyrimidines and platinum compounds, different 

active agents such as docetaxel and irinotecan became available giving physicians the 

opportunity to administer to patients further lines of treatment. Second-line 

chemotherapy with docetaxel or irinotecan showed improved overall survival over best 

supportive care. There are many patients progressed after two lines of therapy who 

maintain a good performance status that could be evaluated for further treatment. 

Methods: The aim of this retrospective analysis was to evaluate the activity of the 

combination of 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) as third-line 

treatment for metastatic gastric adenocarcinoma patients. 

Results: A total of twenty-one patients (M/F 16/5; ECOG Performance Status 0/1: 3/ 

18) treated between 2009 and 2011 were included in the study; median age was 64 

years (range 38-77). All the patients had received first-line fluoropyrimidine plus 

platinum compound chemotherapy; in 7 of them a triple-drug combination with 

epirubicin was used; one patient with HER-2 positive tumor was treated with 

trastuzumab in combination with chemotherapy. All patients had received taxanes in 

second-line (docetaxel in 18 and paclitaxel in 3 patients), in 5 cases in association with 

5-fluorouracil. A total of 151 cycles of third-line FOLFIRI were administered (median 

number 7; range 2-18). Treatment was well tolerated; grade 3 or 4 toxicities included 

neutropenia in 3 patients, diarrhea in 3 patients, asthenia and vomiting in 1 patient 

each; delay of treatment was required in 9 patients and a reduction of doses only in 3 

cases. Among the twenty evaluable patients, two (10%) partial responses and 8 (40%) 

stable disease were observed, thus obtaining a disease control in half of patients. 

Median duration of response was 7 months. Median progression-free survival was 3.8 

months. Median overall survival from the start of third-line treatment was 9.1 months. 

Conclusions: FOLFIRI was feasible and showed interesting activity also in third-line 

setting of largely pretreated selected metastatic gastric cancer patients. 


763 EPIDEMIOLOGICAL DATA OF PATIENTS WITH GASTRIC 

CANCER IN MEXICO 

G.C. Ruiz1 , N. Reynoso1 , C. Diaz1 , E.B. Ruiz1 , E. Trejo1 , A. Mohar-Betancourt2 1 

Medical Oncology, Instituto Nacional de Cancerologia, Mexico City, MEXICO, 

2 

Biomedical Research, Instituto Nacional de Cancerología (INCan), Mexico City, 

MEXICO 

Introduction: The gastric cancer is very common neaplasm in Asia and Central and 

SouthAmerica. With large differences among patients diagnosed and treated in 

Europe, America and Asia. We present some epidemiological data of patients with 

gastric cancer. 

Methods: Methodology was analyzed the database of all patients diagnosed of 

adenocarcinoma of the stomach from January 1999 to December 2011 served in the 

Medical Oncology service. 

Results: We identified 1179 patients evaluated by Medical Oncology, these 1130 with 

histology adenocarcinoma, 40 with stromal tumor gastro-intestinal, 3 with 

leiomiosarcoma, 3 with scamous cell and 3 with neuroendocrine tumor. Of the cases 

with adenocarcinoma, 56% were men with a mean age of 55.8 years +/- 13.6 and 

44% occured in women with a mean age of 52.2 years +/- 13.4 (p < 0.0001). The 

17.5% is presented in patients with 40 years o less. The more common histologic 

subtipe is diffuse in 54% versus 30% intestinal y 5% mixed (in 11% nondeterminate). 

In patients with diffuse type-adenocarcinoma 88% are poorly 

differentiated and 72% with signet ring cells. Gender difference was no observed, but 

in relation to age, for patients under 40 years 72% is diffuse versus 40% in over 40 

years (p < 0.0001). The location of the tumor is in the stomach in 86% of the cases 

versus 14% in the esophago-gastric junction, noting a significant difference in 

relation to sex, with 8.6% in women versus 18% in men (p < 0.0001). The stages 

were: 33 cases (2.8%) stage I, 34 cases (2.9%) stage II, 103 patients (8.7%) stage III, 

194 cases (18.8%) with disease locally advanced, non-surgical and 766 patients 

(68.0%) stage IV. Of the patients with stage IV, 18% was confirmed by surgical and 

histological findings or T4 or N3, M0 (AJCC 6th edition). The most common sites 

of metastases are the peritoneum/ascitis in 58%, liver 26%, retroperitoneal 13%, 

ovarian 9.6% and lung 7.3%. 

Conclusions: Gastric cancer in Mexico is a serious health problem, is diagnosed in 

young patients with poor prognostic factors as the diffuse histological type, poorly 

differentiated and signet-ring cells. The location of the tumor in esophago-gastric 

junction is more common in men. The diagnosis in made in most patients in 

advanced stages (III-IV). 


764 FORTY-ONE CASES OF METASTASIS FROM GASTRIC CANCER 

TO THE CENTRAL NERVE SYSTEM: EXPERIENCE AT SINGLE 

CENTER 

H. Shoji1 , T. Hamaguchi1 , Y. Honma1 , S. Iwasa1 ,K.Kato1 , Y. Yamada2 , 

Y. Shimada1 1 

Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, JAPAN, 

2 

Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, 

JAPAN 

Background: Metastasis from gastric cancer to the central nerve system (CNS) is a 

rare entity, and there is little information available regarding evaluation of these 

patients. The purpose of this study was to evaluate the clinical characteristics of 


gastric cancer patients with CNS metastasis and to clarify treatment outcomes in 

metastatic gastric cancer to the CNS. 

Methods: This retrospective study reviewed data from gastric cancer patients with 

CNS metastasis treated at our institution from 2000 to 2011. 

Results: 2195 patients with metastatic gastric cancer were included in this study. 

41 of these patients (1.87%) were found to have CNS metastasis (32 men, 9 

women; median age, 62.0 years). Leptomeningeal metastases and brain metastases 

were identified in 11 and 30 patients; Stage IV disease and recurrence were 

identified in 25 and 16 cases; and main metastatic sites were lymph nodes, 

peritoneum, liver, and bone in 22, 12, 7 and 6 cases, respectively. 

Histopathologically, 29 patients (70.7%) had diffuse-type adenocarcinoma. Most 

frequent symptoms were headache, nausea/emesis, cataplexy, and convulsion. 

Thirty-six patients received systemic chemotherapy. The median interval from the 

initiation of systemic chemotherapy to the diagnosis of CNS metastasis was 7.4 

months. Among leptomeningeal patients, 9 patients received symptomatic therapy 

such as steroid and 2 patients received intrathecal chemotherapy. Median survival 

time from the diagnosis of leptomeningeal metastases was 27 days. Among brain 

metastasis patients, 47% had a solitary lesion, while 53% had multiple lesions. 

Five patients received symptomatic therapy (group 1), 18 patients received 

radiotherapy (group 2) such as whole-brain radiation therapy or gamma knife 

radiosurgery, and 7 patients received resection ± radiotherapy (group 3). Median 

survival time from the diagnosis of brain metastases was approximately 1.8 

months for patients in group 1 and 2. Group 3 patients survived longer than 

group 1 and 2 patients at median 8.4 months. 

Conclusions: The treatment outcome in metastatic gastric cancer to the CNS was 

poor. Among brain metastases patients, patients who received resection ± 

radiotherapy showed a more favorable outcome compared to other treatment groups. 


765 RESULTS OF SURGERY OF GASTRIC LYMPHOMAS 

COMPLICATED WITH BLEEDING, STENOSIS AND 

PERFORATION 

V. Shalenkov, S. Nered, I. Stilidi 

Abdominal Surgery, N.N. Blokhin Russian Cancer Research Center of Russian 

Academy of Medical Sciences, RUSSIAN FEDERATION 

Background: Our purpose is to study results of surgery of patients with primary 

non-Hodgkin’s lymphomas complicated with bleeding, stenosis and perforation. 

Materials and methods: 66 patients with primary non-Hodgkin’s lymphomas were 

treated in our centre between 1984 and 2009 because of bleeding – 49, stenosis – 11, 

gastric perforation – 6. Group under study included 28 females and 38 males, mean 

age was 49. Bleedings from benign gastric ulcers and gastric perforations outside of 

tumor lesions’ zones were excluded from the study. The histological types: diffuse 

large B cell lymphoma – 50 patients (76%), MALT-lymphoma – 12 (18,5%), Burkitt’s 

lymphoma – 4 (6%). Localization of the lesions: overall – 29 patients (44%), antrum 

– 22 (33%), stomach’s body – 9 (15%), proximal part – 6 (9%). 26 patients (39%) 

had stage I, 19 (29%) – II, 21 (31,5%) – IV. 45 patients (68%) had complications 

before chemotherapy, 8 (12%) – during the course, 13 (20%) – after. Patients after 

chemotherapy had gastric perforation more frequent (in 20% of cases) than 

chemo-naive patients (4,3%, p = 0,063). Gastrectomy was performed for 47 patients 

(71%), subtotal gastrectomy – 12 (19%). 

Results: 43 (65,1%) patients had radical operations, 14 (21,2%) had palliative 

gastrectomy or gastric resection, 4 (6%) had bypass operations and 5 (7,5%) had only 

explorative laparotomy. Overall postoperative mortality was 11%. 35% patients had 

postoperative complications. The most frequent complications were 

subdiaphragmatic abscess (5,2%), postoperative wound infection (5,2%) and 

pneumonia (5,2%). Overall 3-, 10- and 10-year survival rate in the group under study 

was 75%, 65% and 40%, respectively; median survival was 100 months. Patients after 

radical operations had higher three- and five-year survival rates than patients after 

palliative gastrectomies and resections (82% and 73% vs. 51% and 44%), however 

ten-year survival rates in both groups were practically the same. 

Summary: Complications of gastric lymphomas can occur at any stage of the disease. 

Aggressive surgical approach allows to ablate affected organ and remove the source of 

fatal complications for 86% of patients. Due to postoperative chemotherapy, more 

than half of patients survive 5 years after surgery. 


766 19-YEAR SINGLE CENTER EXPERIENCE IN THE 

MANAGEMENT OF PATIENTS WITH PRIMARY 

GASTROINTESTINAL (GI) LYMPHOMA 


W. Fischbach, N. Mueller 

Medizinische Klinik Ii, Klinikum Aschaffenburg, Aschaffenburg, GERMANY 

Introduction: Primay GI lymphoma are a rare disease. Multicenter studies were, 

therefore, initiated in the 90ies with various published results in subgroups of GI 

lymphoma who were not treated within a controlled clinical trial. 

Method: As a German reference center patients with GI lymphoma are regulary 

presented to our institution. From 1993 on, we saw 102 consecutive patients (59 

male and 43 female, age 31-89 years) with primary GI lymphoma: gastric MALT 

lymphoma = 76 (63 stage I, 6 stage II, 7 stage III/IV); secondary high MALT 

lymphoma = 3; diffuse large B-cell lymphoma (DLBCL) = 14 (stage I/II/III-IV) = 

8/4/2); Burkitt lymphoma = 1; intestinal follicular lymphoma (FL) grade I/II = 8 

(stage I/II/III-IV = 5/1/2). Treatment strategies were as follows: MALT-lymphoma: 

H. pylori eradication; radiation (RTx) and/or chemotherapy (CTx) in stages ≥ II or 

in case of eradication failure; DLBCL: CTx except in 3 cases who were treated by 

H. pylori eradication only; FL: no therapy, CTx or RTx. 

Results: 26/47 patients (55%) with MALT lymphoma achieved complete remission 

(CR) after exclusive H. pylori eradication. Application of all therapeutic procedures 

resulted in CR = 53/76 (70%) and PR with watch-and-wait = 22/76 (29%). There was 

only 1 patient revealing progression. In DLBCL, 12 (86 5) achieved CR after 1-3 line 

therapies. In FL, watch-and-wait resulted in long-term stable disease in n = 5, CR 

after RTx in 1 case, and stable disease after CTx in 2 cases. 

Conclusion: Despite a negative selection of patients being presented to our reference 

center the overall treatment results in all subgroups of GI lymphoma are excellent 

when all treatment options are offered in a sequential therapeutic strategy. 

Watch-and-wait is a promising approach in MALT lymphoma with residual disease 

following H. pylori eradication and in FL. 


767 THE DIAGNOSIS OF MALIGNANT PANCREATIC TUMOURS BY 

CIRCULATING TUMOUR CELL DETECTION 

P. Basile 1 , I. Iwanicki-Caron 2 , E. Toure 3 , M. Antonietti 1 , S. Lecleire 1 , F. Di Fiore 4 , 

J.C. Sabourin 3 , P. Michel 2 

1 Gastroenterology and Digestive Oncology, University Hospital of Rouen, Rouen, 

FRANCE, 2 Gastroenterology and Digestive Oncology, CHU de Rouen, Rouen, 

FRANCE, 3 Department of Pathology, Inserm U614, Rouen University Hospital, 

Rouen, FRANCE, 4 Digestive Oncology Unit, C.H.U. Charles Nicolle, Rouen, 

FRANCE 

Introduction: The fine needle aspiration by endoscopic ultrasound guide (EUS FNA) 

is a diagnostic examination of choice in solid tumour of the pancreas. This invasive 

technique has a sensitivity of about 70%. The search for circulating tumour cells 

(CTC) is a non invasive procedure, which could represent an alternative or 

complement to EUS FNA diagnostic. The objective of this prospective pilot study 

was to evaluate the diagnostic value of research CTC versus EUS FNA for the 

diagnosis of a solid tumour of the pancreas (STP). 

Patients and methods: From 01/01 to 30/09/2011, all patients undergoing an EUS 

FNA for a STP were included. EUS FNA was performed with a 22 gauge needle and 

analyzed by two experienced pathologists. For detection of CTC, 10 ml of blood 

collected in the periphery before FNA was filtered by technology ScreencellCyto â, 

stained with Giemsa and analyzed by a cytologist. Peripheral cells were considered 

tumour if they had the following morphology: kernel> 7 m, anisocytosis, membrane 

irregularities, presence of a large nucleolus. 

Results: Twenty six patients with TSP were included (14 men and 12 women), mean 

age was 64.2 years. The tumor was potentially resectable in 11 cases, 8 cases had a 

locoregional recurrence and 7 a metastatic extension. In total, 23/26 cases were 

analyzed due to technical failure of the CTC research (insufficient material) and two 

technical failures of EUS FNA. 20 patients had cancer objectified (including 15 

adenocarcinomas or 57%) by EUS FNA pancreatic histological analysis of the 

specimen and/or clinical course. In this population of 26 patients the sensitivity of 

the search CTC was 60%, specificity 100%, positive predictive value 100% and 

negative predictive value of 27%. On the results of FNA sensitivity for the diagnosis 

of cancer was 75%, specificity 100%, PPV of 100% and NPV of 37.5%. In patients 

whose FNA was contributory to the sensitivity of CTC research was 83%, specificity 

54%, PPV of 66% and NPV of 75%. 



Conclusion: The detection of CTC for the diagnosis of adenocarcinoma in case of 

tumours of the pancreas is a technique feasible, non-invasive, with a satisfactory 

diagnostic yield. The results of this pilot study, the continued progress in the analysis 

of CTC and a confirmation of this results in a higher independent population could 

allow us to propose this procedure in a first diagnostic step. 


768 GEMOX PLUS ERLOTINIB FOR THE TREATMENT OF 

METASTATIC PANCREATIC ADENOCARCINOMA 

T. Füreder 1 , G.V. Kornek 1 , I. Kührer 2 , C. Zielinski 3 , J. Klech 1 , W. Scheithauer 1 

1 Internal Medicine I, Medical University of Vienna, Vienna, AUSTRIA, 2 Surgery, 

Medical University of Vienna, Vienna, AUSTRIA, 3 Department of Medicine I and 

Clinical Division of Oncology, Medical University of Vienna and Central European 

Cooperative Oncology Group (CECOG), Vienna, AUSTRIA 

Introduction: Based on demonstration of a significant improvement in overall 

survival in a placebo-controlled phase III trial, gemcitabine in combination with 

erlotinib has been approved for the treatment of metastatic pancreatic cancer. 

In patients with good performance status, gemcitabine combination chemotherapy, 

i.e. with oxaliplatin (GEMOX) is commonly being used. Although there is some 

evidence that GEMOX plus erlotinib is beneficial in a subgroup of patients compared 

to GEMOX alone in cholangiocellular carcinoma no such data exist for pancreatic 

cancer. Thus, we performed this retrospective analysis in unselected patients to 

investigate the efficacy and safety of this chemotherapy regimen. 

Patients and methods: Forty-four patients with metastatic adenocarcinoma of the 

pancreas receiving off-protocol GEMOX in combination with erlotinib at a single 

institution between January 2006 and September 2011 were included in this analysis. 

Data collection included baseline demographic, clinical and toxicity data as well as 

objective response according to RECIST criteria, progression-free survival (PFS) and 

overall survival (OS). 

Results: A total of 44 patients were included in this study. The mean age was 60.5 

years, and the median ECOG performance score was 1 (range, 0-1). GEMOX in 

combination with erlotinib was first line regimen in 84% of the patients. Clinical 

response and disease stabilization was achieved in 45% of the patients. The median 

PFS was 4 months (range 0.5-43) and median overall survival was 9.6 months (range 

0.7-54.7). However, the subgroup of 20 patients, who benefited from this regimen in 

terms of abrogation of progression, had a PFS of 11.2 and an OS of 15.4 months. 

Myelosuppression was the most frequent side effect. The most common severe 

nonhematological toxicity was diarrhea (5/44). 

Conclusions: These data suggest that the combination of GEMOX plus erlotinib is 

safe and active in about half of the patients treated with this regimen. Identification 

of (bio)markers would be desirable in order to be able to select patients, who are 

most likely to benefit from this therapeutic strategy. 


769 CYCLIN E1 SUPPRESSION CONTRIBUTES TO 

SORAFENIB-INDUCED APOPTOSIS IN HEPATOCELLULAR 


C. Hsu 1 ,D.Ou 2 , Y. Cheng 3 ,Y.Lin 1 , Y. Chang 4 ,K.Yeh 2 , A. Cheng 5 

1 Department of Oncology, National Taiwan University Hospital, Taipei, TAIWAN, 

2 Graduate Institute of Oncology, National Taiwan University College of Medicine, 

Taipei, TAIWAN, 3 Gradualte Institute of Medical Technology, National Taiwan 

University College of Medicine, Taipei, TAIWAN, 4 Oncology, National Taiwan 

University Hospital, Taipei, TAIWAN, 5 Internal Medicine, National Taiwan 

University Hospital, Taipei, TAIWAN 

Background: We have found that sorafenib can inhibit cyclin E1 expression in HCC 

cells, which is independent of the inhibitory effects of sorafenib on mitogen-activated 

protein kinase-extracellular signal-regulated kinase/extracellular signal-regulated 

kinase signaling. The present study sought to clarify the role of cyclin E1 in 

sorafenib-induced apoptosis in HCC. 

Methods: A panel of HCC cell lines, including sorafenib-sensitive (Huh-7, HepG2) 

and sorafenib-resistant (Hep3B, Huh-7R and HepG2R) HCC cells, was tested. 

Apoptosis was measured by flow cytometry. Knockdown of cyclin E1 expression 

were used by RNA-interference. Over-expression of cyclin E1 was done by transient 

transfection of pCMV6-AC-GFP-CCNE1 vector (RG204289; Origene Technologies). 

The activity of pertinent signaling pathways, cell cycles-related proteins and 

expression of apoptosis-related proteins were measured by Western blotting. 

Results: Cyclin E1 mRNA and protein expressions were suppressed after sorafenib 

treatment in sorafenib-sensitive but not in sorafenib-resistant HCC cells. The changes 

in cyclin E2 or cyclin D1 expression after sorafenib treatment were not correlated 

with sorafenib sensitivity of HCC cells. Knockdown of cyclin E1 expression reversed 

the resistance of HCC cells to sorafenib in terms of cell growth and apoptosis 

induction, whereas over-expression of cyclin E1 increased the resistance of HCC cells 

to sorafenib. Combination of sorafenib and the cyclin-dependent kinase (CDK) 

inhibitor flavopiridol synergistically inhibited cell growth and induced apoptosis in 

HCC cells. The synergistic efficacy was associated with suppression of Bcl-XL 

expression in HCC cells. 

Conclusion: Cyclin E1 expression in HCC cells may serve a predictive biomarker 

for treatment efficacy. Combination of sorafenib and CDK inhibitors may improve 

the therapeutic efficacy of sorafenib in HCC. (Supported by grants: 

NSC100-2314-B-002-058-MY3, NSC101-2325-B-002-039, and 

NHRI-EX101-9911BC) 

Disclosure: C. Hsu: Dr Chiun Hsu is a member of the speaker’s bureau of 

Bayer-Schering Pharma. A. Cheng: Dr Ann-Lii Cheng is a consultant for 

Sanofi-Aventis Inc.; Pfizer, Bayer Schering Pharma; Bristol-Myers Squibb (Taiwan) 

Ltd.; Boehringer Ingelheim Taiwan Limited; Novartis Inc. All other authors have 


770 SORAFENIB VERSUS CAPECITABINE IN THE MANAGEMENT 

OF ADVANCED HEPATOCELLULAR CARCINOMA 

M. Abdelwahab 1 , M. Shaker 2 , S. Abdelwahab 1 , M. Elbassiouny 1 , M. Ellithy 1 , 

O. Abdelrhman 1 

1 Clinical Oncology, Ain Shams University, Cairo, EGYPT, 2 Tropical Medicine, 

Ain Shams University, Cairo, EGYPT 

Background: The only approved systemic therapy for patients with advanced 

hepatocellular carcinoma (HCC) till now is sorafenib. a preliminary study suggested 

that capecitabine, an oral fluoropyrimidine may be effective in advanced HCC. We 

have tested this hypothesis in this phase 2 study. 

Methods: In this single centre, phase 2, open label trial, we randomly assigned 52 

patients with advanced HCC who had not received previous systemic treatment to 

receive either sorafenib (at a dose of 400 mg twice daily) or capecitabine 1000 mg/m 2 

twice daily (day 1-day 14). Primary outcomes were progression free survival. 

Secondary outcomes included the overall survival and safety. 

Results: Median overall survival was 7.05 months in the sorafenib group and 5.07 

months in the placebo group (hazard ratio in the capecitabine group, 2.36; 95% 

confidence interval, 1.174-4.74; P < 0.016). The median progression free survival was 

6 months in the sorafenib group and 4 months in the capecitabine group (P < 0.005). 

Three patients in the sorafenib group (11.5%) and 1 patient in the capecitabine 

group (3%) had a partial response; one patient (3%) had a complete response in the 

sorafenib group. hand–foot skin reaction was more frequent in the sorafenib group, 

hyperbilirubinemia was more common in the capecitabine group and diarrhea was 

equivalent between both groups. 

Conclusions: In patients with advanced HCC, capecitabine monotherapy is inferior 

to sorafenib in terms of median progression free survival and overall survival and it 

should not be used alone for the treatment of advanced HCC but rather combination 

therapy of capecitabine plus sorafenib should be considered for further randomized 



771 LIVER SPECIFIC GRADED PROGNOSTIC ASSESSMENT CAN 

PREDICT THE OUTCOME FOR PATIENTS WITH BRAIN 

METASTASES FROM HEPATOCELLULAR CARCINOMA 

S. Lim 1 , S. Lee 1 , K. Han 2 , H. Choi 1 

1 Medical Oncology, Severance Hospital, Seoul, KOREA, 2 Gastroenterology, 

Severance Hospital, Seoul, KOREA 

Background: After the introduction of sorafenib which showed prolongation of 

survival in patients with advanced HCC, the incidence of brain metastasis seemed to 

increase. Assessment of prognostic factors might useful to decide treatment in 

patients with brain metastases. Although diagnosis-specific Graded Prognostic 

Assessment (GPA) has been identified for several cancer types, optimal treatment 

strategy for brain metastasis from HCC has not been well established. 

Methods: A total of 128 HCC patients were newly diagnosed with brain metastasis at 

Yonsei University Health Center between 1995 and 2011. Using SPSS program, 

univariate and multivariate analyses of the prognostic factors were performed. With 

the P value less than 0.10 as cutoff value, the significant prognostic factors were used 

to develop the HCC specific-GPA (HCC-GPA). 

Result: The median overall survival after brain metastasis in all patients was only 6.1 

weeks (95% confidence interval: 4.8-7.4 week). Significant prognostic factors were the 

presence of extracranial lesion, and Child-Pugh-Class score. Using those variables, we 

newly developed HCC-GPA: extracranial metastasis (Yes: 0, No: 1 point), and 

Child-Pugh-Score (C:0, B:1, A:2 point). The median survival time from brain metastasis 

were significantly separated by HCC-GPA grouping (3.1 weeks in group 1 (HCC-GPA 

score 0 or 1.0, N = 50), 8.0 weeks in group 2 (HCC-GPA score 2.0, N = 55), and 22.0 

weeks in group 3 (HCC-GPA score 3.0, N = 13); p< 0.001 by log rank test). 

Conclusion: Although the overall prognosis of patients with brain metastasis from 

HCC is dismal, the present data showed that newly developed HCC-GPA score can 


discriminate the prognosis of HCC patients with brain metastasis. It can be used as a 

valuable tool to select patients who can be good candidates for active local treatment. 


772 TRANSCATHETER ARTERIAL CHEMOEMBOLISATION FOR 

HEPATOCELLULAR CARCINOMA IN CIRRHOSIS: FEASIBILITY 

OF HEPATIC RESECTION 

O. Nematov 1 , S. Navruzov 2 , M. Djuraev 1 , S. Khudayorov 1 , D. Egamberdiev 1 , 

H. Tuyev 1 

1 Abdominal Oncology, National Cancer Center of Uzbekistan, Tashkent, 

UZBEKISTAN, 2 Administration, National Cancer Center of Uzbekistan, Tashkent, 

UZBEKISTAN 

Background: Hepatocelullar carcinoma (HCC) is the fifth most common cancer in 

the world. It mostly occurs in patients with cirrhosis. The aim of investigation is to 

evaluate the efficiency of transcatheter arterial chemoembolization (TACE) for 

unresectable HCC in cirrhosis and use of it in preoperative stage. 

Materials and methods: We evaluated data from 49 patients who had a confirmed 

diagnosis of HCC on cirrhosis. Median age of the patients was 56 years. Male – 35 

(71.4%, female – 14 (28.6%). In 33 (67.3%) cases tumor located in right lobe and in 

16 (32.7%) cases located in left lobe. In 7 (14.3%) cases tumor size consisted 8-12 cm, 

in 32 (65.3%) 12-15 cm and in 10 (20.4%) cases more than 15 cm. The underlying 

cirrhosis was staged as Child-Pugh A in 14(28.6%) cases and Child-Pugh B in 35 

(71.4%). We selectively catheterized the tumour via arteria femoralis and used 

Doxorubicin with Lipiodol as embolic material. 

Results: In follow up, we carried out laboratory studies and CT. Three weeks after 

TACE there are dominated tumours with the sizes 8-12 cm (in 16 (32.7 patients)) 

due to reduction of tumour sizes. Reduction of tumour sizes averaged 26.7 ± 0.4 mm. 

There is noted physiological increase of opposite part of live from 1 up to 3 cm, 

averagely 23 ± 0.32 mm in 46 (93.9%) patients. Alpha-fetoprotein normalized in 37 

patients, which was high before manipulation. After TACE patients were restaged 

and Child-Pugh class A noted in 25 (51%), class B noted in 24 (49%) patients. There 

is not noted full clinical effect, partial effect noted in 21 (42.9%) patients, stable 

process in 13 (26.5%) patients. Twenty one of the 49 patients (49%) selected for 

surgical treatment according objective changes, reduction of tumour sizes and 

improvement of opposite part of liver after TACE. 

Conclusions: TACE is safe method, it provides reduction of tumour sizes, intensifies 

influx of arterial blood to the opposite part of liver which improves liver function 

and conducts to hypertrophy of remaining part of liver. In 49% of unresectable HCC 

patients TACE conducts to curative hepatic resection. 


773 IMPACT OF LYMPH NODE LEVEL ASSESSMENT FOR SURVIVAL 

ON TIME TO RELAPSE IN BILIARY TRACT CANCERS 

J. Martinez-Galan 1 , P. Ballesteros 2 , B. Gonzalez-Astorga 1 , J.A. Ortega 1 , 

A. González-Vicente 1 , J. Soberino García 1 , C. González-Rivas 2 , 

J. Ruíz Vozmediano 1 , T. Villegas 3 , J.R. Delgado 1 

1 Medical Oncology Department, Hospital Universitario Virgen de las Nieves, 

Granada, SPAIN, 2 Medical Oncology Department, Hospital Universitario de 

Ceuta, Ceuta, SPAIN, 3 Surgical Department, Hospital Virgen de las Nieves, 

Granada, SPAIN 

Background: Biliary tract cancers (BTCs) are relatively rare neoplasms encompass both 

cholangiocarcinoma (CC). The role of routine lymphadenectomy at the time of surgical 

resection remains poorly defined. We sought to identify factors associated with outcome 

following and examine the impact of lymph node (LN) assessment on survival. 

Methods: 43 patients who underwent curative intent surgery between 2000-2010 

were identified from a database. We calculated prognostic factors and impact lymph 

node (LN) assessment for survival. 

Results: A total of 43 patients were identified with no metastatic BTCs. The median 

age was 65 years (29–82 years); performance status of 0 in 33/43 (76%); PS1 in 8/43 

(19%) and PS2 in 2/43 (5%) pts. A histological diagnosis of adenocarcinoma was 

confirmed in 100%. Surgical resection was performed in all patients. After resection 

42% (18/43) had positive nodes.Adjuvant chemotherapy had 31/43(72%), preferred 

with gemcitabine and a median number of cycles 6. Grade 3 or 4 toxicities rarely 

occurred. During median follow-up of 6.6 years tumor recurrence or metastatic 

disease occurred in 63% with median survival global were 2 years and 1.5 years for 

disease free survival.For stage T, the median survival global rates were 58 months 

(95% CI 44.6-71.3) for T1-T2 and 35 months (95% CI 23.3-46.8) for T3-T4 (p = 

0.015) and for median recidive-free survival were 23 months (95% CI 11.8-34) for 

T1-T2 and 14 months (95% CI 6.5-21) for T3-T4 (p = 0.05). For N stage, the median 

survival global were 58 months (95% CI 50.5-65.4) for negative nodes and 26 

months (95% CI 3.7-48.2) for positive nodes (p = 0.003) and for median recidive-free 

survival were 55 months (95% CI 31.7-57.5) for negative nodes and 10 months (95% 

CI 6.8-13) for positive nodes (p = 0.006). The patients who had nodal affectation in 

hepatic hilio had better recidive-free survival that those patients who had nodal 

affectation in celiac trunk p < 0.05. 

Conclusions: This represents a biliary cancer cohort with survival benchmarks 

obtained in the modern era of multidisciplinary care. Surgical resection and adjuvant 

chemotherapy offers the optimal treatment outcome in patients with ICC. From our 

results depth of tumor invasion (T), the presence the lymph node metastases (N) 

and level nosal affections are the strongest predictors of relapse and survival 


774 PSEUDOMYXOMA PERITONEI: PATHOLOGICAL AND 

THERAPEUTIC ASPECTS OF 26 CASES 


M. Nesrine 1 , A. Aloui 1 , R. Hela 1 , M. Ayadi 1 , N. Chaiet 1 , B. Allani 2 , H. Raies 1 , 

A. Mezlini 1 

1 Medical Oncology, Salah Azaeiz Institute, Tunis, TUNISIA, 2 Medical Oncology, 

Institut Salah Azaiz, Tunis, TUNISIA 

Introduction: Pseudomyxoma peritonei is defined by mucus collection in the 

peritoneal cavity with or without presence of neoplastic cells. Recent 

immunohistochemical and cytogenetic applications have confirmed the appendiceal 

origin. Surgical removal combined with hyperthermic intraperitoneal chemotherapy 

(HIPEC) is the main treatment. The aim of this study is to evaluate pathological and 

therapeutic aspects of a Tunisian series of 25 cases. 

Methods: We retrospectively studied 25 patients, in a 17-year period from 1994 to 

2011. Data were collected from surgical records and included: Patient presentation, 

radiologic histological findings, surgical procedure, adjuvant therapy and follow up. 

Initial and subsequent surgical treatment were conducted at the Salah Azaiez institute. 

Results: The mean age was 38 years (range 32-83 years) and 92% (23/25) were females. 

The most frequent symptom was abdominal distension (68%). Pathologic specimen 

showed peritoneal mucinosis carcinomatosis in 40% of patients and dessiminated 

peritoneal adenomucinosis in 20% of patients. The appendiceal origin was found in 60% 

of cases and ovarian origin in 28% of cases. All patients have been operated, one patient 

had neoadjuvant chemotherapy. Only two patients had HIPEC. 52% (13 cases) has 

post-operative systemic chemotherapy with complete response in 8 cases. Disease 

recurrence was noted in 48% of patients (12 cases). Second-look surgery has been 

performed in 8 cases. 8 patients had chemotherapy after recurrence. The median patient 

follow-up was 36 months (range, 1 to 120 months). 1 and 3-year progression free 

survival was 40% and 12% respectively. Overall survival at 1, 3, 5 year was 80%, 40%, 

20% respectively. One patient developed bone metastases after 13 months of follow up. 

Conclusion: Pseudomyxoma peritonei is a rare disease that must be treated in 

specialized centers with complete surgical removal, per or immediate post operative 

intraperitoneal chemotherapy and accurate histological classification. 


775 RELATIONS OF QOL TO TUMOR RESPONSE AND ADVERSE 

EVENTS IN UNRESECTABLE ADVANCED PANCREATIC 

CANCER PATIENTS IN THE GEST STUDY 

Y. Ohashi1 , T. Ioka2 , T. Okusaka3 1 

Department of Biostatistics, School of Public Health, The University of Tokyo, 

Tokyo, JAPAN, 2 Division of Hepatobiliary and Pancreatic Oncology, Osaka 

Medical Center for Cancer and Cardiovascular Diseases, Osaka, JAPAN, 

3 

Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center 


Background: The GEST study demonstrated the non-inferiority of S-1, but not the 

superiority of gemcitabine plus S-1 (GS) to gemcitabine alone (G) with respect to 

overall survival in unresectable advanced pancreatic cancer patients (Ioka et al. 

ASCO 2011, Abstract 4007). The results of QOL evaluation based on EQ-5D 

demonstrated that S-1 and G were equivalent and GS was superior to G (Ohashi 

et al. ASCO 2011, Abstract 9070). We report the relations of QOL to adverse events 

and tumor response. 

Methods: Chemotherapy was administered until PD, consent withdrawal, or 

unacceptable adverse events. EQ-5D questionnaires were filled in at baseline and 

6, 12, 24, 48, and 72 weeks and converted to 0-1 utility scores by the Japanese value 

set. We estimated the effects of adverse events (nausea, vomiting, diarrhea, fatigue, 

and anorexia leveled from 0 to 4 by CTC-AE) and of tumor response on EQ-5D 

utility scores, using a mixed-effects model for repeated measurements. Response was 

classified into 4 levels (CR/PR/SD or NE/PD). 

Results: A total of 736 patients were analyzed. Fatigue and anorexia were 

significantly associated with EQ-5D utility score; they decreased the estimated score 

by 0.034/level (p < 0.001) and 0.032/level (p < 0.001), respectively. EQ-5D utility 

scores were not related to nausea, vomiting, or diarrhea after adjustment of fatigue 

and anorexia. Tumor response (leveled from 0(PD) to 3(CR)) significantly improved 

the estimated score by 0.054/level (p < 0.001); interactions between response and 

treatments were not significant. The improvement in EQ-5D utility score associated 

with a better response was most strongly attributed to decreased pain among 5 

questions. 



Conclusions: QOL in the studied patient population was negatively affected by 

fatigue and anorexia, and was improved by good response probably through 

decreased pain. 

Disclosure: Y. Ohashi: I have an advisory relationship and research funding to 

disclose. Name of Entity: Taiho Pharmaceutical Co. Ltd. T. Ioka: I have an advisory 

relationship and research funding to disclose. Name of Entity: Taiho Pharmaceutical 

Co. Ltd. T. Okusaka: I have an advisory relationship and research funding to disclose. 

Name of Entity: Taiho Pharmaceutical Co. Ltd 

776TiP GAMMA (GEMCITABINE AND AMG 479 FOR METASTATIC 

ADENOCARCINOMA OF THE PANCREAS): A PHASE 3, 

MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 

PLACEBO-CONTROLLED TRIAL OF GANITUMAB PLUS 

GEMCITABINE (G) OR PLACEBO PLUS G AS FIRST-LINE 

THERAPY FOR METASTATIC PANCREATIC CANCER 

Abstract withdrawn in exceptional circumstances. 

777TiP SECOND INTERIM ANALYSIS OF THE GLOBAL 

INVESTIGATION OF THERAPEUTIC DECISIONS IN 

HEPATOCELLULAR CARCINOMA AND OF ITS TREATMENT 

WITH SORAFENIB (GIDEON) STUDY ACCORDING TO 

DISEASE STAGE 

B. Daniele 1 , J. Turnes 2 , G. Bodoky 3 , C. Papandreou 4 , A. Hubert 5 , P. Stål 6 , 

V.A. Gorbunova 7 , F. Serejo 8 , A. Croitoru 9 , P. Mathurin 10 

1 Medical Oncology Unit, G. Rummo Hospital, Benevento, ITALY, 

2 Gastroenterology Department, Hospital de Montecelo, Pontevedra, SPAIN, 

3 Department of Oncology, St László Hospital, Budapest, HUNGARY, 

4 Department of Medical Oncology, University Hospital of Larissa, Larissa, 

GREECE, 5 Gastrointestinal Cancer Center, Sharett Institute of Oncology, 

Jerusalem, ISRAEL, 6 Department of Gastroenterology and Hepatology, 

Karolinska University Hospital, Stockholm, SWEDEN, 7 Russian Scientific 

Research Oncology Centre, N. N. Blokhin Russian Cancer Research Center, 

Moscow, RUSSIAN FEDERATION, 8 Center of Gastroenterology, Liver Unit, 

Hospital de Santa Maria, Faculty of Medicine, Lisbon, PORTUGAL, 9 Hepatic 

Fundeni, FUNDENI Clinical Institute, Bucharest, ROMANIA, 10 Service Des 

Maladies De L’appareil Digestif, Hôpital Claude Huriez, Lille, FRANCE 

Background: GIDEON (NCT00812175) is an ongoing, global, prospective, 

non-interventional study of patients with unresectable hepatocellular carcinoma 

(HCC) receiving sorafenib (Nexavar®) in real-life practice. The aim is to evaluate 

sorafenib safety and efficacy in diverse settings and patient groups. The second 

interim analysis was triggered when ∼1500 patients had been treated for ≥ 4 months. 

We describe sorafenib use in Europe according to disease stage. 

Methods: Patient/disease characteristics (including Barcelona Clinic Liver Cancer 

[BCLC], tumour node metastases [TNM], Cancer for the Liver Italian Programme 

[CLIP]) and treatment history were recorded at enrolment; sorafenib dose, 

concomitant medications, performance status, liver function, adverse events (AEs) 

and efficacy are recorded at follow-up visits. 

Results: Of 1571 patients in the safety population, 588 are in Europe (see table). The 

majority of patients were BCLC-C (52.9%), TNM III (40.3%) or CLIP 1/2 (26.0%/ 

25.9%), although sorafenib was also used in patients with early, intermediate and 

end-stage disease. Generally, AEs and serious AEs (SAEs) increased with advancing 

disease (AEs: 66.0%, 87.4%, 85.5%, 89.7%; SAEs: 22.6%, 37.8%, 38.3%, 58.6%; for 

BCLC-A, B, C and D; respectively), whereas sorafenib-related AEs and SAEs were 

comparable across BCLC groups (AEs: 60.4%, 74.1%, 68.5%, 41.4%; SAEs: 7.5%, 

15.4%, 10.3%, 10.3%; for BCLC-A, B, C and D; respectively). Evaluation will 

continue with more mature data. 

Medical oncologist 

(n = 189) 

Hepatologist/ 

GI specialist 

(n = 332) 

EU total 

(n = 588) 

BCLC stage at study entry, % of n 

A 6.9 8.7 9.0 

B 19.6 27.7 24.3 

C 59.3 50.6 52.9 

D 3.2 5.4 4.9 

NE/missing 11.1 7.5 8.8 

TNM stage at study entry, % of n 

I 3.2 10.5 8.8 

II 8.5 12.3 10.2 

III 39.2 41.9 40.3 

IV 40.2 19.9 26.9 

NE/missing 9.0 15.4 13.8 

Child-Pugh score at start 

of sorafenib therapy, % of n 

A 68.3 64.8 66.3 

B 13.8 26.8 21.6 

C 1.1 1.8 1.5 

NE/missing 16.9 6.6 10.5 

CLIP score at start of sorafenib therapy, % of n 

0 14.8 8.4 11.9 

1 24.3 26.5 26.0 

2 24.3 26.5 25.9 

3 5.8 15.7 11.4 

4–6 4.2 11.4 8.7 

NE/missing 26.5 11.4 16.2 

NE, not evaluable 

Conclusions: These data reflect real-world sorafenib given to a broad range of 

patients, indicating a similar safety profile across the different disease stages. 

Evaluation is ongoing, with more mature data expected from the final analysis. 

Disclosure: B. Daniele: Dr B. Daniele has participated in advisory boards and 

received lecture fees from Bayer. J. Turnes: Dr J Turnes has participated in advisory 

boards for Roche Pharma. C. Papandreou: Prof. C Papandreou has participated in 

advisory boards for Bayer, Sanofi Aventis, Novartis, Bristol Meyers Squibb and 

Janssen. P. Stål: Prof. Stål has advised and received a grant from Bayer. A. Croitoru: 

Dr A Croitoru has consulted for and received an investigator fee from Bayer. P: 

Mathurin: Dr. P . Mathurin was paid speaking at symposia for Roche, 

Schering-Plough, Gilead Sciences, Bristol-Myers Squibb, Janssen-Cilag and Bayer 

Healthcare pharmaceutical companies. He is an investigator for Roche, 

Schering-Plough, Bristol-Myers Squibb, Gilead Sciences, Vertex pharmaceuticals 

Janssen-Cilag, Boeringher, Novartis and Bayer Healthcare companies. He is a 

member of the French boards of experts in Hepatology for Roche Schering-Plough, 

Gilead Sciences, Bayer Healthcare and Bristol-Myers Squibb pharmaceutical 

companies. He is consulting for the Gilead Sciences, Bristol-Myers Squibb, Bayer 

Healthcare and Vertex pharmaceutical Companies. All other authors have declared 


778TiP INTERIM ANALYSIS OF OVERALL SURVIVAL PER 

SUBGROUPS IN THE PROSPECTIVE, 

NON-INTERVENTIONAL INSIGHT STUDY IN PATIENTS WITH 

HEPATOCELLULAR CARCINOMA TREATED WITH 

SORAFENIB 

T. Ganten 1 , E. Schott 2 , P. Galle 3 , T. Göhler 4 , P. Malfertheiner 5 , R. Stauber 6 , 

R. Buder 7 , K. Achilles 8 , G. Gerken 9 

1 Medizinische Klinik, Gastroenterologie, Hepatologie und Infektiologie, 

Universitätsklinik Heidelberg, Heidelberg, GERMANY, 2 Medizinische Klinik, 

Hepatologie und Gastroenterologie, Charité- Campus Virchow Klinikum, Berlin, 

GERMANY, 3 I. Medizinische Klinik und Poliklinik, Universitätsmedizin der 

Johannes Gutenberg-Universität Mainz, Mainz, GERMANY, 4 Onkologische 

Praxis, Dresden, GERMANY, 5 Universitätsklinik für Gastroenterologie, 

Hepatologie und Infektiologie, Otto-von-Guericke Universität Magdeburg, 

Magdeburg, GERMANY, 6 Karl-Franzens-Universität Graz, Abteilung Innere 

Medizin, Gastroenterologie und Hepatologie, Graz, AUSTRIA, 7 Abteilung Innere 

Medizin, Konventspital Barmherzige Brüder, Linz, AUSTRIA, 8 Bayer HealthCare, 

Leverkusen, GERMANY, 9 Abteilung Gastroenterologie und Hepatologie, 

Universitätsklinik Essen, Essen, GERMANY 

Background: The efficacy of Sorafenib in patients (pts) with hepatocellular 

carcinoma (HCC) has been proven in randomized, controlled trials. INSIGHT is a 


prospective, non-interventional study, conducted in Germany and Austria in pts with 

HCC. The objectives of this study are the evaluation of safety and efficacy under 

practice conditions in both hospitals and private practices. Enrollment into INSIGHT 

is not restricted to a particular tumor stage. Recruitment into the study is ongoing. 

Methods: The second interim analysis (data cut-off 23 FEB 2012) evaluated overall 

survival and safety data in relevant subgroups. All patients with HCC were observed 

for the duration of their sorafenib therapy. In addition to baseline data the 

performance status, tumor status (clinical and/or radiological), time to progression 

and overall survival time are documented. Documentation of adverse events 

comprises relationship with drug, seriousness, grade (CTCAE version 3.0), and 

outcome. 

Results: Until the data cut-off 623 pts have been enrolled; 618 of which are evaluable 

for safety and efficacy analyses. The table summarises major baseline characteristics 

together with median overall survival (mOS) data for relevant subpopulations. 

Patients recruited n, Male n (%) 618, 528 (85) 

ECOG PS, n (%), 0, 1, 2 203 (33); 310 (50); 98 (16) 

BCLC-Stage n (%), A, B, C, D 80 (13); 149 (24); 319 (52); 12 (2) 

Child Pugh Stage, n (%), A(9), Missing 

264 (43); 99 (16); 12 (2); 243 (39) 

Months 

mOS total population (Events n = 164) 17,1 

mPFS total population (Events n = 408) 4,1 

mOS according to BCLC A, B, C, D 29,2; 19,6; 14,5; 4,0 

mOS according to Child Pugh A, B, C n.r.; 7,2; 4,0 

mOS Child Pugh B: 7, 8, 9 points 11,5; 9,5; 2,5 

mOS Duration of therapy > 24 weeks 

(n = 176); >40 weeks (n = 91) 

19,8; 26,7 

n.r.-not reached 

Conclusions: Results of mOS in pts with HCC treated under daily practice 

conditions in hospitals and private practices confirm the general efficacy of Sorafenib 

known from registration trials and gives further insight into pts with Child B/C 

cirrhosis and BCLC stage A/B. Further demographic data and efficacy and safety 

results will be presented. 

Disclosure: T. Ganten: Advisory Boards and Cooperate-sponsored research (Bayer 

HealthCare Germany). E. Schott: ES has received lecture fees and travel support from 

Bayer and has acted as an advisor to Bayer. P. Galle: Advisory Boards, Speaker for 

Bayer. P. Malfertheiner: - Anstellungsverhältnis, Führungsposition: Klinikdirektor - 

Beratungs- bzw. Gutachtertätigkeit: Aptalis, Novartis - Honorare: Aptalis, Falk 

Foundation, Abbott, AstraZeneca - Finanzierung wissenschaftlicher Untersuchungen: 

Bayer, Novartis. K. Achilles: I am employee of Bayer Vital. All other authors have 


779TiP A RANDOMIZED PHASE II TRIAL OF BIWEEKLY S-1 WITH 

PACLITAXEL (SPA) OR OXALIPLATIN (SOX) AS FIRST-LINE 

CHEMOTHERAPY IN ADVANCED GASTRIC CANCER 

PATIENTS: PRELIMINARY RESULTS 

M. Haibo, W. Fang, Y. Zheng, P. Zhao, C. Mao, X. Zhang, J. Qian, H. Jiang, 

Y. Zheng, N. Xu 

Department of Medical Oncology, The First Affiliated Hospital, School of 

Medicine, Zhejiang University, Hangzhou, CHINA 

Background: Gastric cancer patients are commonly treated with S-1-based 

chemotherapy for three weeks or more to ensure two weeks of exposure at 

therapeutic doses. Severe side effects of S-1 such as mucositis, diarrhea and 

neutropenia often occur in the second week of treatment. We evaluated the activity 

and safety of every other week S-1 regimens with paclitaxel or oxaliplatin 

combinations as first-line chemotherapy in advanced gastric cancer patients. Patients 

and methods: Eligible patients with pathologically confirmed advanced gastric cancer 

patients were randomized into two arms. S-1 was administered orally (80 mg/m 2 / 

day) for 7 consecutive days in combination with paclitaxel 120 mg/m 2 (SPA) or 

oxaliplatin 85 mg/m 2 (SOX) on day 1 followed by a 7-day rest. Treatment continued 

in a biweekly manner until disease progressed, unacceptable toxicity was observed or 

the patient refused to continue. The primary endpoint was overall response rate 

(ORR). The secondary endpoints were progression-free survival (PFS), overall 

survival (OS) and safety. 

Results: Eighty-one gastric cancer patients were enrolled from June 2010 to March 

2012. Patients were randomized to receive SPA (43) or SOX (38). Results are 

presented for 76 patients. The ORR for arm A was 43.6%, and that for arm B was 

33.3% with no significant difference between the two arms (p = 0.35). The median 

PFS was 6.2 months for arm A vs. 5.1 months for arm B (p = 0.80); the median OS 

was 10.8 months for arm A and 10.0 months for arm B (p = 0.17). No 

treatment-related deaths occurred during the study. The most frequent toxicity was 

neutropenia (30.8% and 17.4% of grade 3/4 in arms A and B, respectively). The most 

common non-hematological toxicities were mucositis, diarrhea, and peripheral 

neuropathy, all in less than 5% of patients. 

Conclusions: These preliminary findings suggest that biweekly S-1-based regimens 

have an acceptable ORR with tolerable side effects in advanced gastric cancer 

patients. The study will continue until 100 patients have been enrolled. 


780TiP SAFETY AND EFFICACY OF ALBUMIN-BOUND PACLITAXEL 

AND OXALIPLATIN AND S-1 AS FIRST-LINE TREATMENT OF 

PATIENTS WITH ADVANCED GASTRIC CANCER 

H. Lou, H. Pan, Q. Pan, D. Li, W. Jin 

Medical Oncology, Sir Run Run Shaw Hospital,College of Medicine,Zhejiang 

University, Hangzhou, CHINA 

Background: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel 

formulation of paclitaxel that does not require solvents such as polyoxyethylated 

castor oil and ethanol. Use of these solvents has been associated with toxic response, 

including hypersensitivity reactions and prolonged sensory neuropathy. This study 

was conducted to evaluate the efficacy and safety of combination chemotherapy with 

nab-paclitaxel plus oxaliplatin and S-1 as first-line treatment for patients with 

advanced gastric cancer. 

Patients and methods: Eligible patients (pts) with histologically confirmed 

advanced gastric cancer,


Conclusion: The combination of everolimus and capecitabine has a reasonable 

toxicity profile and may show significant activity in patients with advanced HCC 

pretreated with sorafenib. This combination therapy warrants further investigation as 

a possible second line treatment for selected patients with HCC. 


782TiP REVIEW OF THE MANAGEMENT OF ADVANCED GASTRIC 

CANCER; AN EXPERIENCE FROM A LOW RESOURCE 

SETTING 

K. Beecham 1 , V.D.N.K. Vanderpuye 1 , N.A. Adu-Aryee 2 

1 Radiotherapy, Korlebu Teaching Hospital, Accra, GHANA, 2 Surgery, Korlebu 

Teaching Hospital, Accra, GHANA 

Purpose: Adjuvant treatment combines Epirubicin, Cisplatin and 5-FU (ECF). 

Replacement of 5FU and Cisplatin with Capecitabine (X) and Oxaliplatin (O) has 

shown an efficacy similar to ECF, with improved tolerability and safety. The outcome 

of management of advanced gastric cancer at the Oncology Unit was assessed, with 

emphasis on the use of Capecitabine alone or in combination. 

Patients & methods: 27 patients adenocarcinoma of the stomach between 2004 and 

2008 were eligible. Time to disease progression (TTP) as well as tolerability of 

treatment was assessed retrospectively. 

Results: Median follow up was 12 months (1 to 60 months). No adjuvant treatment 

was given in 36%. 26% received concurrent chemoradiation with Capecitabine. 11.1% 

received palliative radiotherapy only. One patient did not complete radiotherapy due 

to side effects. 26.6% received Capecitabine alone and combined with Oxaliplatin in 

11.1% Grade 3/4 diarrhoea was reported in 7.4%; neuropathy and neutropenia were 

seen in 3.7%. Median time to progression in patients who had adjuvant treatment 

was 6.4 months (2 to 13 months). 

Conclusion: There is a favorable tolerability of Capecitabine used alone or in 

combination with radiotherapy or other chemotherapy drugs. 



abstracts 

genitourinary tumors, non-prostate 

783O RANDOMIZED PHASE II STUDY OF FIRST-LINE EVEROLIMUS 

(EVE) + BEVACIZUMAB (BEV) VERSUS INTERFERON ALFA-2A 

(IFN) + BEV IN PATIENTS (PTS) WITH METASTATIC RENAL 

CELL CARCINOMA (MRCC): RECORD-2 

A. Ravaud 1 , C. Barrios 2 , Ö. Anak 3 , D. Pelov 4 , A. Louveau 5 , B. Alekseev 6 , 

T. M-H 7 , S.S. Agarwala 8 , S. Yalcin 9 , B. Melichar 10 

1 Medical Oncology, Bordeaux University, Bordeaux, FRANCE, 2 Department of 

Medicine, PUCRS School of Medicine, Porto Alegre, BRAZIL, 3 Oncology Global 

Development, Novartis Pharma AG, Basel, SWITZERLAND, 4 Oncology, Novartis 

Pharmaceuticals Corporation, Florham Park, NJ, UNITED STATES OF AMERICA, 

5 Oncology, Novartis Pharma S.A.S., Paris, FRANCE, 6 Oncourological 

Department, Moscow Hertzen Oncology Institute, Moscow, RUSSIAN 

FEDERATION, 7 Oncology, OncoCare Cancer Centre, Singapore, SINGAPORE, 

8 Cancer Center, St. Luke’s Hospital & Health Network, Bethlehem, PA, UNITED 

STATES OF AMERICA, 9 Medical Oncology, Hacettepe University Institute of 

Oncology, Ankara, TURKEY, 10 Department of Oncology, Palacky Univeristy 

Medical School and Teaching Hospital, Olomouc, CZECH REPUBLIC 

Background: Study results demonstrated that IFN augments BEV activity and 

improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a 

standard first-line treatment option for mRCC. Combining BEV with the mTOR 

inhibitor EVE may be an efficacious and well-tolerated treatment option. The 

open-label, phase II RECORD-2 trial compared first-line EVE + BEV and IFN + BEV 

in mRCC. Patients and methods: Therapy-naive pts with clear cell mRCC and prior 

nephrectomy were randomized 1:1 to BEV 10 mg/kg IV every 2 weeks with either 

EVE 10 mg oral daily or IFN (9 MIU SC 3 times/week, if tolerated). Tumour 

assessments were every 12 weeks. Primary objective was treatment effect on 

progression-free survival (PFS) per central review based on an estimate of the chance 

of a subsequent phase III trial success (50% threshold for phase II success). 

Results: In EVE + BEV (n = 182) and IFN + BEV (n = 183) arms, median age was 

60/60 years, 76/72% of pts were men, MSKCC risk was favourable/intermediate/poor 

in 36/57/7% and 36/57/7% of pts, and 43/46% of pts had >2 organs involved, 

respectively. For EVE + BEV and IFN + BEV, median treatment duration was 8.5/8.3 

months, respectively; 23/26% of pts discontinued due to AEs. In EVE + BEV and 

IFN + BEV arms, median PFS by central review was 9.3/10.0 months (HRIFN/EVE, 

0.91; 95% CI, 0.69-1.19; P =0.485), respectively; probability of subsequent phase III 

success was 5.1%. Results of central and local PFS analysis were consistent. Objective 

response rate was 27/28% in EVE + BEV and IFN + BEV arms, respectively. Median 

overall survival (OS) was not reached in the EVE + BEV arm and was 25.9 months 

(95% CI: 21.1, 30.2) in the IFN + BEV arm. Most frequent AEs (%) were stomatitis 

(63), proteinuria (49), diarrhoea (39), hypertension (38), and epistaxis (35) in EVE + 

BEV arm and decreased appetite (45), fatigue (41), proteinuria (37), and pyrexia (35) 

in IFN + BEV arm. 

Conclusions: In RECORD-2, PFS and tolerability were similar for first-line EVE + 

BEV and IFN + BEV. Final OS analysis will occur after 2-year follow-up. 

Disclosure: A. Ravaud: Alain Ravaud is a member of global, European, and/or 

French boards on urological tumors for Pfizer, Novartis, GlaxoSmithKline, 

Bayer-Schering, and Dendreon, and has received institutional grant support from 

Pfizer, Novartis, and Roche. Ö. Anak: Ozlem Anak is an employee of Novartis 

Pharma AG. D. Pelov: Diana Pelov is an employee of Novartis Pharmaceuticals 

Corporation. A. Louveau: Anne-Laure Louveau is an employee of Novartis Pharma S. 

A.S. T. M-H: Tay M-H is a speaker for an advisory board for Novartis 

Pharmaceuticals Corporation. B. Melichar: Bohuslav Melichar has received honoraria 

from Novartis and Roche and served on an advisory board for Roche. All other 


784O CLINICAL ACTIVITY AND SAFETY OF ANTI-PROGRAMMED 

DEATH-1 (PD-1) (BMS-936558/MDX-1106/ONO-4538) IN 

PATIENTS (PTS) WITH PREVIOUSLY TREATED, METASTATIC 

RENAL CELL CARCINOMA (MRCC) 

D.F. McDermott 1 , C.G. Drake 2 , M. Sznol 3 , T.K. Choueiri 4 , J.D. Powderly 5 , 

D.C. Smith 6 , J.M. Wigginton 7 , G. Kollia 8 , A. Gupta 9 , M.B. Atkins 10 

1 Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 

Boston, MA, UNITED STATES OF AMERICA, 2 Department of Urology, Sidney 

Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, 

MD, UNITED STATES OF AMERICA, 3 Section of Medicine Oncology, Yale 

Cancer Center, New Haven, CT, UNITED STATES OF AMERICA, 4 Lank Center 

for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women’s 

Hospital, Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA, 

5 Oncology, Carolina Bio-Oncology Institute, Huntersville, NC, UNITED STATES 

OF AMERICA, 6 Department of Internal Medicine, University of Michigan, Ann 

Arbor, MI, UNITED STATES OF AMERICA, 7 Discovery Medicine-clinical 

Oncology, Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA, 

8 Biostatistics and Data Management, Bristol-Myers Squibb, Princeton, NJ, 

UNITED STATES OF AMERICA, 9 Discovery Medicine, Immuno-oncology, 

Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA, 10 Internal 

Medicine, Georgetown Lombardi Comprehensive Cancer Center, Washington 

DC, UNITED STATES OF AMERICA 

Purpose: BMS-936558 is a fully human monoclonal antibody that blocks the PD-1 

co-inhibitory receptor expressed by activated T cells. In the initial portion of a phase 

1 study, BMS-936558 showed promising activity in pts with various solid tumors, 

including mRCC. Accrual was expanded to better characterize antitumor, safety, and 

dose effects. 

Methods: Pts with RCC were treated with BMS-936558 IV q2wk at 10 mg/kg 

initially, followed by additional pts at 1 mg/kg. Pts received up to 12 cycles (4 doses/ 

cycle) of treatment or until unacceptable toxicity, confirmed progressive disease, or 

complete response (CR). Clinical activity was assessed by RECIST v1.0. 

Results: As of Feb 24, 2012, 34 mRCC pts had been treated at 1 mg/kg (n = 18) or 

10 mg/kg (n = 16). ECOG performance status was 0 in 13 pts and 1 in 21 pts. The 

number of prior therapies was 1 (n = 10), 2 (n = 9), or ≥3 (n = 15), and included 

prior immunotherapy (n = 20) or antiangiogenic therapy (n = 25); 32/34 pts had 

prior nephrectomy. Sites of metastatic disease included lymph node (n = 28), liver 

(n = 9), lung (n = 30), and bone (n = 10). Median duration of therapy was 32 wks 

(range 4 − 97.3 wks). The incidence of grade 3 − 4 related adverse events was 18% 

and included hypophosphatemia (6%), elevated ALT (3%), and cough (3%); there 

were no drug-related deaths among mRCC pts. Clinical activity (response or 

prolonged stable disease) was observed at both doses (Table). Two pts had a 

persistent reduction in target lesion tumor burden in the presence of new lesions and 

were not categorized as responders. There were responses in all sites of disease. 

Conclusions: BMS-936558 is well tolerated and has durable clinical activity in pts 

with previously treated, mRCC. Additional long-term follow-up data will be reported. 

Dose 

(mg/kg) 

No. 

pts a 

ORR 

No. pts (%) 

[95% CI] 

1 17 4 (24) 

[7 − 50] 

10 16 5 (31) 

[11 − 59]* 



Response 

duration 

(months) 

17.5 + , 

9.2 + , 9.2, 

5.6+ 

22.3 + , 

21.7 + , 

12.9, 12.0, 

8.4 

SD ≥24 wk 

No. pts (%) 

[95% CI] 

4 (24) 

[7 − 50] 

5 (31) 

[11 − 59] 

PFSR at 

24 wk (%) 

[95% CI] 

47 [23 − 71] 

67 [43 − 91] 

a Response-evaluable pts dosed by 07/01/2011 *1 CR ORR = objective response rate 

([{CR + PR} ÷ n] × 100); SD = stable disease; PFSR = progression-free survival rate. 

Disclosure: D.F. McDermott: Advisory Role: Bristol-Myers Squibb (myself, Ad board 

participation). C.G. Drake: Consultant or Advisory Role: Bristol-Myers Squibb, 

Dendreon Inc., and Amplimmune Inc. (myself, compensated). Stock Ownership: 

Amplimmune (myself). Other Renumerations: Patents Licensed, Bristol-Myers 

Squibb (myself). M. Sznol: Consultant or Advisory Role: Bristol-Myers Squibb 

(myself, compensated). Research Funding: Bristol-Myers Squibb (clinical trials 

funding, myself). T.K. Choueiri: Consultant or Advisory Role: GlaxoSmithKline, 

Aveo, Novartis and Pfizer (myself, compensated). Research Funding: Pfizer (myself). 




J.D. Powderly: Consultant or Advisory Role: MedicineX and Bristol-Myers Squibb 

(myself, compensated). Research Funding: Bristol-Myers Squibb (clinical trials 

funding, myself). Honoraria: Bristol-Myers Squibb (ipilimumab speakers bureau, 

myself). D.C. Smith: Research Funding: Bristol-Myers Squibb Oncology (myself). J. 

M. Wigginton: Employment or Leadership Role: Bristol-Myers Squibb (employment, 

myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). G. Kollia: 

Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, 

compensated). Stock Ownership: Bristol-Myers Squibb (BMY) (myself). A. Gupta: 

Employment or Advisory Role: Bristol-Myers Squibb (employment, myself, 

compensated). Stock Ownership: Bristol-Myers Squibb (myself). M.B. Atkins: 

Advisory or Consultant Role: Bristol-Myers Squibb, Curetech, and Merck (myself, 

compensated). 

785O COMPARATIVE ASSESSMENT OF SUNITINIB-ASSOCIATED 

ADVERSE EVENTS (AES) AS POTENTIAL BIOMARKERS OF 

EFFICACY IN METASTATIC RENAL CELL CARCINOMA 

(MRCC) 

F. Donskov 1 , M.D. Michaelson 2 , I. Puzanov 3 , M.P. Davis 4 , G.A. Bjarnason 5 , 

R.J. Motzer 6 , X. Lin 7 , D.P. Cohen 7 , R. Wiltshire 8 , B.I. Rini 9 

1 Department of Oncology, Aarhus University Hospital, Aarhus, DENMARK, 

2 Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, 

MA, UNITED STATES OF AMERICA, 3 Division of Hematology-oncology, 

Vanderbilt University Medical Center, Nashville, TN, UNITED STATES OF 

AMERICA, 4 Medical Oncology, Cleveland Clinic, Cleveland, OH, UNITED 

STATES OF AMERICA, 5 Medical Oncology, Sunnybrook Odette Cancer Centre, 

Toronto, CANADA, 6 Genitourinary Oncology Service, Memorial Sloan-Kettering 

Cancer Center, New York, NY, UNITED STATES OF AMERICA, 7 Reseach and 

Development, Pfizer Oncology, La Jolla, CA, UNITED STATES OF AMERICA, 

8 Research and Development, Pfizer Oncology, Tadworth, UNITED KINGDOM, 

9 Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic Taussig Cancer 

Institute, Cleveland, OH, UNITED STATES OF AMERICA 

Background: Previous retrospective analyses have separately identified 

treatment-associated hypertension (HTN), hand–foot syndrome (HFS), asthenia/ 

fatigue (A/F), neutropenia (N), and thrombocytopenia (T) as potential biomarkers of 

sunitinib efficacy in mRCC patients using a pooled database of five clinical trials 

(NCT00054886, NCT00077974, NCT00083889, NCT00338884, NCT00137423; 

Pfizer). We assessed the relative strength and independence of each biomarker in a 

combined analysis of the same database. 

Methods: Data from 770 mRCC patients who received sunitinib 50 mg/d on the 

approved 4-wk-on-2-wk-off schedule (Schedule 4/2; n = 544; 71%) or 37.5 mg/d 

continuous daily dosing (n = 226; 29%) were included. Combined multivariate 

analysis, repeated using a 12-wk landmark to address potential bias from longer 

treatment, was performed (for Schedule 4/2 and both schedules combined). The 

following were included as covariates for prediction of PFS and OS: previously 

identified prognostic factors; HTN (SBP ≥140 mmHg); N and T (CTCAE grade >1); 

and any CTCAE grade HFS and A/F. 

Results: HTN, HFS, and A/F remained significant independent biomarkers in 

sunitinib-treated mRCC patients on Schedule 4/2, with HTN and HFS supported 

by the strongest data (table). N and T were not significant in any analyses, possibly 

due to a strong correlation of both with HTN and A/F (P < 0.05; Fisher’s exact 

test), but not with HFS. Dose reduction, adjusted for time on treatment, was not 

associated with clinical outcome. Results were similar with both schedules 

combined. 

Conclusions: Combined multivariate analyses indicate that HTN and HFS, and to a 

lesser degree A/F, may serve as independent biomarkers of sunitinib efficacy in 

mRCC patients. Providers who observe these AEs are therefore encouraged to 

continue sunitinib therapy, managing AEs with standard medical treatment with or 

without dose reduction as clinically indicated. 

Final multivariate models of associations between AEs and efficacy outcomes for 

mRCC patients on Schedule 4/2 

Efficacy 

endpoint 

AE at any time point AE by the 12-wk landmark 

HR (95% CI) P* HR (95% CI) P* 

HTN during treatment 

PFS 0.291 (0.220–0.399)

787O EXTERNAL VALIDATION OF THE ASSOCIATION OF 

PROGRESSION-FREE SURVIVAL AT 6 MONTHS (PFS6) WITH 

OVERALL SURVIVAL AT 12 MONTHS (OS12) IN SECOND-LINE 

THERAPY FOR ADVANCED UROTHELIAL CARCINOMA (UC) 

G. Sonpavde 1 , B. Maughan 2 , K.M. Boucher 3 , R. Fougeray 4 , T.K. Choueiri 5 , 

G. Niegisch 6 ,Y.Wong 7 , S.S. Sridhar 8 , C.N. Sternberg 9 , J. Bellmunt 10 

1 Medical Oncology, Texas Oncology, Baylor College of Medicine, Webster, TX, 

UNITED STATES OF AMERICA, 2 Medicine, University of Utah, Salt Lake City, UT, 

UNITED STATES OF AMERICA, 3 Biostatistics, University of Utah, Salt Lake City, 

UT, UNITED STATES OF AMERICA, 4 Statistics, 5Institut de Recherche Pierre 

Fabre, Boulogne, FRANCE, 5 Medical Oncology, Dana Farber Cancer Institute, 

Boston, MA, UNITED STATES OF AMERICA, 6 Urologic Oncology, 6 Heinrich 

Heine University, Dusseldorf, GERMANY, 7 Medical Oncology, Fox Chase Cancer 

Center, Philadelphia, PA, UNITED STATES OF AMERICA, 8 Medical Oncology, 

Princess Margaret Hospital, Toronto, ON, CANADA, 9 Medical Oncology, San 

Camillo Forlanini Hospital, Rome, ITALY, 10 Medical Oncology, University Hospital 

del Mar-IMIM, Barcelona, SPAIN 

Background: We hypothesized that PFS at 6 months (PFS6) correlates with OS12 

and may be a robust intermediate endpoint for phase II trials of second-line therapy 

for advanced UC. 

Methods: Ten phase II trials of second-line chemotherapy and/or biologics were 

pooled. Progression was defined as tumor progression or death from any cause. 

Adjustment of PFS6 and OS12 were performed for variability between trials using 

random effects models. The relationship between PFS6 and OS12 was assessed at the 

trial level using Pearson correlation and weighted linear regression. The relationship 

between PFS6 and OS12 at the individual level was assessed using Pearson chi-square 

test with Yates continuity correction. Statistical analyses employed “R” statistical 

computing software, version 2.8.0. External validation was conducted in a phase III 

trial comparing best supportive care (BSC) with vinflunine plus BSC. 

Results: Results from the pooled phase II dataset (n = 646) have been reported 

(ASCO 2012): the Pearson correlation between trial level PFS6 and OS12 was 0.66 

(p = 0.037), and individual level agreement was seen in 82% of patients (kappa = 

0.45), Pearson correlation between trial level response and OS12 was 0.37 (p = 0.30) 

and individual level agreement was seen in 78% (kappa = 0.36). Of the 357 patients 

in the external validation dataset, 17 had PFS censored before 6 months or OS 

censored before 12 months, leaving 340 evaluable patients. Of the progression events, 

231 were objective progression, 104 were deaths and 5 were alive with PFS > 6 

months and OS > 12 months. The PFS6 was 13.25% with BSC and 26.48% with 

vinflunine plus BSC. The individual level agreement of PFS6 and OS12 was 81% 

(κ= 0.44, p < 0.001) and of response and OS12 was 76% (κ= 0.17, p = 0.0002). 

Excluding the BSC arm showed an individual level agreement between response 

and OS12 of 82% (κ= 0.53, p < 0.0001). 

Conclusion: PFS6 is robustly associated with OS12 at the trial and individual levels 

in the setting of second-line therapy for advanced UC. Given the suboptimal 

association of response and OS12 at the trial level, PFS6 may be a more optimal 

endpoint to capture the durable benefits of agents. 

Disclosure: R. Fougeray: Employee of Pierre Fabre. T.K. Choueiri: Research support 

from Astrazeneca. Y. Wong: Research support from Imclone. S.S. Sridhar: Research 

support from Celgene. J. Bellmunt: Research support to institution from Pierre Fabre. 


788O NEOADJUVANT (NACT) AND ADJUVANT CHEMOTHERAPY 

(ACT) FOR MUSCLE-INVASIVE BLADDER CANCER: A 

POPULATION-BASED OUTCOMES STUDY 

C.M. Booth 1 , D.R. Siemens 1 ,G.Li 1 ,Y.Peng 1 , I.F. Tannock 2 , D.M. Berman 1 , 

W. Kong 1 , W.J. Mackillop 1 

1 Dept of Oncology, Queen’s University Cancer Research Institute, Kingston, ON, 

CANADA, 2 Medical Oncology, Princess Margaret Hospital, Toronto, ON, 

CANADA 

Background: Utilization of NACT and ACT for bladder cancer in the general 

population and the survival benefit associated with therapy is not well described. 

Here we report practice patterns and outcomes associated with NACT/ACT in the 

general population of Ontario, Canada. 

Methods: Electronic records of treatment were linked to the population-based 

Ontario Cancer Registry to identify all patients who underwent cystectomy for 

bladder cancer in Ontario 1994–2008. Surgical pathology reports were obtained to 

identify cases with muscle-invasive disease. Utilization of NACT/ACT was compared 

across 3 study periods: 1994–98, 1999–03, 2004–08. Logistic regression was used to 


analyze factors associated with use of NACT/ACT. A Cox model and propensity 

score analysis was used to explore the association between ACT and survival. 

Results: In 1994–2008 4876 patients underwent cystectomy. Surgical pathology 

reports were identified for 3429 cases; 2738 had muscle-invasive disease. While use 

of NACT did not change over the 3 study periods (5%, 3%, 6%; p = 0.004), utilization 

of ACT increased with time (16%, 19%, 23%; p = 0.001). In adjusted analyses 

younger age and less co-morbidity were associated with greater utilization of NACT/ 

ACT. T3/T4 tumors (OR 2.1, 95%CI 1.6–2.8), node positive disease (OR 7.2, 95%CI 

5.5–9.5), and lymphovascular invasion (OR 1.7, 95%CI 1.2–2.3) were associated with 

greater utilization of ACT. While there was no substantial variation in utilization of 

NACT across geographic regions (range 3% to 5%), use of ACT varied considerably 

(range 12% to 31%). Five year overall (OS) and cancer-specific survival (CSS) for all 

muscle-invasive cases was 30% (95%CI 28–31%) and 34% (95%CI 32–36%). In Cox 

analysis T3/T4 tumors (HR 1.7, 95%CI 1.6-2.0), node positive disease (HR 1.9, 95% 

CI 1.7–2.1), and lymphovascular invasion (HR 1.8, 95%CI 1.6–2.1) were associated 

with inferior OS. Utilization of ACT was associated with improved OS (HR 0.70, 

95%CI 0.6–0.8) and improved CSS (HR 0.70, 95%CI 0.6–0.8). This result was 

consistent in the Cox model and propensity score analysis. 

Conclusions: Despite accumulating evidence and guidelines, NACT/ACT remains 

substantially underutilized in routine clinical practice. Our results suggest that ACT 

is associated with a substantial survival benefit in the general population. 


789O THE TAXIF II PROTOCOL FINAL RESULTS: A PHASE II TRIAL 

OF HIGH-DOSE CHEMOTHERAPY SUPPORTED BY 

HAEMATOPOIETIC STEM CELL TRANSPLANTATION IN 

PATIENTS WITH DISSEMINATED GERM-CELL TUMORS 

FAILING CHEMOTHERAPY AND WITH ADVERSE 

PROGNOSTIC FACTORS 

F. Selle1 , K. Fizazi2 , P. Biron3 , G. Gravis-Mescam4 , B. Bui5 ,J.Bay6 , A. Flechon3 , 

C. Dubot1 ,A.Caty7 , D. Burcoveanu1 , R. Delva8 , T. de Revel9 , J.M. Miclea10 , 

M. Gaulet11 , E. Horn12 , S. Provent1 , I. Temby1 , I. Brindel10 , J. Khalil1 , 

J. Gligorov1 , J.-P. Lotz7 1 2 

Medical Oncology, Hôpital Tenon, Paris, FRANCE, Medical Oncology, Institut 

Gustave Roussy, Villejuif, FRANCE, 3 Medical Oncology, Centre Léon Bérard, 

Lyon, FRANCE, 4 Medical Oncology, Institut Paoli Calmettes, Marseille, FRANCE, 

5 6 

Medical Oncology, Institute Bergonie, Bordeaux , FRANCE, Medical Oncology, 

Centre Hospitalier Universitaire, Clermont-Ferrand, FRANCE, 7 Medical Oncology, 

Centre Oscar Lambret, Lille, FRANCE, 8 Medical Oncology Centre Paul Papin, 

Angers, FRANCE, 9 Service d’Hématologie, Hôpital d'Instruction des Armées 

Percy, Clamart, FRANCE, 10 Unité de Cytaphérèse et Thérapie Cellulaire et 

Département de la Recherche Clinique et du Développement, Hôpital St-Louis, 

AP-HP, Paris, FRANCE, 11 3ES-Cegedim Strategic Data, Boulogne, FRANCE, 

12 

Brown University, Alpert Medical School, Providence, RI, UNITED STATES OF 

AMERICA 

Background: High-dose chemotherapy (HDCT) has been shown to circumvent 

resistance in poor-prognosis germ cell tumors (GCT), mainly for patients whose 

relapses occur more than 4 weeks after cisplatin-based CT. 

Patients and methods: This multicentric phase II trial was addressed to patients 

with poor-prognosis non-refractory GCTs. The main objectives were to determine 

the complete response rate and to monitor treatment-associated toxicities. Patients 

with adverse prognostic factors failing CT were to receive 2 cycles combining 

Epirubicin and Paclitaxel (EpiTax), followed by 3 consecutive HDCT [one using a 

Paclitaxel/Thiotepa association, 2 using the 5-day Ifosfamide-Carboplatine-Etoposide 

regimen]. Inclusion criteria included seminomatous GCT in relapse after 2 lines of 

CT, non-seminomatous GCT in relapse after 1 or 2 lines, partial remission after 

1 line, primary mediastinal GCT in first relapse. Peripheral blood stem cells were 

collected after the EpiTax cycles. 

Results: Between 09/2004 and 12/2007, 45 patients were included: 45 received 1 

HDCT, 39 two HDCT, 29 patients received the complete protocol. Sixteen patients 

did not received the entire protocol, 8 (53%) for toxic side effects. Two patients 

(4.4%) died of toxicities, 17 (37.7%) of disease progression. For a median follow-up 

time of 26 months (4–51 m), the final overall response rate was 66,7% (CR, 20,6%). 

The median PFS was 16 months (95%CI, 9-NA) and the median OS was 32 months 

(95%CI, 32–49). The 2-year PFS was a plateau set up at 50% (95%CI, 32-67%) and 

the 2-year OS was 71% (95%CI, 52–83%). 

Conclusion: The TAXIF II protocol was highly effective in non-refractory GCT 

patients failing CT. 

Disclosure: F. Selle: consultancy for roche and Pharmamar. All other authors have 




790O GEMCITABINE, OXALIPLATIN, AND PACLITAXEL (GOT) ON 

A 2-WEEKLY SCHEDULE IN PATIENTS (PTS) WITH 

REFRACTORY GERM CELL CARCINOMA: A PHASE II STUDY 

CONDUCTED AT THE UNIVERSITY OF SOUTHERN 

CALIFORNIA 

D.I. Quinn 1 , O. Hamid 2 , D. Tsao-Wei 3 ,J.Hu 1 , J. Pinski 1 , A. Schuckman 4 , 

S. Daneshmand 4 , S. Groshen 5 , D. Raghavan 6 ,C.Korn 7 , K. Massopust 7 , 

C. Ketchens 7 , A.M. Aparicio 8 , T.B. Dorff 1 

1 USC Norris Comprehensive Cancer Center, University of Southern California, 

Keck School of Medicine, Los Angeles, CA, UNITED STATES OF AMERICA, 

2 Neuro-oncology Clinic, The Angeles Clinic and Research Institute, Los Angeles, 

CA, UNITED STATES OF AMERICA, 3 Biostatistics, USC Norris Comprehensive 

Cancer Center, Los Angeles, CA, UNITED STATES OF AMERICA, 4 Institute of 

Urology, Keck School of Medicine, Los Angeles, CA, UNITED STATES OF 

AMERICA, 5 Biostatistics, USC Norris Comprehensive Cancer Center, Los 

Angeles, CA, UNITED STATES OF AMERICA, 6 Carolinas Healthcare, Levine 

Cancer Institute, Charlotte, NC, UNITED STATES OF AMERICA, 7 Division of 

Medical Oncology, USC Norris Comprehensive Cancer Center, Los Angeles, CA, 

UNITED STATES OF AMERICA, 8 Department of Genitourinary Medical Oncology, 

MD Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA 

Background: Modern therapy for GCT has transformed the disease but challenges 

remain in managing primary poor risk and refractory cancer. 

Methods: Phase II study: 30 men with GCT progression ≤4 wks of a standard 

regimen (12) or after salvage (14) or stem cell regimen (3). Growing teratoma 

syndrome pts excluded. PS < =2, Age > 16, PD by RECIST/marker criteria. Regimen: 

Paclitaxel 170mg/m2/3h; Gemcitabine 800mg/m2/80mins; Oxaliplatin 100mg/m2/ 

90min, increased to 125mg/m2 in cycle 2 if no major toxicity. Mg2+ & Ca2+ infused 

before oxaliplatin. G-CSF was not given prophylactically. The regimen was designed 

to maximize oxaliplatin density with full dosing of pts with recovering marrow & 

dose escalation for pts with limited toxicity in cycle 1. Retreatment criteria: ANC 

≥1000 or 700 with monocytosis, platelets >75K. Pts with marker normalization had 

3 further cycles. Primary endpoint: Response; 2nd: OS, PFS, toxicity Patient 

characterisitcs: Med age 32y, Race: white 41%, Hispanic 48%, Asian 10%, KPS ≥ 90% 

66%, Primary site: testis 27, mediastinal 2: Histology: Seminoma: 7% Chorio 10%, 

YST 7%, Emb 3%, teratocarcinoma 13%, Undifferentiated 5%, mixed NSGCT 55%. 

Prior surgery for primary: 20, met resection 13. Med prior chemotherapy lines: 2 

(R 1–7). Med (range) pre-GOT LDH: 173 (109-4504), AFP 22 (1–363002), bHCG 

2.4 (2–247040) Endpoints: Median cycles 6 (1–14). Best RECIST response: CR2, PR7, 

uPR2, SD 11, PD 5; RR 31% (95%CIs 17-50%). 5 pts (4PR, 1SD) who underwent 

definitive surgery after trial therapy were rendered NED. Med FU 28 mos (R 3-81). 

Med OS: 16.7 mos (95%CIs 11.9–30.7), med PFS 10.8 (95%CIs 3.0−27.5), 2yr OS 

prob: 0.42 + /−0.10. Marker responses: 29% normalized. 7pts (24%) remain alive & 

NED >= 1 year. No association between ethnicity and RRor OS.Toxicity: 1pt died: 

pneumonia, gr 3/4 neutropenia 17pts, febrile neutropenia 7pt, neuropathy gr1/2: 

19 pts, gr3 4pts, gr4 1pt, GI toxicity gr2/3 12 pts. 

Conclusion: GOT given 2-wkly for refractory GCT produced high rates of marker & 

RECIST response & rendered 5 patients resectable. The median OS of 16.7 mos 

compares favorably with 6–13.5 mos in other series (Oechsle K Eur Urol 60: 850, 

2011). ClinicalTrials.gov Identifier: NCT00183820 


791PD MULTIVARIATE ANALYSIS OF CYTOKINES AND 

ANGIOGENIC FACTORS (CAFS) AND ESTABLISHED 

PROGNOSTIC PARAMETERS IN METASTATIC RENAL 

CELL CARCINOMA (MRCC) PATIENTS (PTS) RECEIVING 

PAZOPANIB OR PLACEBO 

A. Zurita-Saavedra 1 ,Y.Liu 2 ,Y.Lin 2 , H.T. Tran 3 , VEG105192 Team and 

investigators 4 , L.N. Pandite 5 , J.V. Heymach 6 

1 Dept. of Genitourinary Medical Oncology, The University of Texas M.D. 

Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA, 

2 Oncology Research and Development, GlaxoSmithKline, Philadelphia, PA, 

UNITED STATES OF AMERICA, 3 Cancer Medicine, UT MD Anderson Cancer 

Center, Houston, TX, UNITED STATES OF AMERICA, 4 VEG105192 Team and 

investigators, 5 Clinical Lead, GlaxoSmithKline, Research Triangle Park, NC, 

UNITED STATES OF AMERICA, 6 Thoracic/head and Neck Medical Oncology, 


Background: In mRCC, prognosis is still solely determined based on clinical criteria. 

Although multiple candidate biomarkers exist, none has yet been incorporated into 

practice. We identified CAFs associated with PFS in mRCC pts with ECOG PS £1 

treated in a randomized, placebo-controlled, phase III clinical trial of pazopanib 

(Sternberg, JCO 2010, Tran, ASCO 2010 #4522). In this study, we evaluated the 

prognostic significance of these CAFs relative to established clinical parameters. 

Methods: Seven candidate CAFs (IL-6, IL-8, VEGF, HGF, TIMP1, osteopontin 

[OPN], E-Selectin) in plasma obtained pretreatment, and 5 clinical variables 

indicative of poor prognosis (time from diagnosis to treatment

patient preference for P over S, and should be considered in light of their 

comparative efficacy. 

Disclosure: D. Cella: Dr. Cella has consulted to GSK and has received research grant 

support from GSK. K. Kaiser: Dr. Kaiser has received research grant support from 

GSK. J. Beaumont: Ms. Beaumont has received research grant support from GSK. J. 

Diaz: Dr. Jose Diaz is a GSK employee and stock owner. L. McCann: Dr. McCann is 

a GSK employee and stock owner. F. Mehmud: Dr. Mehmud is a GSK employee and 

stock owner. S. Lata: Dr. Lata is a GSK employee and stock owner. P. Bono: Dr. 

Bono has received honorarium from GSK and Pfizer. C. Porta: Dr. Porta has acted as 

consultant or speaker for GSK, Bayer-Schering, Pfizer, Novartis, Roche, Aveo, 

Astellas, Boehringer Ingellheim and Recordat and received research funding from 

Novartis and Bayer-Schering. B. Escudier: Dr. Escudier has received honorarium 

from GSK, Pfizer, Novartis, Bayer, Aveo, and BMS. 

793PD AXITINIB VS SORAFENIB FOR ADVANCED RENAL CELL 

CARCINOMA: PHASE III OVERALL SURVIVAL RESULTS AND 

ANALYSIS OF PROGNOSTIC FACTORS 

R.J. Motzer 1 , B. Escudier 2 , P. Tomczak 3 , S. Negrier 4 , M.E. Gore 5 , J. Tarazi 6 , 

S. Hariharan 7 , B. Rosbrook 6 , S. Kim 6 , B.I. Rini 8 

1 Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, 

New York, NY, UNITED STATES OF AMERICA, 2 Service d’Immunotherapie, 

Institut Gustave Roussy, Villejuif, FRANCE, 3 Uniwersytet Medyczny, Klinika 

Onkologii, Poznań, POLAND, 4 Dept. of Oncology, Centre Léon Bérard, Lyon, 

FRANCE, 5 Department of Medicine, Royal Marsden Hospital NHS Foundation 

Trust, London, UNITED KINGDOM, 6 Pfizer Oncology, Pfizer Oncology, San 

Diego, CA, UNITED STATES OF AMERICA, 7 Pfizer Inc, Pfizer Inc, New York, NY, 

UNITED STATES OF AMERICA, 8 Cleveland Clinic Taussig Cancer Institute, 

Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, UNITED STATES OF 

AMERICA 

Purpose: In the phase III AXIS trial, axitinib prolonged progression-free survival 

(PFS) compared with sorafenib as 2 nd -line therapy for metastatic renal cell carcinoma 

(mRCC) (Lancet 2011;378:1931). Mature overall survival (OS) data (as of Nov 1, 

2011) are reported. 

Methods: 723 patients (pts) with clear cell mRCC, progressive disease after 1 

systemic therapy, and Eastern Cooperative Oncology Group performance status 

(ECOG PS) 0 or 1 were stratified by ECOG PS and prior therapy and randomised 

1:1 to axitinib 5 mg twice daily (BID) or sorafenib 400 mg BID. OS was analysed as a 

secondary endpoint based on 425 events and compared using a 1-sided log-rank test 

stratified by ECOG PS and prior therapy. Pretreatment prognostic factors were 

studied by multivariate analyses. Pts were grouped by diastolic blood pressure (dBP) 

on therapy (≥1 dBP measurement ≥90 vs dBP


trial (TIVO-1) comparing TIVO with sorafenib (SOR) in patients (pts) with mRCC 

showed superior efficacy to SOR and a favorable safety profile with a low incidence 

of off-target adverse events (AEs). Here we provide detailed drug-related AE data 

from the TIVO-1 trial. 

Methods: Pts were randomized 1:1 to TIVO 1.5 mg once daily for 3 weeks (wks) 

followed by 1 wk rest, or SOR 400 mg twice daily continuously in a 4-wk cycle. AEs 

were recorded from the time pts signed the informed consent until 30 days after last 

dose of study drug. Blood pressure (mm Hg) was measured after a 5-minute rest 

period and taken on Days 1 and 15 of Cycle 1, on Day 1 of subsequent cycles, at the 

end-of-treatment visit, and at the 30-day follow-up visit. Descriptive statistics of 

drug-related AEs are presented. 

Results: Pts on the TIVO arm (175 [67.6%]) had fewer drug-related AEs than pts on 

the SOR arm (214 [83.3%]). The most common (≥10%) drug-related AEs and 

discontinuations are shown in the table. 

TIVO (n = 259) n (%) SOR (n = 257) n (%) 

AE All Grades Grade ≥3 All Grades Grade ≥3 

Hypertension 109 (42.1) 61 (23.6) 79 (30.7) 39 (15.2) 

Dysphonia 47 (18.1) – 11 (4.3) – 

Diarrhea 47 (18.1) 5 (1.9) 71 (27.6) 15 (5.8) 

Hand–foot syndrome 34 (13.1) 5 (1.9) 137 (53.3) 43 (16.7) 

Fatigue 28 (10.8) 7 (2.7) 28 (10.9) 7 (2.7) 

Alopecia 6 (2.3) – 53 (20.6) – 

Discontinuations 11 (4.2) – 14 (5.4) – 

Hypertension was the most frequent TIVO-related AE but was easily managed with 

standard antihypertensives. Fewer pts in the TIVO arm had ≥Grade 3 drug-related 

AEs than in the SOR arm (94 [36.3%] and 131 [51.0%], respectively). Pts in the 

TIVO arm required fewer overall dose reductions than did pts in the SOR arm (36 

[13.9%] vs 114 [44.4%], respectively). Two deaths in the TIVO arm were due to 

myocardial infarction; cardiac failure was responsible for 2 deaths in each arm. 

Conclusion: Pts on the TIVO arm experienced more hypertension and dysphonia, 

but less diarrhea, hand-foot syndrome, alopecia and discontinuations than pts on the 

SOR arm. Pts on the TIVO arm also had fewer overall dose reductions. These data 

demonstrate that TIVO is well-tolerated in pts with mRCC. 

Disclosure: T.Q.G. Eisen: Consultancy fee/honorarium: AVEO before trial period, 

Bayer Support for travel to mtgs for the study or other purposes: AVEO Board 

Membership: AVEO, Bayer (ad boards) Grants/pending: Bayer Payment for lectures, 

service on speakers bureau: Bayer. C.N. Sternberg: Consultancy: Astellas. B. Esteves: 

AVEO Pharmaceuticals employee with stock options. R.J. Motzer: Consultant: Pfizer 

Research Funding: AVEO, GSK, Novartis. All other authors have declared no 


796PD TIVOZANIB PHARMACOKINETIC (PK)/PHARMACODYNAMIC 

(PD) ANALYSIS OF BLOOD PRESSURE (BP) AND SOLUBLE 

VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2 

(SVEGFR2) IN PATIENTS WITH ADVANCED RENAL CELL 

CARCINOMA (RCC) 

D. Nosov 1 , R.J. Motzer 2 , J. Loewy 3 , L. Hodge 3 , B. Esteves 4 , A. Berkenblit 4 , 

W. Yin 5 , K. Dykstra 6 , T.E. Hutson 7 , M. Cotreau 5 

1 Clinical Pharmacology and Chemotherapy, N.N. Blokhin Russian Cancer 

Research Center, Moscow, RUSSIAN FEDERATION, 2 Genitourinary Oncology 

Service, Memorial Sloan-Kettering Cancer Center, New York, NY, UNITED 

STATES OF AMERICA, 3 Biostatistics, qPharmetra, Andover, MA, UNITED 

STATES OF AMERICA, 4 Clinical Research, AVEO Pharmaceuticals, Cambridge, 

MA, UNITED STATES OF AMERICA, 5 Oncology, AVEO Pharmaceuticals, Inc, 

Cambridge, MA, UNITED STATES OF AMERICA, 6 qPharmetra, Andover, MA, 

UNITED STATES OF AMERICA, 7 GU Center of Excellence Texas Oncology, 

Charles A. Sammons Cancer Center / Baylor University Medical Center / Texas 

AM Health Science Center College of Medicine, Dallas, TX, UNITED STATES OF 

AMERICA 

Background: Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor 

of VEGF receptors (VEGFRs) 1, 2, and 3, demonstrating activity against advanced 

RCC in Phase (Ph) II–III trials. This analysis explored the relationship between 

tivozanib PK and BP, as hypertension is a mechanism-based adverse event and a 

potential surrogate of response. The relationship between exposure and sVEGFR2 

also was explored. 

Methods: Pharmacokinetic, BP, and sVEGRF2 data from tivozanib-treated RCC 

patients (pts) from a Ph II (n = 21) and a Ph III (n = 259) study were pooled; pts 

were treated with 1.5 mg tivozanib daily for 21 days followed by a 7-day rest (28-day 

treatment cycle) in each study. A population PK model of tivozanib was constructed 

from PK data from Ph I–III studies, to obtain individualized predictions of 

steady-state values for Cavg. BP was measured at baseline and on Cycle 1 Day 15 

(C1D15), C2D1, and C3D1 in the Ph II and Ph III studies, and was binned to the 

nearest 5 mm Hg. Analysis focused on BP shifts in 5 mm Hg increments. Serum 

samples for sVEGFR2 (Ph III only) were collected at baseline and on C1D15, C2D1, 

and C2D22–28. Models of drug exposure as predictors of longitudinal changes in BP 

and/or sVEGFR2 were constructed by non-linear mixed-effects modeling. 

Results: Across pts, there was a statistically significant median 5 mm Hg increase in 

diastolic BP on C1D15, with similar increases noted on C2D1. There was a 

curvilinear decrease in sVEGFR2 with time. An Emax model vs time showed a 

half-maximal effect occurring in 19.4 (SE = 1.7) days, and a maximal 53% (%CV = 

4%) decrease in sVEGFR2. There was a statistically significant effect of Cavg on 

Emax, with the magnitude of Emax increasing 6% per 10 ng/mL increase in Cavg. 

Conclusion: PK/PD analysis of data from tivozanib Ph II–III studies showed that pts 

had a median increase in diastolic BP of 5 mm Hg on C1D15 and C2D1. Levels of 

serum sVEGFR2 were found to decrease significantly with time, and the effect size 

increased with tivozanib exposure. Relationships between exposure, BP, and 

sVEGFR2 and outcome are being explored. 

Disclosure: R.J. Motzer: Only disclosure is research funding from AVEO Oncology. J. 

Loewy: Consulting fee or honoraria from qPharmetra LLC. L. Hodge: Consulting or 

honoraria from qPharmetra LLC. B. Esteves: AVEO Pharmaceuticals employee with 

stock options. A. Berkenblit: AVEO Pharmaceuticals employee with stock options. W. 

Yin: AVEO Pharmaceuticals employee with stock options. K. Dykstra: -Consultancy 

fee or honorarium: qPharmetra LLC -Fees for participation in review activities such 

as data monitoring boards, statistical analysis, end point committees and the like: 

qPharmetra LLC. T.E. Hutson: - Consultancy or honoraria: AVEO Pharmaceuticals - 

Consultancy: Pfizer, Bayer, GSK, Novartis – Grants, grants pending: Pfizer, Bayer, 

GSK, Novartis – Payment for lectures includes service on speakers bureau:Pfizer, 

Bayer, GSK, Novartis. M. Cotreau: AVEO Pharmaceuticals employee with stock 

options. All other authors have declared no conflicts of interest. 

797PD FIRST LINE SUNITINIB IN TYPE I AND II PAPILLARY RENAL 

CELL CARCINOMA (PRCC): SUPAP- A PHASE II STUDY OF 

THE FRENCH GENITO-URINARY GROUP (GETUG) AND THE 

GROUP OF EARLY PHASE TRIALS (GEP) 

A. Ravaud 1 , S. Oudard 2 , M. De Fromont 3 , C. Chevreau 4 , G. Gravis 5 , S. Zanetta 6 , 

C. Theodore 7 , M. Jimenez 8 , E. Sevin 9 , B. Escudier 10 

1 Oncology Unit, C.H.U. Bordeaux Hopital St. André, Bordeaux, FRANCE, 

2 Oncology Department, Georges Pompidou Hospital and Rene Descartes 

University, Paris, FRANCE, 3 Pathology, Prado-Pathologie, Marseille, FRANCE, 

4 Medical Oncology, Institut Claudius Régaud, Toulouse, FRANCE, 5 Department 

of Medical Oncology, Institut Paoli Calmettes, Marseille, FRANCE, 6 Oncology 

Department, Centre Georges François Leclerc, Dijon, FRANCE, 7 Medical 

Oncology, Hôpital Foch, Suresnes, FRANCE, 8 R&D, Unicancer, Paris, FRANCE, 

9 Medical Oncology, Centre François Baclesse, Caen, FRANCE, 10 Service 

d’Immunotherapie, Institut Gustave Roussy, Villejuif, FRANCE 

Background: Sunitinib has been approved in metastatic clear cell carcinoma due to a 

prolonged progression-free survival (PFS). Subgroups analysis of previous studies 

hypothesized that sunitinib may be active in PRCC. This is the first prospective 

clinical trial reported with an anti-angiogenic agent in PRCC, which is an unmet 

need. 

Methods: SUPAP is a single-arm study using a 2-stage design including 21 patients 

(pts) to achieve a 20% ORR and if ≥ 2 pts have an OR, 20 additional pts would be 

included. Type I and II PRCC were included separately with an identical design. 

Main eligibility criteria included type I and II PRCC confirmed by central 

pathological review, PS 0-1, measurable disease, 1st line treatment. Sunitinb was 

given at 50mg/d, 4/6 weeks. Primary endpoint was ORR, while safety, PFS and 

overall survival (OS) were secondary endpoints. 

Results: From 10/07 to 02/11, 15 and 46 pts with type I and II were included, 

respectively. The median age was 64 year-old. Fifty-three (87%) pts had a 

nephrectomy. PS was 0 on 31 (50%) pts and 1 in 30 pts. Fifty-five (90%) pts had ≥ 1 

metastatic site. Using the MSKCC scoring system: 12 (19%), 33 (54%) and 9 (14%) 

pts were in the favorable, intermediate or poor risk group and 7 undetermined. With 

a median follow-up of 12.2 months [0.2-46.4], 60 and 61 pts were evaluable for 

efficacy and toxicity respectively. The median number of cycles was 4 [1-30] and 23 

pts (37.7%) required a dose reduction. In type I PRCC, 2/15 (13%) pts had a partial 

response (PR), 10 had a stable disease (SD) with 5 (33%) ≥ 12 weeks. In type II 

PRCC, 5/45 (11%) pts had a PR, 25 had a SD with 10 (22%) ≥ 12 weeks and 15 a 

progression. The median PFS was 6.6 months [CI 95%: 2.8–14.8] in type I and 5.5 

months [CI 95%: 3.8–7.1] in type II. The median overall survival was 17.8 [CI 95%: 

5.7–26.1] and 12.4 [CI 95%: 8.2–16] months in type I and II respectively. Toxicity 

was similar as in pivotal phase III with sunitinib in metastatic RCC. One patient died 

from a pulmonary embolism eventually due to sunitinib. 

Conclusion: Sunitinib has a modest activity in PRCC whatever type I or II, but still 

represents a treatment option in the lack of better therapy. 

Disclosure: A. Ravaud: myself ADVISORY ROLE Pfizer Novartis Bayer Schering 

GSK Astellas Dendreon Compensated HONORARIA Pfizer Novartis Bayer Schering 

Roche GSK Astellas Dendreon OTHER Travel financial support Pfizer Novartis 

Institution RESEARCH FUNDING Pfizer Novartis. S. Oudard: Myself ADVISORY 

ROLE Pfizer Bayer-Schering Roche GSK Novartis Sanofi Aventis Compensated 

HONORARIA Pfizer Bayer-Schering Roche GSK Novartis Sanofi Aventis. B. 

Escudier: Honoraria from Pfizer, Novartis, GSK, Bayer, Aveo, BMS. All other authors 



798PD OPEN-LABEL PHASE II TRIAL OF FIRST-LINE EVEROLIMUS 

MONOTHERAPY IN PATIENTS WITH ADVANCED PAPILLARY 

RENAL CELL CARCINOMA: RAPTOR INTERIM ANALYSIS 

B. Escudier 1 , S. Bracarda 2 , J.P. Maroto 3 , C. Szczylik 4 , P. Nathan 5 , S. Negrier 6 , 

K. Slimane 7 , C. May 8 , C. Porta 9 , V. Grünwald 10 

1 Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 2 Medical Oncology, 

Ospedale San Donato, Arezzo, ITALY, 3 Medical Oncology, Hospital de la Santa 

Creu i Sant Pau, Barcelona, SPAIN, 4 Clinical Oncology, Wojskowy Instytut 

Medyczny, Warsaw, POLAND, 5 Cancer Services, Mount Vernon Cancer Centre, 

Northwood, UNITED KINGDOM, 6 Oncology, Centre Leon Berard, Lyon, 

FRANCE, 7 Oncology, Novartis Pharmaceuticals, Rueil-Malmaison, FRANCE, 

8 Oncology, Novartis Pharma GmbH, Nuremberg, GERMANY, 9 Medical 

Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, ITALY, 

10 Clinic for Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 

Hannover Medical School, Hannover, GERMANY 

Background: Treatment options for patients with papillary renal cell carcinoma 

(RCC) are limited. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, 

has demonstrated efficacy in clear cell metastatic RCC; mTOR signaling is also 

dysregulated in papillary RCC. The ongoing RAPTOR (RAD001 in Advanced 

Papillary Tumor Program in Europe; ClinicalTrials.gov, NCT00688753) trial is 

evaluating everolimus monotherapy in treatment-naive patients with advanced 

papillary RCC. Here, we present the results of a preliminary analysis. 

Patients and methods: RAPTOR is an open-label, single-arm, multicentre phase II 

trial. Adult patients with advanced type I or type II papillary RCC and ECOG 

performance status of 0 or 1 were enrolled. Prior systemic therapy for RCC was not 

permitted. Patients received oral everolimus 10 mg once daily until disease 

progression or unacceptable toxicity. The primary end point is proportion of patients 

progression free at 6 months. 

Results: At data cut-off (April 11, 2012), 71 of 92 (77%) enrolled patients were 

eligible for analysis according to central pathology review (confirmed papillary renal 

cancer); 16 of the 92 patients were still on treatment. Most patients were men (73%) 

and most were


801P COMPARISON BETWEEN STANDARD AND REDUCED 

VOLUME RADIOTHERAPY IN BLADDER PRESERVATION 

TRIMODALITY PROTOCOL FOR MUSCLE INVASIVE BLADDER 

CANCER PATIENT 

W. Arafat, A. Darwish, G. El Hussiny 

Clinical Oncology, University of Alexandria, Alexandria, EGYPT 

Invasive bladder cancer is the most common tumor in Egypt. Preservation protocol 

consists of transurethral resection followed by concomitant chemo/ radiotherapy. The 

induction part of Radiotherapy is usually delivered to the whole pelvis, The role of 

omitting pelvic nodal irradiation has not been addressed before. 

Aim: To compare the toxicity, pelvic nodal relapse and overall survival of whole 

bladder irradiation only to standard technique of whole pelvis irradiation followed by 

bladder boost in patients with muscle invasive bladder carcinoma undergoing 

bladder preservation protocol. 

Material and method: A total of 63 patients with transitional cell carcinoma, stage 

T2-3,N0,M0 bladder cancer were subjected to maximal TURB. Then, patients 

randomized into two groups: group I (32 patients) to receive whole pelvis 

radiotherapy 44Gy followed by 20 Gy bladder boost. While Group II (31 patients) 

were randomized to receive whole bladder radiotherapy alone for a total dose of 64 

Gy. In both groups, concomittant cisplatin and paclitaxel were given weekly 

throughout the whole course of radiotherapy where conventional 2 Gy/ fraction were 

used. additionally, 4 cycles of Adjuvant cisplatin and paclitaxel were given after the 

end of chemo radiotherapy induction course. 

Results: Three patients, two in group I and one in group II discontinued due to 

grade 3 toxicity. After a median follow up of 2 years, regional relapse occurred in 

7.1% of patients in group I and 10.3% in group II. (p = 1). Distant metastases were 

detected in 17.9% of patient in group 1 and 13.8% in group II.(p = 0.73). The 2-year 

disease free survival was 60% in group I and 63.3% in group II (p = 0.79). The whole 

2-years overall survival was 75% in group I and 79.3% in group II (p = 0.689). 

Radiation gastrointestinal (GI) Acute toxicity was higher in group I than in group II 

(p = 0.001), while late GI radiation toxicity was comparable in both groups. 

Conclusion: treating the bladder only without elective pelvic nodal irradiation, did not 

compromise pelvic control rate, but significantly decreased the acute radiation toxicity. 


802P EFFICACY AND PROGNOSTIC FACTORS OF NEOADJUVANT 

CHEMOTHERAPY IN RESECTABLE LOCALLY-ADVANCED 

MUSCLE-INVASIVE BLADDER CANCER (MIBC) PATIENTS (P) 

IN AN OFF-PROTOCOL CLINICAL SETTING 

J.L. Cuadra Urteaga 1 , M. Domenech 2 , P. Celiz 1 , J.J. Sánchez 3 , N. Pardo 1 , 

C. Buges 1 , J. Malet 4 , M. Arzoz 5 , J. Areal 5 , A. Font 1 

1 Medical Oncology, Catalan Institute of Oncology ICO Badalona Hospital 

Germans Trias i Pujol, Medical Oncology, Badalona, SPAIN, 2 Oncology, ALthaia, 

Xarxa Assistencial de Manresa, Manresa, SPAIN, 3 Statistics, Autonomous 

University of Madrid, Madrid, SPAIN, 4 Urology, ALthaia, Xarxa Assistencial de 

Manresa, Manresa, SPAIN, 5 Urology, Hospital Germans Trias i Pujol, Badalona, 

SPAIN 

Introduction: Although neoadjuvant chemotherapy is a recommended treatment in 

MIBC, it has not gained widespread acceptance in clinical practice, due to the lack of 

predictive markers of efficacy and the absence of a standard chemotherapy regimen. 

Furthermore, since few studies have assessed the role of neoadjuvant chemotherapy 

in an off-protocol setting, there may be doubts about its feasibility. 

Material and methods: We retrospectively analyzed 124 p with MIBC treated with 

neoadjuvant cisplatin-based chemotherapy at two centers from 1991 to 2010. Clinical 

and pathological variables were correlated with survival. All patients were classified 

as stage cT2-4N0M0 based on TUR (trans-urethral resection) and CT scan findings 

and were candidates for neoadjuvant chemotherapy followed by cystectomy. 

Results: 10 p (8%) were cT2N0, 83 p (66%) cT3N0, and 31 p (26%) cT4aN0. 60 p 

(48%) were treated with CMV (cisplatin, methotrexate and vinblastine) and 64 p 

(52%) with cisplatin/gemcitabine (CG). One patient died from treatment-related 

toxicity. A complete resection was performed in 109 p (87%). A significant 

pathological response (pR) (pT0-1) was obtained in 60 p (48%). Median survival 

(MS) and 5-year (5y) survival were 59 months (m) and 50%, respectively. Median 

cancer-specific survival (CSS) was not reached and 5y CSS was 64%. 5y overall 

survival was similar (50.3% vs 50.9%) in p treated with CMV or CG. In p with a 

significant pR, 5y survival was 77%, while for p who did not respond to 

chemotherapy (pT3-4NO or N+), it was 8.3%. Only complete resection (HR:3.36, 

P = 0.006) and lymphovascular invasion (LVI) (HR:17.29, P < 0.0001) were significant 

in the multivariate analysis. 

Conclusions: Neoadjuvant chemotherapy followed by cystectomy is feasible in p 

with locally-advanced MIBC. Both CMV and CG are active regimens, with 5-y 

survival that compares favorably with surgery alone. p responding to neoadjuvant 

chemotherapy have an excellent prognosis, while those who do not respond should 

be considered for non-cross-resistant adjuvant chemotherapy. 


803P SELECTIVE BLADDER PRESERVATION BY TRI-MODALITY 

THERAPY FOR MUSCLE INVASIVE BLADDER CARCINOMA 

A. Darwish 1 , G. Elhussiny 1 ,W.Arafat 2 

1 Clinical Oncology, University of Alexandria, Alexandria, EGYPT, 2 Clinical 

Oncology, Alexandria International Hospital, Alexandria, EGYPT 

Purpose: To access safety, tolerance, local control and survival of transurethral 

resection of Bladder tumor (TURB) followed by concomitant cisplatin, paclitaxel and 

radiation therapy as selective organ preservation in patients with Muscle Invasive 

bladder. Addionally, Surviving and ERCC1 gene expression analysis and response to 

treatmentis also studied. 

Methods and materials: A total of 63 patients with transional cell carcinoma (TCC), 

stage T2–T3, No, Mo bladder carcinoma were enrolled in a protocol of TURP 

followed by one daily radiotherapy (2Gy/ fraction for a total dose of 44 GY) with 

concomitant cis-platin 15mg/m2/ day,d1-3 weekly and paclitaxel 50mg/m2/day, 

weekly.Four weeks later, all patients were evaluated by cytoscopy and biopsy. Patients 

with complete response proceeded to consolidation Radiotherapy (2Gy/fr for a total 

20GY with concomitant cisplatin and paclitaxel, while those with recurrent tumor 

went on to salavage. Cystectomy. Following consolidation or salvage surgery, 

all patients went to complete 4 cycles of cisplatin75mg/m2/ day and paclitaxel 

175 mg/day every 21 days. RNA extraction from Biopsy before and after treatment 

was analysed for survivin and ERCC1 gene expression using real time PCR. 

Results: Three patients could not tolerate the treatment and discontinued the 

protocol during the induction phase while the remaining sixty patients complete the 

induction phase. The complete response after the induction phase was 75%. Eleven 

percent of the complete responders developed superficial relapse with a median time 

of relapse of 16 months, while 8.9% developed invasive relapse with a median time of 

18 months. 2-year disease for survival was 61.7%. Distant metastases we detected in 

15.8% the patients. 2year overall survival was 77.2%. RNA was succifully extracted 

from 65% of patient, real time PCR for ERCC1 and survivin was done, interpretation 

of data will be presented. 

Conclusion: Maximal transurethral resection followed by concomitant cis-platin and 

paclitaxel, as a bladder preservation therapy, can be considered a valid alternative for 

treating selected patients with localized muscle invasive TCC of the bladder. ERCC1 

and survivn might be a predictive model of treatment response. 


804P PROGNOSTIC STRATIFICATION OF ADVANCED UROTHELIAL 

CARCINOMA (UC) RECEIVING SECOND-LINE SYSTEMIC 

THERAPY INCLUDING TIME FROM PRIOR CHEMOTHERAPY 

(TFPC) AS A PROGNOSTIC FACTOR 

G. Sonpavde 1 , G.R. Pond 2 , T.K. Choueiri 3 , R. Fougeray 4 , G. Niegisch 5 , 

Y. Wong 6 , S.S. Sridhar 7 , W.M. Stadler 8 , C.N. Sternberg 9 , J. Bellmunt 10 

1 Medical Oncology, Texas Oncology, Baylor College of Medicine, Webster, TX, 

UNITED STATES OF AMERICA, 2 Biostatistics, Ontario Clinical Oncology Group 

and McMaster University, Hamilton, CANADA, 3 Medical Oncology, Dana Farber 

Cancer Institute, Boston, MA, UNITED STATES OF AMERICA, 4 Statistics, Institut 

de Recherche Pierre Fabre, Boulogne, FRANCE, 5 Urologic Oncology, Heinrich 

Heine University, Dusseldorf, GERMANY, 6 Medical Oncology, Fox Chase Cancer 

Center, Philadelphia, PA, UNITED STATES OF AMERICA, 7 Medical Oncology, 

Princess Margaret Hospital, Toronto, ON, CANADA, 8 Medical Oncology, 

University of Chicago, Chicago, IL, UNITED STATES OF AMERICA, 9 Medical 

Oncology, San Camillo Forlanini Hospital, Rome, ITALY, 10 Medical Oncology, 

University Hospital del Mar, Barcelona, SPAIN 

Background: Prognostic factors for overall survival (OS) in patients receiving 

second-line chemotherapy for advanced platinum-pretreated urothelial carcinoma 

(UC) include ECOG performance status (PS) >0, hemoglobin (Hb)

Hb, PS and LM. Median PFS for patients with 0, 1, 2 and 3-4 factors (PS > 0, Hb < 

10g/dL, LM, TFPC 0, Hb


808P SELECTING PATIENTS FOR HIGH-DOSE INTERLEUKIN-2 ON 

THE BASIS OF TUMOUR HISTOLOGY 

R. Hawkins 1 , V. Galvis 1 , A. Shablak 1 , A. Spencer-Shaw 1 , F. Thistlethwaite 1 , 

J. Shanks 2 , N. Dalal 2 


KINGDOM, 2 Pathology, The Christie NHS Foundation Trust, Manchester, 


Background: High-Dose Interleukin-2 (HD IL2) remains an option for treatment of 

metastatic renal cancer. In carefully selected patients, it can produce high rates of 

response with many durable remissions (Shablak A et al., J Immunotherapy 2011, 

34(1):107–122). There remain uncertainties about the optimal way to select patients 

for treatment and here we update our approach to selecting patients for HD IL2 and 

include the analysis of carbonic anhydrase IX(CAIX) expression which has been 

previously suggested to correlate with response. 

Methods: We present the outcomes of 103 patients with “favourable histology” (less 

than 10% papillary features and at least one of: >50% alveolar/solid (A/S) or >50% 

clear cell features) treated with first-line immunotherapy (including 19 who have 

failed prior targeted therapy) with HD-IL2. We examine the response rate in relation 

to histology and CAIX expression. 

Results: Overall the response rate was 59/103 (57%) and the CR rate is 23/103 

(22% - with 4 patients in PR and continuing treatment at the time of writing). 

Examination of the different features in relation to response suggested that the most 

important features were ≥ 50% A/S pattern as only 1/5 patients who had < 50% A/S 

responded and that was not a CR. CAIX staining was only available for 47 patients 

but may provide further modest benefit in selecting patients for therapy. Certainly, 

no patient with < 80% CAIX staining achieved a CR although 3/10 did respond. 

In the group with >50% A/S pattern and >80% CAIX staining the response rate was 

22/37 (59%) and the CR rate was 9/37(24% with 4 patients in PR and continuing 

treatment at the time of writing). 

Conclusions: These results extend and confirm our previously reported series (of 57 

patients) and the overall response rate remains around 50% and that, combined with 

many durable complete remissions, results in an overall median survival 55 months 

(for all 103 patients) with an apparent plateau of 40% long term survivors. HD-IL2 

remains an attractive option for carefully selected patients with metastatic clear cell 

renal cancer. The most tangible benefit of HD-IL2 is the ability to achieve durable 

complete remissions and our series suggests the optimal histological type in which to 

achieve this is patients whose tumour has < 10% papillary features, ≥50% A/S pattern 

and expresses ≥80% CAIX. 


809P BEVACIZUMAB (BEV) + LOW-DOSE INTERFERON-a2A (IFN) 

FOR FIRST-LINE TREATMENT OF METASTATIC RENAL CELL 

CARCINOMA (MRCC): FINAL SAFETY AND EFFICACY DATA 

FROM THE PROSPECTIVE BEVLIN STUDY 

B. Melichar 1 , S. Bracarda 2 , V. Matveev 3 , A. Kaprin 4 , B. Alekseev 5 , 

R. Janciauskiene 6 , B. Lutiger 7 , M.E. Gore 8 , G. Mickisch 9 , J. Bellmunt 10 

1 Oncology, University Hospital Olomouc Palacky University, Faculty of Medicine, 

Olomouc, CZECH REPUBLIC, 2 Department of Oncology, Ospedale San Donato 

and U.O.C. of Medical Oncology, Arezzo, ITALY, 3 Department of Urology, N.N. 

Blokhin Cancer Research Center, Moscow, RUSSIAN FEDERATION, 

4 Department of Oncology, Russian Research Centre of Roentgenology and 

Radiology, Moscow, RUSSIAN FEDERATION, 5 Department of Oncology, 

Research Oncology Institute, Moscow, RUSSIAN FEDERATION, 6 Clinic of 

Oncology, Kaunas University of Medicine, Kaunas, LITHUANIA, 7 GPS-MO, 

F. Hoffmann-La Roche AG, Basel, SWITZERLAND, 8 Department of Medicine, 

Royal Marsden Hospital NHS Foundation Trust, London, UNITED KINGDOM, 

9 Department of Urology, Center of Operative Urology Bremen, Bremen, 

GERMANY, 10 Department of Medical Oncology, University Hospital del Mar, 


Background: In the AVOREN trial, first-line BEV + IFN (9 MIU three times in a 

week [tiw]) was effective in patients (pts) with mRCC. A retrospective analysis found 

that efficacy was maintained and IFN-related toxicity was improved in pts with IFN 

dose reduced to 6 or 3 MIU. BEVLiN (MO21609) prospectively assesses the safety 

and efficacy of BEV with low-dose IFN (3 MIU) in mRCC. 

Methods: BEVLiN is an open-label single arm, multinational phase 2 study. 

Nephrectomized, treatment-naive pts with clear cell mRCC and favourable/ 

intermediate Motzer scores were treated with BEV 10mg/kg q2w + IFN 3 MIU tiw 

until disease progression. BEVLiN was designed to allow descriptive, cross-trial 

comparison with the BEV + IFN 9 MIU-treated favourable/intermediate Motzer score 

AVOREN subgroup. Primary end points are safety (specific grade [Gr] ≥3 

IFN-associated adverse events [AEs]) and progression-free survival (PFS). Secondary 

end points are overall survival (OS); overall response rate (ORR); any Gr ≥3, overall, 

and serious AEs. 

Results: 147 pts were enrolled in BEVLiN. Baseline pt characteristics were similar to 

the comparator AVOREN subgroup. The median follow-up was 29.4 months. Pts 

received a median of 22.5 cycles of BEV (18.0 in the AVOREN subgroup). Median 

PFS was 15.3 mos (95% CI: 11.7; 18.0) vs 10.5 mos (95% CI: 10.1; 12.9); median OS 

was 30.7 mos (95% CI: 25.7; not reached) vs 25.8 mos (95% CI: 22.7; 29.4); and ORR 

was 29% vs 36% in BEVLiN and the AVOREN subgroup, respectively. The rates of 

any-Gr and Gr ≥3 IFN-associated AEs were markedly lower in BEVLiN than in the 

AVOREN subgroup (Table). Overall rates of AEs of special interest were similar 

between studies, despite longer BEV duration in BEVLiN. 

AE, % (95% CI) BEVLiN n = 146 a AVOREN subgroup n = 283 a 

Any Gr Gr ≥3 Any Gr Gr ≥3 

Any IFN-related AE 53 (45–62) 10 (6–16) 89 (85–92) 27 (22–32) 

· Asthenia/fatigue 37 (29–45) 10 (5–16) 63 (57–68) 21 (16–26) 

· Pyrexia 19 (13–27) 0 (0–2) 45 (39-51) 2 (1–4) 

· Nausea 9 (5–15) 1 (0–4) 29 (23–34) 1 (0–3) 

· Anorexia 0 (0–2) 0 (0–2) 36 (30–42) 3 (1–5) 

Any BEV-related AE of 

special interest b 

59 (50–67) 23 (17–31) 60 (54–66) 23 (18–28) 

a Treated pts. b Includes hypertension, proteinuria, bleeding, and other AEs. 

Conclusions: Use of low-dose IFN with BEV in BEVLiN resulted in a reduction in 

IFN-related AEs without compromising efficacy outcomes compared with a control 

AVOREN subgroup. 

Disclosure: B. Melichar: Dr. Bohuslav Melichar has received honoraria for lectures 

from Roche and participated in an advisory board meeting. S. Bracarda: Dr. Sergio 

Bracarda is an Advisory Board Member for Novartis, Pfizer, GSK, Bayer, Aveo/ 

Astellas, Jannsen &Jannsen and Sanofi-Aventis. He has received honoraria for 

lectures from Novartis, Sanofi-Aventis and Pfizer. R. Janciauskiene: Dr. Janciauskiene 

has been principal investigator in a Hoffmann-La Roche sponsored trial and has 

been an invited speaker for Hoffmann-La Roche. B. Lutiger: Beatrix Lutiger is an 

employee of F. Hoffmann-La Roche AG. M.E. Gore: Dr. Martin Gore has 

participated advisory board meetings and is on the speaker’s bureau for Roche. G. 

Mickisch: Dr. Gerald Mickisch is a member of the BEVLiN Steering Committee. J. 

Bellmunt: Dr. Joaquim Bellmunt has participated in an advisory board meeting, and 

received a lectures fee from Roche. All other authors have declared no conflicts of 

interest. 

810P TOLERABILITY OF TARGETED AGENTS IN FIRST-LINE 

TREATMENT OF METASTATIC RENAL CELL CARCINOMA 

(MRCC) 

Y. Su 1 , N. Shi 2 , P. Landsman-Blumberg 3 , C. Poehlein 4 , I. Waxman 5 

1 Global Health Economics & Outcomes Research, Bristol-Myers Squibb, 

Princeton, NJ, UNITED STATES OF AMERICA, 2 Pharma/Biotech, Thomson 

Reuters Healthcare, Cambridge, MA, UNITED STATES OF AMERICA, 

3 Outcomes Research, Thomson Reuters, Washington DC, UNITED STATES OF 

AMERICA, 4 HQ Global Medical Affairs, Immuno-Oncology, Bristol-Myers Squibb, 

Princeton, NJ, UNITED STATES OF AMERICA, 5 Oncology, Bristol-Myers Squibb, 

Princeton, NJ, UNITED STATES OF AMERICA 

Objectives: Between 2005 and 2009, six targeted agents were approved for the 

treatment of mRCC in the US. Clinical trials have reported median progression-free 

survival (PFS) of up to 11 months for treatment-naive patients. None has 

demonstrated an improvement in median overall survival versus another targeted 

agent. This study aims to determine the tolerability of these agents in real-world 

practices. 

Methods: Adult patients with mRCC diagnosed between Jan 1, 2006 and Dec 31, 

2010 were identified from a large commercial insurance claims and Medicare 

supplemental database in the US. A minimum follow-up of 3 months and ≥1 

pharmacy or medical claims on or after metastasis diagnosis date were required for 

one of the targeted agents: sunitinib (SUN), sorafenib (SOR), pazopanib (PAZ), 

everolimus (EVE), temsirolimus (TEM), or bevacizumab with or without interferon 

alpha (BEV). Tolerability was measured by rate of dose reduction and duration of 

treatment. Median duration of treatment was assessed using the Kaplan-Meier 

method. Adverse events (AE) were based on diagnosis or treatment indicative of AEs 

commonly associated with these agents. 

Results: 1,622 patients were identified, of which 1,079 received first-line SUN, 284 

SOR, 168 TEM, 40 PAZ, 26 EVE, and 25 BEV. With a median follow up of 13 

months, median duration of treatment was the longest for PAZ (6.9 mos), followed 

by SOR and EVE (both 4.9 mos), SUN (4.8 mos), TEM (3.5 mos) and BEV (1.0 

mo). Dose reduction was observed in a higher percentage of patients receiving SUN 

(26%) compared to TEM (18.5%), BEV (12.5%), EVE (7.7%), PAZ (7.5%), and SOR 

(6%). Claims of AEs were 93%, 86%, 86%, 85%, 80%, and 56% for TEM, SUN, SOR, 

EVE, PAZ, and BEV, respectively. 

Conclusions: Rates of AEs appear to be high among commonly used first-line 

agents, including the recently approved PAZ and EVE, and there was substantial 

need for dose reduction for the most prescribed SUN. Duration of treatment 

appeared to be substantially shorter than published PFS values, assuming treatment 

until progression for the majority of patients. It is important to determine if AEs 


may have led to reduced dose and shortened duration of treatment and how costs of 

care and patient outcomes might be affected. 

Disclosure: Y. Su: Employment and Leadership Role: Bristol-Myers Squibb 

(employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb 

(myself). P. Landsman-Blumberg: Stock Ownership: Merck & Co., Inc. (myself). 

C. Poehlein: Employment and Leadership Role: Bristol-Myers Squibb (employment, 

myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). I. Waxman: 

Employment and Leadership Role: Bristol-Myers Squibb (employment, myself, 

compensated). Stock Ownership: Bristol-Myers Squibb (myself). All other authors 


811P CLINIC AND HOME BLOOD PRESSURE MEASUREMENTS 

ARE RELIABLE FOR GUIDING THERAPY IN PATIENTS WITH 

METASTATIC RENAL CELL CARCINOMA RECEIVING 

AXITINIB AS FIRST-LINE THERAPY 

V. Grünwald 1 , M.N. Fishman 2 , M. Carducci 3 , A. Bair 4 , Y. Chen 4 , S. Kim 4 , 

B.I. Rini 5 

1 Clinic for Hematology, Hemostasis, Oncology, Hannover Medical School, 

Hannover, GERMANY, 2 Genitourinary Program, H. Lee Moffitt Cancer 

CenterUniversity of South Florida, Tampa, FL, UNITED STATES OF AMERICA, 

3 Kimmel Cancer Center, Kimmel Cancer Center, Baltimore, MD, UNITED 

STATES OF AMERICA, 4 Pfizer Oncology, Pfizer Oncology, San Diego, CA, 

UNITED STATES OF AMERICA, 5 Cleveland Clinic Taussig Cancer Institute, 

Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, UNITED STATES OF 

AMERICA 

Background: Axitinib, a potent and selective inhibitor of vascular endothelial growth 

factor receptors 1, 2, and 3, is approved in the US in patients (pts) with metastatic renal 

cell carcinoma (mRCC) who failed 1 prior systemic therapy. Blood pressure (BP) 

increases are commonly observed with axitinib. BP measurements are subject to error and 

can vary by method employed, eg, home measurements by pts, ambulatory monitoring, 

and in-clinic assessments. As part of a phase II study evaluating safety and efficacy of 

axitinib for treatment-naïve mRCC, we prospectively characterised and compared BP 

measurements from clinic, home, and 24-hr ambulatory BP monitoring (ABPM). 

Methods: Clinic BP was obtained at baseline, Days 1 and 15 of the first 2 treatment 

cycles, and Day 1 of subsequent 28-day cycles. Home BP was obtained by pts twice 

daily during the treatment period. In a subset of pts, 24-hr ABPM was performed at 

baseline and Days 4 and 15. 

Results: 213 pts enrolled. Mean age was 61 years; 67% were men. Pooled median 

progression-free survival was 14.5 months. No pts had uncontrolled hypertension 

(HTN) at study entry. All-grade HTN occurred in 63% and grade 3 in 29%, with no 

grade 4 HTN. By 24-hr ABPM, median increases from baseline in systolic BP/ 

diastolic BP (sBP/dBP) were 10/8 mmHg by Day 4, with modest incremental 

increases by Day 15 and stabilisation thereafter; changes in BP were generally 

consistent at all clock times of day. dBP outcomes were highly consistent between 

clinic and home measurements (mean 83 ± 9 vs 83 ± 9 mmHg on Cycle 1 Day 15, 

n = 200; 84 ± 11 vs 84 ± 10 mmHg on Cycle 3 Day 1, n = 171). Similarly, dBP 

measurements were consistent between clinic and 24-hr ABPM (mean 84 ± 10 vs 84 

± 9 mmHg on Cycle 1 Day 15, n = 63). Consistent sBP outcomes were also observed 

across various time points and measurement modalities. 

Conclusions: BP increased early with axitinib and was generally well-managed. 24-hr 

ABPM suggests there is no best time of day to measure BP; rather, measuring at a 

consistent time of day in individual pts would provide the most useful data. Results 

from clinic and home monitoring appear consistent and both could be reliable in 

measuring BP and guiding axitinib therapy. 

Disclosure: V. Grünwald: Advisory and honoraria: GSK, Pfizer, Roche, Novartis, 

Bayer. Research grant: Pfizer. M.N. Fishman: Dr Fishman has received research 

funding, participated in compensated advisory board and promotional presentations 

from the manufacturer of the study drug. M. Carducci: Pfizer DSMB for unrelated 

product (compensated). JHU received research funding for conduct of the trial. A. 

Bair: Employee of and own stock in Pfizer. Y. Chen: Employee of and own stock in 

Pfizer. S. Kim: Employee of and own stock in Pfizer. B.I. Rini: Consulting and 

research funding from Pfizer. 

812P ROLE OF GENETIC VARIANTS IN THE PI3K/AKT/MTOR 

PATHWAY IN RENAL CELL CARCINOMA PATIENTS TREATED 

WITH EVEROLIMUS- A PILOT STUDY 

L. Bodnar 1 , R. Stec 1 , M. Cichowicz 2 , S. Cierniak 3 , M. Smoter 4 ,W.Kozłowski 2 , 

C. Szczylik 1 

1 Department of Oncology, Military Institute of Medicine, Warsaw, POLAND, 

2 Department of Pathology, Military Institute of Medicine, Warsaw, POLAND, 

3 Pathology, Military Institute of Medicine, Warsaw, POLAND, 4 Oncology, Military 

Institute of Medicine, Warsaw, POLAND 

Background: The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is 

involved in growth regulation, proliferation control and metabolism in renal cell 


carcinoma (RCC). In our prospective pilot study, we determined whether common 

genetic variations in the AKT/ PI3K, FRAP1 (encoding mTOR) are associated with 

clinical outcomes in RCC patients who underwent palliative therapy with everolimus. 

Patients and methods: Our pilot study was designed to assess everolimus efficacy in 

RCC patients relapsed after TKI inhibitors (sunitinib and/or sorafenib). Patients were 

treated with everolimus 10 mg daily orally until disease progression. The genomic 

DNA was extracted from formalin-fixed, paraffin-embedded primary tumor RCC 

tissues. 12 potentially functional SNPs in 4 key genes (AKT1, AKT2, FRAP1, 

PIK3CA) were determined using a real-time PCR genotyping assay and analyzed for 

association with response to therapy, progression free survival (PFS) and overall 

survival (OS). 

Results: Median age of 45 enrolled patients was 62 years (range, 41–78). At a median 

follow-up duration of 8,6 months, the 6-month PFS rate was 53.3%. Partial response 

was observed in 4,4% (2/45) of the patients. Median PFS was significantly prolonged 

in the PIK3CA rs6443624 for the CC genotype in comparison to the AA/AC 

genotype (8.9 months versus 5.5 months, log rank, p= 0.0157). In the multivariate 

analysis elevated corrected serum calcium and PIK3CA rs6443624 for the AA/AC 

genotype were unfavorable predictors of PFS (HR 5.25; 95% CI, 1.75–15.75 and HR 

3.48; 95%CI, 1.47–8.25, respectively, p < 0.05). 1-year OS rate for patients with 

PIK3CA rs6443624 CC and AA/AC genotype was 86% and 51%, respectively (p = 

0.0018). In multivariate analysis PIK3CA rs6443624 for the AA/AC genotype and 

elevated LDH serum level remained significant for OS (HR 18.7; 95% CI,2.70–129.38 

and HR 9.7; 95% CI,2.18 – 43.07, respectively; p < 0.05). 

Conclusion: These results suggest that PIK3CA rs6443624 genetic variation in PI3K/ 

AKT/mTOR pathway may modulate clinical outcomes in patients with RCC who 

undergo chemotherapy with everolimus. Further clinical studies are needed to 

confirm these findings. 


813P THE NOVEL CANCER VACCINE, CONSISTING OF 

GENETICALLY MODIFIED ALLOGENEIC TUMOR CELLS AND 

IMMUNOMODULATOR MGN1601: UPDATED RESULTS OF A 

PHASE 1-2 STUDY IN PATIENTS WITH ADVANCED RENAL 

CELL CARCINOMA 

I.G. Schmidt-Wolf 1 , S. Hauser 2 , S. Weikert 3 , V. Grünwald 4 , M. Schroff 5 , 

M. Schmidt 6 , E. Weith 6 , M. Tschaika 6 , B. Wittig 7 

1 Department of Medicine III, Center for Integrated Oncology, University of Bonn, 

Bonn, GERMANY, 2 Department of Urology, University of Bonn, Bonn, 

GERMANY, 3 Clinic for Urology, Charite, Berlin, GERMANY, 4 Clinic for 

Hematology, Hemostaseology, Oncology, Hannover Medical School, Hannover, 

GERMANY, 5 Board, Mologen AG, Berlin, GERMANY, 6 Clinical Development, 

Mologen AG, Berlin, GERMANY, 7 6Foundation Institute Molecular Biology and 

Bioinformatics, Freie Universität Berlin, Berlin, GERMANY 

Background: MGN1601 consists of two active pharmaceutical ingredients: genetically 

modified allogeneic tumor cells expressing IL-7, GM-CSF, CD80 and CD154 and a 

TLR9 agonist, synthetic DNA-based immunomodulator dSLIM®. The first-in-man 

phase 1–2 clinical trial (ASET trial) has been conducted in patients with advanced 

renal cell carcinoma failed previous therapy lines and without further available 

standard therapy. 

Methods: The ASET study is a multicentric, open, single-arm phase 1-2 clinical 

study and consists of the treatment, extension and follow up phases. The safety, 

efficacy and immunogenicity parameters were evaluated based on clinical and 

laboratory assessments, monitoring of patients’ quality of life (QoL) with QLQ-C30, 

immunological tests, and central radiological investigations according to RECIST 1.1 

as well as immune related Response Criteria. 

Results: Ten of nineteen study patients completed the treatment per protocol (TPP). 

Two patients with disease control after 12-weeks continued treatment in the 

extension phase. One of them is still under therapy showing tumor remission since 

48 weeks. The second patient developed radiological PD after 60 weeks of treatment. 

Seven patients from the TPP population are still alive with stable disease for up to 65 

weeks. Evaluation of the QoL showed that patients of the TPP group have improved 

median symptom score from 45.8 to 58.3 in course of treatment. Drug-related AE 

included mild fever, edema, exanthema, pruritus, intermittent arthralgia, fatigue, and 

moderate soft tissue infection. Local reactions on injection site consisted mostly of 

redness up to 50 mm, which were available up to 7 days. The local reactions have no 

negative impact on the quality of life and daily activities of the patients. Six of ten 

TPP patients showed significant improvement in the immune status in lymphocyte 

transformation test. 

Conclusions: The allogeneic tumor cell-based cancer vaccine MGN1601 shows 

promising efficacy and a favourable safety profile in the late stage mRCC patients. A 

phase 2 clinical study in mRCC patients with MGN1601 as third-line therapy is 

under development. 

Disclosure: M. Schroff: Board member of Mologen. M. Schmidt: Mologen employee. 

E. Weith: Mologen empoyee. M. Tschaika: Mologen employee. B. Wittig: Member of 

Scientific Advisory Board of Mologen. All other authors have declared no conflicts of 

interest. 



814P A PHASE IB CLINICAL TRIAL OF THE MULTITARGETED 

KINASE INHIBITOR LENVATINIB (E7080) IN COMBINATION 

WITH EVEROLIMUS FOR TREATMENT OF METASTATIC 

RENAL CELL CARCINOMA (RCC) 

A.M. Molina 1 , T.E. Hutson 2 , J. Larkin 3 , A. Gold 4 , C. Andresen 4 , K. Wood 5 , 

R.J. Motzer 1 , M.D. Michaelson 6 


New York, NY, UNITED STATES OF AMERICA, 2 GU Oncology Program, Baylor 

Sammons Cancer Center, Dallas, TX, UNITED STATES OF AMERICA, 

3 Department of Medicine, Royal Marsden Hospital, London, UNITED KINGDOM, 

4 PCU, Eisai Inc, Woodcliff Lake, NJ, UNITED STATES OF AMERICA, 5 Oncology 

Pcu, Eisai Ltd, Hatfield, UNITED KINGDOM, 6 Medical Oncology, Massachusetts 

General Hospital Cancer Center, Boston, MA, UNITED STATES OF AMERICA 

Background: Lenvatinib (L) is an oral tyrosine kinase inhibitor targeting VEGFR1-3, 

FGFR 1-4, RET, KIT, and PDGFβ. Everolimus (E) is an oral mTOR inhibitor 

approved for RCC. This Phase (Ph) 1b/2 study investigates the combination of L plus 

E in RCC patients (pts) (NCT01136733). The Ph 1b component reported here 

assessed safety, tolerability, and maximum tolerated dose (MTD). The 3-arm 

randomised Ph 2 comparing PFS of L plus E and L alone versus E alone is ongoing. 

Methods: Pts with advanced unresectable or metastatic RCC, ECOG PS 0-1, age ≥18 

y were eligible for Ph 1b. Pts received L plus E, daily, in 28-day cycles. A standard 

3 + 3 dose-escalation design with expansion cohort was used to identify the MTD. 

Results: 20 pts (M/F: 14/6; median age: 59 y [range 46-72]; median of 2 prior 

therapeutic regimens [range 0-5]; 17/20 pts [85%] had received prior anti-VEGF 

treatment (tx); 7/20 pts [35%] had also received prior mTOR-targeted tx) were 

treated at 3 dose levels of L (12 mg [n = 7]; 18 mg [n = 11]; 24 mg [n = 2]) in 

combination with E 5 mg. 4 DLTs were observed: G3 nausea and vomiting (1 pt) and 

G2 mucositis (1 pt) at 24 mg; G3 elevated CPK at 18 mg; G3 abdominal pain at 12 

mg. The MTD was L 18 mg plus E 5 mg. Median duration of tx was 14.5 wk (range 

1-68, 7/20 (35%) pts ongoing). The most common tx-related adverse events (AEs), 

all grades were fatigue 45% (G3, 5%); mucosal inflammation 40%; proteinuria 35% 

(G3, 10%); diarrhoea 30% (G3, 5%); rash 30%; hypertension 25%; nausea, vomiting 

each 25% (each G3 5%); constipation, decreased appetite, epistaxis each 20%. There 

was 1 G4 related AE of hypercholesterolemia. PR was observed in 6/18 (33%) pts in 

the MTD and lower dosing cohorts. Durable stable disease (≥23 wk) or PR were 

achieved in 8/16 (50%) pts with postbaseline tumor assessments (and 3 pts ongoing 

with SD $10,000. M.D. Michaelson: Dr. 

Michaelson discloses institutional research funding from: EISAI, Pfizer, Abbott, 

GlaxoSmithKline, Genentech Consultant or advisory role (UNCOMPENSATED): 

Pfizer, EISAI. All other authors have declared no conflicts of interest. 

815P SUNITINIB (SU) DOSING SCHEDULE AND DATA COLLECTION 

TIMEPOINTS: IMPACT ON QUALITY OF LIFE (QOL) 

OUTCOMES IN METASTATIC RENAL CELL CARCINOMA 

(MRCC) 

A. Bushmakin 1 , J.C. Cappelleri 1 , B. Korytowsky 2 , R. Sandin 3 , E. Matczak 4 , 

D. Cella 5 

1 Statistics, Pfizer Inc., Groton, CT, UNITED STATES OF AMERICA, 2 Oncology 

Health Economics Outcomes Research, Pfizer Global Pharmaceuticals, 

New York, NY, UNITED STATES OF AMERICA, 3 Global Health Economics and 

Outcomes Research, Pfizer Oncology, Sollentuna, SWEDEN, 4 Oncology, Pfizer, 

New York, NY, UNITED STATES OF AMERICA, 5 Medical Social Sciences, 

Northwestern University Feinberg School of Medicine, Chicago, IL, UNITED 


Background: In a randomized phase III trial, SU was associated with superior QoL 

compared with interferon-alfa (IFN). Here, we report implications related to the 

timing of collection of QoL data as it relates to SU-approved dosing in mRCC 

(4 weeks on treatment, 2 weeks off treatment; Schedule 4/2) and the extent to which 

such timing affects reported outcomes. 

Methods: 750 treatment-naïve patients with mRCC were randomized 1:1 to receive 

SU 50 mg orally once daily on Schedule 4/2 or IFN 9 MU subcutaneously thrice 

weekly. QoL measures included FACT-G, FKSI-15, FKSI-DRS, EQ-5D, and EQ-VAS. 

Higher scores indicated better outcomes (better QoL or fewer symptoms). Patients 

completed QoL questionnaires on Days 1 and 28 of each cycle, up to a maximum of 

30 cycles. SU data were analyzed to describe how the timing of QoL collection may 

affect results. Random coefficients mixed-effects models were used. 

Results: Data were used from all assessments collected (Days 1 and 28 at every 

cycle). The model indicated that QoL results based on Day 28 collection were 

consistently and statistically worse (lower QoL scores) than results based on Day 1 

(table). Based on a comparison with previously reported between-arm differences 

with SU vs. IFN, such variation could potentially diminish or increase the observed 

treatment effect by 38% to 62%. 

Conclusions: To account for overall patient QoL experience on therapy, in this case, 

SU on Schedule 4/2, careful consideration must be given to the timing of QoL data 

collection. For SU in mRCC, QoL data should be collected both on and off treatment 

within a cycle. If QoL data are collected at only the last or first dose, scores will be 

overly negative or positive, respectively. Hence, if QoL data are collected at only a 

single timepoint within a cycle, it may not represent the full extent of QoL as 

experienced by patients on SU and may lead to misinterpretation of the true QoL 

outcomes. 

Model means of QoL endpoints with SU by assessment day 

Day 1 Day 28 

Difference between 

Day 1 and Day 28 

(i.e., after (i.e., after Difference 

as percentage of 

2 weeks 4 weeks between Day 

treatment effect* 

Endpoint off drug) on drug) 1 and Day 28 P value (SU vs. IFN) 

FKSI-15 46.3 44.3 2.0

Results: 1,622 patients were identified. 1,079 received first-line SUN, 284 SOR, 168 

TEM, 40 PAZ, 26 EVE, and 25 BEV. With a median follow-up of 13 months, the 

mean healthcare cost PPPM was: 

Cost PPPM 

1st-line Agent 

Total Inpatient Other outpatient mRCC drugs 

TEM $15,900 $6,480 $4,959 $3,532 

BEV $15,429 $6,529 $3,795 $4,021 

EVE $14,519 $3,585 $6,007 $4,063 

SUN $14,084 $6,208 $3,834 $2,965 

PAZ $12,461 $5,049 $3,895 $2,766 

SOR $12,266 $4,759 $3,662 $3,938 

Inpatient costs accounted for the largest share of total cost. Other outpatient services 

and mRCC drug costs were the next largest cost drivers. ER and office visits and 

other Rx each averaged less than $500 PPPM. OOP cost averaged $453 PPPM, but 

ranged from $380 for EVE to $2,045 for BEV. 

Conclusions: Different first-line targeted agents appear to be associated with 

different total costs of care in mRCC. Patient characteristics, incidence and severity of 

adverse events, rates and duration of response, and choice of subsequent therapies 

may all play a role. Further characterization of such underlying factors may help 

optimize patient care and reduce cost. 

Disclosure: Y. Su: Employment or Leadership Role: Bristol-Myers Squibb 


(myself). P. Landsman-Blumberg: Stock Ownership: Merck & Co., Inc. (myself). 

C. Poehlein: Employment or Leadership Role: Bristol-Myers Squibb (employment, 

myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). I. Waxman: 

Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, 

compensated). Stock Ownership: Bristol-Myers Squibb (myself). All other authors 


817P SORAFENIB IN PATIENTS WITH RENAL CELL CARCINOMA 

AND BRAIN, BONE OR LUNG METASTASES: SUBANALYSIS 

OF THE NON-INTERVENTIONAL PREDICT STUDY 

J. Mardiak 1 ,J.Ma 2 , E. Korbenfeld 3 , M. Zemanova 4 , N. Leonhartsberger 5 , 

K. Stauch 6 , A. Boeckenhoff 7 ,J.Yu 8 , B. Escudier 9 , D. Jäger 10 

1 Department of Medical Oncology, National Cancer Institute, Bratislava, SLOVAK 

REPUBLIC, 2 Cancer Institute and Hospital, Chinese Academy of Medical 

Sciences, Beijing, CHINA, 3 Oncology, Hospital Británico de Buenos Aires, 

Buenos Aires, ARGENTINA, 4 First Faculty of Medicine, Charles University, 

Prague, CZECH REPUBLIC, 5 Department of Urology, Medical University 

Innsbruck, Innsbruck, AUSTRIA, 6 Global Non-interventional Studies, Bayer 

HealthCare, Leverkusen, GERMANY, 7 Global Development – Global Clinical 

Development, Bayer HealthCare, Wuppertal, GERMANY, 8 Global Medical Affairs, 

Bayer HealthCare, Montville, NJ, UNITED STATES OF AMERICA, 9 Department of 

Immunotherapy, Institut Gustave Roussy, Villejuif, FRANCE, 10 National Center for 

Tumor Diseases, University Medical Center Heidelberg, Heidelberg, GERMANY 

Background: Clinical trials in advanced renal cell carcinoma (RCC) tend to exclude 

patients (pts) with brain metastases (mets). We report safety and efficacy outcomes 

from a subanalysis of PREDICT (NCT 00895674), a large, non-interventional study 

of sorafenib in pts with advanced RCC, according to sites of mets. 

Methods: Pts were eligible based on a diagnosis of advanced RCC and a decision by 

the investigator to prescribe sorafenib under compliance of the local product label. 

Physician assessments of efficacy and tolerability were collected for up to 12 months. 

Results: Of the efficacy population (n = 2311), 1079 pts (47%) had mets in >1 organ. 

Sites included bone (n = 635), brain (n = 113), lung (n = 1639); 750 pts had mets only 

in the lung (‘lung only’). Baseline characteristics across disease-site subsets were: 69– 

Table: 817P 

74% male; 73–82% aged 1 site (6.2 months). Median DOT was longest in pts 

with lung only mets (9.1 months); in the other subsets it was numerically similar to 

overall median DOT (brain, 7.0 months; bone, 6.4 months; lung, 7.5 months). 

Sorafenib was generally well tolerated (Table). Serious adverse event rates were 

numerically higher in pts with brain mets vs the other subsets, but no 

cerebrovascular events were reported. 

Conclusions: In pts with RCC treated in clinical practice, sorafenib DOT was >6 

months regardless of number or location of metastases, and sorafenib was generally 

well tolerated regardless of disease site. Number (%) patients with AEs (safety 

population). 

Disclosure: J. Mardiak: Jozef Mardiak has received Research Grants from Novartis 

and has received honoraria from Pfizer and Pierre Fabre. J. Ma: Jianhui Ma has 

received Research Grants from Bayer. M. Zemanova: Milada Zemanova has 

received consulting and lecture fees from Glaxo Smith Kline and Roche. N. 

Leonhartsberger: Nicolai Leonhartsberger has received honoraria from Bayer, 

Pfizer and Roche. K. Stauch: Kathrin Stauch is an employee of Bayer HealthCare 

and owns stock in Bayer Pharma AG. A. Boeckenhoff: Annette Boeckenhoff is an 

employee of Bayer HealthCare and owns stock in Bayer Pharma AG. J. Yu: Jian 

Yu is an employee of Bayer HealthCare. B. Escudier: Bernard Escudier has served 

in an advisory role for Pfizer, Novartis, Roche, GSK, Bayer and Aveo, and has 

received honoraria from Pfizer, Novartis, Roche, GSK, Bayer and Aveo. D. Jäger: 

Dirk Jäger has received honoraria from Bayer, Amgen, Pfizer, Novartis, Roche, 

Fresenius Kabi and Hoffmann-La Roche. All other authors have declared no 


818P PROGRESSION FREE SURVIVAL (PFS) AND OVERALL 

SURVIVAL (OS) IN PATIENTS RECEIVING 3 TARGETED 

THERAPIES (TTS) FOR METASTATIC RENAL-CELL 

CARCINOMA (MRCC) 

R. Iacovelli 1 , M. Santoni 2 , G. Di Lorenzo 3 , L. Cerbone 4 , M. Aglietta 5 , C. Masini 6 , 

M.O. Giganti 7 , C. Messina 8 , C.N. Sternberg 9 , G. Procopio 10 

1 Department of Radiology, Oncology and Human Pathology, Sapienza University 

of Rome, Rome, ITALY, 2 Medical Oncology, Università Politecnica delle Marche, 

Ancona, ITALY, 3 Department of Oncology, Cattedra di Oncologia Medica, 

Università degli Studi Federico II, Napoli, ITALY, 4 Medical Oncology, San Camillo 

and Forlanini Hospital, Rome, ITALY, 5 Div Oncologia ed Ematologia, Fondazione 

Piemontese per la Ricerca sul Cancro Onlus, Candiolo, ITALY, 6 Dept. of 

Hematology/Oncology, Ospedale Policlinico-Modena, Modena, ITALY, 7 Medical 

Oncology, Niguarda Cà Grande Hospital, Milan, ITALY, 8 Medical Oncology, 

Ospedali Riuniti di Bergamo, Bergamo, ITALY, 9 Medical Oncology, San Camillo 

Forlanini Hospital, Rome, ITALY, 10 Medical Oncology, Fondazione IRCCS – 

Istituto Nazionale dei Tumori, Milano, ITALY 

Background: In recent years, TTs have improved the prognosis of mRCC patients 

(pts). Despite a not negligible number of pts received 3 TTs in clinical practice, no 

TTs have been evaluated as 3 rd line. Aim of this study is to investigate the clinical 

outcome in pts who received 3 TTs. 

Patients and methods: Pts with clear-cell mRCC who received 3 TTs were included. 

A questionnaire was sent to main Italian centers involved in the treatment of mRCC. 

Demographic data, history of RCC, type and length of first, second and third line 

were collected; MSKCC risk class was calculated before starting the 1 st and 3 rd lines, 

Heng class before the 3 rd line. Sequences of class and specific TTs were evaluated: 

TKIàTKIàmTOR and TKIàmTORàTKI or sunitinib (SU)-sorafenib(SO)- everolimus 

(EV) and SU-EV-SO. Median PFS, OS and Time to Strategy Failure (TTSF: from 

start of 1 st to end of 3 rd line) were estimated with the Kaplan-Meyer method with 

Event 

Metastases subsets 

Brain (n = 121) Bone (n = 673) Lung, all (n = 1723) Lung, only (n = 779) Overall (n = 2599) 

Any AE 77 (63.6) 401 (59.6) 1011 (58.7) 406 (52.1) 1479 (56.9) 

Any drug-related AE 58 (47.9) 316 (47.0) 861 (50.0) 366 (47.0) 1240 (47.7) 

Any SAE 39 (32.2) 156 (23.2) 297 (17.2) 90 (11.6) 477 (18.4) 

Any drug-related SAE 12 (9.9) 42 (6.2) 89 (5.2) 30 (3.9) 140 (5.4) 

Most frequent any grade drug-related AEs* 

Hand–foot skin reaction 20 (16.5) 106 (15.8) 366 (21.2) 188 (24.1) 520 (20.0) 

Diarrhea 19 (15.7) 111 (16.5) 306 (17.8) 114 (14.6) 443 (17.1) 

Rash † 


8 (6.6) 58 (8.6) 155 (9.0) 65 (8.3) 220 (8.5) 

Alopecia 5 (4.1) 36 (5.4) 96 (5.6) 44 (5.7) 145 (5.6) 

Decreased appetite 7 (5.8) 24 (3.6) 44 (2.6) 12 (1.5) 76 (2.9) 



95% CI and curves were compared with log-rank test. The study had the ethical 

approval. 

Results: 1905 pts were screened and 252 pts (13%) were treated with 3 TTs. The 

median age was 60 yrs (range 52–68), 73% were male, 96% underwent nephrectomy 

and 38% were metastatic at diagnosis. At 1 st line, the Motzer class was good, 

intermediate, and poor in 48%, 47% and 5% of pts, respectively. PFS for type and 

line of therapy are reported in the table below. The TTSF was 36.4 (30.5–42.2) vs. 

30.6 (26.5–34.6) mos (p = 0.11), and the OS was 52.1 (41.6–62.6) vs. 36.3 (31.2–41.4) 

mos (p = 0.01), for TKIàTKIàm-TOR and and TKIàm-TORàTKI, respectively. TTSF 

for SU-SO-EV was 36.5 vs. 30.4 mos for SU-EV-SO (p = 0.011). When stratified by 

ECOG-PS before 3 rd line or baseline MSKCC, TS maintained its independent 

prognostic role (p = 0.002 and p = 0.004, respectively). 

Conclusions: Only few patients received 3 lines of TTs. The sequence 

sunitinib-sorafenib-everolimus was associated with a better TTSF and OS as 

compared to the sequence sunitinib-everolimus-sorafenib. 

Therapy 

1 st line 2 nd line 3 rd line 

% PFS % PFS % PFS 

Sunitinib 60 10.1 31 11.2 8 14.1 

Sorafenib 25 13.1 35 7.7 28 5.2 

Pazopanib 2 6.4 0 / 0 / 

Bevac. + IFN 11 11.3 0 / 1 4.3 

Everolimus 0 / 30 4.7 55 6.9 

Temsirolimus 2 5.1 3 5.6 5 2.6 

Other 0 / 0 / 3 3.2 

TOTAL 100 11.6 100 6.8 100 6.2 


819P IMPLEMENTATION OF TARGETED THERAPY IN DENMARK 

FOR PATIENTS WITH METASTATIC RENAL CELL 

CARCINOMA: RESULTS FROM THE DANISH RENAL 

CANCER GROUP (DARENCA) STUDY-2 

A.V. Soerensen 1 , F. Donskov 2 , G.G. Hermann 3 , N.V. Jensen 4 , H. Spliid 5 , 

E.Q. Bergan 6 , K. Fode 2 , P.F. Geertsen 1 

1 Department of Oncology, University Hospital of Copenhagen Herlev, Herlev, 

DENMARK, 2 Department of Oncology, Aarhus University Hospital, Aarhus, 

DENMARK, 3 Department of Urology, University Hospital of Copenhagen 

Rigshospitalet, Copenhagen, DENMARK, 4 Department of Oncology, Odense 

University Hospital, Odense, DENMARK, 5 Section for Statistics, Informatics and 

Mathematical Modelling, Technical University of Denmark, Kongens Lyngby, 

DENMARK, 6 Denmark, Pfizer, Ballerup, DENMARK 

Background: Treatment options for metastatic renal cell carcinoma (mRCC) have 

expanded since the introduction of targeted therapies. The impact of these new 

treatment options on overall survival in a complete national cohort of patients is 

unclear. 

Objective: To analyze Overall Survival (OS), Progression Free Survival (PFS) and 

Time to Treatment Failure (TTF) in a complete national cohort of patients. 

Design, setting and participants: All Danish patients with mRCC starting first line 

treatment with immunotherapy, TKIs or mTOR-inhibitors between 2006 and 2010 

were included. Baseline and outcome data were collected retrospectively. Untreated 

patients referred for treatment were also assessed. 

Outcome measurements and statistical analysis: OS, PFS and TTF was calculated 

using the Kaplan-Meier method. Differences between OS and treatment year were 

assessed using the log rank test. Differences in distributions were tested with the 

Chi-square test. 

Results and limitations: Between 2006 and 2010, a total of 1073 patients were 

referred. Of these, 759 patients received first line treatment and 314 received no 

systemic treatment. The proportion of treated patients increased from 64% in 2006 to 

75% in 2010 (p = 0.02). In 2006 22% received targeted therapy and this increased to 

75% in 2010 (p < 0.00001). In 2006 21% of first line patients received second line 

treatment compared to 41% in 2010 (p = 0.01). From 2006 to 2010 we observed an 

improved median OS from 11.5 to 15.7 months (p = 0.03), improved median PFS 

from 4.1 to 5.5 months (p = 0.001) and an improved median TTF from 3.1 to 4.9 

months (p = 0.006) for first line treatment. The untreated population of 314 patients 

had a median OS of 3.1 months from date of metastatic disease with no significant 

change from 2006 to 2010. 

Conclusions: In a complete national cohort of patients, implementation of targeted 

therapy has resulted in improved treatment options and outcome for patients with 

mRCC. 

Disclosure: A.V. Soerensen: has received a research grant/funding from Pfizer. F. 

Donskov: has received a research grant from Novartis. E.Q. Bergan: Employee of 

Pfizer Denmark Aps. All other authors have declared no conflicts of interest. 

820P SUNITINIB GLOBAL EXPANDED-ACCESS TRIAL IN 

METASTATIC RENAL CELL CARCINOMA (MRCC) – FINAL 

RESULTS 

M.E. Gore 1 , C. Porta 2 , S. Bracarda 3 , G.A. Bjarnason 4 , S. Oudard 5 , S. Lee 6 , 

L. Crino 7 , T.M. Kim 8 , K. Fly 9 , C. Szczylik 10 

1 Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, 

London, UNITED KINGDOM, 2 Medical Oncology, IRCCS San Matteo University 

Hospital Foundation, Pavia, ITALY, 3 Ospedale San Donato, Medical Oncology 

Arezzo, Arezzo, ITALY, 4 Division of Medical Oncology, Sunnybrook Odette 

Cancer Centre, Toronto, ON, CANADA, 5 Medical Oncology, Georges Pompidou 

Hospital and Rene Descartes University, Paris, FRANCE, 6 Oncology, Seoul 

National University Hospital, Seoul, KOREA, 7 Medical Oncology, S. Maria della 

Misericordia Hospital, Perugia, ITALY, 8 Medical Oncology, Seoul National 

University Hospital, Seoul, KOREA, 9 Oncology, Pfizer Inc., Groton, CT, UNITED 

STATES OF AMERICA, 10 Oncology, Military Medical Institute, Warsaw, POLAND 

Background: Sunitinib had a manageable safety profile and encouraging efficacy in a 

global expanded-access mRCC study (ClinicalTrials.gov, NCT00130897; Pfizer) 

initiated prior to regulatory approval, in patients (pts) ineligible for other trials (Gore 

et al, 2009). Here we report final results. 

Methods: Pts aged ≥18 yrs with treatment-naïve or previously treated mRCC 

received oral sunitinib on the approved 50 mg/day 4-wk-on/2-wk-off schedule. Safety 

was assessed regularly and tumor measurements were done as per local standard 

practice using RECIST-defined response. Analyses included all pts who received ≥1 

dose of sunitinib. 

Results: 4,577 pts were enrolled. From July 2005 to November 2011, 4,543 pts 

received treatment, including poor prognosis pts with brain metastases (7%), Eastern 

Cooperative Oncology Group performance status (ECOG PS) ≥2 (14%), non-clear 

cell RCC (12%) and age ≥65 yrs (33%). Median treatment duration was 7.5 mths 

and median follow-up was 13.6 mths. 4,298 pts (95%) discontinued; reasons included 

lack of efficacy (37%), death (20%) and adverse events (AEs; 15%). The most 

common treatment-related AEs of any grade were diarrhea (47%), fatigue (40%), 

nausea (36%), decreased appetite (31%), mucosal inflammation (29%), stomatitis and 

vomiting (both 28%), hand–foot syndrome (HFS; 27%), dysgeusia (25%), 

hypertension (24%), thrombocytopenia (23%) and asthenia (22%). The most 

common treatment-related grade 3/4 AEs were fatigue (9%), thrombocytopenia (8%), 

HFS and asthenia (both 7%), hypertension and neutropenia (both 6%) and diarrhea 

(5%). In 4,219 evaluable pts, the objective response rate (ORR) was 16% (n = 660) 

with subgroup ORR as follows: baseline brain metastases (30/324 [9%]), ECOG PS 

≥2 (32/587 [5%]), non-clear cell RCC (42/505 [8%]), and age ≥65 yrs (195/1,386 

[14%]). Overall median progression-free survival was 9.4 mths (95% CI: 8.8, 10.0) 

and overall survival was 18.7 mths (95% CI: 17.5, 19.5). 

Conclusions: Results from this global expanded-access mRCC trial confirm the 

safety and efficacy of sunitinib in >4,500 pts with wide-ranging disease states in a 

real-world setting. The sunitinib AE profile in this broad population was manageable 

and consistent with prior trial results. 

Disclosure: M.E. Gore: Advisory relationships with Roche, Pfizer, Bristol Myers, 

Novartis, GSK, Aveo\\Astellas, Bayer. Honoraria to disclose from Roche, Pfizer, 

Bristol Myers, Novartis.C. Porta: Advisory relationship Pfizer Bayer-Schering 

Hoffman La Roche GSK Novartis Astellas Boehringer Recordati. Honoraria: Pfizer 

Bayer-Schering Hoffman La Roche GSK Novartis Astellas Boehringer Recordati 

Research funding Bayer-Schering Novartis. S. Bracarda: Advisory relationship with 

Novartis Bayer Schering Pfizer GSK Aveo/Astellas Boheringer-Ingelheim. Honoraria 

to disclose from Novartis and Pfizer. G.A. Bjarnason: Advisory relationship with 

Pfizer. Honoraria to disclose from Pfizer. Research funding to disclose from Pfizer.. 

S. Oudard: Advisory relationships: Pfizer, Bayer-Schering, Hoffman La Roche, Glaxo 

SmithKline, Novartis Pharma, Sanofi Aventis Honoraria: Pfizer, Bayer-Schering, 

Hoffman La Roche, Glaxo SmithKline, Novartis Pharma, Sanofi Aventis. S. Lee: 

Advisory relationships with Pfizer, Novartis, Bayer. Honoraria to disclose from 

Pfizer, Novartis, Bayer. K. Fly: Employed by Pfizer Inc. as an Oncology Clinician. 

Hold Pfizer stock as does an immediate family member. C. Szczylik: Advisory 

relationship with Pfizer, GSK, Bayer. Honoraria from Pfizer, GSK, Bayer. All other 


821P EVEROLIMUS IN PATIENTS WITH METASTATIC RENAL CELL 

CARCINOMA WHO PROGRESS AFTER INITIAL VASCULAR 

ENDOTHELIAL GROWTH FACTOR RECEPTOR-TYROSINE 

KINASE INHIBITOR (VEGFR-TKI) THERAPY: UK RESULTS 

FROM THE REACT TRIAL ON BEHALF OF THE UK REACT 

INVESTIGATORS 

S. Chowdhury 1 , J. Larkin 2 

1 Department of Medical Oncology, Guy’s and St. Thomas’ Hospital NHS Trust, 

London, UNITED KINGDOM, 2 Department of Medicine, Royal Marsden Hospital, 

London, UNITED KINGDOM 

Background: The phase III RECORD-1 trial demonstrated clinical benefit of 

everolimus in patients with metastatic renal cell carcinoma (mRCC) who had failed 

initial VEGFr-TKI therapy. REACT (RAD001 Expanded Access Clinical Trial in 


RCC) was designed to address an unmet medical need by providing everolimus to 

patients with mRCC prior to regulatory approval. UK results from the REACT trial 

are reported here. 

Methods: REACT was an open-label, international, expanded-access program. 

Eligible patients had measurable or nonmeasurable mRCC of any histology, and had 

progressed on, or were intolerant of, VEGFr-TKI therapy. Patients received a 

once-daily oral 10 mg dose of everolimus. The primary objective of REACT was to 

evaluate long-term safety of everolimus. Tumour response was also assessed 

according to RECIST. 

Results: A total of 120 patients were enrolled in the UK, 9% of worldwide 

enrolment. Prior sunitinib was received by 76% of patients; only 5.8% of patients 

received more than one VEGFr-TKI. Everolimus was received for a median duration 

of 21.8 weeks (range, 2.0–59.0), numerically longer than reported overall for REACT 

(14.0 weeks; range, 0.1–83.7). Safety findings and tumour responses were consistent 

with those observed in the global patient population. The most commonly reported 

grade 3/4 AEs were anaemia (20.8%), hyperglycaemia (10%), and lower respiratory 

tract infection (7.5%). Stomatitis and pneumonitis occurred in 13.3% and 10% of 

patients, respectively (all grades); grade 3 events were reported in 6.7% and 3.3% of 

patients (no grade 4 events). Investigator-assessed best overall responses were stable 

disease in 67 (55.8%) patients and a partial response in 1 patient (0.8%), comparable 

with the overall population. No complete responses were documented in this trial. 

Conclusions: The REACT trial provided everolimus in advance of regulatory 

approval and commercial availability to mRCC patients in the UK who failed initial 

VEGFr-TKI therapy. Everolimus was well tolerated, and safety findings were 

consistent with those reported for global REACT. 

Disclosure: S. Chowdhury: Consultant or Advisory: Novartis, Pfizer, GSK, 

Sanofi-Aventis, Janssen-Cilag, Dendreon. All other authors have declared no conflicts 

of interest. 

822P A PHASE I DOSE ESCALATION STUDY INVESTIGATING 

DOVITINIB AND EVEROLMUS IN COMBINATION IN 

METASTATIC CLEAR CELL RENAL CANCER PATIENTS WHO 

HAVE PREVIOUSLY FAILED VEGF TARGETED THERAPY 

T.B. Powles 1 , R.J. Jones 2 , S. Crabb 3 , S. Sarker 1 , E. Boleti 4 , J. Shamash 1 , 

N. Sarwar 1 , S. Chowdhury 5 

1 QMUL, Barts Cancer Insititute, London, UNITED KINGDOM, 2 Medical 

Oncology, Beatson West of Scotland Cancer Centre Gartnavel General Hospital, 

Glasgow, UNITED KINGDOM, 3 Oncology, Southampton University, London, 

UNITED KINGDOM, 4 Oncology, Royal Free Hospital, London, UNITED 

KINGDOM, 5 Oncology, Guys and St Thomas Hospital, London, UNITED 

KINGDOM 

Introduction: Both dovitinib and everolimus are agents used, or under investigation 

in patients with renal cancer refractory to VEGF targeted therapy. It is potentially 

attractive to use these agents in combination in patients with VEGF TKI refractory 

disease. Together they target mTOR, VEGF and FGF-2. The purpose of this study is 

to establish a dose for this combination to take forward in randomised trials. 

Method: This phase I study (EUDRACT 2010-021250-19) followed a classic dose 

escalation 3 + 3 designed. Sequential patients with metastatic clear cell renal cancer, 

who had previously failed VEGF tyrosine kinase inhibitors were included. Patients 

received fixed doses of drug in each escalating cohort (maximum n = 6) until dose 

limiting toxicity (DLT) was reached. DLT included grade 3 toxicity during the first 

6 weeks of therapy. If 2 episodes of grade 3 or more toxicity occurred in a specific 

cohort the DLT cohort had been reached. The study has appropriate ethical approval. 

Assement of response and progression free survival was by RECIST v1.1 

Results: Patients were entered into 2 cohorts before DLT occurred (cohort 0: 

dovitinib 200 mg/everolimus 5mg [n = 6]; cohort 1: dovitinib 300 mg/everolimus 5mg 

[n = 3]) . DLT in cohort 1 included grade 3 fatigue (2/3) after 2 and 3 week of 

therapy. In cohort 0 the following toxicity was identified: Lethargy grade 2 3/6 and 

3 1/6; Diarrhoea Grade 2 2/6 and 3 0/6 mucositis; grade 2 0/6 and 3 0/6; nausea/ 

vomiting grade 2 0/6 and 3 1/6, pulmonary fibrosis grade 2 1/6 3 0/6 . Grade 3 

toxicity after the first 6 weeks of therapy included pulmonary fibrosis 1/6, lipid 

abnormalities 2/6. Overall 1 patient (11%) had a partial response to therapy. Of the 

5 patients who did not stop therapy during the first 6 weeks due to toxicity, 

3 continued for 6 months or more without progression. 

Conclusion: The maximum tolerable dose for this combination was dovitinib 200mg 

and everolimus 5mg. This dose is being taken forward in an expansion cohort which 

will explore efficacy. 

Disclosure: T.B. Powles: Novarits Has supplied an educational grant for this project. 

Advisroy role for Novratis. S. Chowdhury: Advisory role. All other authors have 



823P SURVIVAL AMONG ADVANCED RENAL CELL CARCINOMA 

(ARCC) PATIENTS WITH >2 PRIOR TARGETED THERAPIES 

E. Calvo 1 , R. Casciano 2 , L. Stern 2 , T. Brechenmacher 3 , S. Stergiopoulos 3 , 

J. Coombs 4 

1 Start Madrid, Early Clinical Drug Development Unit, Hospital Madrid Norte San 

Chinarro Centro Integral Oncologico Clara Campal, Madrid, SPAIN, 2 Global 

Outcomes Research and Pricing, Analytica LA-SER, New York, NY, UNITED 

STATES OF AMERICA, 3 Oncology, Novartis Pharmaceuticals, East Hanover, NJ, 

UNITED STATES OF AMERICA, 4 Global Health Economics and Market Access, 

Novartis Oncology, East Hanover, NJ, UNITED STATES OF AMERICA 

Background: Despite the emergence of VEGFR-TKIs and mTORs in aRCC, 

considerable unmet medical needs remain. There are no published guidelines for 3rd 

line treatment in aRCC and, despite significant advances, these patients have limited 

treatment options. This analysis examines the overall survival of patients after 

discontinuation from a phase III, randomized, double-blind, placebo-controlled trial 

(RECORD-1), who received at least two targeted therapies. 

Methods: All patients in RECORD-1 received at least one prior VEGFR-TKI before 

randomization to everolimus (EVE) or placebo. Demographics, treatment sequence 

and overall survival were reported for patients who discontinued EVE for reasons 

other than death and received additional targeted therapy with either sorafenib or 

sunitinib. 

Results: Of the 416 patients in RECORD-1, 274 received EVE, 258 discontinued 

EVE for reasons other than death and approximately one third of those (N = 87) 

received sunitinib or sorafenib as additional targeted therapy following EVE (49.4% 

sorafenib only, 40.2% sunitinib only and 10.3% both). Baseline patient demographics 

at RECORD-1 enrollment are provided in the Table. Median time from EVE 

discontinuation to additional sunitinib or sorafenib therapy was 0.9 months (mean 

1.7, SD 2.5). The median overall survival for patients from start of the additional 

sunitinib or sorafenib therapy after EVE discontinuation was 13.9 months (95% CI 

10.6–17.2 mo). 

Baseline Characteristics Patients receiving sorafenib or sunitinib post-EVE 

N=87 

Male, n (%) 73 (83.9%) 

>= 65 years, n (%) 35 (40.2%) 

MSKCC Intermediate Risk n (%) 52 (59.8%) 

MSKCC Favorable Risk n (%) 29 (33.3%) 

KPS— > =90 n (%) 63 (72.4%) 

KPS—80 n (%) 20 (23.0%) 

Conclusions: In this heavily pre-treated sub-population, following EVE 

discontinuation in RECORD-1, some patients experienced meaningful rescue therapy 

with a TKI, with a median overall survival of more than a year Clinical trials with 

investigational targeted therapies are ongoing, and may provide additional treatment 

options. 

Disclosure: R. Casciano: Roman Casciano is an employee of Analytica LA-SER, 

which received funding for the research. L. Stern: Lee Stern is an employee of 

Analytica LA-SER, which received funding for the research. T. Brechenmacher: 

Thomas Brechenmacher is employed by Novartis Pharmaceuticals, which provided 

funding for the research. S. Stergiopoulos: Sotirios Stergiopoulos is employed by 

Novartis Pharmaceuticals, which provided funding for the research. J. Coombs: John 

Coombs is employed by Novartis Pharmaceuticals, which provided funding for the 

research. All other authors have declared no conflicts of interest. 

824P OVERALL SURVIVAL (OS) IN METASTATIC RENAL CELL 

CARCINOMA (MRCC) SEQUENTIALLY TREATED WITH 

DIFFERENT TARGETED THERAPIES (TTS): RESULTS 

FROM A LARGE COHORT OF PATIENTS 

G. Procopio 1 , E. Verzoni 1 , I. Testa 1 , R. Iacovelli 2 , E. Garanzini 1 , F.G.M. De Braud 1 

1 Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, 

ITALY, 2 Dipartimento di Medicina Sperimentale, Policlinico Umberto I, Roma, 

ITALY 

Introduction: Targeted Therapies (TTs) have improved survival in patients with 

mRCC. However expert opinion on the optimal therapeutic strategy is not entirely 

shared. This study was performed to assess the overall survival (OS) in a consecutive 

series of mRCC patients receiving TTs. 



Methods: Baseline characteristics and outcomes of 336 patients affected by mRCC 

receiving TTs were collected from the database of IRCCS Istituto Nazionale Tumori 

of Milan. The main characteristics of patients were: ECOG PS 0/1/2 186 (55%)/131 

(39%)/19 (6%); clear-cell histology 291 (87 %); previous nephrectomy 293 (87%). 

According to Motzer criteria 32% of patients showed low risk, 48 % intermediate 

and 20% had poor prognosis. Overall, 167 (50%) patients received one TTs, while 

116 (34%), 42 (13%) and 11 (3.3%) received 2, 3 and 4 TTs, respectively. Altogether, 

245 (73%) patients received sorafenib (So), 212 (63%) sunitinib (Su), 33 (10%) a 

bevacizumab regimen and 73 (22%) other TTs, including everolimus, temsirolimus 

and axitinib. Kaplan Meier curves were used to describe the survival of these patients 

according to the identified prognostic factors. The uni- and multi-variate analyses for 

OS were carried out by means of Cox proportional hazard regression analysis. 

Results: At a median follow-up of 43 months, 199 patients (57%) had died. The 

median OS was 24 months (95%CI: 20.0-27.0) and the 5-year OS was 24.6 % (95% 

CI: 18.7-30.8). In the univariate analyses, there were no significant differences in the 

hazard ratios (HR) for sorafenib followed by sunitinib compared to sunitinib 

followed by sorafenib (HRSU−SO / SO-SU = 1.16; 95%CI: 0.57-2.33) or compared with 

other therapies (HR Other sequential th. / SO-SU = 1.21; 95%CI: 0.78-1.88; p = 0.674). In the 

multivariate analysis, in terms of OS no statistical difference was reported as regards 

the sequence used (Su/So vs So/Su; p > 0.05) or bevacizumab regimen as compared to 

Su and/or So used sequentially (p > 0.05). In the uni and multivariate analysis ECOG 

PS, nephrectomy status, Fuhrman grade and previous cytokines treatments are 

independent predictive factors of outcome (p< 0.01). 

Conclusions: These efficacy data suggest that TTs improve OS in mRCC without any 

statistical difference when using different sequences of TTs. No cross-resistance 

between different TTs was documented. 


825P RELATIONSHIP BETWEEN PROGRESSION-FREE (PFS) AND 

OVERALL SURVIVAL (OS) IN I-LINE RANDOMIZED CLINICAL 

TRIALS (RCT) FOR ADVANCED RENAL CELL CARCINOMA 

(RCC): CORRELATION AND POWER ANALYSIS 

E. Bria 1 , F. Massari 2 , F. Maines 2 , M. Bonomi 3 , C. Porta 4 , S. Bracarda 5 , 

F. Cognetti 6 , D. Giannarelli 7 , G. Tortora 1 , M. Milella 6 

1 Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona-“Borgo 

Roma”, Verona, ITALY, 2 Oncologia Medica, Azienda Ospedaliera Universitaria 

Integrata Verona-“Borgo Roma”, Verona, ITALY, 3 Oncologia Medica, Azienda 

Ospedaliera Universitaria Integrata Verona, Verona, ITALY, 4 Medical Oncology, 

IRCCS San Matteo University Hospital Foundation, Pavia, ITALY, 5 Department of 

Oncology, Ospedale San Donato and U.O.C. of Medical Oncology, Arezzo, 

ITALY, 6 Divisione di Oncologia Medica A, Istituto Nazionale Tumori Regina Elena, 

Roma, ITALY, 7 Medical Oncology, Regina Elena National Cancer Institute, Roma, 

ITALY 

Purpose: Targeted agents (TA) have become standard 1st-line treatment for 

advanced RCC based on evidence of PFS advantage over IFN or placebo. 

Retrospective series suggest that PFS may be considered a reliable intermediate 

end-point in this setting; however, correlation, surrogacy testing, and validation are 

required. 

Methods: RCT evaluating the efficacy of TA as 1st line targeted treatment for 

advanced RCC were considered eligible. PFS/OS Response/Disease Control rates 

(ORR, DCR) and Hazard Ratios were extracted from papers/updated presentations. 

Correlations between 3-, 6-, 9-, and 12-mo PFS and OS rates according to parametric 

(Pearson’s r) and non-parametric (Spearman’s Rho and Kendall’s Tau) coefficients 

(with 95% CI) were analyzed to avoid lead-time biases. Regression analysis 

(parametric R2) and a power-analysis-model in order to determine patients’ sample 

necessary to determine 3%, 5% and 10% OS gain were developed. 

Results: Six RCT (4096 patients) were gathered. The best overall correlation between 

PFS and OS at concurrent timepoints was found at 9 months. With regard to overall 

rates, 3- and 6-months PFS significantly correlated with 9-mo OS, particularly in the 

TA arms (Pearson’s 0.69/P = n.s. and 0.90/p = 0.01; Spearman’s 0.94/p = 0.03 and 

0.90/p = 0.04; Tau 0.85/p = 0.02 and 0.82/p = 0.03; respectively). Pearson’s coefficients 

for the correlation between 3-mo PFS and 6-, and 12-mo OS were 0.70 (p = 0.01) 

and 0.67 (p = 0.01), respectively; the correlation between 6-mo PFS and 12-mo OS 

were significant as well (Pearson 0.74, p = 0.005; Spearman 0.83, p = 0.005; Tau 0.71, 

p = 0.001). The regression equation was Y = 0.391861 + 0.4914X [R2 0.44, p(slope) = 

0.01]; based on this model, the demonstration of a 3-mo PFS absolute difference of 

6%, 10% and 21% (corresponding to a 9-mo OS benefit of 3%, 5% and 10%) would 

require 2043, 696 and 155 patients, respectively. A significant correlation was found 

between DCR and OS. 

Conclusions: PFS is an acceptable intermediate end-point for OS in the context of 

1st line TA treatment of advanced RCC. Individual patient data analysis to verify 

Prentice’s criteria would be required for definitive confirmation. 


826P DESCRIPTION OF A SUBPOPULATION OF RENAL PATIENTS 

WITH LONG-TERM PROGRESSION FREE SURVIVAL (PFS) 

WITH SUNITINIB: A SOG_GU EXPERIENCE 

E. Esteban 1 , L. Anton-Aparicio 2 , S. Vazquez-Estevez 3 , U. Anido 4 , F.J. Afonso 5 , 

O. Fernandez 6 , M. Lazaro 7 , L. Santomé 8 , M. Ramos Vazquez 9 

1 Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, SPAIN, 

2 Medical Oncology, Complejo Hospitalario A Coruña, A Coruña, SPAIN, 

3 Oncology, Hospital Universitario Lucus Augusti, Lugo, SPAIN, 4 Dept. of Medical 

Oncology, Complejo Hospitalario Universitario de Santiagode Compostela 

SERGAS, Santiago de Compostela, SPAIN, 5 Medical Oncology, Complejo 

Hospitalario Arquitecto Marcide, Ferrol, SPAIN, 6 Medical Oncology, Complexo 

Hospitario de Ourense, Ourense, SPAIN, 7 Oncoloxia Médica, Complexo 

Hospitalario Universitario de Vigo, Vigo, SPAIN, 8 Medical Oncology, Hospital 

Povisa de Vigo, Vigo, SPAIN, 9 Medical Oncology, Centro Oncológico de Galicia, 

A Coruña, SPAIN 

A multicenter retrospective analysis was performed in patients with metastatic RCC 

who achieved long-term progression-free survival (PFS) defined as ≥18 months 

during treatment with sunitinib. Forty six patients (87% male) treated with sunitinib 

in first (74%) or subsequent lines were included. Median age was 59 years and most 

common histology was clear cell (93,5%); 89% had undergone prior nephrectomy, 

28.3% were metastatic at diagnosis and 58.7% presented one site of metastasis, 28.3% 

two sites and 13% three or more sites. Twelve patients (26%) had bone metastases. 

Good, medium and poor prognosis (MKSCC) was presented in 30,4%, 67,4% and 

2,2% of patients respectively. Five patients (11%) achieved a complete response (CR), 

28 (61%) partial response (PR) and 13 (28.3%) a stable disease with 9 patients 

(69.2%) achieving stabilization for ≥25 months. Median duration of response was 

22.7 months Median time from diagnosis to sunitinib treatment was 2.23 years and 

median duration of therapy was 27 months. At the time of analysis 37% were still on 

sunitinib. Median time from start Sunitinib until PR and CR was 4.7 and 12.1 

months respectively. Median PFS in the first line setting was 35.4 months (IC95% = 

[27,52-43,28]) and 31.6 months (IC95% = [5,13-58,13]) in subsequent lines. Median 

overall survival was not reached at the time of analysis. Reasons for discontinuation 

were progressive disease (83%), toxicity (10.3%) and death (3.4%). Incidence of 

adverse events was as expected, with asthenia, hand food syndrome (HFS), 

hypertension (HTA) and mucositis as main toxicities. Efficacy results are described 

in the table. The emergence of drug related toxicities, the lack of bone metastasis and 

the fact of non being metastatic at the time of diagnosis were independenly 

associated with a trend towards an improvement in PFS (p = NS). A comparison 

with a population of Sunitinib refractory patients is already ongoing. 

Median PFS Months (p = NS) 

With vs. without HTA 44.8 vs. 31.10 

With vs. without Asthenia 35.5 vs. 32.43 

with vs. without HFS 44.8 vs. 31 

with vs. without Hypothiroidism 47.4 vs. 43.66 

with vs. without bone metastasis 31 vs. 37.5 

with vs. without metastasis at diagnosis 32.43 vs. 37.50 

Disclosure: E. Esteban: Compensated Consultant/Advisory role at PfizerAll other 


827P INTERIM RESULTS OF A PHASE II STUDY OF SUNITINIB 

AND LOW DOSE METRONOMIC CYCLOPHOSPHAMIDE IN 

ADVANCED RENAL CELL CANCER 

M.A. Khattak 1 , K. Edmonds 1 , K. Khabra 2 , A. Sohaib 3 , K. Pennert 2 , L. Pickering 1 , 

M.E. Gore 1 , J. Larkin 1 

1 Medical Oncology, Royal Marsden NHS Trust, London, UNITED KINGDOM, 

2 Statistics, Royal Marsden NHS Trust, London, UNITED KINGDOM, 3 Radiology, 

Royal Marsden NHS Trust, London, UNITED KINGDOM 

Introduction: Sunitinib is a standard 1 st line treatment for advanced renal cell 

carcinoma (RCC) but 2/3rd of patients do not respond to treatment and the 2 weeks 

‘off’ treatment is sometimes associated with tumour regrowth and recrudescence of 

disease symptoms. Both sunitinib and low dose metronomic cyclophosphamide 

(Sun-Cyclo) are anti-angiogenic therapies that act via different pathways. The 

possibility therefore exists that by combining these two drugs, more complete 

blockade of angiogenesis may be achieved. 

Aims and objectives: The primary objective of the study is to evaluate the efficacy 

and toxicity of Sun-Cyclo. The primary endpoints are to establish the maximum 

tolerated dose (MTD) and the response rate (RR). The secondary endpoints are to 

assess the toxicity, progression-free survival (PFS) and overall survival (OS). 


Patients and methods: This is a single arm, open label phase 2 study. Treatment 

naïve patients with ECOG 0/1 and a histological/cytological diagnosis of RCC, who 

were considered suitable for treatment with sunitinib were enrolled into this study. 

The study is being conducted in 2 parts. The objective of Stage A is to establish the 

MTD of Sun-Cyclo and evaluate the efficacy and toxicity of Sun-Cyclo in a small 

cohort (n = 19) of patients. The objective of Stage B is to further evaluate efficacy and 

toxicity in an expanded population (n = 35). Sun-Cyclo was given as per following 

schedule: Sunitinib 50mg OD (4on/2off) and cyclosphosphamide 50mg OD 

continuously. We report here the interim results of Stage A. 

Results: A total of 19 patients have been enrolled into this study out of which 17 

were evaluable for analysis. The MTD of Sun-Cyclo was 50mg Sunitinib (4on/2off) 

and 50mg Cyclophosphamide. The RR was: partial response 4 (25%), stable disease 

10 (62.5%) and progressive disease 2 (12.5%). The median PFS was 11.0m (95% CI 

7.9-14.1m) and the 1year PFS rate was 46.8%. The commonest grade 3 toxicities were 

fatigue (12.5%), neutropaenia (37.5%) and thrombocytopaenia (18.8%). 10 patients 

had dose reductions [4 (40%) had 1 dose reduction to 37.5mg and 6 (60%) had 2 

dose reductions to 25mg]. 12 patients had treatment delays with a median of 7 days 

(range: 2–28). 

Conclusion: The combination of Sun-Cyclo was relatively well tolerated. The RR and 

PFS with Sun-Cyclo are similar to phase III results with sunitinib alone in RCC. 

Disclosure: K. Edmonds: Nil related to this research. K. Khabra: Nil related to this 

research. A. Sohaib: Nil related to this research. K. Pennert: Nil related to this 

research. L. Pickering: Pfizer: Research funding, honoraria, consultant role. M.E. 

Gore: Pfizer, Speaker bureau, advisory board. J. Larkin: Pfizer: Research funding, 

honoraria, consultant role. All other authors have declared no conflicts of interest. 

828P EVALUATION OF SAFETY, TOLERABILITY AND ACTIVITY OF 

TEMSIROLIMUS IN PATIENTS WITH ADVANCED OR 

METASTATIC RENAL CELL CARCINOMA (A/MRCC) IN THE 

USUAL HEALTH CARE SETTING 

U. Mueller 1 , G. Krekeler 1 , L. Bergmann 2 , T. Steiner 3 , D. Kalanovic 1 

1 Oncology, Pfizer Pharma GmbH, Berlin, GERMANY, 2 Medical Clinic III, 

Universitätsklinikum Frankfurt(Johannes-Wolfgang Goethe Institute), Frankfurt am 

Main, GERMANY, 3 Urology, Helios Klinikum, Erfurt, GERMANY 

Introduction: Temsirolimus (TEMS), an i.v. mTOR inhibitor, is approved in the EU 

for the first-line treatment of patients with a/mRCC who have at least 3 of 6 

prognostic risk factors. A pivotal study had demonstrated significantly increased 

overall survival with TEMS in poor risk patients compared to the former standard 

Interferon (10.9 vs. 7.3 mo; p = 0.0078). To better identify the safety profile and 

efficacy of TEMS during clinical routine, collection of data in a postapproval 

non-interventional trial seems to be adequate. 

Methods: A registry for a/mRCC patients treated with TEMS was started in 

Germany in January 2008 (NCT00700258). Primary objective: evaluation of the 

safety profile of TEMS. Secondary objectives: tolerability and anti-tumor activity of 

TEMS; profile of patients; sequence of systemic therapies. Inclusion criteria: 

histologically confirmed a/mRCC treated with TEMS and written informed consent 

by the patient. 

Results: 118 active study centers recruited 455 patients from Feb. 2008 to April 2012. 

Preliminary data are available for 430 patients: 68.7% male, median age 68 years, 

median Karnofsky index 80%. Histological subtype: 75.3% clear cell, 10.9% papillary 

and 2.6% chromophobe RCC. According to modified MSKCC criteria 96.0% of 

patients (n = 323) were classified as poor risk and 4.0% as intermediate risk patients. 

Adverse events (AE) and serious adverse events (SAE) defined as drug related were 

observed in 41.2% and 10.2%, respectively. Skin disorders, fatigue, nausea, diarrhea, 

peripheral edema, anemia and dyspnea of any grade were the most frequent AEs. 

Median progression-free survival for the total patient population was 151 days (d), 

for the subgroup of 1 st line patients 162 d, for patients ≥ 65 yrs 155 d. Median overall 

survival for all patients was 381 d. 

Conclusions: Patient population in the registry represents the expected pattern in a/ 

mRCC regarding distribution of age, sex, and histology. Safety profile and clinical 

efficacy of TEMS in the usual health care setting confirm the phase-III data. In 

addition, for patients ≥ 65 years safety and clinical efficacy of TEMS are comparable 

to results of the overall study population. 

Disclosure: U. Mueller: Employment by Pfizer. G. Krekeler: Employment by Pfizer. 

L. Bergmann: Advisory boards: Bayer, GSK, Novartis, Pfizer, Roche, Astellas; 

Honoraria: Novartis, Pfizer, Roche. D. Kalanovic: Employment by Pfizer. All other 



829P TUMOUR VASCULAR ENDOTHELIAL GROWTH FACTOR 

(VEGF) AND VASCULAR ENDOTHELIAL GROWTH FACTOR 

RECEPTORS (VEGFR) POLYMORPHISMS AND CLINICAL 

OUTCOME IN ADVANCED RENAL CELL CARCINOMA 

PATIENTS RECEIVING FIRST LINE SUNITINIB 

M. Bianconi 1 , M. Scartozzi 1 , L. Faloppi 1 , C. Loretelli 1 , L. Burattini 1 , A. Bittoni 1 , 

M. Del Prete 1 , R. Giampieri 1 , R. Montironi 2 , S. Cascinu 1 

1 Clinica Di Oncologia Medica, AOU Ospedali Riuniti Ancona Università 

Politecnica delle Marche, Ancona, ITALY, 2 Institute of Pathological Anatomy, 

Università Pollitecnica delle Marche, Ancona, ITALY 

Background: The introduction of novel treatments has radically changed the 

approach to the treatment of metastatic renal cell carcinoma (mRCC). Currently 

TKIs directed against the VEGF pathway are the therapeutic strongholds. However, 

criteria for treatment selection are largely lacking. In this study we assessed the role 

of VEGF and VEGFR polymorphisms, in the prediction of the clinical outcome in 

mRCC patients. 

Methods: Forty-one formalin-fixed paraffin-embedded tissue blocks from mRCC 

patients receiving first-line sunitinib were tested for VEGF-A, VEGF-C and 

VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). SNPs results were correlated 

with progression free survival (PFS) and overall survival (OS). 

Results: Forty-one patients with metastatic renal cell carcinoma were available for 

our analysis. All patients received sunitinib as fist-line treatment with standard 

schedule, dose reduction was applied in patients with grade 3 and 4 toxicities. 

Median PFS was of 8,22 months, while median OS was of 32,13 months. VEGF A 

rs833061 polymorphism resulted statistically significant in PFS (17 months for CC + 

CT vs 4 months for TT; p = 0,0001) and OS (36 months for CC + CT vs 8 months 

for TT; p = 0,0040). VEGF A rs699947 was statistically significant for PFS (17 

months for AA + AC vs 4 months for CC; p = 0,0001) and OS (36 months for AA + 

AC vs 11 for CC; p = 0,0059). VEGF A rs2010963 was significant in PFS (17 months 

for GG vs 5 for GC vs 3 for CC; p = 0,0186). VEGR3 rs6877011 was significant in 

PFS (12 months for CC vs 4 for CG; p = 0,0221) and OS (36 months for CC vs 17 

for CG; p = 0,0052). 

Conclusions: in our analysis patients with TT polymorphism of rs833061, CC 

polymorphism rs699947 and CC polymorphism of rs2010963 seem to have a worse 

PFS and OS in first line. VEGF-A gene polimorphisms are probably connected with 

the control of the neoangiogenesis, maybe controlling vasculature normalization. 

Patients with CG polymorphism of rs6877011 seem equally to have a poor impact of 

first line therapy. VEGFR-3 seems to be involved in vessels sprouting and 

architecture. 


830P THE PREDICTIVE AND PROGNOSTIC ROLE OF 

O6-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT) 

AND TISSUE TRANSGLUTAMINASE-2 (TGASE-2) IN 

METASTATIC RENAL CELL CARCINOMA (MRCC) PATIENTS 

TREATED WITH SUNITINIB 

D. Tunali 1 , B. Sarsık 2 , R. Durusoy 3 ,S.S¸en 2 , E. Gökmen 4 

1 Medical Oncology, Ege University Medical School, Izmir, TURKEY, 2 Department 

of Pathology, Ege University Medical School, Izmir, TURKEY, 3 Department of 

Public Health, Ege University Medical School, Izmir, TURKEY, 4 Department of 

Medical Oncology, Ege University Medical School, Izmir, TURKEY 

Background: Altough anti-angiogenic drugs are widely used in mRCC, the predictive 

markers for these agents cannot be well defined yet. MGMT is recently shown to be 

anti-angiogenic and responsible for the anti-proliferative effect of sunitinib in 

glioblastome cell lines. In preclinical studies, MGMT positive cells demonstrate high 

sVEGFR-1/VEGFA ratio, increased VEGFR-1 and decreased VEGFR-2.TGase-2 is 

known to be responsible for drug resistance, cell proliferation, migration and 

angiogenesis. In vitro studies showed that TGase-2 inhibits VHL and this leads to 

increase of HIF-1α and IGF-1R. 

Objective: To investigate the predictive and prognostic role of MGMT and TGase-2 

in mRCC patients who were treated with sunitinib. 

Methods: We analyzed 82 RCC patients retrospectively. 43 of 82 survive without 

recurrence (non-metastatic group), 39 of 82 were already metastatic at the diagnosis 

or had metastasis during follow up (metastatic group). Expression of MGMT and 

TGase-2 proteins were assessed by immunohistochemical (IHC) staining in tissue 

samples.In the metastatic group, all patients received sunitinib as anti-angiogenic 

therapy and the overall survival (OS) analysis of these patients were performed 



according to time of sunitinib initiation. OS analysis of the entire group (metastatic 

and non-metastatic) were performed according to the time of diagnosis. 

Results: In the metastatic group (n = 39), the ones with low MGMT had median OS 

of 30 months while ones with high MGMT had median OS of 47 months (p = 

0.498). The ones with low TGase-2 had mean OS of 35.2 months while ones with 

high TGase-2 had mean OS of 27.9 months (p = 0.366).In the entire group, the ones 

with low MGMT had mean OS of 115 months while ones with high MGMT had 

median OS of 189 months (p = 0.498). The ones with low TGase-2 had mean OS of 

212 months while ones with high TGase-2 had mean OS of 133 months (p = 0.281). 

Conclusions: Higher MGMT and lower TGase-2 may be predictors of good response 

to sunitinib. Independent of the treatment, in the entire group the ones with higher 

MGMT and lower TGase-2 have better survival. All these results are not statistically 

significant. 


831P A RETROSPECTIVE STUDY OF METASTASECTOMY IN 

METASTATIC RENAL CELL CARCINOMA 

A. Suder 1 , K. Thillai 2 , S. Rudman 3 , A. Chandra 4 , G. Rottenberg 5 , 

B. Challacombe 6 , G. Kooiman 7 , P. Srinivasan 8 ,T.O’Brien 6 , S. Chowdhury 2 

1 Medical Oncology, Guy’s and St Thomas’s NHS Trust, London, UNITED 

KINGDOM, 2 Medical Oncology, Guys Hospital, London, UNITED KINGDOM, 

3 Medical Oncology Offices, 4th Floor Bermondsey Wing, Guys Hospital, Guys 

and St Thomas’s NHS Trust, London, UNITED KINGDOM, 4 Pathology, Guys 

Hospital, London, UNITED KINGDOM, 5 Radiology, Guy’s Hospital, London, 

UNITED KINGDOM, 6 Urology, Guys and St Thomas’s NHS Trust, London, 

UNITED KINGDOM, 7 Urology, Kings College, London, UNITED KINGDOM, 

8 Institute of Liver Studies, Kings College, London, UNITED KINGDOM 

Introduction: Despite significant advances in the systemic therapy for metastatic 

renal cell carcinoma (mRCC) long term survival is rare. Systemic VEGF directed 

therapy can be toxic and is expensive. Metastatectomy can delay or even completely 

avoid systemic therapy. 5-year cancer specific survival rates of up to 73% have been 

reported in select patients. 

Methods: Patients who underwent metastasectomy for RCC recurrence in our 

institution between 2001–2011 were identified through a clinical database that was 

cross-referenced with a pathology database and multi-disciplinary team records. 

Patient characteristics N= 36 % 

Male/Female 25/11 70/30 

Median Age (range 44-85) 65 NA 

Primary tumour pT2 or less 4 10 

Radical nephrectomy 31 97* 

Clear cell histology 20 100** 

Median time to metastasectomy months (range) 24 5-230 

Number of metastases 1 27 77 

2-3 7 20 

3+ 1 3 

Site of metastases Lung 12 

Adrenal 7 

Bone 4 

Other*** 4 

Upper GI 2 

Liver 2 

Minimum Heng risk score at time of metastasectomy Favourable 21 

Intermediate 11 

Poor 1 

Results: *evaluable patients n= 32, **n = 20 *** includes chest wall, ovary, thyroid, 

contralateral kidney Median time to first progression from surgery was 21 months 

(range 0-50). On progression 17/18 patients had repeat metastasectomy with 10/17 

relapsing at a site different to the original surgery. To date 11/36 have received 

additional therapy including tyrosine kinase inhibitors (n = 7), radiotherapy (n = 3) 

and interferon (n = 1). Median overall survival from first metastasectomy has not 

been reached at mean follow up of 27 months. 27 patients are alive at last follow up 

with 14 disease free. Of the 13 evaluable patients, none are free from recurrence at 5 

years. 

Discussion: Despite limitations of retrospective design, selection bias and size, this 

data shows that metastasectomy is feasible in selected patients with mRCC. Our 

patients included a group with characteristics that have previously been described as 

less favourable for resection. Despite this preliminary overall survival data is 

encouraging. 

Conclusion: Metastatectomy is an important treatment option for selected patients 

with metastatic renal cell carcinoma. All patients should be managed in a 

multi-disciplinary manner to ensure that patients are considered for metastasectomy 

when appropriate. 


832P C-MYC AS A NEW PREDICTIVE BIOMARKER FOR SUNITINIB 

IN METASTATIC RENAL CLEAR CELL CARCINOMA 

P. Maroto 1 , E. Esteban 2 , E. Fernández-Parra 3 , M.J. Méndez-Vidal 4 , 

M. Domenech 5 , L. León 6 , B. Pérez-Valderrama 7 , V. Calderero 8 , 

J.L. Perez Gracia 9 , F. Algaba 10 

1 Dept. of Medical Oncology, Hospital de la Sta. Creu i St. Pau, Barcelona, 

SPAIN, 2 Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, 

SPAIN, 3 Medical Oncology, Hospital Nuestra Señora de Valme, Seville, SPAIN, 

4 Medical Oncology, Hospital Reina Sofía, Cordoba, SPAIN, 5 Oncology, ALthaia, 

Xarxa Assistencial de Manresa, Manresa, SPAIN, 6 Medical Oncology, Hospital 

General de Santiago, Santiago de Compostela, SPAIN, 7 Medical Oncology, 

Hospital Virgen del Rocío, Seville, SPAIN, 8 Medical Oncology, Hospital 

Universitario Miguel Servet, Zaragoza, SPAIN, 9 Clinical Oncology, Clinica 

Universitaria de Navarra, Pamplona, SPAIN, 10 Medical Oncology, Fundación 

Puigvert, Barcelona, SPAIN 

Background: Sunitinib is a tyrosin kinase inhibitor with proven efficacy in renal clear 

cell carcinoma (RCC). However we still lack properly validated molecular predictors 

of response. Two subtypes of sporadic VHL-deficient RCC were proposed based on 

HIF1α and HIF2α expression and c-Myc activation. This molecular subclassification 

could provide a framework for current targeted therapies. This study aims to explore 

the predictive value of this molecular signature. 

Methods: An observational prospective study involving 10 Spanish Hospitals was 

designed to collect formalin-fixed paraffin-embedded primary tumor tissue samples. We 

enrolled consecutively attending adults who had a centralized pathologically confirmed 

diagnosis of RCC with a clear-cell histology and advanced disease. Eligible patients were 

treatment naive and scheduled for sunitinib following routine clinical practice. The 

protocol was approved by the medical ethics committee of all participating institutions, 

and signed informed consent was obtained for all patients. Selected biomarkers were 

analyzed by immunohistochemistry following established protocols. 

Results: From March 2009 to February 2011, 80 patients were included. At the time 

of the analysis, tumor samples were available for 64 patients and 58 were evaluable 

for c-Myc expression. Only 33% (19/58) showed c-Myc immunostainig (any score: 

1–3) and 67% (39/58) were negative for c-Myc expression (scored as 0). Both groups 

were well balanced and non significant differences in risk prognostic factors were 

found. Regarding Sunitinib efficacy, significant differences in PFS were found 

between both molecular subgroups. A median PFS of 5.4 months was found in 

patients with c-Myc positive primary tumors vs. 11.4 months in patients with c-Myc 

negative primary tumors (HR = 2.54, 95%CI (1.28, 5.07), p = 0.0062). Correlation of 

c-Myc expression with other related biomarkers is underway. 

Conclusions: Although, this is a small sample and validation is still needed, these 

results suggest a promising value for c-Myc immunostaining as a novel tool to 

identify those patients with RCC with more probabilities of obtaining benefit with 

Sunitinib through an accessible and reproducible technique.This study was supported 

by an Independent Investigator Research grant from Pfizer Inc. 

Disclosure: P. Maroto: Compensation of consultant/Advisory role at Pfizer. E. 

Esteban: Compensation of consultant/Advisory role at Pfizer. All other authors have 


833P DYNAMIC CHANGES IN PLASMA OSTEOPONTIN AS A 

MARKERS OF TUMOR RESPONSE IN METASTATIC RENAL 

CELL CARCINOMA (RCC) PATIENTS TREATED WITH 

PAZOPANIB 

H.T. Tran 1 , Y. Liu 2 ,Y.Lin 2 , A.J. Zurita Saavedra, 3 , K.L. Baker-Neblett 4 , 

VEG105192 Team and investigators 5 , L.N. Pandite 6 , J.V. Heymach 7 

1 Cancer Medicine, UT MD Anderson Cancer Center, Houston, TX, UNITED 

STATES OF AMERICA, 2 Oncology Research and Development, GlaxoSmithKline, 

Philadelphia, PA, UNITED STATES OF AMERICA, 3 Genitourinary Med Oncology 

Dept, MD Anderson Cancer Center, Houston, TX, UNITED STATES OF 

AMERICA, 4 Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, 

Research Triangle Park, NC, UNITED STATES OF AMERICA, 5 VEG102616 

Investigators, patients and team, 6 GlaxoSmithKline, Research Triangle Park, NC, 

UNITED STATES OF AMERICA, 7 Thoracic/Head and Neck Medical Oncology, 


Background: In a Phase II RCC study of pazopanib (VEG102616) a response rate of 

34.7% and disease control rate (CR + PR +SD) of 80% were observed (Hutson, JCO 

2009. Previously, we reported that elevated levels of E-Selectin, lower levels of IL-6 

and HGF were correlated with longer PFS and decrease in tumor shrinkage. Higher 

levels of IL-6 and IL-8 correlated with greater tumor burden (Tran ASCO 2010). 

IL-8, OPN, HGF and TIMP1 correlated with PFS and IL-6, IL-8 and OPN were 

prognostic markers (Yuan GU ASCO 2011, Tran ESMO 2011). In this study, we 

measured CAF levels at baseline, week 4 and week 12 after inititation of pazopanib 

therapy and evaluated for dynamic changes in CAF as potential marker for tumor 

response and clinical benefits 

Methods: Six candidate CAFs (TIMP1, IL-6, IL-8, HGF, E-Selectin, and OPN) were 

measured in 173 patients (pts) whose plasma samples were collected during the 


treatment at week 4, and week 12 by using Searchlight Protein Array (Aushon). CAF 

levels at each time point and changes of CAF levels from baseline at week 4 and 

week 12 were correlated with maximum tumor shrinkage (MTS) by linear regression; 

PFS by Cox regression; baseline tumor burden using baseline sum of longest tumor 

diameter and best response by Spearman. 

Results: Decreases in OPN levels from baseline at week 4 (p = 0.030) and week 12 

(p = 0.006) show significant correlations with MTS. At week 4, changes in E-Selectin 

from baseline was trending (p = 0.053) in correlation with MTS. With PFS, changes 

in IL-6 level from baseline at week 12 has near significant correlation with PFS (p = 

0.05). E-Selectin has an inverse baseline to week 4 significant correlation with best 

response status week 4 (p = 0.0245) but not at week 12. 

Conclusion: Decreasing levels of osteopontin from baseline at week 4 and 12 

correlated with improved tumor shrinkage; while increase in IL-6 portends shorter 

PFS and E-Selectin was inversely correlated with best response status. Additional 

investigation is needed to evaluate the dynamic changes of CAFs as an approach to 

monitor patients while on pazopanib therapy as marker of tumor response. 

Disclosure: Y. Liu: Stock ownership: Yes; GSK Membership on an advisory board or 

board of directors: No Corporate-sponsored research: No Other substantive 

relationships: NoA. Martin: Stock ownership: Yes; GSK Membership on an advisory 

board or board of directors: No Corporate-sponsored research: No Other substantive 

relationships: NoK.L. Baker-Neblett: Stock ownership: Yes; GSK Membership on an 

advisory board or board of directors: No Corporate-sponsored research: No Other 

substantive relationships: No. L.N. Pandite: Stock ownership: Yes; GSK Membership 

on an advisory board or board of directors: No Corporate-sponsored research: No 

Other substantive relationships: No. J.V. Heymach: Stock ownership: No Membership 

on an advisory board or board of directors: Yes; GSK Corporate-sponsored research: 

Yes; GSK for biomarker analysis. Other substantive relationships: No. All other 


834P RECIST RESPONSE OF THE PRIMARY LESION IN 

METASTATIC RENAL CELL CARCINOMAS TREATED WITH 

SUNITINIB: DOES THE PRIMARY LESION HAVE TO BE 

REGARDED AS A TARGET LESION? 

I. Park 1 , K. Park 1 , S. Park 1 ,Y.Ahn 1 , J. Ahn 1 , H.J. Choi 2 , C. Song 3 , H. Ahn 3 , 

J.H. Hong 3 , J. Lee 1 

1 Department of Oncology, Asan Medical Center, University of Ulsan College of 

Medicine, Seoul, KOREA, 2 Department of Radiology, Asan Medical Center, 

University of Ulsan College of Medicine, Seoul, KOREA, 3 Department of Urology, 

Asan Medical Center, University of Ulsan College of Medicine, Seoul, KOREA 

Background: There is no consensus on including the primary lesion as the target 

lesion when evaluating the response of non-nephrectomized metastatic renal cell 

carcinoma (mRCC) patients (pts). We evaluated whether best overall response 

changes by designating primary renal lesions as either target or non-target lesions 

and assessing response per RECIST in mRCC pts treated with sunitinib. In addition, 

we evaluated whether discordance, if any, leads to a difference in predictive value of 

response in terms of time-to-progression (TTP) and overall survival (OS). 

Patients and methods: Among pts with histologically confirmed mRCC treated with 

sunitinib at Asan Medical Center, pts with an intact primary tumor and at least one 

extra-renal measurable lesion were included. To measure the influence of including 

the primary lesion as the target lesion, the variation of the sum of diameters (ΔSOD) 

of target lesions and best overall response, assessed from all target lesions and from 

metastasis-only target lesions, was documented separately. For examining differences 

of two methods in predictive function in estimating TTP and OS, pts were 

categorized according to their best overall responses as responders [complete 

response (CR) and partial response (PR)] or non-responders [stable disease (SD) and 

progressive disease (PD)] for all target lesions and metastasis-only target lesions, 

respectively, and then analyzed for survival. 

Results: Forty-one pts were included in this study. Median ΔSOD of the primary 

lesion and metastatic target lesion were −6.0% (range, −34.0–17.6%), and −18.0% 

(range, −100.0–120.0%), respectively. For metastasis-only target lesions, the best 

overall response of two pts (4.9%) changed from SD to PR. When we categorized pts 

into responders and non-responders, response determination using metastasis-only 

target lesions resulted in significantly better discrimination of TTP (14.9 vs 4.3 

months, P = 0.001) and OS (18.5 vs 9.6 months, P = 0.036) between two groups. 

Using all target lesions, both TTP (14.9 vs 5.4 months, P = 0.056) and OS (18.0 vs 

10.6 months, P = 0.155) were not statistically significant. 

Conclusion: When treating non-nephrectomized mRCC pts, selecting 

metastasis-only lesions as target lesions might be better to determine response, which 

might be more representative of TTP and OS. 



835P TISSUE MICROARRAY (TMA) AND VHL MUTATIONS AS 

PREDICTORS OF OUTCOME IN ADVANCED CLEAR CELL 

RENAL CELL CARCINOMA (CCRCC) TREATED WITH FIRS 

LINE SUNITINIB 

J.F. Rodríguez-Moreno 1 , E. Esteban 2 , M. Morente 3 , I. Alemany 4 , 

D.E. Castellano 5 , A. Gonzalez Del Alba 6 , M. Climent 7 , 

C. Rodriguez-Antona 3 , J. Garcia-Donas 1 

1 Medical Oncology, Centro Integral Oncológico Clara Campal, Madrid, SPAIN, 


3 Human Genetic, Spanish National Cancer Research Center, Madrid, SPAIN, 

4 Medical Oncology, Hospital Universitario Fundacion Alcorcon, Alcorcon, SPAIN, 

5 Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, SPAIN, 

6 Medical Oncology, Hospital Universitario Son Espases, Palma de Mallorca, 

SPAIN, 7 Medical Oncology, Instituto Valenciano de Oncologia, Valencia, SPAIN 

Introduction: Sunitinib is a standard treatment for kidney cancer, however in some 

patients response is lacking. Molecular predictors of outcome could deeply impact 

patient care. 

Methods: We conducted an observational, prospective study in 15 institutions 

members of the Spanish Oncology Genitourinary Group (SOGUG). Inclusion criteria 

were patients with confirmed advanced clear cell renal cell carcinoma with no prior 

treatment, planned to receive sunitinib according to local practice.From paraffin 

embedded tumor samples a Tissue MicroArray (TMA) was constructed and 

evaluated independently by two pathologists, also blinded to clinical data. Expression 

of Carbonic Anhydrase IX, P-glicoprotein, Vascular Endothelial Growth Factor 

(VEGF), VEGF-Receptor 1,2 and 3 (VEGFR1,2 and 3), Platelet-Derived Growth 

Factor Receptor (PDGFR-Beta), Hypoxia-Inducible Factor 2 alpha (HIF2α) and Von 

Hippel-Lindau protein (pVHL) was assessed. In addition the presence of VHL gene 

mutations was studied. 

Results: 101 patients were recruited from 2007 to 2010. TMA was constructed from 

69 tumor samples. In multivariable analysis, HIF2α (HR 0.17 (0.05-0.64) p = 0.0083) 

and PDGFRβ (HR 0.042 (0.003-0.70) p = 0.028) overexpression correlated with 

progressive disease (PD) as best response. A similar trend in PFS and OS was 

observed for HIF-alfa but did not reach statistical significance.Progression free 

survival (PFS) was longer in cases with high VEGFR3 expression (HR 0.42 

(0.21-0.83) p = 0.013). Interestingly, low levels of this protein strongly correlated 

(r = -0.441 P = 0.0003) with the presence of a germline SNP (VEGFR3 rs307826) that 

has been previously identified as a sunitinib resistance predictor by our group.Finally 

overexpression of VEGF (HR 4.6 (1.5-13.6), p= 0.0063), and VEGFR1 (HR 6.2 

(1.2-32.2) p = 0.031) were associated with poor overall survival (OS).VHL gene 

alterations could only be determined in 30 cases, with 20 (66%) presenting a 

pathological mutation. No association with outcome could be established. 

Conclusion: Expression of some proteins involved in neoangiogenesis pathway could 

play a role in sunitinib sensitivity and resistance. A significant association between 

low expression of VEGFR3 and one SNP in such gene, both correlated with poor 

outcome, deserves further investigation. 


836P PROGNOSTIC FACTORS AND VALIDATION OF PROGNOSTIC 

NOMOGRAMS IN PATIENTS (PTS) TREATED WITH 3 

TARGETED THERAPIES (TTS) FOR METASTATIC RENAL CELL 

CARCINOMA (MRCC): RESULTS FROM AN ITALIAN SURVEY 

R. Iacovelli 1 , M. Rizzo 2 , V. Lorusso 3 , F. Atzori 4 , P.A. Zucali 5 , C. Sacco 6 , 

F. Boccardo 7 , F. Valduga 8 , F. Massari 9 , G. Procopio 10 


of Rome, Rome, ITALY, 2 Medical Oncology, Azienda Ospedaliera Antonio 

Cardarelli, Naples, ITALY, 3 Medical Oncology Unit, Ospedale Vito Fazzi, Lecce, 

ITALY, 4 Medical Oncology, Azienda Ospedaliero Universitaria Cagliari, 

Monserrato, ITALY, 5 Department of Oncology, Humanitas Cancer Center IRCCS, 

Rozzano, ITALY, 6 Medical Oncology, University Hospital, Udine, ITALY, 7 Dept. of 

Medical Oncology B, IRCCS AOU San Martino - IST-Istituto Nazionale per la 

Ricerca sul Cancro, Genova, ITALY, 8 Medical Oncology, St Chiara Hospital, 

Trento, ITALY, 9 Medical Oncology, Azienda Ospedaliera Universitaria Integrata 

Verona-“Borgo Roma”, Verona, ITALY, 10 Medical Oncology, Fondazione IRCCS - 

Istituto Nazionale dei Tumori, Milano, ITALY 

Background: Outcomes of pts treated with three TTs for mRCC have not been well 

characterized. Survival data as well as existing prognostic criteria in this population 

were evaluated. 



Table: 836P 

Cleveland Clinic French Heng MSKCC 

P Group Pts (%) PFS (mos) p Pts (%) PFS (mos) p Pts (%) PFS (mos) P Pts (%) PFS (mos) p 

Good 20 NR ULN; PLT > ULN; Neu > ULN, and 

sites of disease >2 had negative prognostic role. Multivariate analysis shows an 

independent prognostic role only for ECOG-PS ≥ 2 (HR: 1.8; 95%CI: 1.1–2.8), Hb < 

LLN (HR: 1.8; 95%CI: 1.2–2.6) and neu > ULN (HR: 2.1; 95%CI: 1.2–3.8). Pts were 

stratified in 3 groups according to the presence of none, 1 or ≥2 prognostic factors. 

The median OS was 20.3, 13.6 and 7.8 months, respectively (p < 0.0001) 

Conclusions: Current nomograms are able to predict survival in patients with mRCC 

before the 3 rd line with TT. Neutrophils, platelets and ECOG-PS were the most 

important prognostic factors. 


837P SECOND LINE TREATMENT IN METASTATIC PAPILLARY 

RENAL CELL CARCINOMA: RETROSPECTIVE ANALYSIS OF A 

48 PATIENTS COHORT 

L. Albiges 1 , F. Riet 1 , C. Massard 1 , S. Le Moulec 2 , Y. Loriot 1 , A. Levy 1 , K. Fizazi 1 , 

B. Escudier 1 

1 Department of Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 

2 Oncology and Radiation Oncology, Hôpital d’Instruction des Armées du 

Val-de-Grâce, Paris, FRANCE 

Background: Papillary renal cell carcinoma (pRCC) accounts for 10-15% of mRCC. 

Although standard VEGF/mTOR inhibitors were retrospectively assessed in this 

setting, there is no specific recommendation for this subtype. First line prospective 

dedicated studies are to be released shortly. No second line data have been reported 

so far. 

Material and methods: All pts with metastatic pRCC treated in first line from May 

2006 to Nov 2011 at Institut Gustave Roussy, were retrospectively analysed. Clinical 

data, prognosis classifications and treatments were assessed; PFS after first and 

second line treatments and OS were calculated. 

Results: Forty-eight pts with metastatic pRCC were identified. Median age at 

diagnosis was 62, sex ratio 41M / 7F. Histological subtypes were type 2 (67%), type I 

(10%), and unclassified (23%). Nephrectomy had been performed in 38 pts (78%). 

Most pts presented with synchronous metastatic disease (68%). Metastatic sites were 

respectively: lung (52%), retroperitoneal LN (44%), mediastinal LN (46%), bone 

(25%), liver (23%). Prognostic classification by MSKCC was good in 14, intermediate 

in 27 and poor in 4 pts. Median OS was 16.2 months [1-70], 21/48 pts are still alive 

with a median follow up of 24 months. A majority of pts (77%) was enrolled in 

prospective phase II and III clinical trials as first or second line treatment, others 

were treated according to guidelines. As first line treatment, pts received: sunitinib 

(25), everolimus (19), sorafenib (2), bevacizumab based regimen (2). Median first line 

PFS is 8.0 months [1-43]. Thirty-two (73 %) pts received a second line treatment 

after first line failure. Second line treatment included VEGFR-TKI (19) including 

sunitinib (11), sorafenib (6) and pazopanib (2) or mTOR inhibitor (12). Median 

second line PFS is 3.3 months [1-34]. Median PFS is 3.0 months after TKI and 3.7 

months after mTOR inhibitors. Noteworthy fourteen patients (29%) received a third 

line treatment. 

Conclusions: This is the first report of second line data in pRCC. Median second 

line PFS is 3.3 months, similar for mTOR inhibitors and VEGFR-TKI agents. 

Nevertheless PFS post-second line treatment in pRCC is lower than that observed in 

clear cell RCC, pointing out their poorer prognosis and the need for biology-driven 

dedicated targeted therapy development. 

Disclosure: L. Albiges: Laurence Albiges declares Novartis (compensated) and pfizer 

(uncompensated) consultant role and honoraria from novartis for other topic. No 

funding or honoraria related to the submitted abstract. K. Fizazi: Participation to 

advisory boards and/or speaker for: – Amgen – Astrazeneca – Novartis – Sanofi– 

Aventis – Keocyt – Ipsen – Janssen – Astellas – BMS – Bayer. B. Escudier: 

Consultant: Bayer, Pfizer, Roche, GSK, Aveo Honorario: Bayer, Roche, Pfizer, 

Genentech, Novartis, aveo. All other authors have declared no conflicts of interest. 

838P EXPRESSION AND CLINICAL IMPORTANCE OF E-CADHERIN, 

DYSADHERIN AND CHEMOKINE LIGAND 2 (CCL2) IN RENAL 

CELL CARCINOMA (RCC) 

U. Demirci 1 , M. Yaman 2 , S. Buyukberber 3 , O. Ekinci 4 , S. Ozkan 5 , U. Coskun 3 , 

M. Benekli 3 , A. Ozet 3 , Ü.E. Bagriacik 2 

1 Medical Oncology, Atatürk Education and Research Hospital, Ankara, TURKEY, 

2 Immunology, Gazi University Faculty of Medicine, Ankara, TURKEY, 3 Medical 

Oncology, Gazi University Faculty of Medicine, Ankara, TURKEY, 4 Pathology, 

Gazi University Faculty of Medicine, Ankara, TURKEY, 5 Public Health, Gazi 

University Faculty of Medicine, Ankara, TURKEY 

Aim: Dysadherin is a cell adhesion molecule that related with aggresiveness and 

progression in many cancers. Dysadherin acts role either with E-cadherine 

dependent or CCL-2 mediated that E-cadherin independent. We studied expression 

and clinical importance of dysadherin and e-cadherin as adhesion molecules and 

CCL2 in RCC. 

Method: Between 2006 and 2010, 38 patients with RCC were evaluated 

retrospectively. Median age of the patients (27 male, 11 female) was 60 (range, 33– 

84). While median tumor size was 5.75 cm (range, 2–30 cm), 13 patients were stage 

4, one patient was stage 3, 5 patients were stage 2, 19 patients were stage 1. 15 

patients were Fuhrmann grade ¾, 21 patients (55.3%) had capsule invasion, 10 

patients (26.3%) had perirenal fat tissue involvement and 4 patients had (10.5%) 

renal vein thrombosis. Dysadherin did not express in 10 patients. Low expression 

(less than %30) was detected in 25 patients (65.8%), enhanced expression (more than 

30%) was detected in 3 patients (%7.9). E-cadherin did not express in 11 patients 

(28.9%), low expression was detected in 23 patients (60.5%), moderate-high 

expression was detedcted 4 patients (10.6%). CCL2 did not express in 14 patients, 

low expression was detected in 7 patients (%18.4), moderate-high expression was 

detected in 17 patients (44.3%). Although moderate positive correlation between 

dysadherin and CCL2 (r= +0,25, p = 0.49), e-cadherin and CCL2 (r= +0.25, p = 0.33) 

were detected, moderate negative correlation between dysadherin and e-cadherin was 

detected (r= +0.22, p = 0.66). Moderate negative correlation was detected between 

grade of tumor and e-cadherin (r= -0.25, p = 0.49). Median overall survival (OS) was 

46.6 months (range, 38.9-54.3), In univariate analysis, stage, grade of tumor, capsule 

invasion, tumor thrombosis, perirenal fat tissue involvement were significant 

interaction on OS (p < 0.05), however dysadherin, E-cadherin and CCL2 were not 

associated with OS (>0.05). Stage and vascular thrombosis were significant on overall 

survival in multivariate analysis. 

Conclusion: This is the first study that evaluated adhesion molecules in RCC and 

there is no association these parameters and clinical outcome. 


839P EFFICACY AND SAFETY OF TEMSIROLIMUS IN PATIENTS 

WITH METASTATIC RENAL CELL CARCINOMA: RESULTS 

FROM THE SPANISH EXPERIENCE 

L. Ruiz 1 , E. Esteban 1 , L. León 2 , A. Pinto 3 , C. Suarez 4 , I. Duran 5 , N. Lainez 6 , 

A. Lopez 7 , A. Viqueira 8 , P. Maroto 9 


2 Medical Oncology, Hospital General de Santiago, Santiago de Compostela, 

SPAIN, 3 Medical Oncology, Hospital Universitario La Paz, Madrid, SPAIN, 

4 Oncology, Hospital Vall d’Hebron, Barcelona, SPAIN, 5 Departamento de 

Oncologia, Hospital Madrid Norte San ChinarroCentro Integral Oncologico Clara 

Campal, Madrid, SPAIN, 6 Medical Oncology, Complejo Hospitalario de Navarra, 

Pamplona, SPAIN, 7 CRA, Trial Form Support, Madrid, SPAIN, 8 Oncology, Pfizer, 

Madrid, SPAIN, 9 Dept. of Medical Oncology, Hospital de la Sta. Creu i St. Pau, 


Temsirolimus (TEM) is an mTOR inhibitor approved for first-line treatment of 

patients with poor-prognosis metastatic renal cell carcinoma (RCC). In a phase III 

trial TEM showed a statistically significant benefit in overall survival when compared 

to interferon-α. Recently, several authors have described that TEM also appears to be 


effective in second or further lines of treatment. Here we report the Spanish 

experience with TEM both in first and subsequent lines of treatment. 

A retrospective, observational and multicenter study of TEM used following routine 

clinical practice in patients with RCC was carried out. Patients treated with TEM 

between 2007 and 2012 were included. The objective of the study was to analyze the 

efficacy and safety of TEM. A total of 101 patients were included, 70% were male and 

the median age was 62. According to Motzer Criteria, 13% patients had a favorable 

prognosis, 44% an intermediate prognosis and 43% a poor prognosis. Of the 101 

patients, 53% were treated with TEM in 1st line, 18% in 2nd line, 23% in 3rd line 

and 4% in 4th or further lines; 23% were patients with non-clear cell RCC and 28% 

were non-nephrectomized. Median PFS for all patients was 3 months. The clinical 

benefit rate was 59% with an ORR of 17% (all partial responses) and 42% of disease 

stabilization. In patients treated in 1st line, median PFS was 3 months, in patients 

treated in subsequent lines median PFS were 5, 4 and 1 months in 2nd, 3rd and 4th 

line respectively. In non-nephrectomized patients and patients with non-clear RCC 

median PFS was 3 months for both subgroups. In terms of tolerability, 79% of the 

patients developed at least one adverse event (AE). Most common AE (all grades) 

were anemia (39%), asthenia (22%), stomatitis (20%) and rash (15%). TEM appears 

to have a modest efficacy and an acceptable toxicity profile in patients with RCC, 

both in first and subsequent lines of treatment. TEM seems to achieve similar efficacy 

in patient subgroups such as non-nephrectomized patients and patients with 

non-clear histologies. Efficacy seems to be consistent with previous reports in second 

and third lines of treatment, but seems to be somewhat lower in first line, probably 

due to the poor-risk profile of the patients. 

Disclosure: E. Esteban: Compensated advisory/consultant role for Pfizer. A. Lopez: 

CRA at TFS working for Pfizer. A. Viqueira: Pfizer Employee. P. Maroto: 

Compensated advisory/consultant role for Pfizer. All other authors have declared no 


840P SEQUENTIAL TARGETED THERAPY FOLLOWING PAZOPANIB 

(PZ) IN PATIENTS (PTS) WITH METASTATIC RENAL CELL 

CANCER (MRCC): EFFICACY AND TOXICITY 

F. Pons Valladares 1 , T.K. Choueiri 2 , T.E. Hutson 3 , T.B. Powles 4 , C. Porta 5 , 

S. Bracarda 6 , M.E. Lampron 2 , L. Cerbone 7 , C.N. Sternberg 7 , J. Bellmunt 1 

1 Medical Oncology, University Hospital del Mar, Barcelona, SPAIN, 2 Medical 

Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital and 

Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA, 3 Gu 

Center of Excellence Texas Oncology, Charles A. Sammons Cancer Center / 

Baylor University Medical Center / Texas AM Health Science Center College of 

Medicine, Dallas, TX, UNITED STATES OF AMERICA, 4 Department of Medical 

Oncology, St. Bartholomew’s Hospital, London, UNITED KINGDOM, 5 Oncologia 

Medica, Ospedale San Matteo, Pavia, ITALY, 6 Department of Oncology, 

Ospedale San Donatoand U.O.C. of Medical Oncology, Arezzo, ITALY, 7 Medical 

Oncology, San Camillo and Forlanini Hospital, Rome, ITALY 

Background: The optimal sequence for a switch from pazopanib (PZ) to another 

targeted therapy (VEGF or mTOR inhibitor) is not yet defined. Recent findings 

suggest that the sequential use of anti-VEGF therapies may provide similar PFS 

(Progression Free Survival) benefit than mTOR inhibitors. We embarked on 

characterizing the clinical outcome to targeted therapies after the use of PZ from a 

multicenter retrospective study. 

Methods: We reviewed the records of 36 pts with mRCC from 6 sites in Europe and 

US who received either a VEGF or an mTOR inhibitor after PZ. Pts and disease 

characteristics (demographic data, MSKCC and Heng prognostic score), disease 

outcome (objective response, PFS) and toxicity were compared between the two 

sequential treatment options. 

Results: The median age was 62 (range 30–79) and 89% were males, mostly with 

clear-cell histology (97.2%) and good or intermediate MSKCC (97%) and Heng 

(93%) prognostic score. PZ was given as second line therapy after cytokines (n= 7) or 

sunitinib (n = 2) in 25% of pts, and as first line in 75%. Median PFS for PZ 

treatment was 9.3 months (mo) (CI 95%: 6,3–12,4 mo). Post- PZ therapies were: 

anti-VEGF in 23 patients (sorafenib n = 10, sunitinb n = 3, cediranib n = 4, 

cabozantinib n = 3 and bevacizumab n = 3) and mTOR inhibitors in 13 (everolimus 

(EV)). Median duration of post-PZ therapy was 6.2 mo in anti-VEGF and 2.6 mo in 

EV-treated pts (p = 0.017). Partial Response (PR) was only observed in 2 pts treated 

with anti-VEGF agents. Clinical benefit (PR+ Stable Disease) was observed in 80% 

and 33% of anti-VEGF and EV treated patients (p = 0.021). The most common 

Grade 1-2 adverse events (AE) were asthenia (50%), diarrhea (31,8%), Hand-foot 

syndrome (27%), rash (22,7%) and stomatitis (13,6%) for the anti-VEGF treated 

group; and asthenia (30,8%), respiratory toxicity (23%) and metabolic alterations 

(15,4%) for EV. Grade 3-4 AE occurred in 18% of anti-VEGF and 23% of EV 

groups. Median PFS was 7,3 mo for anti-VEGF and 2,4 mo for EV, with a HR of 

0,36 (CI 95% 0.16 – 0.81; p = 0.014). 

Conclusions: In this retrospective study, anti-VEGF therapy resulted in acceptable 

PFS benefit in post-PZ treated patients, and was well tolerated. These findings 

support the sequential use of an anti-VEGF in post PZ progression. The different 

type of anti-VEGF agents in this study is a major limitation. 



841P POOLED ANALYSIS OF NON-INTERVENTIONAL STUDIES OF 

EVEROLIMUS IN PATIENTS WITH METASTATIC RENAL CELL 

CARCINOMA (MRCC) REFRACTORY TO ANTI-VEGF THERAPY 

L. Bergmann 1 , U. Kube 2 , L. Albiges 3 , J. Eymard 4 , M. Schmidinger 5 , A. Bamias 6 , 

M. Ktiouet 7 , G. Fischer 8 , D. Xanthaki 9 , G. Guderian 10 

1 Tumor Center Rhein-Main, University Hospital Frankfurt, Frankfurt/Main, 

GERMANY, 2 Urology, Private practice, Chemnitz, GERMANY, 3 Department of 

Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 4 Clinical Research 

and Cell Therapy, Institut Jean Godinot, Reims, FRANCE, 5 Department of 

Medicine I, Medical University of Vienna, Vienna, AUSTRIA, 6 Department of 

Clinical Therapeutics, Athens University, Medical School, Athens, GREECE, 

7 Solid Tumors, Novartis Pharma, Paris, FRANCE, 8 Oncology, Novartis Pharma 

GmbH, Vienna, AUSTRIA, 9 Oncology, Novartis (Hellas) S.A.C.I., Athens, 

GREECE, 10 Solid Tumors and Early Clinical Development, Novartis Pharma 

GmbH, Nuremberg, GERMANY 

Background: The oral mTOR inhibitor everolimus has demonstrated statistically 

significant PFS benefit over placebo in patients with mRCC refractory to 1 or 2 

previous VEGFr-tyrosine kinase inhibitors. Here, we report prospective data on 

everolimus in routine clinical practice from four European countries after failure of 

anti-VEGF therapy. 

Patients and methods: Data were pooled from four prospective, non-interventional 

studies to evaluate the safety and effectiveness of everolimus in Germany, France, 

Greece, and Austria. 

Results: Data from the first 6 months of treatment of 534 patients were pooled for 

this analysis. At baseline, median time since diagnosis of RCC was 2.6 years and 

median time since diagnosis of first metastasis was 1.8 years. Most patients had 

predominantly clear cell mRCC (90%), had previously undergone nephrectomy 

(89%), and at initiation of everolimus therapy were of favourable or intermediate 

MSKCC risk prognosis (91%). According to investigator’s assessment, 13% of 

patients achieved partial response and 56% of patients achieved stable disease. 

Overall, 77% of patients reported at least one adverse event (AE) and 22% of patients 

reported at least one serious AE. The most common AEs (all grades) were stomatitis 

(25%), anaemia (13%), asthenia (9%), fatigue (8%), pneumonitis (8%), rash (8%), 

diarrhoea (7%), decreased appetite (7%), hypertriglyceridaemia (6%), dyspnoea (6%), 

and nausea (6%). The most common serious AEs were stomatitis (3.4%), general 

health deterioration (2.2%), anaemia (2.1%), dyspnoea (2.1%), and pneumonitis 

(2.1%). A total of 24% of patients discontinued due to AEs. Percentages of patients 

with Karnofsky performance status ≥70 were similar at baseline (86%) and at end of 

this analysis (80%). 

Conclusions: Results of this pooled analysis of European non-interventional studies of 

everolimus in patients with mRCC who failed previous anti-VEGF therapy confirm its 

safety previously reported in the pivotal multi-national RECORD-1 trial and provide 

preliminary information about the effectiveness of everolimus in routine use. The results 

support everolimus as standard of care in VEGF-refractory patients with mRCC. 

Disclosure: L. Bergmann: Lothar Bergmann has served on advisory boards for 

Novartis, Pfizer, Roche, Astellas, and GlaxoSmithKline and has received honoraria 

from Novartis, Pfizer, Roche, and GlaxoSmithKline. L. Albiges: Laurence Albiges is 

consultant to Novartis and Pfizer; has received honoraria from Novartis, Bayer, and 

Sanofi-Aventis; and has received research funding from Novartis. M. Schmidinger: 

Manuela Schmidinger has received honoraria from Pfizer, GlaxoSmithKline, 

Novartis, Roche, and Astellas; has served as advisor for Pfizer, Roche, 

GlaxoSmithKline, Novartis, and Astellas; and has received research grants from 

Pfizer and Roche. M. Ktiouet: Meryem Ktiouet is an employee of Novartis Pharma. 

G. Fischer: Gregor Fischer is an employee of Novartis Pharma GmbH. D. Xanthaki: 

Despoina Xanthaki is an employee of Novartis (Hellas) S.A.C.I. G. Guderian: Gernot 

Guderian is an employee of Novartis Pharma GmbH. All other authors have declared 


842P BIOMARKERS OF EVEROLIMUS EFFICACY IN PATIENTS WITH 

METASTATIC RENAL CELL CARCINOMA (MRCC): ANALYSIS 

OF THE PHASE III RECORD-1 TRIAL 

S. Oudard 1 , B. Escudier 2 , J. Thompson 3 , V. Grünwald 4 , P.F. Conte 5 , 

S. Bracarda 6 , A. Panneerselvam 7 , S. Gogov 8 , D. Chen 7 , R.J. Motzer 9 

1 Oncology Translational Research Unit, Hopital Europeen Georges-Pompidou, 

Paris, FRANCE, 2 Immunotherapy Unit, Institut Gustave Roussy, Villejuif, FRANCE, 

3 Medical Oncology, Seattle Cancer Care Alliance, Seattle, WA, UNITED STATES 

OF AMERICA, 4 Clinic for Hematology, Hemostasis, Oncology, and Stem Cell 

Transplantation, Hannover Medical School, Hannover, GERMANY, 5 Oncology, 

Universita degli Studi di Modena e Reggio Emilia, Modena, ITALY, 6 Medical 

Oncology, Ospedale San Donato, Arezzo, ITALY, 7 Oncology Biometrics and Data 

Management, Novartis Pharmaceuticals Corporation, Florham Park, NJ, UNITED 

STATES OF AMERICA, 8 Oncology, Novartis Pharma AG, Basel, SWITZERLAND, 


New York, NY, UNITED STATES OF AMERICA 

Background: In RECORD-1, everolimus significantly increased median PFS 

(primary end point) over placebo in VEGFr-TKI-refractory patients with mRCC. We 



investigated angiogenesis pathway molecules, sVEGFR-2, VEGF-A, and bFGF, in 

plasma as potential biomarkers of everolimus efficacy in RECORD-1. 

Material and methods: Patients received everolimus 10 mg daily (n = 277) or placebo 

(n = 139), both with BSC; placebo patients could cross over to everolimus at disease 

progression. Pre-dose blood samples were collected on day 1 of the first four 28-day 

treatment cycles; plasma levels of sVEGFR-2, VEGF-A, and bFGF were assessed 

using ELISA. A mixed effects model was used to assess treatment effect over time on 

each biomarker. Hazard ratios (HR) for prognostic effects were obtained using log 

baseline biomarker values as continuous variables in a stratified Cox proportional 

hazards model. 

Results: Plasma values for sVEGFR-2, VEGF-A, and bFGF were available for 45/45/ 

39% of everolimus patients and 50/50/45% of placebo patients. Baseline 

characteristics of patients with biomarker data were similar to the overall population. 

Mean log baseline values for sVEGFR-2, VEGF-A, and bFGF were similar for both 

arms; 9.1/5.1/1.6 for everolimus and 9.1/5.2/1.8 for placebo, respectively. Median PFS 

was significantly improved with everolimus vs placebo, regardless of baseline levels of 

any of the biomarkers analyzed (P < .001), suggesting that none of them is predictive 

of everolimus efficacy. Lower VEGF-A baseline level (HR, 1.27; 95% CI, 1.03-1.57; 

P = .028) was significantly associated with longer PFS in the trial population, 

suggesting that this biomarker may be prognostic for mRCC. Over the time course of 

the study, a significant everolimus treatment effect over placebo on reducing bFGF 

and sVEGFR-2 levels was observed (P = .0095 and P < .001, respectively), but not on 

VEGF-A level. 

Conclusions: Everolimus provided significant clinical benefit over placebo, regardless 

of baseline biomarker levels. However, lower VEGF-A level was seen as a potential 

prognostic factor for longer PFS. Plasma levels of bFGF and sVEGFR-2 were 

significantly down-regulated from baseline by everolimus treatment. 

Disclosure: S. Oudard: Stephane Oudard received honoraria from Bayer, Novartis, 

Pfizer, Roche, and Sanofi-Aventis. B. Escudier: Bernard Escudier has received 

honorariumfromNovartis,Pfizer,GSK,Aveo,andBayer.J.Thompson:John 

Thompson received clinical study support from Novartis. V. Grünwald: Viktor 

Grunwald served as consultant to Roche, Bayer, Novartis, Pfizer, 

GlaxoSmithKline, and Aveo/Astellas, received honoraria from GlaxoSmithKline, 

Novartis, and Pfizer, and received research funding from Pfizer and 

GlaxoSmithKline. S. Bracarda: Sergio Bracarda has served as advisor for Pfizer, 

Bayer-Schering, GlaxoSmithKline, Novartis, Aveo/Astellas, Boheringer-Ingelheim, 

Johnson & Johnson, and Sanofi-Aventis and has received speaker fees from Pfizer, 

Novartis,andSanofi-Aventis.A.Panneerselvam:AshokPanneerselvamisan 

employee of Novartis Pharmaceuticals Corporation. S. Gogov: Sven Gogov is an 

employee of Novartis Pharma AG. D. Chen: David Chen is an employee of 

Novartis Pharmaceuticals Corporation. R.J. Motzer: Robert Motzer has received 

research funding from Novartis. All other authors have declared no conflicts of 

interest. 

843P AXITINIB (AXI) AND EVEROLIMUS (EVE) IN THE TREATMENT 

(TX) OF SUNITINIB-REFRACTORY (SU-R) PATIENTS (PTS) 

WITH METASTATIC RENAL CELL CARCINOMA (MRCC): 

RESULTS OF A SIMULATED TX COMPARISON (STC) 

ANALYSES 

I. Proskorovsky 1 , A. Benedict 2 , S. Negrier 3 , J. Larkin 4 , R. Sandin 5 , C. Chen 6 

1 Biostatistics, United BioSource Corporation, Dorval, QC, CANADA, 2 Health 

Economics, United BioSource Corporation, Budapest, HUNGARY, 3 Medical 

Oncology, Comprehensive Cancer Center Leon Berard, Lyon Cedex, FRANCE, 

4 Medical and Clinical Oncology, Royal Marsden Hospital London, London, 

UNITED KINGDOM, 5 Global Outcomes Research, Pfizer AB, Sollentuna, 

SWEDEN, 6 Global Health Outcomes, Pfizer, New York, NY, UNITED STATES OF 

AMERICA 

Background: Axi is a novel VEGF targeted agent for mRCC pts who failed 1 prior 

systemic therapy. the The AXIS trial compared axi to sorafenib and showed a 

significantly longer PFS in pts treated with axi, including the su-r subgroup. No 

direct comparison is available between axi and eve but is an important clinical 

question. The goal of this analysis was to compare OS and PFS in su-r pts treated 

with axi and eve. 

Methods: Pts who were su-r and received axi in the AXIS trial and eve in 

RECORD-1 trial were considered for this analysis. A STC method (Caro et al 2010) 

was used to derive OS and PFS curves for a hypothetical cohort of “axi like” pts had 

they received eve in the AXIS trial. Pt level AXIS data was used to derive predictive 

equations for OS and PFS. Parametric survival analysis identified the best fitting 

distribution and significant predictors of OS and PFS. These equations were 

calibrated using pt characteristics and median OS and PFS reported in the literature. 

Results: 194 axi and 124 eve pts who were su-r were analyzed. While AXIS trial 

included only pts that progressed on 1 line of tx, 65% of su-r eve pts had 3 plus 

lines of therapy. Some pts were included in the eve trial without having 

progressed on 1 st line tx. Available pt characteristics were comparable across two 

groups, except for difference in MSKCC risk categories (36% vs 17% poor risk pts 

in axi and eve respectively), mean duration of prior su (57 vs 44 weeks) and 

ECOG score (52% vs 60% with ECOG 0). A log-normal distribution provided the 

best fit for both OS and PFS. MSKCC risk category and duration of prior 

sunitinib were significant predictors of OS. The final PFS equation included 

MSKCC risk group and age. Estimated median OS and PFS was 15.2 and 5.1 

months for axi compared to 10.6 and 3.6 months for eve group respectively. 

Estimated difference in mean OS and PFS between axi and eve was 7.6 and 2.6 

months. 

Conclusion: This analysis suggest that su-r RCC pts treated with axi may have an 

improved OS and PFS compared to pts treated with eve. Our analysis could not 

account for all differences between trials, such as number of prior therapies, however, 

a STC can provide additional comparative context. 

Disclosure: I. Proskorovsky: I am an employee of United BioSource Corporation. As 

a research consulting organization, it received funding from Pfizer for the research 

undertaken in this abstract. A. Benedict: I am an employee of United BioSource 

Corporation. As a research consulting organization, it received funding from Pfizer 

for the research undertaken in this abstract. S. Negrier: Dr. Negrier has received 

honorariums from Pfizer and Novartis as well as research grants from 

GlaxoSmithKline and Roche. J. Larkin: research funding from Pfizer and Novartis, 

advisory role to Pfizer, Novartis, GSK, BMS, Aveo. R. Sandin: Employee of Pfizer AB. 

Stock or other ownership interests in Pfizer Inc. C. Chen: Employee and stockholder 

of Pfizer only 

844P SORAFENIB IN PATIENTS WITH RENAL CELL CARCINOMA 

(RCC) AND BASELINE HYPERTENSION OR DIABETES: 

SUBANALYSIS OF THE NON-INTERVENTIONAL PREDICT 

STUDY 

D. Jäger 1 , J. Guo 2 , E. Korbenfeld 3 , M. Zemanova 4 , N. Leonhartsberger 5 , 

K. Stauch 6 , A. Boeckenhoff 7 ,J.Yu 8 , J. Mardiak 9 , B. Escudier 10 

1 National Center for Tumor Diseases, University Medical Center Heidelberg, 

Heidelberg, GERMANY, 2 Renal Cancer and Melanoma Unit, Peking University 

Cancer Hospital and Institute, Beijing, CHINA, 3 Oncology, Hospital Británico de 

Buenos Aires, Buenos Aires, ARGENTINA, 4 First Faculty of Medicine, Charles 

University, Prague, CZECH REPUBLIC, 5 Department of Urology, Medical 

University Innsbruck, Innsbruck, AUSTRIA, 6 Global Non-interventional Studies, 

Bayer HealthCare, Leverkusen, GERMANY, 7 Global Development - Global 

Clinical Development, Bayer HealthCare, Wuppertal, GERMANY, 8 Global Medical 

Affairs, Bayer HealthCare, Montville, NJ, UNITED STATES OF AMERICA, 

9 Department of Medical Oncology, National Cancer Institute, Bratislava, SLOVAK 

REPUBLIC, 10 Department of Immunotherapy, Institut Gustave Roussy, Villejuif, 

FRANCE 

Background: Many patients (pts) with advanced RCC have comorbidities 

(particularly elderly pts), but pts with comorbidities are often underrepresented in 

clinical trials. PREDICT (NCT 00895674) was a large, non-interventional study of 

sorafenib (Sor) in pts with advanced RCC in clinical practice. We report findings in 

pts with baseline comorbidities. 

Methods: Pts diagnosed with advanced RCC and prescribed Sor under compliance 

of the local product label were eligible. Physician assessments of efficacy and 

tolerability were collected for ≤12 months. 

Results: The most frequent comorbidities were hypertension (HTN; n = 674) 

and diabetes (n = 225); baseline characteristics in these pts (71–73% male, 82– 

87% prior nephrectomy, 82–83% clear cell histology) were similar to the total 

efficacy population (n = 2311; 71% male, 84% prior nephrectomy, 83% clear cell 

histology). Pts with HTN (38%; n = 254) and diabetes (38%; n = 85) were more 

likely to be aged ≥70 years vs the total efficacy population (23%; n = 532). 

Median duration of therapy (DOT) in pts with HTN (6.7 months) or diabetes 

(7.0 months) was similar to the total efficacy population (7.3 months). A 

similar trend was seen for all pts aged ≥70 years (median DOT: total efficacy 

population, 6.1 months; HTN subset, 6.0 months; diabetes subset, 6.4 months). 

Best tumor response per RECIST was similar in the total group (complete 

response [CR], 2%; partial response [PR], 22%; stable disease [SD], 47%; and 

progressive disease [PD], 4%) and comorbid groups (CR, 1–2%; PR, 22–23%; 

SD, 43–48%; PD, 4–5%). In general, adverse event (AE) rates were 

slightly higher in pts with comorbidities than in the total safety population 

(Table). 


Conclusions: In pts with RCC treated in clinical practice settings, some AE rates 

were numerically higher in pts with comorbidities. There were no notable differences 

in duration of Sor therapy. Number (%) pts with AEs (safety population) 

Comorbidity subset 

Hypertension Diabetes 

Total 

population 

Event 

(n = 760) 

(n = 267) (n = 2599) 

Any AE 524 (69.0) 177 (66.3) 1479 (56.9) 

Any 

drug-related 

AE 

436 (57.4) 146 (54.7) 1240 (47.7) 

Any SAE 191 (25.1) 71 (26.6) 477 (18.4) 

Any 

drug-related 

SAE 

59 (7.8) 20 (7.5) 140 (5.4) 

Most frequently reported any grade drug-related AEs (preferred term)* 

Hand–foot skin 

reaction 

173 (22.8) 55 (20.6) 520 (20.0) 

Diarrhea 177 (23.3) 62 (23.2) 443 (17.1) 

Rash † 

62 (8.2) 14 (5.2) 220 (8.5) 

Alopecia 49 (6.5) 15 (5.6) 145 (5.6) 

Hypertension 52 (6.8) 10 (3.8) 110 (4.2) 

Nausea 33 (4.3) 15 (5.6) 67 (2.6) 

Other AEs in relevant system organ classes 

Cardiac 

disorders 

7 (0.9) 1 (0.4) 16 (0.6) 

Renal and 

urinary 

disorders 

7 (0.9) 3 (1.1) 13 (0.5) 

Vascular 

disorders 

(excluding 

hypertension) 

7 (0.9) 2 (0.7) 15 (0.6) 

*Occurring in ≥5% of patients in any subset. † Including rash, rash generalized, rash 

erythematous, rash maculo-papular, rash pustular, rash macular, rash pruritic, 

exfoliative rash, rash papular. AE, adverse event; SAE, serious adverse event 

Disclosure: D. Jäger: Dirk Jäger has received honoraria from Bayer, Amgen, Pfizer, 

Novartis, Roche, Fresenius Kabi and Hoffmann-La Roche. M. Zemanova: Milada 

Zemanova has received consulting and lecture fees from Glaxo Smith Kline and 

Roche. N. Leonhartsberger: Nicolai Leonhartsberger has received honoraria from 

Bayer, Pfizer and Roche. K. Stauch: Kathrin Stauch is an employee of Bayer 

HealthCare and owns stock in Bayer Pharma AG. A. Boeckenhoff: Annette 

Boeckenhoff is an employee of Bayer HealthCare and owns stock in Bayer Pharma 

AG. J. Yu: Jian Yu is an employee of Bayer HealthCare. J. Mardiak: Jozef Mardiak 

has received Research Grants from Novartis and has received honoraria from Pfizer 

and Pierre Fabre. B. Escudier: Bernard Escudier has served in an advisory role for 

Pfizer, Novartis, Roche, GSK, Bayer and Aveo, and has received honoraria from 

Pfizer, Novartis, Roche, GSK, Bayer and Aveo. All other authors have declared no 


845P BIOLOGICAL TOXICITY CAN BE A SURROGATE MARKER OF 

EFFICACY IN PATIENTS (PTS) TREATED WITH MTOR 

INHIBITORS (MTORI) FOR MRCC 

M. Jebali 1 , J. Fouque 2 , G. Fargues 2 , A. Jouinot 1 , R.T. Elaidi 3 , S. Oudard 1 , 

J. Medioni 1 

1 Medical Oncology, Hopital Europeen Georges-Pompidou, Paris, FRANCE, 

2 Pharmacy, Hopital Europeen Georges-Pompidou, Paris, FRANCE, 3 Oncology, 

Association pour la Recherche sur les Therapeutiques Innovantes en 

Cancerologie, Paris, FRANCE 

Background: Biological toxicities of mTORi are well characterized. We investigate 

retrospectively if there is a link between biological toxicities and mTORi efficacy. 

Patients and methods: Biological toxicities were retrospectively collected in patients 

treated with an mTORi (Everolimus [Ev], Temsirolimus [Tem]) for mRCC at the 

European G. Pompidou Hospital in Paris, France between 2007 and 2011. Only pts 

having received mTORi for at least 28 days were eligible. Lymphocytes, creatinaemia, 

glycaemia, phosphoraemia, liver transaminases, cholesterolaemia, and 


triglyceridaemia were recorded with onset date and higher grade (NCI-CTC 3.0). 

Time to onset and onset velocity defined as the absolute change from baseline (%) 

divided by the time to onset were calculated for each adverse event. Efficacy was 

assessed with time to progression (TTP) from the initiation of mTORi until disease 

progression/death and objective response according to RECIST criteria 2.0. 

Kaplan-Meier estimates with log-rank test were used to compare categorical data and 

Cox model for continuous data and hazard ratios. 

Results: 75 pts were included. Median age = 56 y (37-86), sex ratio = 4/1 (M/F), pts 

on Ev (N = 44)/Tem (N = 31) according to setting: 1st = 2/6, 2nd = 9/11, 3rd = 14/9, 

≥4th = 20/4. 10 pts on Ev had a dose reduction. Objective response: PR = 6, SD = 40, 

PD = 20. 7 patients discontinued due to toxicity and 2 for personal decision. Median 

follow-up time = 22.8 mo. Median TTP = 7.3 mo (95% CI, 4.7-10.8). Hyperglycaemia 

and hypophosphoraemia are less important in progressors (P < 0.05). TTP was 

significantly associated with onset velocity of lymphocytopaenia (events = 21/44, 

HR = 0.98, P = 0.026), hypophosphoraemia (events = 7/11, HR = 0.94, P = 0.044) and 

hypertriglyceridaemia (events = 23/33, HR = 1.005, P = 0.023). 

Conclusions: Lymphocytopaenia, hyperglycaemia, hypophosphoraemia, and 

hypertriglyceridaemia were significantly related to objective response or TTP. These 

events, together with their onset velocity, should be prospectively monitored to 

investigate their predictive value for efficacy. 


846P MEDICAL OPTIMIZATION OF TORISEL® (MOTOR): A PHASE II 

TRIAL OF TEMSIROLIMUS AS SECOND-LINE TREATMENT 

FOR ADVANCED RCC BY THE ITALIAN KIDNEY CANCER 

GROUP (GIR) 

M. Milella 1 , G. Di Lorenzo 2 , A. Felici 1 , M. Aieta 3 ,G.LoRe 4 , C. Boni 5 , E. Aitini 6 , 

E. Villa 7 , S. De Placido 2 , F. Cognetti 1 

1 Divisione di Oncologia Medica A, Istituto Nazionale Tumori Regina Elena, Roma, 

ITALY, 2 Department of Oncology, Cattedra di Oncologia Medica, Università degli 

Studi Federico II, Napoli, ITALY, 3 Medical Oncology, Department of Medical 

Oncology, National Institute of Cancer, Rionero in Vulture, Rionero, ITALY, 

4 Oncology, Medical Oncology, Pordenone, ITALY, 5 Oncology Dept., Arcispedale 

S. Maria NuovaDivisione di Oncologia, Reggio Emilia, ITALY, 6 Med. Oncology & 

Hematology Dept., Ospedale C. Poma, Mantova, ITALY, 7 Medical Oncology, 

Istituto Scientifico S. Raffaele - IRCCS, Rome, ITALY 

Purpose: The mammalian target of rapamycin (mTOR) kinase is a well-established 

therapeutic target in renal cell carcinoma (RCC). We explored the activity and safety 

of Temsirolimus as II-line treatment for advanced RCC pts in a multicenter phase II 

trial. 

Methodology: in this open-label trial, Temsirolimus (25 mg/wk i.v.) was 

administered to advanced RCC pts with documented progression after any I-line 

treatment. Primary endpoint was PFS rate at 6 mos. Tumor response was assessed 

every 8 wks. Considering a 6-mo PFS rate of 20% unacceptable (p0 = 20%) and a 

6-mo PFS rate of 40% (p1 = 40%) of interest, a minimum targeted accrual of 47 pts 

in the sunitinib-pretreated group was to be pursued in order to reach 90% power at a 

significance level of 5%. 

Results: From May 2009 to January 2012, 76 pts were enrolled (median age: 67 yrs, 

range: 36-86; M/F: 58/18; ECOG PS 0/1/2: 51/19/6); I-line therapy included sunitinib 

(60 pts), bevacizumab (8), sorafenib (3), cytokines (2), or other (3). With 18/57 

evaluable patients free from progression at 6 mos in the sunitinib-pretreated group 

the primary endpoint was met and trial accrual was stopped. Median PFS was 4.0 

mos (95% CI: 2.7–5.3) and 4.6 mos (95% CI: 2.8–6.5) in the overall (n = 71) and 

sunitinib-pretreated (n = 57) populations, respectively; OS in the same groups was 

13.7 mos (95% CI: 9.1–18.3) and 14.6 mos (95% CI: 8.9-20.3), respectively. Six out of 

71 pts (8%) had PR and 33/71 (46%) had SD as their best response. Toxicity (n = 68) 

was mild with G3 anemia, neutropenia and thrombocytopenia in 2, 1, and 1 pts, 

respectively; G3 hyperglycemia and G3 hypertriglyceridemia in 2 and 7 pts, 

respectively; G4 hypercholesterolemia in 2 pts; G3 stomatitis in 5 pts; G3 asthenia in 

3 pts; G3-4 pulmonary toxicity in 2 pts; G3 diarrhea in 2 pts; G3 cutaneous rash in 1 

pt. Only 1 hypersensitivity reaction occurred during Temsirolimus infusion. 

Treatment compliance was good, with


847P CLINICAL EFFICACY OF SUNITINIB AS POST-OPERATIVE 

ADJUVANT THERAPY IN PATIENTS WITH HIGH-RISK RENAL 

CELL CARCINOMA 

X. Zhang 1 , J.Y. Yuan 2 , L. Wang 2 , L. Chen 3 ,J.Pan 4 ,L.Ye 5 , X. Xiao 6 , J. Qiu 7 , 

K. Zhang 8 ,G.Ye 9 

1 Urology Department, The General Hospital of the People’s Liberation Army, 

Beijing, CHINA, 2 Urology Department, Xijin Hospital, the Fourth Military Medical 

University, Xian, CHINA, 3 Urology Department, 307 Hospital of PLA, Beijing, 

CHINA, 4 Urology Department, Southwest Hospital, the Third Military Medical 

University, Chongqing, CHINA, 5 Urology Department, 304 Hospital of PLA, 

Beijing, CHINA, 6 Urology Department, General Hospital of Armed Police Forces, 

Beijing, CHINA, 7 Urology Department, Bethune International Peace Hospital of 

PLA, Jilin, CHINA, 8 Urology Department, Daping Hospital, the Third Military 

Medical University, Chongqing, CHINA, 9 Urology Department, Xinqiao Hospital, 

the Third Military Medical University, Chongqing, CHINA 

Objective: To evaluate the efficacy and safety of Sunitinib as post-operative adjuvant 

therapy in patients with high-risk renal cell carcinoma (RCC). 

Methods: A total of 60 patients with resected, histologically confirmed clear cell RCC 

were enrolled in this study. Patients received orally Sunitinib either at a dose of 50mg 

on treatment schedule 4/2 (once daily for 4 weeks followed by 2 weeks off) or at a 

dose of 37.5mg once daily for three 6-week cycles from 1 month after surgery. 

Results: All 60 patients tolerated Sunitinib treatment well and no patient 

discontinued treatment due to adverse events. Most adverse events were grade I to II. 

The most frequently reported adverse events were neutropenia (56.7%), 

thrombocytopenia (53.3%), leucopenia (48.3%), hand-foot syndrome (46.7%) and 

hypertension (36.7%). The most frequently reported grade 3 or 4 toxicities were 

thrombocytopenia (25%), neutropenia (15%), hand-foot syndrome (11.7%) and 

leucopenia (8.3%). The majority of adverse events occurred within the first 1-2 cycles 

of Sunitinib treatment, and was ameliorated 1 month after 3 cycles finished. No 

irreversible adverse event was observed. As of April 5, 2012, no recurrence occurred 

in patients except one death due to cerebrovascular accident unrelated to treatment, 

with both 6-month and 9-month disease-free survival (DFS) rate of 100%. 

Conclusion: Myelosuppression occurred less frequently in high-risk RCC patients 

treated with Sunitinib as operative adjuvant therapy than in advanced RCC patients, 

with a better benefit trend. However, long-term follow-up data are needed to further 

confirm the efficacy of Sunitinib in the adjuvant setting. 


848P OVERALL SURVIVAL (OS) IN METASTATIC RENAL CELL 

CARCINOMA (MRCC): A COMPARISON BETWEEN SORAFENIB 

(SO) AND BEST SUPPORTIVE CARE (BSC) AFTER FIRST LINE 

TREATMENT WITH SUNITINIB (SU) IN SWEDEN 

P. Sandström 1 , R. Sandin 2 , J. Kowalski 3 , T. Wahlgren 4 , M. Jakobsson 4 , 

S. Lundstam 5 , B. Ljungberg 6 , U. Harmenberg 1 

1 Department of Oncology-pathology, Karolinska University Hospital and 

Karolinska Institutet, Stockholm, SWEDEN, 2 Global Health Economics and 

Outcomes Research, Onology, Pfizer AB, Sollentuna, SWEDEN, 3 Department of 

Clinical Science, Intervention and Technology, Karolinska University Hospital 

Huddinge and Karolinska Institutet, Stockholm, SWEDEN, 4 Oncology, Pfizer AB, 

Sollentuna, SWEDEN, 5 Department of Urology, University Hospital, and the 

Sahlgrenska Academy, Gothenburg, SWEDEN, 6 Department of Surgical and 

Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, 

SWEDEN 

Background: There is a paucity of efficacy data after first line treatment with SU in 

mRCC. This retrospective register study compared OS in patients treated with SO 

and BSC after first line treatment with SU in Sweden. 

Methods: Three Swedish national health registers were used: the Swedish Cancer 

register (diagnosis and death), the National Patient Register (in-/out-patient data), 

and the Swedish Prescribed Drug Register. 135 patients identified with mRCC, 

diagnosed no later than 2009, were recorded as having received 1st-line treatment 

with SU; 59 patients received SO and 76 patients received BSC. Multivariate analysis 

was performed using the Cox proportional hazards model including estimation of 

adjusted OS. The regression model included the covariates: age, gender, 

nephrectomy, time since diagnosis and metastatic disease, time since mRCC 

diagnoses and start of systemic therapy, geographical region, institutional size, and 

duration of first line SU treatment. Sensitivity analysis with combinations of 

explanatory variables, was performed to test the robustness of the results. 

Results: Patients characteristics differed between the SO and BSC patients, but 

available information did not indicate a clear advantage in favor of any treatment 

arm. OS for patients prescribed with SO was improved compared with OS for BSC 

patients. Including all covariates, median adjusted OS was 9,9 vs. 6,6 months, 

respectively for patients treated with SO and BSC (HR = 0.652, 95% CI: 0.412, 1.030; 

P < 0.067). Sensitivity analysis showed a robust and significant reduction in risk of 

death for patients treated with SO; range of 29-42% (HR: 0,58-0,71). In all models, 

nephrectomy was independently associated with significantly improved OS. Other 

individual covariates were generally not statistically significant, likely due to a low 

number of observations. 

Conclusion: An improved OS for mRCC patients was seen in patients receiving 

SO compared to BSC after first line treatment with SU. Some caution should be 

taken with interpreting the results as confounding due to unmeasured covariates 

may exist. 

Disclosure: P. Sandström: Has had an advisory role for Pfizer, Roche, GSK, Novartis, 

and Bayer, has received honoraria from Pfizer, Roche, bayer, GSK and Novartis and 

has received research funding from Pfizer and Bayer. R. Sandin: Rickard Sandin is an 

employee of Pfizer AB and owns Pfizer stock. J. Kowalski: Jan Kowalski is concultant 

and received compensation from Pfizer for the statistical work for the abstract. 

T. Wahlgren: Thomas Wahlgren is an employee of Pfizer AB and owns Pfizer stock. 

M. Jakobsson: Maria Jakobsson is an employee of Pfizer AB and owns Pfizer stock. 

S. Lundstam: Has had an advisory board role for GSK and Bayer, has received 

honoraria from Pfizerand GSK, and has received research funding from Pfizer. 

B. Ljungberg: Has had an advisory role for Pfizer, GSK, Novartis, Astellas and Bayer, 

and has received honoraria from Pfizer, Novartis, GSK and Bayer. U. Harmenberg: 

Has had an advisory role for Pfizer, Roche, GSK, Novartis, and Bayer, has received 

honoraria from Pfizer, Roche, and Novartis and has received research funding from 

Pfizer, GSK and Novartis. 

849P SUNITINIB RECHALLANGE IN METASTATIC RENAL CELL 

CARCINOMA PATIENTS 

K. Nagyivanyi1 , K. Bíró2 , F. Gyergyay2 , Z. Küronya2 , H. Nemeth2 , L. Géczi2 1 

Chemotherapy C, National Institute of Oncology, Budapest, HUNGARY, 

2 

Chemotherapy C and Clinical Pharmacology, National Institute of Oncology, 

Budapest, HUNGARY 

Background: Sunitinib is an active agent in the first line treatment of metastatic clear 

cell kidney cancer, based on the result of a global phase III study. However, complete 

remission is rarely seen and multiply sequential therapies are used in this patient 

population. Since options in third line setting are limited, we assessed the clinical 

activity of sunitinib rechallenge after failure on other therapies. 

Methods: 323 kidney cancer patients were treated with sunitinib from November 

2005 to January 2012 in our department. Retrospective data were collected for those 

9 patients who we rechallenged with sunitinib failing to at least two previous 

therapies, including sunitinib. Patient characteristics, objective response based on 

RECIST criteria and progression-free survival (PFS) were analysed. Tumor 

assessment was performed every 2nd cycle of sunitinib or every 3 months 

Results: Data of 8 men and 1 woman of median age (at sunitinib challenge 59 years, 

at sunitinib rechallenge 63 years) with metastatic clear cell cancer of the kidney were 

analysed. All patients had nephrectomy prior treatment. Initial treatment with 

sunitinib was associated with a median progression free survival (PFS) of 13,7 

months. Objective response was partial remissions (PR) as best response. At the time 

of re-exposure patients again showed clinical benefit which was associated with a 

median PFS of 6,8 months and consisted of 1 (11%) PR and 5 (55%) disease 

stabilizations. PD was seen in 3 (33%) patients. 

Conclusions: In sunitinib-responsive patients, re-challenge with sunitinib has been 

successful and was well tolerated either after an other TKI or mTOR inhibitor and it 

seems to be a valid option as a third line treatment. 


850P GENETIC POLYMORPHISMS AND SUNITINIB TOXICITY IN 

METASTATIC RENAL-CELL CARCINOMA 

J. Sepulveda Sanchez 1 , C. Farfan 2 , F. Villacampa 3 , G. Velasco 4 , J. Benitez 5 , 

C. Rodriguez 6 , M. Calderon 2 , I. Cañamares 7 , H. Cortes-Funes 1 , 

D.E. Castellano 1 

1 Servicio De Oncologia Medica, University Hosptial 12 De Octubre Medical 

Oncology, Madrid, SPAIN, 2 Medical Oncology, Hospital Universitario 12 de 

Octubre, Madrid, SPAIN, 3 Urology- Urooncology Unit, Hospital Universitario 12 

de Octubre, Madrid, SPAIN, 4 Medical Oncology, Hopital 12 de Octubre, Madrid, 

SPAIN, 5 Clinical Pharmacology & Pharmacogenetics, University of Extremadura 

Medical School & Infanta Cristina University Hospital, Badajoz, SPAIN, 6 Biology, 

Centro Nacional de Investigaciones Científicas, Madrid, SPAIN, 7 Pharmacy, 

Hospital Universitario 12 de Octubre, Madrid, SPAIN 

Background: Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor 

that is approved for the treatment of renal cell carcinoma (RCC). However, several 

patients either do not respond to treatment or they experience significant toxicity. 

Our study aims to find genetic markers of toxicity and efficacy using a commercially 

available DNA microarray genotyping system. 

Methods: 30 patients with newly diagnosed metastatic RCC, from January 2010 to 

May 2011, were evaluated prospectively at Hospital 12 de Octubre (Madrid, Spain). 

Pts received SU in repeated 6-wk cycles of 50 mg/day (4 wks on followed by 2 wks 

off treatment). A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes 

in the pharmacokinetic and pharmacodynamic pathways of drugs were analyzed 


using Drug inCode ® pharmacogenetic service. SNPs in candidate genes, together 

with clinical characteristics were tested univariately for association with the number 

of days of SU treatment until the first reduction of dose, PFS and OS. 

Results: Complete analysis was possible in 25 pts. Pts with CYP1A2*1/*1. a low 

metabolizing genotype, had an increased risk of dose reductions due to toxicity 

compare to allele *1F (Median time to dose reduction: 2.33 months Vs NR; p < 

0.006). Pts with CYP2C19*1/*1, wild type genotype, had an increased risk of dose 

reductions due to toxicity versus other genotypes (Median time to dose reduction: 

2.8 months Vs 9.73 months; P < 0.021). No statistically significant associations were 

observed among drug metabolizing genes and PFS or OS. 

Catechol-O-methyltransferase (COMT) V158M polymorphism was associated with 

PFS and OS (Met/Met carriers median PFS and OS NR; Met/Val pts PFS= 15 

months; OS = 17.2 months and Val/Val pts PFS = 3.3 months; OS= 4.4 months; 

p = 0.005 for PFS and P = 0.003 for OS). 

Conclusions: This preliminary analysis suggests that CYP1A2 and CYP2C19 SNPs 

may be associated with toxicity in patients with RCC treated with SU. As CYP1A2 

and CYP2C19 activity could be affected by a variety of non-genetic factors, if 

confirmed, these results could lead to the necessity of controlling toxic and dietary 

habits of pts treated with SU. SNPs associated with toxicity and survival in this 

preliminary analysis are being validated in an independent cohort of RCC treated 

with SU (García-Donas J, et al. Lancet Oncol 2011) and will be presented. 


851P A PHASE IV MULTICENTER STUDY OF THE EFFICACY AND 

SAFETY OF SUNITINIB AS FIRST-LINE THERAPY IN CHINESE 

PATIENTS WITH METASTATIC RENAL CELL CARCINOMA 

(MRCC) 

S. Qin 1 , J. Jin 2 , J. Guo 3 , J. Wang 4 , F. Zhou 5 , Y. Huang 6 ,X.Ren 7 ,D.Ye 8 , 

Q. Wang 9 ,S.Pan 10 

1 Pla Cancer Center, Nanjing Bayi Hospital, Nanjing, CHINA, 2 Urology, Peking 

University First Hospital, Beijing, CHINA, 3 Department of Renal Cancer and 

Melanoma, Peking University Cancer Hospital and Institute, Beijing, CHINA, 

4 Chinese Academy of Medical Sciences and Peking Union Medical College, 

Cancer Hospital/Institute, Beijing, CHINA, 5 Cancer Center, Sun Yat-sen 

University, Guangzhou, CHINA, 6 Urology, Shanghai Renji Hospital, Shanghai, 

CHINA, 7 Biotherapy, Tianjin Medical University Cancer Institute and Hospital, 

Tianjin, CHINA, 8 Urology, Fudan University Shanghai Cancer Center, Shanghai, 

CHINA, 9 Global Research and Development, Pfizer, Shanghai, CHINA, 10 Clinical 

Statistics, Pfizer, New York, NY, UNITED STATES OF AMERICA 

Background: Based on the effectiveness and safety profile established in two 

single-arm phase II trials and a pivotal phase III trial versus interferon-alfa, sunitinib 

is approved worldwide for advanced RCC. Here we report a single-arm, open-label 

phase IV study to assess use of sunitinib as first-line therapy in Chinese patients with 

mRCC. 

Methods: Treatment-naïve patients aged ≥18 yr with ECOG performance status 0/1 

and histologically confirmed mRCC received oral sunitinib 50 mg/d on the approved 

4-wk-on-2-wk-off schedule. Treatment continued until disease progression, 

unacceptable toxicity, or consent withdrawal. The primary endpoint was 

progression-free survival (PFS). Tumor measurements were performed at screening, 

regular intervals, suspected disease progression, to confirm response, and end of 

treatment/withdrawal. Safety was assessed regularly using NCI CTCAE version 3.0. 

Results: 105 patients received treatment. Mean age was 54.6 yr, 75% were male, and 

mean BMI was 23.9 kg/m 2 . The most common site of baseline metastases was the 

lungs (76%). Median (range) number of treatment cycles completed was 8 (0–27). 

All patients discontinued treatment; reasons included disease progression/relapse 

(63%) and treatment-related AEs (8%). In 105 treated patients, median PFS was 61.7 

wk (14.2 mo; 95% CI: 45.1–106.3 wk) and median overall survival (OS) was 133.4 wk 

(30.7 mo; lower bound of 95% CI: 94.1 wk). In 103 evaluable patients, objective 

response rate (ORR) was 31.1% (95% CI: 22.3–40.9%). Most treatment-emergent AEs 

were grade 1/2 severity and the most common were hand-foot syndrome (64%), 

decreased white blood cell count (52%), fatigue (51%), decreased platelet count 

(51%), diarrhea (49%), and decreased appetite (43%). There were no occurrences of 

treatment-emergent congestive heart failure, left ventricular dysfunction, or 

cardiomyopathy. 

Conclusions: With median PFS of 61.7 wk (14.2 mo) and OS of 133.4 wk (30.7 mo), 

these results compare favorably with those of the phase III trial, while ORR of 31.1% 

is comparable. The AE profile is acceptable and generally similar to that in other 

single-agent sunitinib studies and/or in patients with advanced RCC. 

Disclosure: Q. Wang: Employed by Pfizer Inc. as a clinician.S. Pan: Employed by 

Pfizer Inc. as a Director of Clinical Statistics and holds Pfizer stock. All other authors 



852P PREDICTIVE VALUE OF TIME TO BEST RESPONSE FOR 

EFFICACY MTOR INHIBITORS (MTORI) IN METASTATIC 

RENAL CELL CARCINOMA (MRCC) PATIENTS (PTS) 

R.T. Elaidi 1 , C. Teghom 2 , A. Comte 2 , M. Jebali 2 , J. Fouque 3 , J. Medioni 4 , 

S. Oudard 5 

1 Oncology, Hospital G.Pompidou, Paris, FRANCE, 2 Medical Oncology Service, 

Hopital European George Pompidou, Paris, FRANCE, 3 Pharmacy, Hopital 

Europeen Georges-Pompidou, Paris, FRANCE, 4 Medical Oncology, Georges 

Pompidou Hospital and Rene Descartes University, Paris, FRANCE, 5 Medical 

Oncology Department, Georges Pompidou Hospital and Rene Descartes 

University, Paris, FRANCE 

Background: mTORi usually induce stable disease but some patients present with a 

rapid objective response. In order to predict early those patients susceptible to 

respond to mTORi, we investigated the relationship between time to best response 

and time to progression. 

Methods: Data were retrospectively collected in patients treated with mTORi (Ev: 

everolimus, Tem:temsirolimus) for mRCC in 1 st to 4th line setting at the European 

G. Pompidou Hospital in Paris between 2007 and 2011. Time to best response was 

obtained from CT-scan and objective response assessed according to RECIST 2.0. 

Efficacy was assessed by time to progression (TTP) from initiation of 1 st mTORi 

until disease progression/death. Overall survival (OS) was defined as the time from 

1 st mTOR to death/last contact. Kaplan-Meier estimates with Log-Rank test were 

used for categorical data. Cox model was used for continuous data and hazard ratios 

calculation. Only pts having received at least 1 cycle of mTORi were included. 

Results: Among the 75 pts, 63 presented with a documented response: PR = 6, SD = 

40, PD = 17. 12 pts were excluded for mTORi discontinuation due to toxicity before 

any response assessment or uncertain date of best response. The 63 eligible pts had a 

median age = 61 (range: 28-86), sex ratio = 51/12, Ev/Tem = 37/26. Line setting: 1 st 

=7, 2 nd =17, 3 rd =19, 4 th = 17, 5 th = 3. Median follow-up time = 22.8m. Time to 

progression= 7.3m (95%CI: [4.3–9.1]). Time to best response: SD = 2.3 (0.7–8.2), PR 

= 7.6 (0.7–18.8), PD = 2.1 (0.9–5.0). Time to best response was significantly 

associated with TTP (N = 46, 35 events, HR = 0.86, 95% CI [0.76–0.97], p = 0.014), 

but also OS (N = 46, 31 events, HR = 0.83, 95% CI [0.70-0.98], p = 0.03]), an early 

response leading both to a more rapid progression and being of poor prognosis. 

Conclusions: Time to best response was significantly associated to time to 

progression and overall survival in pts treated with mTORi for mRCC. Given the 

small sample and the rough assessment of RECIST criteria, further study is needed 

to investigate the real value of percentage in tumor decrease at each evaluation and 

velocity of response as a more precise predictive marker of efficacy for these drugs. 

Disclosure: S. Oudard: Advisory board to disclose: Sanofi Aventis, Bayer, Novartis, 

Roche, Pfizer Compensated consultant relatioship to disclose: Novartis, Roche 

Honoraria to disclose: Sanofi Aventis, Bayer, Novartis, Roche, PfizerAll other authors 


853P PRELIMINARY RESULTS OF EARLY ASSESSMENT OF 

RESPONSE WITH PERFUSION-CT IN PATIENT WITH 

METASTATIC RENAL CELL CARCINOMA TREATED WITH 

SUNITINIB 

O. Reig Torras 1 , M.C. Sebastia 2 , I. Victoria 1 , B. Paño 3 , M. Campayo 1 , 

C. Nicolau 3 , B. Mellado 1 

1 Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona, SPAIN, 

2 Radiodiagnóstico, Hospital Clínic de Barcelona, Barcelona, SPAIN, 3 Radiology, 

Hospital Clínic de Barcelona, Barcelona, SPAIN 

Introduction: The fact that renal cell carcinoma (RCC) is highly dependent of 

angiogenesis has allowed the development of antiangiogenic drugs (e.g. sunitinib). 

The assessment of response was based on Response Evaluation Criteria in Solid 

Tumors (RECIST) but in RCC there is no good correlation between response rate 

and survival data. So, it is necessary to adopt new image methods that allow a more 

accurate assessment of response. 

Objectives: To evaluate the pattern of response with perfusion-CT one month after 

the beginning of the antiangiogenic treatment and correlate with the radiologic 

evolution. 

Material and methods: Patients (pts) with metastatic RCC and candidates for 

sunitinib treatment were selected. A volumetric study (21 cm) with perfusion-CT 

(Flash Definition, Siemens, Erlangen, Germany) was done in these patients before 

starting the treatment, 1 and 4 months after the antiangiogenic initiation. We defined 

6 types of response patterns based on changes in density (D), perfusion (P) and size 

(S) of the metastases. 



Results: From March 2011 to May 2012, 16 pts were included. The median age was 

62 years (43-79), the majority of pts had clear cell carcinoma (n = 13, 81.25%) and 

good prognosis (n = 14, 87.5%) based on Motzer criteria. We present the results of 

1-month evaluation: In 12 pts (75%) a decrease of D and P was observed. This 

pattern was correlated with a partial response in 8 pts (66.66%). Two pts (16.66%) 

had a stable disease and two more pts were lost before 4 months CT. This pattern 

was correlated with a partial response in 8 pts (66.66%). Two pts (16.66%) had a 

stable disease and two more pts were lost before 4 months CT. The increase of S, 

associated with a decrease of P and D, was related to haemorrhagic necrosis and it 

should not be confused with disease progression. This pattern was found in only 

2 pts (12.5%). In both cases, the changes in D and P preceded the changes in 

S. Stability of D, P and S was found in only one patient (6.25%) who had a papillary 

variant of MRC. An increase of D and P was related with disease progression in one 

patient (6.25%) and with stability in another case (6.25%). 

Conclusion: The changes in D and P precede the changes in S, and could be 

predictive of response to antiangiogenic treatment. Long-term follow-up data and a 

larger series will be presented at the meeting. 


854P SUNITINIB IN ADVANCED RCC: COST-EFFECTIVENESS 

EVALUATION BASED ON CLINICAL PRACTICE 

M.P. Trojniak 1 , A. Cappetta 2 , A.C. Palozzo 1 , S. Imbevaro 3 , P. Rescigno 3 , 

A. Jirillo 3 

1 Pharmacy Department, Istituto Oncologico Veneto IRCCS, Padova, ITALY, 

2 Oncologia Medica 1, Istituto Oncologico Veneto IRCCS, Padova, ITALY, 

3 Evaluation and Introduction of New Drugs in Cancer Therapy Unit, Istituto 

Oncologico Veneto IRCCS, Padova, ITALY 

The approval trials have established sunitinib, multi-targeted TKI, a standard 

treatment in patients with metastatic RCC. RCTs may fail to show relevant clinical 

benefit in wider population and routine use, as certain patient subtypes are 

under-represented, notably those with poorer prognostic factors and pretreated. The 

data were collected through national registry Onco-AIFA as part of the mandatory 

surveillance. RCC patients receiving sunitinib once daily, on schedule 4/2, between 

2007 and 2011, had been checked prospectively for toxicity, clinical outcomes and 

length of treatment. Based on the difference in effectiveness in PFS between approval 

RCT and clinical practice, a new price adjusted for effectiveness has been calculated. 

A total of 106 patients (64 years, M 70/F 36) were reviewed, 77% had prior 

nephrectomy and 74% were treatment-naïve. At first evaluation we found 28% partial 

responses, 25% stable diseases, 45% progressions and one discontinuation due to 

toxicity. The median PFS and OS were 7 and 11.3 months, respectively. Among 79 

RCC patients (pts) with metastases (mets) at first diagnosis, 63% had lung mets, 21% 

pts had liver mets, 21% had bone mets and 9% had brain mets. Cox regression 

model showed in subgroups analysis significantly worse survival prognosis in males, 

brain and liver mets, ECOG PS > 1, non-clear cell histology and non prior 

nephrectomy. Sorafenib treatment after progression on sunitinib (33% pts) did not 

improved OS. Grade 3 thrombocytopenia, neutropenia, mucositis and HFS caused 

dosage reductions. Effectiveness adjusted price was 3,87 euro/mg as opposed to the 

ex-factory price of 2,46 euro/mg proportionally to the difference of PFS form RCTs 

(11 months) and that form clinical practice oncology (7 months). The results show 

that sunitinib clinical benefit in RCC patients was gained in selected responders, but 

in overall the effectiveness was nearly half of that reported in the approval RCTs. 

Evaluating cost-effectiveness ratio, price should be at least 36% lower than actual 

ex-factory price based on net clinical benefit achieved in real life practice. 

Post-marketing studies in real life practice are required in order to verify both 

effectiveness and safety in general population, testing for external validity of 

randomized trials. 


855P EVEROLIMUS-ASSOCIATED NON-INFECTIONS PNEUMONITIS 

(NIP) IN KOREAN PATIENTS WITH RENAL CELL CARCINOMA 

(RCC) 

J. Kim 1 , T.M. Kim 2 , S. Lee 2 , D. Kim 2 ,Y.Kim 2 , D.S. Heo 2 

1 Internal Medicine, Seoul Nat’l University Hospital, SEOUL, KOREA, 2 Internal 

Medicine, Seoul Nat’l University Hospital, Seoul, KOREA 

Background: Everolimus prolonged survival in advanced RCC patients who failed to 

VEGF inhibitors. However, nearly 13.5 to 30% of patients experienced NIP. 

Although a lower incidence of NIP was observed in Japanese patients from 

RECORD-1, the actual incidence of everolimus-associated NIP was unknown in 

Asian patients. Therefore, this study was undertaken to evaluate 

everolimus-associated NIP in Korean RCC patients treated with everolimus. 

Patients and methods: Total 36 patients were enrolled at Seoul National University 

Hospital including advanced RCC patients who participated in REACT (N = 20) and 

in a trial for non-clear cell RCC (N = 16). NIP associated with everolimus was 

diagnosed using sequential computed tomography (CT) of the chest or 

bronchoscopy after an infectious origin and other causes of radiographic infiltrates 

were excluded. Clinico-pathologic findings were compared between NIP and 

non-NIP groups. Factors associated with NIP were identified using a binary logistic 

regression analysis. 

Results: Overall, 10 (27.8%) of 36 RCC patients treated with everolimus developed 

NIP that was radiologically proven: ≥ grade 3, 6 (16.7%) patients; and grade 1, 4 

(11.1%). Two patients died within 1 week after NIP diagnosis, while 8 recovered 

from NIP after cessation of everolimus (N = 4) and steroid use with drug interruption 

(N = 4). The mean cumulative dose of everolimus was 1,293 mg (range, 590-2420mg) 

at NIP diagnosis. There were no differences in NIP occurrence according to age, 

performance status, subtype (clear vs. non-clear), and underlying lung disease (Ps 

> .05). However, patients who experienced NIP had a better response (9 of 10 

patients) than those without NIP (17 of 26) (P = .015). The response to everolimus 

remained predictive of NIP occurrence in multivariate analysis (P = .018). 

Conclusion: NIP is relatively common (27.8%) in Korean patients with RCC who 

receive everolimus. Response to everolimus is an independent predictor for NIP 

development in advanced RCC patients. 


856P SORAFENIB VERSUS AXITINIB FOR SECOND-LINE 

TREATMENT OF SUNITINIB-REFRACTORY PATIENTS WITH 

ADVANCED RENAL CELL CARCINOMA (RCC) IN THE UNITED 

STATES (US) 

I. Ozer-Stillman 1 , R. Keyser 1 , A. Ambavane 1 , P. Cislo 2 

1 Health Economics, United BioSource Corp., Lexington, MA, UNITED STATES 

OF AMERICA, 2 Global Health Economics and Outcomes Research, Bayer 

HealthCare, Montville, NJ, UNITED STATES OF AMERICA 

Introduction: A Phase III randomized trial, AXIS, investigated the efficacy and safety 

of axitinib (Inlyta®) versus sorafenib (Nexavar®), oral targeted therapies licensed in 

the US for the treatment of advanced RCC. The objective of this study was to 

conduct an economic evaluation of sorafenib versus axitinib in 2nd-line, 

sunitinib-refractory patients with advanced RCC from a US perspective. 

Methods: A survival partition model with 3 health states (progression-free, 

post-progression and death) was constructed to estimate the direct lifetime medical 

costs and clinical outcomes for a patient starting in the 2nd-line from a US 

third-party payer perspective. Patients were apportioned into health states based on 

overall survival and progression-free survival Kaplan-Meier curves from the AXIS 

trial. Patients were assumed to receive cancer medication until progression and best 

supportive care thereafter. Utility values and medical resource use were based on 

literature. Adverse event rates and management were informed by the AXIS trial and 

clinical expert opinion, respectively. Model outcomes included total costs, life-years 

(LYs) and quality-adjusted life-years (QALYs), all discounted at 3% per year. 

Probabilistic sensitivity analysis (PSA) evaluated the model’s robustness. 

Results: Total per-patient costs were estimated to be $127,808 for sorafenib and 

$159,800 for axitinib. The cost difference of $31,992 was mainly attributable to 

higher cost of axitinib compared to sorafenib. Model results suggested that sorafenib 

and axitinib provide similar benefit in terms of LYs and QALYs: sorafenib provided 

an average of 1.440 LYs and 1.016 QALYs and axitinib provided an average of 1.423 

LYs and 1.015 QALYs per patient. The lower total per-patient cost for sorafenib 

versus axitinib finding persisted in the PSA, with 95% of iterations resulting in an 

incremental cost difference between $9,000 and $63,000. 

Conclusions: Results of this modeling study suggest that, for the 2nd-line, 

sunitinib-refractory patients with advanced RCC in the US, treatment with sorafenib 

is a less expensive alternative to axitinib that provides similar benefit in terms of LYs 

and QALYs. 

Disclosure: I. Ozer-Stillman: This research is sponsored by Bayer HealthCareR. 

Keyser: This research is sponsored by Bayer HealthCareA. Ambavane: This research 

is sponsored by Bayer HealthCareP. Cislo: Employed by Bayer HealthCare 

857P PITFALLS OF USING THE COCKCROFT-GAULT FORMULA 

WHEN CALCULATING CARBOPLATIN DOSE FOR THE 

ADJUVANT TREATMENT OF PATIENTS WITH STAGE I 

SEMINOMA 

M. Fehr 1 , T. Geldart 2 , H. Sun 3 , P.D. Simmonds 1 , G. Mead 1 , M. Wheater 1 , 

N. Nagaraj 4 , S. Ellis 2 , R. von Moos 5 , R. Cathomas 6 

1 Medical Oncology, University Hospital Southampton, Southampton, UNITED 

KINGDOM, 2 Medical Oncology, Royal Bournemouth Hospital, Bournemouth, 

UNITED KINGDOM, 3 Coordination Center, Swiss Group for Clinical Cancer 

research (SAKK), Bern, SWITZERLAND, 4 Nuclear Medicne, University Hospital 

Southampton, Southampton, UNITED KINGDOM, 5 Medical Oncology, Kantonal 

Hospital Graubünden, Chur, SWITZERLAND, 6 Medizinische Onkologie, Cantonal 

Hospital Graub, Chur, SWITZERLAND 

Introduction: Single dose Carboplatin (C) AUC7 (7 x glomerular filtration rate 

(GFR) mls/min + 25) is a standard adjuvant treatment option for patients with stage 

I seminoma. Measuring GFR by a nuclear medicine method represents the gold 


Table: 857P 

standard, but is not available in all centres. 24h urine collection may be prone to 

sampling errors. Estimating GFR by the Cockroft-Gault formula (CG) is popular 

amongst oncologists but data supporting its use in this situation is limited. Reduction 

of C dose by 10% in the adjuvant treatment of seminoma stage I is associated with a 

trend for higher relapse rate. 

Methods: Data from 202 consecutive, male patients (median age 39, range 23-68 

years) with stage I seminoma with complete documentation of GFR by TC99m 

DTPA, serum-creatinine, age, height and weight were evaluated. Actual C doses 

(ACD) based on GFR measurement by TC99m DTPA were compared with estimated 

C doses (ECD) based on GFR estimation using CG formula. Differences between the 

ACD and ECD were correlated to age and body mass index (BMI) using Fisher’s 

Exact test, Pearson correlation and linear regression. 

858P ADDITION OF DARBEPOETIN ALFA TO SEQUENTIAL HIGH 

DOSE VIP CHEMOTHERAPY FOR PATIENTS WITH ADVANCED 

METASTATIC GERM CELL CANCER 

J.T. Hartmann 1 , B. Metzner 2 , C. Binder 3 , H. Mergenthaler 4 , O. Rick 5 , 

H.G. Sayer 6 , A. Lorch 7 , W.E. Berdel 8 , C. Bokemeyer 9 , T.C. Gauler 10 

1 Medical Oncology, Christian-Albrechts-Universität zu Kiel, Kiel, GERMANY, 

2 Abt. Onkologie/haematologie, Klinikum Oldenburg, Oldenburg, GERMANY, 

3 Hämatologie und Onkologie, Universitätsmedizin Göttingen, Göttingen, 

GERMANY, 4 Klinik F. Onkologie, Klinikum Stuttgart - KatharinenhospitalKlinik 

f. Onkologie, Stuttgart, GERMANY, 5 Oncology, Klinik Reinhardshoehe, Bad 

Wildungen, GERMANY, 6 Klinik für Innere Medizin II, Universitätsklinikum Jena, 

Jena, GERMANY, 7 Urologische Klinik, Universitätsklinikum Düsseldorf, 

Düsseldorf, GERMANY, 8 Medizinische Klinik A, Universitaetsklinikum Münster, 

Münster, GERMANY, 9 Oncology, Haematology and Bone Marrow 

Transplantation, UKE II. Medizinische Klinik und PoliklinikMedizinische Klinik II., 

Hamburg-Eppendorf, GERMANY, 10 Oncology, University Hospital, Essen, 

GERMANY 

Background: High-dose VIP chemotherapy (HD-VIP) plus ABSCT given as first line 

treatment might be a strategy in patients with advanced germ cell tumors (GCT) 

with poor prognosis. The objective of the trial was to investigate the addition of 

darbepoetin alfa to HD-VIP in order to reduce anemia/red blood cell (RBC) 

transfusions. 

Methods: This was a randomized, open-label multicenter phase 2 study conducted in 

20 hospitals. Darbepoetin 2,25 mcg/kg weekly or 500 mcg Q3W s.c., started with 

HD-VIP (dose level 6), was applied in arm B (arm A: HD-VIP alone). The primary 

objective was freedom from blood transfusions (FFT). Secondary objectives included 

objective remission rate (ORR) after chemotherapy, 24-mos PFS and OS, median 

course of hemoglobin (Hb) levels during 3 HD-VIP cycles as well as drug safety. 

Results: Between 7/2003 and 11/2008 108 pts were allocated to the study, and 102 

were included in the intention-to-treat (ITT) analysis. By March 2012, the median 

follow-up time after randomization was 62 (range, 3–100) mos for surviving patients. 

Localisation of primary was gonadal in 66%, retroperitoneal in 19% and mediastinal 

in 14%s. A favourable treatment outcome (CR/NED/PR m-) in conjunction with 

secondary surgery (n = 76 pts) was achieved in 58% of pts with no difference between 

arms A and B. Overall FFT occurred in 2 pts (4.2%) in arm A and 3 pts (5.6%) in 

arm B, and in 23%/15%/15% and 15%/17%/19% of pts during cycles 1-3, 

respectively. No differences in baseline Hb, severity of anemia, number of RBC 

transfusions and area under the curve of Hb levels during HD-VIP was observed. Pts 

assigned to darbepoetin had similar treatment toxicity compared to those assigned to 

HD-VIP alone. 5-year OS in arm A was 74.0% compared to 63.0% (P = .18) in Arm 

B. 5-year DFS was 60.5% in arm A vs 53.1% in Arm B (P = 0.54). Darbepoetin was 

generally well tolerated with 2 pts discontinuing treatment due to thrombosis. A 

per-protocol (PP) analysis revealed comparable outcomes (OS 74.4 vs 67.5, P = 0.38; 

DFS 60.4 vs 58.3, P = 0.70). 

Conclusions: Based on ITT and PP analysis, the addition of darbepoetin alfa to 

HD-VIP compared to HD-VIP alone does not appear to impact FFT, ORR, and 

survival in poor prognosis GCT pts (NCT00204633). 

Results: 202 patients were included in the correlation analysis and 181 patients in 

the comparison of different subgroups, respectively. Lower BMI and higher age were 

significantly associated with lower ECD, Pearson correlation coefficients 0.59 (p < 

0.001) and –0.36 (p < 0.001), respectively. Tables show potential under- and 

overdosing of C when using CG (ECD expressed as percentage of ACD) in different 

age groups (Exact test p = 0.001) and groups with different BMI (Exact test p = 0.026) 

Discussion: CG significantly underestimates GFR in leaner and older patients. 

According to our data over a third of patients with BMI 20–25 or aged 41–50 would 

be at risk for undertreatment if CG were used routinely. Physicans need to be aware 

of these limitations when using CG to calculate C dose in patients with stage I 

seminoma. 



859P MANAGEMENT OF POST ORCHIDECTOMY STAGE I 

CLASSICAL SEMINOMA: 11 YEAR OUTCOME DATA 

OF A UK REGIONAL CANCER UNIT 


Age (years) 110% ACD BMI (kg/m 2 ) 110% ACD 

21-30 n = 29 14% 4 72% 21 14% 4 20-25 n = 60 35% 21 57% 34 8% 5 

31-40 n = 84 14% 12 68% 57 18% 15 25-30 n = 81 21% 17 69% 56 10% 8 

41-50 n = 68 40% 27 56% 38 4% 3 30-40 n = 33 15% 5 58% 19 27% 9 

A.J. McPartlin 1 ,R.Roy 1 , D. Muskett 2 , M. Witkowski 3 , A.J. Birtle 1 

1 Oncology, Royal Preston Hospital, Preston, UNITED KINGDOM, 

2 Histopathology, East Lancashire Hospitals NHS Trust, blackburn, UNITED 

KINGDOM, 3 Pathology, Morcombe bay Hospital Trust, Morcombe Bay, 


Introduction: Stage I classical seminoma has a 95% 5yr OS. Post-orchidectomy 

treatment options include para-aortic radiotherapy, single agent carboplatin or active 

surveillance. This retrospective study reviewed changing practice and outcomes over a 

11 year period in a regional cancer unit. 

Patients and methods: 188 consecutive patients seen from January 2000 to 

December 2010 were identified. Initial risk factors, treatment received and post 

treatment response were recorded and relapse free and overall survival calculated 

Results: Adjuvant radiotherapy was given to 106 patients (56.4%), adjuvant 

chemotherapy to 56 (29.8%) and active surveillance to 26 (13.8%). Five year RFS by 

group was 97.2%, 89.9% and 76.9%. Fifteen patients relapsed with one dying despite 

third line treatment. Overall CSS was 99.4%. In the period before 2005 tumour size 

and rete testis invasion was documented in 9% of patients and active surveillance 

offered to none. After this time the two risk factors were documented in 82% and 

surveillance offered to 19.5%. Management and outcome stratified by presence of risk 

factor. 

Management 

Adjuvant 

Adjuvant Relapse 

Risk factor Surveillance Chemotherapy XRT rate 

None 

(51 patients) 

47.1% 25.6% 27.4% 7.5% 

One (24) 22.0% 42.0% 36.0% 14.0% 

Two (12) 0% 58.3% 41.7% 12.5% 

Conclusion: This review’s outcomes broadly correspond with published data 

although with increased incidence of relapse following standard adjuvant 

chemotherapy- presumably an artifact of small numbers. Adjuvant treatment 

increases 5yr RFS compared to active surveillance but excellent CSS is achieved after 

either. The vast majority of radiotherapy (85%)was offered in the first two thirds of 

the study period and reflects older practice. The absence of risk factors appears to 

reduce the rate of relapse and should guide treatment decisions. The increasing 

awareness of the importance of assessing risk factors when deciding on treatment is 

reflected in their improved identification in later patients and the increasing use of a 

surveillance strategy in those at lower risk of relapse. 




860P EXPERIENCE WITH FIRST SALVAGE VEIP IN GERM CELL 

TUMOR PATIENTS 

S. Kumar, I.A. Muazzam, N. Muzaffar, N. Siddqui, K. Das 

Medical Oncology, Shaukat Khanum Memorial Cancer Hospital and Reserch 

Centre (SKM), Lahore, PAKISTAN 

Introduction: Despite cisplatin-etoposide based induction chemotherapy, 20-30% of 

germ cell tumor (GCT) patients will require salvage treatment. Cisplatin-ifosfamide 

based salvage regimen produces durable remission at the cost of severe toxicity. In 

this study, we report our experience with first salvage chemotherapy. 

Material and methods: Medical records of patients receiving first salvage 

chemotherapy with vinblastine 0.11mg/kg iv d1-d2, ifosfamide 1200mg/m2 iv d1-d5 

and cisplatin 20mg/m2 iv d1-d5 (VeIP) for GCT was reviewed. Those who continued 

to respond were given more than 4 cycles of chemotherapy. Overall response rate 

(ORR) was assessed by CT and/or MRI scans using WHO response criteria at the 

completion of chemotherapy. 

Results: From April 2006 to April 2011, 350 patients of GCT were treated at Shaukat 

Khanum Memorial Cancer Hospital & Research Center, Lahore (Pakistan). Out of 

those 350 patients, 34 were treated with VeIP chemotherapy as first salvage for 

primary progressive (n = 2) or relapsed (n= 32) GCT (non-seminoma = 30; 

seminoma = 4). Thirty three patients were male and only 1 was female. Median age 

at the time of diagnosis was 26 years (range from 17 to 58) and most (54.3%) had 

poor prognostic features according to IGCCC. Median time of relapse after primary 

induction chemotherapy was 8.067 months (95% CI 6.491 to 9.642). Median of 4 

cycles salvage VeIP were administered (range 1-6 cycles). One patient died during 

salvage chemotherapy due to sepsis. Response assessment was possible in 29 patients. 

ORR was 31.4% (CR = 6.7% and PR = 30.0%), SD in 26.7% and PD in 36.7% 

patients. Surgical resection of residual mass was not possible in any of our patients. 

Three patients were further treated with radiation therapy. Twenty patients continued 

follow up (median 1.93 years; from 0.51 to 4.9) after completion of VeIP. At the time 

of analysis, 6 patients died and 21 were alive. Median PFS after VeIP was 6.033 

months (3.608 to 8.459) while median OS had not yet reached. 

Conclusions: VeiP showed radiologic shrinkage of tumor in one-third of our 

patients and resulted in reasonably long survival of our high risk relapsed patients. 

Our results were comparable with International data. 


861P PERSISTANCE OF CD30 EXPRESSION IN EMBRYONAL 

CARCINOMA (EC) CELLS: A RETROSPECTIVE STUDY IN 

MULTI-RELAPSED OR CHEMOTHERAPY (CT) REFRACTORY 

GERM-CELL TUMOR (GCT) 

P. Giannatempo 1 , A. Necchi 2 , M. Colecchia 3 , B. Paolini 3 , N. Nicolai 4 , D. Raggi 2 , 

M. Catanzaro 4 , D. Biasoni 4 , R. Salvioni 4 , A.M. Gianni 1 

1 Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, 

ITALY, 2 Medical Oncology/Urology Unit, Fondazione IRCCS – Istituto Nazionale 

dei Tumori, Milano, ITALY, 3 Pathology, IRCCS Istituto Nazionale dei Tumori 

Milano, Milan, ITALY, 4 Urology, Fondazione IRCCS – Istituto Nazionale dei 

Tumori, Milan, ITALY 

Background: Despite the high rate of long-term surviving patients (pts) with 

advanced GCT, a small but invariable proportion of them fail to be cured with 

conventional or high-dose CT (HDCT) in the salvage setting, followed by surgery. 

New drugable targets should be set. CD30 is invariably expressed by untreated EC. 

We aimed at evaluating the persistence of CD30-positivity after CT, either in 1st-line 

or in the salvage setting. 

Methods: We retrieved paraffin-embedded tumor samples and clinical data of all 

Institutional pts who had persistence of non-teratoma viable cells after ≥ 1 

platinum-based CT for advanced disease. An exclusive or prevalent EC component 

was required and assessed by morphology and Oct-3/4 staining. The entire set was 

re-assessed for CD30 staining by 2 blinded referral pathologists. CD30-positivity was 

defined as a >80% membranous staining with a diffuse moderate-to-strong intensity. 

Clinical data included histology of tumor primary, GCT primitivity, treatment setting 

and type of surgery. 

Results: In the time-frame 12/1990-04/2012, a total of 245 cases with pure EC or 

mixed GCT residuals were treated at our Institute. Among them, 49 (EC: 16; mixed 

GCT: 33) had complete data and were suitable tissue for review and re-assessment. 

41 pts had retroperitoneal or mediastinal nodes, 18 lung metastases, 3 had either 

liver, bone or brain mets. 33/49 cases (67%) preserved CD30 positivity. 18/33 (55%) 

pts had residual disease after 1st-line CT, 15 (45%) after multiple regimens 

(median 3, range 2–5). 2 pts (6%) had undergone HDCT and 4 (12%) were late 

relapses. 31 pts (94%) had gonadal primary GCT, 1 had a retroperitoneal and 

another a mediastinal primary. After a median follow-up of 35 mos (1-249), 16/33 

(48%) of CD30+ its are alive compared to 9/16 (56%) of CD30- cases, with a HR 

(95%,CI) of 1.93 (0.85–4.37). 

Conclusions: Our results on selected relapsed pts suggest that EC samples retained 

CD30 expression even in the far salvage setting, thus confirming to be a reliable 

target for treatment. This may be representative of a significantly larger patient series. 

A trend towards a poorer prognosis and shorter survival characterized CD30+ cases. 


862P CONTINUOUS INFUSION BLEOMYCIN IN THE BEP REGIMEN: 

A THERAPEUTIC ALTERNATIVE IN THE MANAGEMENT OF 

PATIENTS WITH GERM-CELL TUMORS? 

C. Helissey 1 , L. Védrine 2 , B. Ceccaldi 2 , A. Houlgatte 3 , H. Mullot 4 , 

O. Bauduceau 1 , C. Chargari 2 , C. Massard 5 , K. Fizazi 6 , S. Le Moulec 7 

1 Oncology Radiotherapy, HIA Val de Grace, Paris, FRANCE, 2 Oncology and 

Radiation Oncology, Hôpital d’Instruction des Armées du Val-de-Grâce, Paris, 

FRANCE, 3 Urology, HIA Val de Grace, Paris, FRANCE, 4 Pharmacy, HIA Sainte 

Anne, Toulon, FRANCE, 5 Dept. of Medicine, Institut Gustave Roussy, Villejuif 

Cedex, FRANCE, 6 Department of Medical Oncology, Institute Gustave Roussy, 

Villejuif, FRANCE, 7 Department of Oncology, Val de Grace Hospital, Paris, 

FRANCE 

Introduction: Germ-cell tumors (GCTs) are highly curable with cisplatin-based 

chemotherapy. The BEP chemotherapy (Indianapolis) has become a standard in the 

management of GCT. The aim of this study was to evaluate the long-term side effects 

of a modified BEP regimen, with of bleomycin as a continuous infusion. 

Patients and methods: The military hospital of Val de Grâce has developed a 

modified BEP regimen with the aim of reducing bleomycin-induced toxicity in 

patients with GCTs: bleomycin 15mg/d (d1-5) as an IV continuous injection, 

etoposide 100mg/m2 (d1-5) and cisplatin 20mg/m2 (d1-5), repeated every 3 weeks. 

Survivors were asked in 2011 to participate to this study on late toxicity, including 

assessment of laboratory tests, pulmonary function tests (PFT) and a semen analysis. 

Results: Between March 1998 and January 2009, 68 patients with GCTs received first 

line chemotherapy with this modified BEP. Distribution of patients’ was as following: 

Good prognosis (GP): 42, Intermediate and Poor-prognosis (IPP): 20, stage I with 

High risk factors (HP): 6. The median follow-up was 75 months. The 2-years overall 

survival was 90%. The relapse rate was 13%. The main immediate adverse events 

reported grade III-IV were neutropenia (25%), anemia (1%), thombopenia (1%), 

digestive (6%), infection (4%), decreased DLCO (4%) and tromboembolic events 

(3%). Thirty four patients were assessable for the late toxicity of this regimen (18 

patients in GP, 14 patients in IPP and 2 patients in HP).The 5-years overall survival 

was 82%. The analysis of late side effects revealed one patient developed a 

haematologic malignancy (myelodysplasia).Abnormal PFT was observed in 4 

patients, and only 1 patient was clinically symptomatic. In post-treatment analysis, 

we evaluated the fertility of 30 patients. The fertility was preserved in 22 patients 

(73%). Twenty patients have realized a semen analysis after the chemotherapy, and 

azoospermia was observed in only 3 pts (15%). Among 10 patients remaining, 

5 patients had children after the treatment. 

Conclusion: Using bleomycin as a continuous infusion is feasible and seems to 

produce similar results in terms of response rates and overall survival compared to 

the classic BEP chemotherapy regimen, with a total dose less important than 

standard. These results will be compared with those of conventional BEP 


863P MULTI-CYCLE HIGH-DOSE CHEMOTHERAPY WITH TI-CE 

REGIMEN FOR PATIENTS WITH RELAPSED/REFRACTORY 

GERM CELL TUMORS – A SINGLE INSTITUTION EXPERIENCE 

U. De Giorgi 1 , G. Rosti 2 , B. Kopf 1 , C. Ferrario 1 , G. Papiani 3 , R. De Vivo 4 , 

A.L. Gentile 5 , F. Fabbri 1 , M. Bragagni 1 , D. Amadori 1 

1 Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura 

dei Tumori (I.R.S.T.), Meldola, ITALY, 2 Medical Oncology, Ospedale Civile, 

Treviso, ITALY, 3 Medical Oncology, Ospedale Santa Maria delle Croci, Ravenna, 

ITALY, 4 Medical Oncology, Ospedale San Bortolo, Vicenza, ITALY, 5 Oncologia – 

Asl Teramo, Ospedale Mazzini, Teramo, ITALY 

Background: A large international phase III randomized trial (TIGER study) has 

been recently planned to compare the TI-CE multi-cycle high-dose chemotherapy 

(HDCT) with standard chemotherapy as salvage treatment for patients with relapsed 

germ cell tumors (GCT), but to date there are no reported experiences with this 

regimen other than the phase 2 study from MSKCC (Feldman et al – JCO 2010). We 

present preliminary results of our experience with TI-CE in relapsed/refractory GCT 

patients. 

Methods: From August 2009 to April 2012, patients with relapsed/refractory GCT 

received TI-CE comprising a mobilizing phase with paclitaxel and ifosfamide (TI) 

with leukapheresis of peripheral blood progenitor cells (PBPCs), followed by 3 

HDCT courses with CE (carboplatin AUC 21 and etoposide 1200 mg/m2), with 

PBPC reinfusion. Biosimilar filgrastim (Zarzio®) was used in the HDCT phase for all 

patients after PBPC reinfusion. 

Results: 26 patients (25 males, median age 34) started on TI, but 3 of them did not 

receive CE: two had rapidly progressive symptomatic brain metastases, the third one 


efused HDCT. Of 23 patients, 20 completed the TI-CE regimen and are evaluable, 

while 3 are still receiving treatment. There were no treatment-related deaths. The 

median number of days from the start of CE until recovery of neutrophils to 1,000/ 

mm3 was 14. Twelve (60%) of the 20 evaluable patients achieved a complete 

remission (CR) (5 clinical CR, 5 pathological CR, 2 surgical CR), 5 had 

marker-negative partial remissions lasting 2, 2 + , 2 + , 6+ and 21+ months, and 3 

progressed. After a median follow-up of 13 months (range, 2 to 33+), 15 (75%) 

evaluable patients are continuously progression-free. Of 4 mediastinal primary 

nonseminomatous GCT, 2 achieved a CR (1 sCR and 1 pCR) lasting 7 and 12+ 

months, respectively. 

Conclusions: Our experience confirms that the TI-CE regimen is safe and active, 

with a response rate and a recovery time of neutrophils after CE similar to that 

reported in the MSKCC study. Updated results will be presented at the meeting. 


864P TERATOMA WITH MALIGNANT TRANSFORMATION (TMT) IN 

MEN WITH GERM CELL TUMORS (GCTS): RETROSPECTIVE 

STUDY OF 26 CASES FROM A SINGLE INSTITUTION 

N. Bonnin 1 , H. Boyle 1 , M. Rivoire 2 , C. Bailly 3 ,J.Droz 1 , A. Flechon 1 

1 Medical Oncology, Centre Léon Bérard, Lyon Cedex, FRANCE, 2 Surgery, 

Centre Léon Bérard, Lyon Cedex, FRANCE, 3 Pathology, Centre Léon Bérard, 

Lyon Cedex, FRANCE 

Background: GCT is the most common solid tumor in young men. TMT is a rare 

entity. It occurs in less than 2% of GCTs and is associated with poor prognosis. 

Methods: Between Jan 1993 and Jan 2012, we identified retrospectively all pts with 

GCTs with TMT treated at our institution and report here their characteristics, 

treatment and clinical outcome. 

Results: Twenty six patients (pts) with TMT were identified. Median age at initial 

diagnosis was 26 years (19–48). At initial diagnosis 20 pts had a gonadal primary 

(4 stage (sg) I, 8 sg II and 8 sg III) and 6 a primary mediastinal tumor (PMT). Six 

pts were classified as good prognosis, 5 as intermediate, 11 as poor according to the 

IGCCCG and 4 unknown. A teratoma component was described in the primary 

tumor of 22 out of the 25 pts with non seminomatous GCT. Only one pt had a pure 

seminoma (PMT). Four pts had TMT in their primary, 9 in resected 

post-chemotherapy, residual masses and 13 in a relapse. For these 13 pts, median 

time between initial GCT diagnosis and relapse as a TMT was 31.2 months (mo) 

(12.0-357.6). Various subtypes of TMT were observed: 10 adenocarcinomas, 4 

neuroectodermal tumors, 6 rhadomyosarcomas, 2 leiomyosarcomas, 1 blastema, 1 

angiosarcoma and 2 undefined sarcomas. Except 3 pts with sg I disease, all pts 

received first line cisplatin-based chemotherapy (CT). Surgery of residual masses was 

performed in 20 pts. Nineteen out of the 23 pts had initial clinical or surgical 

complete response (CR), 2 had a marker positive partial response and 2 had 

progressive disease. Iterative surgery for relapse was performed in 9 pts. Eight pts 

received CT according to TMT subtype and one achieved CR. With a median 

follow-up of 76.8 mo (9.5-369.0), 8 pts have died of disease (DOD), 1 has died of 

another cause, 2 are alive with disease and 15 alive without disease. Among the 8 pts 

DOD: 3 pts had PMT, 3 were sg III and 2 sg I; all relapsed and surgery was 

incomplete for 4 pts and 1 was inoperable. There was no difference between subtypes 

of TMT. 

Conclusions: TMT is more frequent in GCTs with extensive disease, PMT and 

relapsed disease. Iterative and complete surgical resection is the mainstay of 

treatment. CT is usually palliative but sometimes gives long responses. 


865P A CYTOKINE AND ANGIOGENIC FACTOR (CAF) ANALYSIS IN 

PLASMA IN TESTICULAR GERM CELL TUMOR PATIENTS 

M. Mego 1 , D. Cholujova 2 , P. Gronesova 2 , M. Pastorek 2 , V. Miskovska’ 3 , 

J. Obertova 1 , V. Usakova 4 , D. Ondrus 3 , S. Spanik 3 , J. Mardiak 1 

1 Medical Oncology, National Cancer Institute, Slovakia, Bratislava, SLOVAK 

REPUBLIC, 2 Cancer Immunology, Cancer Research Institute, Slovak Academy of 

Sciences, Bratislava, SLOVAK REPUBLIC, 3 Medical Oncology, St. Elisabeth 

Cancer Institute, Bratislava, SLOVAK REPUBLIC, 4 Clinical Oncology, 

St. Elisabeth Cancer Institute, Bratislava, SLOVAK REPUBLIC 

Background: Testicular germ-cell tumours (TGCTs) represent a model for the cure 

of cancer. Nonetheless, a small proportion of patients develop disease recurrence. We 

investigated cytokines and angiogenic factors (CAFs) in patients with TGCTs. We 

aimed to link the CAF profile to PFS and select candidate predictive and prognostic 

markers for further study. 

Methods: In this ongoing translational study, plasma from 55 patients with TGCTs 

was collected. The concentrations of 51 plasma CAFs were measured pretreatment 

(n = 47) and on day 22 (n = 30) using multiplex bead arrays (Human Group I and II 

cytokine panels and TGF beta by Bio-Plex 200 system (Bio-Rad Laboratories, 

Hercules, CA). We investigated the association between baseline levels of CAFs and 

clinico-pathological variables. 

Results: We observed elevated level of transforming growths factor beta1 (TGF-b1), 

IL-2Ra, CXCL9, CXCL10, IFN-gama, macrophage inflammatory protein-1b 

(MIP-1b), and platelet-derived growth factor-BB (PDGF-BB) in seminoma patients 

compared to non-seminoma. Patients with poor prognosis according to IGCCCG 

have elevated pretreatment level of beta-nerve growth factor (NGF-b) and stromal 

cell-derived factor-1 (SDF-1a) compared to patients with good/intermediate 

prognosis. Patients with metastatic disease had elevated pretreatment level of stem 

cell growth factor beta (SCGF-b) and PDGF-BB compared to patients with stage I 

disease. 

Conclusions: Using CAF profiling, we revealed differences in subgroups of TGCTs 

patients. We suggest that this platform may provide valuable insights into TGCTs 

biology, and could be useful in identification of new therapeutic targets. 


866P HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS BLOOD 

STEM CELL TRANSPLANTATION IN REFRACTORY/ 

METASTATIC NON-SEMINOMATOUS GERM CELL TUMORS: 

GATA SINGLE CENTER RESULTS 

N. Karadurmus 1 , A.S. Ataergin 1 , G. Erdem 1 , M. Cakar 1 , I. Barista 2 , T. Turker 3 , 

S. Ozaydin 1 , M. Ozturk 1 , F. Arpaci 1 

1 Medical Oncology, Gulhane School of Medicine, Ankara, TURKEY, 2 Medical 

Oncology, Hacettepe UniversityFaculty of Medicine, Ankara, TURKEY, 3 Public 

Helth, Gulhane School of Medicine, Ankara, TURKEY 

Introduction: Some patients with testis cancers do not respond to standard 

combination chemotherapy and high-dose chemotherapy (HDC) with autologous 

stem cell transplantation (OSCT) as salvage therapy can achieve a complete 

remission in these patients. 

Materials and methods: 62 patients that received HDC and OSCT between February 

1993 – December 2011 were retrospectively evaluated. 

Results: Median age was 24 (22-32 years). 56 patients (90.3%) had stage III, 6 (9.6%) 

had stage II disease. Histopathologically, embryonal carcinoma (64%), yolk-sac (24%) 

and choriocarcinoma (23%) were present. The primary tumor location was testis in 

51 patients (82.2%), and 11 patients (17.7%) had extragonadal region origin [6 

patients retroperitoneal (9.6%), 5 patients (8.1%) mediastinal]. Evaluation of 

metastatic focuses was as follows: liver (n = 20, 32.2%), extrahepatic (bone, lung) 

involvement (n = 34, 54.8%) and central nervous system involvement (n = 5, 8.1%). 

Six patients with stage II had refractory-high tumor markers and were treated with at 

least two different lines of chemotherapy, underwent later HDC and OSCT. Two 

patients with stage II and 16 patients with stage III disease underwent further 

RPLND. HDC included ifosfamide, carboplatin, etoposide. Median follow-up was 

39 (6-54) months. Pre-OSCT median AFP, β-HCG and LDH were 176 IU / ml 

(4.9-624), 1090 IU / ml (0.6-72000), 346 IU / ml (126–764), respectively; while on 

3rd month of OSCT median AFP, β-hCG and LDH were 20 IU / ml (4–54), 4 IU / 

ml (0.2-20), 124 IU / ml (102-240), respectively. After HDC, 16 patients (25.8%) 

achieved CR, 21 patients (33.8%) had PR, 8 patients (12.9%) had SD and 17 patients 

(27.4%) had PD. Three-year OS rate was 41%. The median neutrophil and platelet 

engraftment time was 14 days (12–17) and 15 days (13–17). The most important 

treatment toxicity was nephrotoxicity (grade 1/2) (11.2%). 

Conclusions: OSCT with HDC is an effective and curative treatment option in 26% 

of cases of refractory/metastatic germ cell testicular cancers. 


867P EXPERIENCE WITH SINGLE AGENT ADJUVANT 

CARBOPLATIN FOR STAGE I SEMINOMA – A 

RETROSPECTIVE ANALYSIS 


H. Nemeth, Z. Küronya, K. Bíró, I. Bodrogi, L. Géczi 

Chemotherapy C and Clinical Pharmacology, National Institute of Oncology, 

Budapest, HUNGARY 

The cure rate for stage I seminoma is above 99%, and current adjuvant strategies aim 

to maintain this favorable result with less therapy related toxicity. Adjuvant 

therapeutic options include irradiation of the para-aortic lymph nodes, single agent 

carboplatin and surveillance. There is an increased risk of relapse in case of tumor 

size > 4 cm and rete testis infiltration, so as a risk adapted strategy, to patient with 

these risk factors, adjuvant therapy can be advised. We retrospectively analyzed the 

data of our patients, who received adjuvant carboplatin for stage I seminoma in 

order to assess the safety and efficacy of this treatment. From November 2006 till the 

end of 2011, 275 patients were treated or intended to treat with two courses of 

adjuvant carboplatin in the dose of area under the curve 7 after orchiectomy. One 

hundred and thirty two patients (48%) had tumors > 4cm, 131 patients (47.6 %) 

had ≤ 4 cm, and we had no data of 12 patients (4.4%). The tumor invaded the rete 

testis in 103 patients (37.4 %), the rete testis was tumor-free in 70 patients (25.4 %) 

and data was not available in 102 patients (37.2%). We had data for both risk factors 

in 166 patients (60%). Fifty one patients (30.7%) had two risk factors, 72 of them 

(43.3%) had one, and 43 patients (26%) had no risk factors. Ten patients received 



only one course of carboplatin. We experienced grade 3 side effects in 4 patients 

(vomiting, low platelets, neutropenia, deep vein thrombosis). No toxicity of higher 

grade developed. Seven patients relapsed. All relapses occurred in the retroperitoneal 

lymph nodes. In two patients, the retroperitoneal lymph node metastases were 

discovered after the first cycle of carboplatin, so these cases are not considered real 

relapses, but rather the mistake of the initial staging. To conclude, single agent 

carboplatin proved to be a safe and effective treatment. The risk adapted strategy is 

not consistently used in our everyday practice. We aim to improve the quality of the 

initial staging to avoid false stage I assessments. We also have to promote the more 

accurate pathologic examination of the specimens to be able to correctly inform the 

patients on the risk of relapse and thus enable them to make a fully informed 

decision on their adjuvant treatment. 


868 PROGNOSTIC SIGNIFICANCE OF EPIDERMAL GROWTH 

FACTOR RECEPTOR OVEREXPRESSION AND CHROMOSOME 

7 POLYSOMY IN CLEAR CELL RENAL CELL CARCINOMA 

F. Lumachi 1 , D. Santeufemia 2 , F. Pili 3 , S.M. M. Basso 4 ,G.LoRe 5 , G. Miolo 6 , 

G.B. Chiara 4 , M. Ermani 7 , S. Tumolo 2 , P. Rocca Cossu 3 

1 Department of Surgical, Oncological & Gastroenterological Sciences (discog), 

University of Padua, School of Medicine, Padova, ITALY, 2 Medical Oncology, 

S. Maria degli Angeli Hospital, Pordenone, ITALY, 3 Department of Pathology, 

University of Sassari, Sassari, ITALY, 4 Chirurgia 1, S. Maria degli Angeli Hospital, 

Pordenone, ITALY, 5 Oncology, Medical Oncology, Pordenone, ITALY, 6 Centro 

Riferimento Oncologico (cro), Medical Oncology, Aviano, ITALY, 7 University of 

Padua, Department of Neurosciences, Padova, ITALY 

Background: Clear cell renal cell carcinoma (ccRCC) is the most common 

histological subtype of renal cell carcinoma. In patients with ccRCC several 

prognostic markers have been suggested, enclosing epidermal growth factor receptor 

(EGFR) expression and chromosome 7 polysomy (C7p). Cancer cells addicted to 

EGFR bear activated mutations in the EGFR gene, and these mutations are useful in 

predicting susceptibility of ccRCC to EGFR inhibitors. The aim of this study was to 

evaluate the prognostic value of EGFR overexpression and C7p. 

Patients and methods: Archival specimens, coupled with clinical and survival data 

of 34 patients (20 men, 14 women, median age 58, range 42–79 years) who had 

undergone radical nephrectomy for ccRCC were analyzed. Immunohistochemistry 

and fluorescence in situ hybridization (FISH) specimens were sections of 

formalin-fixed paraffin-embedded tissue. EGFR expression was detected as 

membranous and cytoplasmic staining of neoplastic cells > 1%, and a ratio between 

gene/centromeric signals of more than two was considered to indicate gene 

amplification. Mean number of centromeric signals per nucleus was also scored to 

evaluate C7p. The log-rank test was used to examine the relationship between 

gender, EGFR overexpression, C7p and survival. Kaplan-Meyer analysis was 

performed to compare parameters with survival. 

Results: The age did not differ significantly (p = 0.79) between men and women. 

Overall, the median survival was 46 months (range 5-150 months). C7p was 

observed in 21 (61.8%) cases. The log-rank test showed a significantly (p = 0.01) 

shorter survival among men in respect of women. We did not find any relationship 

between survival and membranous (p = 0.32) or cytoplasmic (p = 0.51) EGFR 

overexpression, while C7p significantly (p = 0.02) correlated with survival. Similarly, 

no correlation was found (Cox’s regression) between EGFR overexpression and 

survival (R = 0.41, p = 0.21), while the relationship with gender (R = 0.87, p < 0.01) 

was confirmed. 

Conclusions: In our preliminary study, women with ccRCC had an overall better 

survival than men. EGFR was not a useful predictor of outcome, while C7p may have 

a prognostic significance. 


869 ANGIOGENIC AND SIGNALLING PROTEINS CORRELATE 

RESISTANCE AND SEQUENCE OF TREATMENT IN RENAL 

CELL CANCER 

R. Rosa 1 , V. Damiano 1 , L. Nappi 1 , L. Formisano 1 , F. Massari 2 , A. Scarpa 3 , 

G. Martignoni 4 , R. Bianco 1 , G. Tortora 2 

1 Medical Oncology, University Federico II, Napoli, ITALY, 2 Medical Oncology, 

Azienda Ospedaliera Universitaria Integrata Verona-“Borgo Roma”, Verona, 

ITALY, 3 Patologia e Diagnostica, Universit, Verona, ITALY, 4 Pathology and 

Diagnostics, University of Verona, Verona, ITALY 

Background: The multi-tyrosine kinases inhibitors and the mammalian target of 

rapamycin (mTOR) inhibitors have dramatically changed the management of 

metastatic renal cell carcinoma (RCC). However, a relevant issue in RCC treatment is 

still the lack of a biological and molecular rationale able to establish the most 

effective sequence of the different therapeutic options available. 

Methods: To address this issue, we systematically assessed the effect of different 

agents, alone and in sequence, on the growth, expression and secretion of key 

angiogenic and signalling proteins involved in tumor growth and resistance to 

treatment, in a panel of human RCC cell lines with different VHL status and in 

tumors xenografted in nude mice. 

Results: We demonstrated that sunitinib, sorafenib and everolimus are equally active 

as single agents in inhibiting cell proliferation, signal transduction and VEGF 

secretion, both in vitro and in tumors grown in mice. Pre-treatment of tumor cells 

with sunitinib reduced the response to subsequent sunitinib and sorafenib but not to 

everolimus. Lack by sunitinib of a persistent inhibition of key proteins including 

HIF-1, VEGF and MAPK anticipates onset of resistance in xenografted tumors. After 

first line sunitinib, second line everolimus was more effective than sorafenib or 

sunitinib rechallenge to interfere with critical signalling proteins and VEGF and 

Interleukin-8 secretion, translating into an advantage in the long-lasting inhibition of 

tumor growth and significant prolongation of mice survival. 

Conclusions: Our study demonstrates that angiogenic and signalling proteins predict 

treatment failure with sunitinib and that the use of mTOR inhibitor everolimus in 

second line is substantiated by a persistent control of proteins responsible for RCC 

growth and resistance to treatment. 


870 COMPLIANCE WITH SUNITINIB TREATMENT IN PATIENTS 

WITH RENAL CELL CANCER 

A. De Both 1 , V. Kruse 2 , E. De Coene 2 , N. Clottens 3 , A. Somers 3 , S. van Belle 2 , 

L. van Bortel 4 , S. Rottey 2 

1 Internal Medicine, University Hospital Ghent, Ghent, BELGIUM, 2 Medical 

Oncology, University Hospital Ghent, Ghent, BELGIUM, 3 Pharamcy, University 

Hospital Ghent, Ghent, BELGIUM, 4 Clinical Pharamcy, University Hospital Ghent, 

Ghent, BELGIUM 

Introduction: Sunitinib (SUN) is one of the standard treatment options for 

metastatic renal cell cancer (mRCC). There are several possible reasons for 

non-compliance to the prescribed doses: oral intake of the drug, side effects and the 

existence of multiple dosage forms. Prescribers are not always aware of this 

non-compliance. 

Methods: In Belgium SUN can only be delivered by the hospital pharmacy. This 

allows calculation of the used versus the prescribed dose. Based on these data, the 

minimum number of non-compliant weeks per patient were calculated. 

Results: 34 incident patients were considered, treated in the Ghent University 

Hospital between 2007–2012. The total number of treatment weeks for this patient 

group was 1079 (ranging between 1 and 108 weeks). A total of 850 weeks were 

suitable for analysis. 14 out of these 34 patients (41.2%) had at least one week in 

their treatment period of non-compliance (insufficient number of pills), with the 

percentage of time of treatment non-compliance in these individual patients ranging 

from 2–40 % of the total treatment time, the average being 19 % of the weeks. The 

group with one or more weeks of non-compliance were the patients with the longest 

SUN intake: 47.2 versus 20.8 months of intake. On the other hand 5/34 patients 

(14.7%) received considerably more pills from the pharmacy than their treatment 

regimen warranted. 

Conclusions: In our single-center database of patients treated by SUN for mRCC, we 

demonstrated that over 40% of the patients were possibly non-compliant with their 

prescribed SUN dose. This occurred more frequently in long-term treatment. Given 

the average non-compliance time in this subgroup (19% of the weeks) we can 

conclude that this might significantly influence overall survival and response to 

treatment. We thus advocate a tighter patient follow-up and a control of drug 

prescription and delivery, which could result in detection of non-compliance more 

rapidly. 

Disclosure: S. Rottey: Advisory board Pfizer, Novartis, Bayer, GSK Research grant 

Pfizer, Bayer. All other authors have declared no conflicts of interest. 

872 COMPARATIVE EFFICACY OF SUNITINIB VERSUS SORAFENIB 

AS THE FIRST-LINE TREATMENT FOR PATIENTS WITH 

METASTATIC RENAL CELL CARCINOMA 

S.J. Park1 , J. Lee2 , I. Park2 , K. Park2 , J. Ahn2 , D.H. Lee2 , C. Song3 , J.H. Hong3 , 

C. Kim3 , H. Ahn3 1 2 

Oncology, Asan Medical Center, Seoul, KOREA, Department of Oncology, 

Asan Medical Center, University of Ulsan College of Medicine, Seoul, KOREA, 

3 

Department of Urology, Asan Medical Center, University of Ulsan College of 

Medicine, Seoul, KOREA 

Background: Sunitinib has been recommended as the primary treatment in the 

patients with metastatic renal cell carcinoma (mRCC) among the vascular endothelial 

growth factor tyrosine kinase inhibitor (VEGF TKI). However, there are no published 

clinical data that compared directly the efficacy of targeted agents in the first line 

setting. This study investigated the efficacy and toxicity of sorafenib and sunitinib as 

primary treatment for patients with mRCC. 

Methods: To compare the efficacy and toxicities between sorafenib and sunitinb, 

clinical database was used to identify all patients with mRCC treated with VEGF 

TKIs in Asan Medical Center from April 2005 to March 2011. Among 304 patients, 


we identified 49 and 220 patients who were treated first with sorafenib and sunitinib, 

respectively. 

Results: The patients in the sorafenib group were older than those in the sunitinib 

group (62 vs 56.5 years, p = 0.019). Disease control rate (DCR) of 71% and 74% were 

achieved in sorafenib and sunitinib groups, respectively (p = 0.687). After a median 

follow-up duration of 27.6 months, progression free survival (PFS), time to treatment 

failure (TTF), and overall survival (OS) were not significantly different between the 

groups (sorafenib vs. sunitinib, PFS 8.6 months vs. 9.9 months, p = 0.948; TTF 6.6 

months vs. 7.2 months, p = 0.665; OS; 25.7 months vs. 22.6 months, p = 0.774). 

Patients treated with sorafenib required dose reduction due to toxicities less 

frequently than those treated with sunitinib (37% vs. 54%, p = 0.034). Haematological 

toxicities of grade 3 or 4 were more common in the sunitinib group than in the 

sorafenib group (45% vs. 4%, p < 0.001), as was grade 3 or 4 hypertension although 

this was not statistically significant (14% vs. 4%, p = 0.066). Age (>60 years), duration 

from diagnosis to treatment (


multiple locations. As 1 st line therapy, 24% had cytokine or immunotherapy based 

therapies, 52% sunitinib and 17% sorafenib. The duration of 1 st line therapy was 7.0 

months in median for all patients (including cytokines) and 7.8 and 13.7 months for 

those treated with sunitinib or sorafenib, respectively. 50 patients achieved a second 

line therapy prior to everolimus, 22 patients were treated with sorafenib and 26 

patients with sunitinib dependent on the 1 st line therapy. Most patients treated with 

everolimus in 2 nd or 3 rd line therapy had an ECOG of 1 (49.4%) followed by ECOG 

0 (39.5%) and ECOG 2 (9.9%). The median duration of treatment with everolimus 

was 4.5 months (0.6–22.5), 36% of the patients were more than 6 months on 

treatment with everolimus. Best response was CR in 2.5%, PR in 12% and SD in 47% 

of the patients (CBR 61%). Reasons for discontinuation were PD (72%), intolerance 

(16%), patients request (6%) and others (6%). 77/81 patients (95%) received a further 

therapy after discontinuation of everolimus. The agents administered beyond 

everolimus were sunitinib (29%), sorafenib (29%) and 36% received other therapies 

as temsirolimus, pazopanib or dovitinib. Best reported responses have been CR (1%), 

PR (9%), SD (48%) of the reported patients. 27 patients received an additional 

sequence of therapy (4 th to 5 th line). In summary, these data confirm the results of 

the RECORD-1 trial in clinical practice and demonstrate a clinical benefit of 

therapies beyond everolimus. 58% of the patients were still alive at time of evaluation. 

Disclosure: L. Bergmann: The retrospective analysis was supported by a grant of 

Novartis Pharma. The presenter has been an advisor for Novartis Pharma. V. 

Grünwald: Advisory board Novartis. S. Weikert: Advisory board Novartis. T.C. Gauler: 

Advisary board Novartis. All other authors have declared no conflicts of interest. 

876 EFFICACY AND SAFETY OF SEQUENTIAL USAGE OF 

EVEROLIMUS IN PATIENTS WITH METASTATIC RENAL CELL 

CARCINOMA (MRCC) PREVIOUSLY TREATED WITH 

BEVACIZUMAB +/- INTERFERON (INF) THERAPY. RESULTS 

FROM THE EUROPEAN AVATOR RETROSPECTIVE STUDY 

A. Vuillemin 1 , C. Theodore 2 , L. Jacobasch 3 , J. Schmitz 4 , A. Guillot 5 , 

C. Papandreou 6 , C. Emmanouilides 7 , K. Slimane 8 , M. Ktiouet 8 , T. Nguyen 1 

1 Medical Oncology, Hôpital Jean Minjoz, Besançon, FRANCE, 2 Medical 

Oncology, HÔPITAL FOCH, Suresnes, FRANCE, 3 Hematology/Oncology, Private 

Practice for Hematology/Oncology, Dresden, GERMANY, 4 Hematology/ 

Oncology, Fachklinik Lindenberg/Ried, Lindenberg, GERMANY, 5 Medical 

Oncology, Institut de Cancérologie de la Loire, Saint Priest en Jarez Cedex, 

FRANCE, 6 Department of Medical Oncology, University Hospital of Larissa, 

Larissa, GREECE, 7 Oncology, Iatriko Diavalkaniko Thessalonikis, Thessaloniki, 

GREECE, 8 Oncology, Novartis Pharmaceuticals, Rueil-Malmaison, FRANCE 

Background: EVE (Afinitor®) has demonstrated activity in the treatment of mRCC 

after failure of VEGF-targeted tyrosine kinase inhibitors. However, to this date, there 

is no published data evaluating its activity/safety after failure of first line BEV-based 


Methods: Our non-interventional multicenter international study reports 

retrospective data on EVE in routine use. Eligible patients had mRCC; were given 

EVE after 1 prior first-line systemic therapy with BEV +/- INF. The data were 

provided by each center and centralised. The pts were evaluated for differences in 

baseline characteristics and prognostic factors (PFs) validated in mRCC. 

Results: Here are the results from an interim analysis: 20 sites included 43 pts 

between October 2011 and February 2012. Baseline patient characteristics included 

median age of 69 [38–90] years old; 64.3% male; 97.5% with prior nephrectomy. 

First-line therapy was BEV + INF in 69% of patients, only BEV for 31%. Prognostic 

groups at the time of EVE initiation according to Heng (1) and to MSKCC (2) were 

respectively: (1): good 25%, intermediate 59.4% and poor prognosis 15.6% and (2) 

good 28.1%, intermediate 56.3% and poor 15.6%. Median duration of treatment with 

first line therapy was 7.5 months, it was discontinued for disease progression in 61.9 

% of pts. Median EVE treatment duration with was 5 [3.0–7.0] months. Median 

progression free survival (PFS) has not yet been reached as 15 pts are still receiving 

EVE. Overall response rate was 9.5 % and disease stabilization rate was 50%. At least 

one adverse event (AE) occurred in 73.8 % of pts with 13 serious AEs. All grade 

common AEs were consistent with the toxicity profile of EVE with 31% of stomatitis, 

16.7% of pneumonitis, 31% of fatigue. 

Conclusions: This study provided encouraging results for the activity and safety 

profile of EVE in second line mRCC setting and warrants further investigation after 

1 prior first-line therapy with bevacizumab-based regimen. Final results with mature 

PFS data and median overall survival from initiation of first-line therapy will be 

available in 2013. 

Disclosure: A. Vuillemin: Consulting fees : Novartis, Sanofi-Aventis, Ferring Member 

of Novartis Advisory board Honorarium study NovartisC. Theodore: Research grant 

from Novartis Consulting fees from Novartis Honorarium study NovartisL. 

Jacobasch: Honorarium study NovartisA. Guillot: Member of Novartis Advisory 

board Speaker at Novartis regional meetings Honorarium study NovartisC. 

Papandreou: Participated to advisory boards for NovartisC. Emmanouilides: Research 

grants : Novartis, Pfizer, GSKK. Slimane: Novartis employeeM. Ktiouet: Novartis 

EmployeeT. Nguyen: Honorarium study NovartisAll other authors have declared no 


877 A REVIEW OF RADIOLOGICAL ASSESSMENT RESPONSE IN 

METASTATIC RENAL CELL CARCINOMA TREATED WITH 

ANTIANGIOGENIC THERAPY- ARE WE HITTING THE TARGET? 

T. Montella 1 , D. Herchenhorn 2 

1 INCA, Rio de Janeiro, BRAZIL, 2 Medical Oncology, Brazilian National Cancer 

Institute, Rio de Janeiro, BRAZIL 

Background: Targeted therapy has changed the treatment landsacpe of metastatic 

renal cell carcinoma (RCC) in the last years. However, despite the positive results 

with antiangiogenic drugs in the treatment of metastatic RCC, the evaluation of 

response to these therapies remains undefined. This study aimed to review different 

proposed radiologic methods used for response evaluation with antiangiogenic agents 

in RCC. 

Methods: A no systematic literature review using electronic databases PubMed/ 

MEDLINE, EMBASE, Cochrane Library and LILACS with the terms “renal cell 

carcinoma”, “response criteria” and “targeted therapy” and its variables. 

Results: A total of 53 articles were identified, of which 12 were selected and 41 

excluded. After evaluation of the references of the 12 selected studies, two new 

studies were included. The 14 studies were published from August 2009 to October 

2011, 11 of them using computed tomography as a method of response evaluation, 

one with doppler ultrasound and two others with positron emission tomography. A 

total of 927 patients were studied. The drugs used for analysis in the different studies 

were sunitinib, sorafenib, cediranibe, bevacizumab and interferon alpha; but sunitinib 

and sorafenib are variously present in all studies. The retrospective design was the 

basis for most of the analysis (71%) and endpoints analysed for method comparison 

were time to disease progression (TTP) or progression-free survival (PFS). All studies had 

RECIST as the assessment parameters (control). Proposed new methods of radiographic 

response criteria in this context were present in 11 studies (78%). In 3 studies (21%) only 

one radiologist reviewed the images, in the other at least 2 radiologists participated in the 

evaluation. Most studies evaluated a small number of patients and 8 studies (57%) 

included more than one antiangiogenic drugs in its analysis. 

Conclusion: Antiangiogenic drugs are considered standard therapy in the treatment 

of metastatic RCC. Phase III trials are needed to validate the best radiological 

response criteria in this context, new proposed methods should be incorporated as 

secondary end-points in future prospective trials. 


878 THE ROLE OF NEPHRECTOMY IN METASTATIC RENAL CELL 

CARCINOMA – A SINGLE CENTRE ANALYSIS 

J. Neves 1 , I. Fernandes 2 , J. Ribeiro 2 , D. Macedo 2 , L. Costa 2 

1 Faculty of Medicine, University of Lisbon, Lisbon, PORTUGAL, 2 Oncology 

Division, Santa Maria Hospital (HSM-CHLN), Lisbon, PORTUGAL 

The approval of new therapeutic options has increased the survival of metastatic 

renal cell carcinoma (mRCC) patients (pts). These drugs were mostly studied in pts 

who underwent nephrectomy (Sx) prior to the diagnosis of metastatic disease (MD). 

Sx is also indicated for pts with MD who are suitable and have good performance 

status (PS). The aim of this work is to retrospectively analyse the benefit of Sx in the 

pts with mRCC referred to the Oncology Division at Santa Maria Hospital from 01/ 

2006 to 10/2010. Two groups of pts were defined: pts who had Sx and pts who had 

no Sx. The first group was further divided into pts who had Sx whilst with non-MD 

(SxNMD) and pts who did it whilst with MD (SxMD). With significance set at p = 

0.05 and the aid of IBM® SPSS® Statistics 20, statistical analysis was performed using 

descriptive statistics and Fisher’s exact test. Overall survival (OS) - time from 

diagnosis of MD to death - was plotted using the Kaplan–Meier method and 

compared by log-rank test. The population had 44 pts: 72,7% (n = 32) male, 59,1% 

(n = 26) under 65 years old, 90,9% (n = 40) with Karnofsky PS (KPS) ≥80 and 59,1% 

(n = 26) with clear cell carcinoma. Half were diagnosed with non-MD (NMD) (n = 

22) and progressed to MD in a mean of 45,9 months (m). Thirty-eight pts (86,4%) 

did medical therapy, of those 86,8% (n = 33) had favourable or intermediate risk 

according to the Memorial Sloan Kettering Cancer Center (MSKCC) criteria and 

86,8% (n = 33) did target therapy. Thirty pts underwent Sx (68,2%) and 14 didn’t 

(31,8%). There was no statistical difference between groups regarding gender, age, 

KPS, histology, MSKCC risk and medical therapy. The median OS was 14 and 27 m 

respectively for the no Sx group versus the Sx group (p = 0,027). In the pts who had 

Sx, 21 (70%) were part of the SxNMD group and 9 (30%) of the SxMD group. 

Except for Fuhrman grade (p = 0,022), there was no statistical difference between 

groups regarding gender, age, KPS, histology, MSKCC risk and medical therapy. The 

median OS for SxNMD had not been reached while the median OS for SxMD was 

21 m (p = 0,682). In the population studied there was no difference in OS curves 

between the SxNMD group and the SxMD group. This suggests that Sx has a 

valuable role in pts diagnosed with MD in addition to medical therapy, namely 

target therapy. 



879 TREATMENT OF PATIENTS WITH METASTATIC KIDNEY 

CANCER DURING HAEMODIALYSIS WITH MTOR INHIBITORS 

C. Masini 1 , M. Milella 2 , G. Di Lorenzo 3 , A. Onofri 4 , M. Santoni 4 ,V.Prati 5 , 

M. Nicodemo 6 , P.F. Conte 1 , R. Sabbatini 1 

1 Dept. of Hematology/oncology, Ospedale Policlinico-Modena, Modena, ITALY, 

2 Divisione Di Oncologia Medica A, Istituto Nazionale Tumori Regina Elena, Roma, 

ITALY, 3 Genitourinary Cancer Section and Rare-cancer Center, University 

Federico II, Napoli, ITALY, 4 Clinica Di Oncologia Medica, AO Ospedali Riuniti, 

Università Politecnica delle Marche, Ancona, ITALY, 5 Oncologia Medica A 

Direzione Universitaria, Fondazione del Piemonte per l’Oncologia, Istituto per la 

Ricerca e la Cura del Cancro, Torino, ITALY, 6 Divisione Di Oncologia, Ospedale 

“Sacro Cuore-Don Calabria” Negrar, Verona, ITALY 

Background: On the basis of a few published data, sunitinib and sorafenib can be 

administered safely to patients (pts) with metastatic renal cell carcinoma (mRCC) and 

end-stage renal disease on haemodialysis (HD). Aim of this study was to investigate the 

safety and efficacy of temsirolimus and everolimus in pts with mRCC on HD. 

Patients and methods: between September 2007 and February 2012, 13 pts with 

mRCC undergoing HD were treated with temsirolimus and everolimus in 6 Italian 

Institutions. We retrospectively reviewed the medical records of these pts to evaluate the 

doses of mTOR inihibitors administered, the tolerability and the activity of the treatment. 

Results: Gender: 9 males/4 females; median age: 63 years (range 47–79). All pts were 

undergoing HD, in 7 cases for bilateral nephrectomy; the time interval between the 

start of HD and the start of mTOR inhibitors treatment was 37 months. Everolimus 

was administered at 10 mg daily in 5 pts and at 5 mg in one patient; 7 pts received 

temsirolimus at 25 mg weekly. Everolimus was administered as second-line treatment 

in 4 pts, as third and fourth-line in two pts; temsirolimus was given as first-line 

treatment to 4 pts, as second-line to one patient and as third-line to 2 pts. No 

unexpected adverse event (AE) and no grade 4 haematological or 

non-haematological toxicity were reported. The most common grade 1–2 

non-haematological treatment-related AEs were fatigue (9/13 pts), dyslipidemia (4/13 

pts), oral mucositis in 2/13 pts. A grade 3 dyspnea due to interstitial pneumonia led 

to treatment discontinuation. The most frequent grade 1–2 haematologic toxicity was 

anemia (10/13 pts). None of the patients had to change the number of dialysis 

sessions during mTOR inhibitors treatment. None of the pts experienced an objective 

response while a disease stabilization was observed in 7 pts. At the time of the 

analysis, 7 pts had died due to disease progression. The estimated median 

progression-free survival (PFS) of this cohort of pts was 6.1 months. 

Conclusions: In this small retrospective series of pts the incidence of AEs was as 

expected, and a prolonged PFS was observed. The use of temsirolimus and everolimus 

is not contraindicated in pts with mRCC and severe renal impairment on HD. 


880 LIVER TOXICITY IN PATIENTS WITH METASTATIC RENAL CELL 

CARCINOMA TREATED WITH PAZOPANIB THERAPY 

F.L. Lim 1 , J. Shamash 2 , P. Wilson 2 , T. Powles 3 

1 Department of Medical Oncology, St. Bartholomew’s Hospital, London, 

UNITED KINGDOM, 2 QMUL, Barts Cancer Insititute, London, UNITED 

KINGDOM, 3 Barts Cancer Institute, St Bartholomew’s Hospital QMUL, London, 


Purpose: Pazopanib is a vascular endothelial growth factor receptor, platelet derived 

growth factor receptor and c-kit tyrosine kinase inhibitor, used in the treatment of 

metastatic renal cell carcinoma. It is associated with liver toxicity, although timing 

severity management and consequences of this toxicity is not known. 

Patients and methods: Sequential patients who were treated with 1 st line pazopanib 

for their metastatic renal cancer were identified from a prospective data base. Four 

weekly liver monitoring occurred. Specific protocols for the management of grade 

1-4 toxicity were followed. Toxicity was graded based on the clinical toxicity criteria 

(CTC) grading classification. Patients who developed grade 2 or more toxicity had a 

structured treatment interruption and dose reduction according to local policy. 

Results: 44 patients were identified as having received pazopanib treatment between 

2009-2012. Fifteen (34%) of whom developed liver toxicity as evidence by a raise in 

either bilirubin or alkaline transaminase levels (Maximum CTC grade 1 = 4 (27%), 

2 = 6 (40%), 3 = 5 (33%), 4= 0 (0%), 5 = 0 (0%). Maximum toxicity occurred a 

median 60 days after commencing therapy (range 14 – 83 days). Resolution occurred 

in all but 1 patient (grade 1 or less after stopping the treatment for a median of 3-21 

days. All patients restarted pazopanib. Twelve (80%) of these with a dose reduction. 

Recurrence of raised liver function occurred in 4 (27%) patients (grade 1 = 3 (20%) 

grade 2 = 1 (7%) rechallanged with pazopainb. One patient died of progression of 

disease with a concurrent transaminitis (grade 1). The development of a 

transamitinits was associated with increased progression free survival (HR 0.35 95% 

CI 0.15 - 0.87 p = 0.024). 

Conclusion: Liver toxicity in patients treated with pazopanib occurs in 1/3 of 

patients, usually in the first 12 weeks of therapy. Management is facilitated by blood 

monitoring, temporary cessation of therapy and dose reductions. Transaminitis may 

be associated with improved outcomes. 



881 SEQUENTIAL USE OF TREATMENT OPTIONS IN ADVANCED 

RENAL-CELL CARCINOMA (RCC): A RETROSPECTIVE 

ANALYSIS OF 42 PATIENT CASES 

L. Derosa 1 , L. Galli 2 , A. Fontana 1 , E. Biasco 3 , R. Marconcini 1 , C. Cianci 4 , 

A. Farnesi 1 , F. Orlandi 1 , A. Falcone 5 

1 Polo Oncologico, Azienda Ospedaliero Universitaria S.Chiara, Pisa, ITALY, 

2 Azienda Ospedaliero-universitaria Pisana, Istituto Toscano Tumori, Division of 

Medical Oncology, Pisa, ITALY, 3 Azienda Ospedaliero-universitaria Pisana, Istituto 

Toscano Tumori, 1Division of Medical Oncology, Pisa, ITALY, 4 Istituto Toscano 

Tumori, Azienda Ospedaliero-Universitaria Pisana, Pisa, ITALY, 5 Oncologia, 

Trapianti E Nuove Tecnologie In Medicina, Polo Oncologico - Azienda 

Ospedaliero-Universitaria Pisana - Istituto Toscano Tumori, Pisa, ITALY 

The best sequence of targeted therapy options has not been sufficiently defined and 

also the significance of Cytokine (Cy) in TKI (Sorafenib-So, Sunitinib-Su) and 

mTOR era. The objective of this study was to describe the clinical activity of 

sequence options in 2nd line treatment. 

Methods: Retrospective study of 42 patients receiving TKI or Everolimus (EV) 

treatment after progression on first-line therapy. Sequence of systemic targeted treatment 

consisted of an Cy-TKI-sequence (n = 20; Cy-So, n = 12; Cy-Su, n = 8), TKI-TKI-sequence 

(n=15;Su-So,n=11;So-Su,n=4)oranTKI-EV-sequence(n=7;Su-EV,n=7).We 

measured response to treatment (RECIST 1.0). Progression free survival (PFS) and overall 

survival (OS) were determined using the Kaplan-Meier method. 

Results: Sequence treatment groups did not significantly differ by gender, MSKCC 

prognostic group, or ECOG PS. Best response to 2nd line therapy included CR (Su: 

n = 2, sequential therapy after Cy), PR (So: n = 3, after Cy) and SD (EV: n = 5, after 

TKI; TKI: n = 13; So: n = 5 after Cy, Su: n= 3 after So, n= 5 after Cy). The estimated 

2nd line PFS was 5.2 months for EV and 5.86 months for So sequential therapy after 

Su, 6.56 months for So sequential Cy, 6.7 months for Su sequential therapy after So, 

6.54 months for Su sequential Cy. The estimated OS was longer for the group of 

patients receiving the Cy-TKI-sequence (49.87 months; 95% CI:16–26 for the group 

Cy-So and 40.36 months; 95% CI:16–26 for the group Cy-Su) and TKI-EV sequence 

(40.72 months; 95%CI:32–48) than for those receiving the TKI-TKI sequence So-Su 

(33.36 months, 95%CI:21–62) and Su-So (16.32 months, 95%CI:13–37). However, 

the TKI-TKI group was characterized by a relatively short first-line PFS (6.12 months 

of the Su-So group to 12.37 So-Su compared to 12.8 months of the TKI-EV group) 

which may at least in part explain the observed OS difference. 

Conclusions: Common sequence treatment options may have comparable efficacy in 

terms of PFS and response. The observed differences in OS await further 

confirmation in prospective randomized trials. 


882 USING OF LACTOBACTERIN IN COMBINED TREATMENT OF 

SUPERFICIAL URINARY BLADDER CANCER 

S. Babakulov 1 , S. Navruzov 2 

1 Urology, National Cancer Center of Uzbekistan, Tashkent, UZBEKISTAN, 

2 Coloproctology, National Cancer Center of Uzbekistan, Tashkent, UZBEKISTAN 

Background: to improve combined treatment results of bladder cancer in 

combination with intra-bladder introduction of Lactobacterine. Materials and 

methods: During 2010 and 2011 years in National cancer research centre underwent 

a course of treatment 50 patients with superficial bladder cancer. Those patients 

divided in two groups. Main group 25 patients and control group 25 accordingly. All 

patients had morphological confirmed transitional cell carcinoma with histological 

differentiation G1-G2. Patients before hospitalization had bacteriological study of 

urine. Bacteriological analysis of urine revealed in 14 (28 %) patients presence of - E. 

Coli, in 16 (32 %) – S. aureus, in 12 (24%) - Ps. Aeruginosa and in 8 (16%) 

Klebsiella. After diagnosing of histological structure of the tumor and bladder 

microflora patients undergone transurethral resection of tumor. Patients in control 

group after TUR took intravisical chemotherapy with doxorubicin 50 mg once in a 

week 6 courses. Patients in main group after TUR took intravisical chemotherapy 

with doxorubicin 50 mg once in a week 6 courses and instillation of collibacterin. 

Treatment regimen was everyday instillation of probiotic collibacterin 20 mg (5 

doses) dissolving in 30 ml of 5% glucose solution per day during 5 days. After the 

course patients took 3 mg of dried collibacterin per os during the year. 

Results: It was detected that side effects of intravisical chemotherapy in the form of 

bladder disorders in control group was revealed almost in every case. Patients of 

main group only 2 of them had insignificant pain during urination. Study of one 

year recurrent free survival rate showed that in main group one patient had 

recurrence of cancer in 310 th day after surgery. In control group 8 (32%) patients 

had recurrence in the course of year after operation. 

Conclusions: Using of intravisical probioticotherapy in combined treatment of 

superficial urinary bladder cancer allows to decrease side effects of chemotherapy and 

prolong one year recurrent free survival rate with superficial urinary bladder cancer. 




883 EXPERIENCE OF ORGAN PRESERVATION IN URINARY 

BLADDER 

P. Singh, R.R. Prasad 

Radiation Oncology, Regional Cancer Centre, Indira Gandhi Institute of Medical 

Sciences, Patna, INDIA 

Aims: A retrospective analysis to evaluate the toxicity profile, protocol completion 

rate, tumor response rate, and disease free interval in patients undergoing 

chemoradiotherapy with muscle-invasive bladder cancer. 

Materials and methods: Following transurethral resection of the tumor in patients 

with Stage T2-T4a bladder cancer, induction chemotherapy with paclitaxel and 

cisplatin / gemcitabine and cisplatin was administered for two–three cycles. 

Thereafter radiotherapy with low dose chemotherapy was administered with weekly 

review. Adjuvant chemotherapy based on the neoadjuvant protocol was given to all 

patients. 

Results: Between May 2005 to April 2008 total of 109 patients database were 

available for review. Paclitaxel and cisplatin chemotherapy resulted in mildly grater 

grade 3-4 acute toxicity, mainly gastrointestinal (25%) as compared with 

gemcitabine and cisplatin 17%. Four cycles of adjuvant chemotherapy were 

completed per protocol or with minor deviations in 45% of the patients in both 

the arms together. Late bladder radiation toxicity was evaluated in 47 patients with 

>/ = 2 years of follow-up. Of these 47 patients, 3 experienced self-limited, late 

grade 3 bladder toxicity. The post induction complete response rate was 81% and 

76% in the Paclitaxel and cisplatin group and gemcitabine and cisplatin group 

respectively. At a median follow-up of 39.4 months, the disease free survival was 

69% and 71%, respectively. 

Conclusions: Thesefavorabletumorresponserateswithpossibleincreased 

bladder preservation rates suggest that this treatment regimen deserves further 

study. 


884 DOES THE FINDING OF PROSTATIC MALIGNANCY AT RADICAL 

CISTECTOMY FOR BLADDER CANCER AFFECT PROGNOSIS? 

E. Paze, F. Brusa, L. Ciuffreda, I. Chiappino 

Oncologia Medica 1, Azienda Ospedaliera Universitaria S. Giovanni Battista - 

Molinette, Torino, ITALY 

Radical surgery for muscle invasive male bladder cancer includes prostatectomy. It is 

not rare to find incidental prostate carcinoma at histological examination. Whether 

the two diseases have any relationship and if this finding may affect survival in this 

subset of patients is not well known. We reviewed histological reports in a series of 

110 patients who underwent radical cystectomy for bladder cancer and were seen at 

our Institution between 2005 and 2009. Prostate tissue was found to harbour 

adenocarcinoma in 42 cases, prostatic intraepithelial neoplasia (PIN) in 24 cases and 

benign prostatic hyperplasia, prostatitis or normal findings in the remaining 44 case. 

Incidental prostate adenocarcinomas were between pT1a and pT3b, with Gleason 

scores between 5 and 9. High grade PIN was found in 18 patients and low grade in 6 

pts. We compared patient and disease characteristics in these 3 groups of patients, 

and the results are shown in the table. 

Conclusions: although based on a small number of patients we did not notice any 

difference among patients with and without prostatic malignancy undergoing surgery 

with curative intent for bladder cancer. 3 and 5 yrs overall survival does not seem to 

be different among the three groups of patients. 


Table: 884 

885 THE EFFICACY OF GEMCITABINE-BASED 

CHEMORADIOTHERAPY FOR THE DEFINITIVE TREATMENT OF 

LOCALLY-ADVANCED BLADDER CANCER 

M. Kurt 1 , H. Ozturk 2 , S. Cetintas 3 , E. Kurt 4 , L. Ozkan 3 

1 Radiation Oncology, Uludag University School of Medicine, Bursa, TURKEY, 

2 Radiation Oncology, Yunus Emre Hastahanesi, Eskisehir, TURKEY, 3 Radiation 

Oncology, Uludag University, Bursa, TURKEY, 4 Medical Oncology, Uludag 

University, Bursa, TURKEY 

Aim: The aim of the present study was to investigate the efficacy and the tolerability 

of gemcitabine-based chemoradiotherapy (CRT) for the definitive treatment of 

locally-advanced bladder cancer. 

Methods: Patients with the diagnosis of locally-advanced, transitional cell bladder 

cancer, who had been treated with gemcitabine-based CRT at the Radiation 

Oncology department of the Uludag University between January 2005 and January 

2009, were enrolled in this retrospective analysis. After maximal transurethral 

resection of tumor, three-dimensional radiotherapy (RT) was administered at an 

initial dose of 45 Gy to the primary tumor site plus regional lymphatics followed by 

a 20 Gy boost to the whole bladder with additional 2 cm margins (1.8 Gy daily 

fractions, five days a week). All patients received weekly gemcitabine at a dose of 350 

mg/m2 on Mondays during the course of RT. Response evaluations were performed 

every three months by systoscopic examinations and appropriate radiologic studies. 

Results: A total of 20 patients were entered into the study. There were 18 male and 2 

female with a median age of 72 (range: 40–78). The median disease-free survival was 

35,0 ± 8,2 months (95% CI: 18,7–51,2), and the median overall survival was 

37,0 ± 4,4 (95% CI: 28,3–45,7). Acute treatment-related grade ¾ hematologic 

toxicities were seen in 4 patients (20%). Although 3 patients (15%) exhibited 

grade ½ gastrointestinal toxicities, there were no grade ¾ non-hematologic toxicities. 

Conclusion: Gemcitabine-based definitive CRT seems to be effective and tolerable 

treatment option for the treatment of locally-advanced bladder cancer. 


886 CLINICAL MANAGEMENT OF SMALL-CELL CARCINOMA OF 

THE URINARY TRACT(SCCUT): A 10-YEAR SINGLE-CENTER’S 

EXPERIENCE 

I. Gil-Bazo 1 , E. Castanon Alvarez 1 , L.E. Abella 1 , M.E. Zudaire 1 , A. Castillo 1 , 

E. Arevalo 1 , J.P. Fusco 1 , J.J. Zudaire 2 , R. Martínez-Monge 3 , O.E. Carranza 1 

1 Department of Oncology, Clínica Universidad de Navarra, Pamplona, SPAIN, 

2 Urology, Clínica Universidad de Navarra, Pamplona, SPAIN, 3 Department of 

Radiation Oncology, Clínica Universidad de Navarra, Pamplona, SPAIN 

Purpose: This study aimed to review the clinical features, therapeutic management 

and natural course of patients with small-cell carcinoma of the urinary tract 

(SCCUT), based on our own clinical experience. 

Material and methods: From March 2002 to February 2012 twelve patients were 

diagnosed with SCCUT and started treatment at the Clínica Universidad de Navarra, 

Pamplona (Spain). 

Results: The primary tumor site was prostate in 6/12 (50%), urinary bladder in 5/12 

(41.7%) and kidney in 1/12 (8.3%) of the cases. Overall, 5 patients (41.7%) had 

limited disease (LD) and 7 (58.3%) had extensive disease (ED) at the time of 

diagnosis. Neuron-Specific Enolase (NSE) serum levels were determined in 5 patients 

at onset. In all of them, levels over the upper-limit were observed. Detailed treatment 

information was available in 10 patients, 5 with LD and 5 with ED. LD patients were 

treated in a multimodality fashion. After a median follow-up of 26 months, median 

progression-free survival (PFS) for patients with LD was 22 months (range 7–40). 

No malignancy PIN Adenocarcinoma 

Patients age - mean - median 

(range) 

Bladder cancer: - stage I-II - stage 

68 yrs 71 yrs (37-85) 66 yrs 66 yrs (51-82) 70 yrs 70 yrs (57-84) 

III-IV 12 pts (27%) 32 pts (73%) 9 pts (38%) 15 pts (63%) 15 pts (36%) 27 pts (64%) 

Perioperative treatment for 

bladder cancer 

5 / 35 pts (4 pts unknown) 9/19 pts (5 pts unknown) 10/39 pts (3 pts unknown) 

Perineural and/or lymphovascular 

invasion 

17/43 pts (1 unknown) 8/24 pts 13/39 pts (3 unknown) 

Positive margins after cystectomy 3 pts 5 pts 2 pts 

3 yrs overall survival (CI 95%) 41.6% (24.8-58.4%) 77.2% (57.3-97.0%) 65.6% (48.6-82.7%) 

5 yrs overall survival (CI 95%) 41.6% (24.8-58.4%) 57.9% (21.9-93.8%) 65.6% (48.6-82.7%) 


Median overall survival (OS) was 26 months (range 11–40). Patients showing ED 

mostly received palliative chemotherapy. The overall response rate for chemotherapy 

in this cohort was 75%; 2/4 achieved a complete response, 1/4 a partial response and 

1/4 showed disease stabilization. After a median follow-up of 12 months, the median 

PFS was 11 months (range 3–14). The median OS was 14 months (range 12–38) for 

the ED cohort. However, the differences observed in PFS and OS between LD and 

ED cohorts did not achieve statistical significance. In addition, patients with bladder 

SCCUT showed a statistically significant longer PFS (22 months) compared to 

patients with a prostatic origin (6 months). 

Conclusions: Despite its chemosensitivity, SCCUT showed an aggressive clinical 

course and poor prognosis in our series. Bladder origin SCCUT may have a better 

prognosis than those from prostate origin. NSE serum levels may help to achieve an 

early diagnosis and to provide a proper systemic treatment up-front. 


887 PERI-OPERATIVE CHEMOTHERAPY OR SURVEILLANCE IN 

UPPER TRACT UROTHELIAL CANCER (POUT - CRUK/11/027) - 

A NEW RANDOMISED CONTROLLED TRIAL TO DEFINE 

STANDARD POST-OPERATIVE MANAGEMENT 

A.J. Birtle 1 , R. Lewis 2 , J. Chester 3 , J. Donovan 4 , M. Johnson 5 , R.J. Jones 6 , 

R. Kockelbergh 7 , T.B. Powles 8 , E. Jones 9 , E. Hall 2 

1 Rosemere Cancer Centre, Lancashire Teaching Hospitals NHS Foundation 

Trust, Preston, UNITED KINGDOM, 2 Clinical Trials and Statistics Unit, Institute of 

Cancer Research, Surrey, UNITED KINGDOM, 3 Velindre Hospital, Cardiff 

University, Cardiff, UNITED KINGDOM, 4 School of Social and Community 

Medicine, University of Bristol, Bristol, UNITED KINGDOM, 5 Freeman Hospital, 

Newcastle upon tyne hospitals NHS Trust, Newcastle, UNITED KINGDOM, 

6 Medical Oncology, Beatson West of Scotland Cancer Centre Gartnavel General 

Hospital, Glasgow, UNITED KINGDOM, 7 Department of Urology, University 

Hospitals Leicester, Leicester, UNITED KINGDOM, 8 Department of Medical 

Oncology, St. Bartholomew’s Hospital, London, UNITED KINGDOM, 9 Clincial 

Trials and Statistics Unit, Institute of Cancer Research, Surrey, 


Background: The POUT trial aims to establish whether platinum-based combination 

chemotherapy is superior to surveillance following nephro-ureterectomy with 

curative intent for upper tract transitional cell carcinoma (utTCC). 

Methods: We aim to randomise 345 participants world-wide, over a 5-year period. 

Previous trials of adjuvant chemotherapy for urothelial cancers suggest that potential 

challenges to recruitment include randomisation between “no treatment” vs 

chemotherapy with its potential toxicity, and early identification of eligible patients. 

To support trial design and the development of patient information, we therefore 

conducted a survey of participating UK centres’ current standard treatment and also 

held a dedicated consumer focus group. During the trial set up period, additional 

sites expressed interest in participating and the survey was recirculated; results are 

presented here. 

Results: 26 of 44 UK centres questioned routinely place utTCC patients on 

surveillance following surgery; 18 give chemotherapy if the patient is considered fit 

enough. The 9 respondents who specified chemotherapy regimens give gemcitabine 

and cisplatin or carboplatin, dependent on renal function. All centres discuss patients 

pre-operatively in a multi-disciplinary team meeting, but 6 centres do not routinely 

discuss patients post-operatively. The consumer group welcomed the opportunity for 

utTCC patients to participate in research. They approved of the proposed 

randomisation between surveillance and chemotherapy and supported the use of a 

two stage pre- and post-operative information giving process. 

Conclusions: There is no consensus among UK clinicians regarding optimum 

post-operative treatment of muscle invasive utTCC. The POUT trial offers the 

opportunity to standardise post-operative management of utTCC internationally and 

is supported by urologists, oncologists and consumer representatives from the target 

patient population. The trial design incorporates an initial two-year recruitment 

optimisation phase which includes qualitative research to inform recruitment 

practices. 


888 LAPAROSCOPIC LYMPH NODE RESECTION OF 

POST-CHEMOTHERAPY (POST-CHT) RESIDUAL 

RETROPERITONEAL (RP) TUMOR MASSES IN PATIENTS WITH 

NON-SEMINOMATOUS TESTICULAR GERM-CELL TUMORS 

(NSTGCT) 

I.G. Sullivan 1 , G. Anguera 1 , C. Arqueros 1 , D. Condori 1 , J. Palou 2 , J.A. Peña 2 , 

H. Villavicencio 2 , P. Maroto 1 

1 Medical Oncology, Hospital de Sant Pau, Barcelona, SPAIN, 2 Urology 

Department, Fundacio Puigvert, Barcelona, SPAIN 

Introduction: Resection of post-CHT residual masses, usually located in 

retroperitoneum, is an essential part of the management of NSTGCT. Presently, 


surgical procedure consists in an open unilateral retroperitoneal lymph node 

dissection (RPLND) of a modified template. Laparoscopic procedures have reduced 

morbidity compared to open surgery; in addition, limited lymphadenectomies or 

resection of essentially the residual mass may help to reduce morbidity, although it 

might have a higher incidence of local relapses. 

Objective: To analyze relapse rate, morbidity and toxicity associated to laparoscopic 

RPLND in a series of patients (pts) with NSTGCT of a single tertiary referral center 

with surgeons who have extensive experience in post-CHT resection between January 

2002 and January 2012. 

Results: Retrospective analysis of 14 pts with a median follow-up of 40 months (m). 

Median age at diagnosis was 30 (18-43) years. Pathologic evaluation of the testis 

tumor revealed mixed NSTGCT with teratomatous elements in 11/14, and pure 

teratoma in 1. Embryonal carcinoma was presented in 12/14. Royal Marsden staging 

classification was: IIA: 2; IIB: 7; IIC: 2; IIIB: 1; IVB: 1, IVC: 1. All pts received a 

median of 4 cycles of BEP and had a complete serum marker response after 

induction CHT. RP masses showed a partial response in 8 and stable disease in 6 pts. 

Median size of the post-CHT retroperitoneum masses was 2,5 cm (1-10). Histologic 

examination showed fibrosis or necrosis in 4 (28%) and mature teratoma in 10 (64%) 

pts. Toxicity: Median days of hospitalization were 4 (2-9). 5 pts showed decrease of 

at least 2 points in hemoglobin, not requiring transfusion support. Chylous ascites 

was reported in 1 and an infected RP hematoma in another 1 pts. 2 pts developed 

ejaculatory dysfunction. Only 1 patient experienced an early relapse (3 m after 

RPLND) requiring salvage laparotomy. Pathology of the RP mass in this case 

reported a growing teratoma. All pts are alive and presently free of disease. 

Conclusion: In our series, in a Hospital with long expertise in RP surgery, 

laparoscopic RPLND provided a low rate of complications and RP relapses, reducing 

morbidity comparing to historical series with open procedures. 


889TiP SUNITINIB TREATMENT OF RENAL ADJUVANT CANCER 

(S-TRAC): A RANDOMIZED, DOUBLE-BLIND, PHASE III 

STUDY OF SUNITINIB VS. PLACEBO IN SUBJECTS AT HIGH 

RISK OF RECURRENT RENAL CELL CARCINOMA (RCC) 

A. Ravaud 1 , R.J. Motzer 2 , H. Pandha 3 , M. Staehler 4 , D.J. George 5 , A. Pantuck 6 , 

A. Patel 7 , P. Gerletti 8 , L. Chen 9 , J. Patard 10 

1 Medical Oncology, Hôpital Saint André, Bordeux, FRANCE, 2 Genitourinary 

Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, 

UNITED STATES OF AMERICA, 3 Postgraduate Medical School, Postgraduate 

Medical School, Surrey, UNITED KINGDOM, 4 Department of Urology, University 

of Munich, Munich, GERMANY, 5 Oncology, Duke University Medical Center, 

Durham, NC, UNITED STATES OF AMERICA, 6 Urology, David Geffen School of 

Medicine at UCLA, Los Angeles, CA, UNITED STATES OF AMERICA, 

7 Oncology, Whipps Cross University Hospital, Leytonstone, UNITED KINGDOM, 

8 Pfizer Oncology Business Unit, Pfizer Italia S.r.l., Milan, ITALY, 9 Biostatistics, 

Pfizer, New York, NY, UNITED STATES OF AMERICA, 10 Urology, Paris XI Bicetre 

University Hospital, Paris, FRANCE 

Background: Surgical resection alone may fail to cure high-risk RCC. Progression to 

metastatic recurrence directly relates to tumor size in subjects with clinically localized 

RCC, and 25–50% of subjects treated for localized disease eventually experience 

recurrence. Sunitinib is an oral, multitargeted tyrosine kinase inhibitor approved in 

2006 for the treatment of advanced RCC based on robust results from randomized 

clinical trials. Sunitinib led to metastatic deposit size reduction in most cases. These 

observations provided the rationale to investigate sunitinib as an adjuvant 

monotherapy in subjects at high risk of recurrence after nephrectomy for clinically 

localized RCC. 

Methods: In this ongoing prospective, double-blind, placebo-controlled, randomized, 

multicenter, phase III study, eligible subjects have histologically confirmed, 

predominantly (>50%) clear cell RCC diagnosed by the UISS staging system and are 

at high risk of recurrence, with no evidence of residual macroscopic disease. Within 

12 weeks after nephrectomy, subjects will be randomized 1:1 to oral sunitinib 50 mg/ 

day on Schedule 4/2 (4 weeks on/2 weeks off) or placebo, for 1 year (9 cycles). Dose 

reduction to 37.5 mg/day but not to 25 mg/day is permitted. Subjects will be followed 

for disease recurrence every 12 weeks for 1–3 years and every 6 months thereafter, 

until final analysis. Safety and efficacy data are under review by an independent data 

monitoring committee (IDMC). The primary objective is to compare disease-free 

survival (DFS) for sunitinib vs. placebo based on independent blinded review. Other 

objectives include safety monitoring, overall survival (OS) and health-related quality 

of life (EORTC QLQ-C30 and EQ-5D). 

Results: 900 subjects were screened and 630 have been randomized (reasons for 

screening failures will be presented). The trial is currently ongoing; enrolment closed 

worldwide in April 2011, except in China. 615 subjects have completed 1 year of 

treatment and are in follow-up for DFS and/or OS. At last review, there were no 

unexpected toxicity warnings and the IDMC recommended continuing the trial. 

NCT00375674 

Disclosure: A. Ravaud: Advisory relationship with Pfizer, Novartis, Bayer Schering, 

GSK, Astellas, Dendreon. Honoraria from Pfizer, Novartis, Bayer Schering, Roche, 

GSK, Astellas, Dendreon. Research funding from Pfizer, Novartis. Travel 

renumeration from Pfizer and Novartis. R.J. Motzer: Advisory relationship with 



Pfizer. Research funding from Pfizer. M. Staehler: Advisory relationship with Pfizer. 

Honoraria from Pfizer. Research Funding from Pfizer. Expert testimony for Pfizer. D. 

J. George: Advisory relationship with Pfizer. Honoraria to disclose from Pfizer. 

Research funding from Pfizer. A. Pantuck: Advisory relationship with Pfizer. A. Patel: 

Advisory relationship with Pfizer; Global S-TRAC Steering Committee Member. 

Travel Reimbursement for Steering Committee Meetings. P. Gerletti: Compensated 

employment with Pfizer. Pfizer stock ownership. L. Chen: Compensated employment 

with Pfizer. Pfizer stock ownership. J. Patard: Advisory relationship with Pfizer, Bayer 

and Novartis. Honoraria from Pfizer, Bayer, Novartis and Baxter. All other authors 


890TiP PHASE II STUDY OF EVEROLIMUS (E) IN REFRACTORY 

GERM CELL TUMORS (GCTS) 

M. Reckova 1 , M. Mego 1 , D. Svetlovska 2 , V. Miskovska’ 3 , J. Obertova 1 , 

Z. Sycova-Mila 1 , P. Palacka 1 , J. Rajec 1 , S. Liskova 1 , J. Mardiak 1 

1 Medical Oncology, National Cancer Institute, Slovakia, Bratislava, SLOVAK 

REPUBLIC, 2 Clinical Research, National Cancer Institute, Bratislava, SLOVAK 

REPUBLIC, 3 Medical Oncology, St. Elisabeth Cancer Institute, Bratislava, 

SLOVAK REPUBLIC 

Background: GCTs represent a model for the cure of cancer. Nonetheless, a small 

proportion of patients (pts) develop disease recurrence. Loss of the tumor suppressor 

gene PTEN (phosphatase and tensin homolog) marks the transition from 

intratubular germ cell neoplasias (ITGCN) to invasive GCTs. PTEN inactivation is 

associated with dysregulation of PI3K/Akt pathway and increased mTOR signalling. 

We hypothesize that dysregulation of PI3K/Akt pathway due to PTEN inactivation in 

GCTs suggests that these pts would have greater benefit from mTOR inhibition. 

Methods: In December 2011, National Cancer Institute of Slovakia launched a one 

arm, two-staged phase II study aimed to evaluate the efficacy and toxicity of 

Everolimus (E) in pts with refractory GCTs. The primary objective is to determine 

the efficacy of E in pts with refractory GCTs. The pts with radiological and/or 

serological proof of relapsed GCTs, who were not amenable to be cured by 

chemotherapy or surgery and who failed at least two platinum-based regimens or 

one platinum regimen in case of platinum-refractory disease or primary mediastinal 

non-seminomatous GCTs have been eligible. E has been administered at a dose of 

10mg daily until progression or unacceptable toxicity. 

Results: From December 2011, 4 patients have been enrolled. Median age of patients 

is 28 years. All patients were pretreated with at least 3 cisplatin-based therapy, three 

patients were absolute cisplatin refractory, progressed directly on cisplatin-based 

therapy. We observed no unexpected toxicity. One patient experienced pneumonitis 

grade 3, and dose reduction was needed. One patient progressed early, while three 

patients are still on treatment for 1 + , 3+ and 5+ months. 

Conclusion: Our preliminary data suggests that, Everolimus is safe and well tolerated 

drug in patients with GCT. Efficacy data is warranted. 


891TiP PHASE II STUDY OF DOVITINIB IN FIRST LINE METASTATIC 

OR (NON RESECTABLE PRIMARY) ADRENOCORTICAL 

CARCINOMA (ACC). SOGUG STUDY 2011-03 

S. Hernando 1 , J. Garcia-Donas 2 , M. Climent 3 

1 Medical Oncology, Hospital Universitario Fundación Alcorcón, Alcorcón 

(Madrid), SPAIN, 2 Madrid, Hospital Madrid Norte San Chinarro Centro Integral 

Oncologico Clara Campal, Madrid, SPAIN, 3 Medical Oncology Department, 

Instituto Valenciano de Oncologia, Valencia, SPAIN 

Background: Dovitinib is a novel targeted therapy, that has proven to inhibit, among 

other tyrosin kinases, the fibroblast growth factor receptor (FGFR). Since this 

pathway has been proposed to play a major role in ACC, we aim to test the clinical 

efficacy of dovitinib in this tumor. 

Methods: An open label phase II trial has been designed in patients with advanced 

non-resectable ACC. The objective will be to obtain at least a 15% response rate 

according to RECIST criteria. Taking as a basis the two-stage Gehan model, 15 

patients would need to be included in the first stage to demonstrate a treatment 

efficacy of at least 15%. Sample size calculation was done based on the following 

parameters, probability of Type I error α = 0.05, power of the test (1 - β) = 0.8. Main 

inclusion criteria are advanced non-resectable disease and no prior therapy (other 

than mitotane). Since this is an extremely unfrequent disease 7 institutions, members 

of the SOGUG (Spanish Oncology Genitourinary Group), will participate. The active 

support of a big collaborative group will guarantee candidate patients to be refereed 

to such institutions. So far 6 patients have already been included. Starting January 

26th 2012 recruitment is scheduled to last around 12 months. Updated data 

regarding population of study and toxicity will be presented at the ESMO meeting. A 

translational research, including whole exome analysis, will be performed in order to 

improve our scarce knowledge of ACC. 


892TiP PATIENT PREFERENCE FOR TIVOZANIB HYDROCHLORIDE 

OR SUNITINIB IN THE TREATMENT OF METASTATIC RENAL 

CELL CARCINOMA (MRCC): TAURUS STUDY 

B. Escudier 1 , L. Steelman 2 , D. Cesic 2 , A. Berkenblit 2 

1 Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 2 Oncology, AVEO 

Pharmaceuticals, Cambridge, MA, UNITED STATES OF AMERICA 

Purpose: Tivozanib hydrochloride is a potent, selective, long half-life inhibitor of 

vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. Inhibition of 

VEGF-driven angiogenesis is known to reduce vascularization and tumor growth. 

Currently, sunitinib is most commonly used as first-line treatment in patients with 

mRCC. Previous Phase II and Phase III studies have demonstrated the promising 

efficacy and safety of tivozanib in patients with mRCC. The primary objective of this 

study is to compare patient preferences for tivozanib or sunitinib. Secondary 

objectives include assessing overall safety and tolerability, frequency of dose 

modifications, and quality of life in patients treated with tivozanib and sunitinib. 

Study design: This Phase II, randomized, double-blind, multinational, crossover study 

will compare the preference of mRCC patients for tivozanib or sunitinib as treatment 

for metastatic disease. Recruitment of 160 patients is planned. Patients will be 

randomized to tivozanib 1.5 mg/d for 12 weeks (wks) (Cycle = 3 wks on, 1 wk off) or 

sunitinib 50 mg/d for 12 wks (Cycle = 4 wks on, 2 wks off). After a washout period, 

patients will cross over to the alternate treatment (sunitinib or tivozanib). 

Methods: After 12 wks of treatment, tumor response will be assessed using Response 

Evaluation Criteria In Solid Tumors (version 1.1). Patients are expected to cross over 

to the second treatment for 12 wks; however patients with a significant clinical 

response (defined as >50% tumor reduction or complete response for 

non-measurable disease) will be given the option to continue the first treatment if 

they choose. Patients with Grade 3/4 adverse events may have a dose interruption of 

≤2 wks to manage toxicities, after which they may continue at the same or reduced 

dose; dose reductions to 1.0 mg/d for tivozanib and 37.5 mg/d for sunitinib will be 

allowed. After the second 12-wk period, patients’ drug preferences, based on a 

questionnaire, and their tumor response will be assessed and reviewed prior to a final 

tumor assessment. 

Conclusion: The double-blind design of this study will enable comprehensive 

assessment of patient preference for tivozanib and sunitinib as treatment for mRCC. 

Disclosure: B. Escudier: Board Membership:Pfizer, GSK, Bayer, AVEO, Novartis 

Consultancy: Pfizer, GSK, Bayer, Payment for lectures, service on spkrs bureaus: 

Pfizer, Novartis Payment for development of educational presentations: Pfizer, GSK, 

Bayer, AVEO, Novartis. L. Steelman: Current Employment: AVEO with stock options 

Employment: Novartis until 8/11 Employment: ARIAD until 11/09. D. Cesic: AVEO 

Pharmaceuticals employee with stock options. A. Berkenblit: AVEO Pharmaceuticals 

employee with stock options 


abstracts 

Genitourinary tumors, prostate 

893O SURVIVAL ANALYSIS OF A RANDOMIZED PHASE III TRIAL 

COMPARING ANDROGEN DEPRIVATION THERAPY (ADT) 

PLUS DOCETAXEL VERSUS ADT ALONE IN 

HORMONE-SENSITIVE METASTATIC PROSTATE CANCER 

(GETUG-AFU 15/0403) 

G. Gravis 1 , K. Fizazi 2 , F. Joly Lobbedez 3 , S. Oudard 4 , F. Priou 5 , I. Latorzeff 6 , 

R. Delva 7 , I. Krakowski 8 , B. Laguerre 9 , F. Rolland 10 , C. Théodore 11 , 

G. Deplanque 12 , J.M. Ferrero 13 , D. Pouessel 14 , L. Mourey 15 , P. Beuzeboc 16 , 

S. Zanetta 17 , B. Esterni 18 , M. Habibian 19 , M. Soulie 20 

1 Service d’Oncologie, Institut Paoli Calmettes, Marseille, FRANCE, 2 Department 

of Medical Oncology, Institute Gustave Roussy, Villejuif, FRANCE, 3 Service 

d’Oncologie Médicale, Centre François Baclesse, Caen, FRANCE, 4 Medical 

Oncology Department, Georges Pompidou Hospital and Rene Descartes 

University, Paris, FRANCE, 5 Service d’Onco-Hématologie, Centre Hospitalier Les 

Oudairies, La Roche-sur-Yon, FRANCE, 6 Service de Radiothérapie, Clinique 

Pasteur, Toulouse, FRANCE, 7 Dept. of Medical Oncology, Centre Paul Papin, 

Angers, FRANCE, 8 Unité de Soins Oncologiques de Support, Centre Alexis 

Vautrin, Vandoeuvre-les-Nancy, FRANCE, 9 Service d’oncologie Médicale, Centre 

Eugène Marquis, Rennes, FRANCE, 10 Service d’Oncologie Médicale, Centre 

René Gauducheau, Saint-Herblain, FRANCE, 11 Service d’Onco-Hématologie, 

Hôpital Foch, Suresnes, FRANCE, 12 Service d’Oncologie, Groupe Hospitalier 

Saint Joseph, Paris, FRANCE, 13 Service d’Oncologie Médicale, Centre Antoine 

Lacassagne, Nice, FRANCE, 14 Service d’Oncologie Médicale, Centre Val 

d’Aurelle-Paul Lamarque, Montpellier, FRANCE, 15 Service d’Oncologie Médicale, 

Institut Claudius Régaud, Toulouse, FRANCE, 16 Département d’Oncologie 

Médicale, Institut Curie, Paris, FRANCE, 17 Service d’Oncologie Médicale, Centre 

Georges François Leclerc, Dijon, FRANCE, 18 Biostatistic, Paoli Calmette, 

Marseille, FRANCE, 19 R&D UNICANCER, PARIS Cedex, FRANCE, 20 Chirurgie 

Urologique, Centre Hospitalier Universitaire Rangueil, Toulouse, France 

Background: Androgen deprivation therapy (ADT) is the standard treatment of 

hormone-sensitive metastatic prostate cancer (HSMPC). We performed a phase III 

multicentre trial to compare ADT alone with ADT plus docetaxel (D) in HNMPC. 

Methods: Patients (pts) with HSMPC were randomly assigned to either arm A 

(ADT + D: 75mg/m q3w, up to 9 cycles) or arm B (ADT). The primary endpoint was 

overall survival (OS). The planned number of pts was 378 to detect an improvement 

in OS with a hazard ratio (HR) of 0.62, a power of 80% and an alpha risk of 0.05 

(two-sided test). Secondary endpoints were biological progression-free survival (PFS) 

and clinical PFS. Data on toxicity and quality of life have been previously presented. 

Results: From October 2004 to December 2008, 385pts were included. Baseline 

characteristics were well balanced between the two arms. Median age was 63 years 

(43-84), median PSA was 26.4 ng/ml (0.1-11900), Gleason score was ≥ 8 in 57%. 

Prognostic classification was as follows: good prognosis (49%), intermediate (29%) and 

poor (22%). The majority of pts had metastases at the time of diagnosis (72%), 28% 

developed metastases after local treatment failure. Median number of D cycles was 8 

(range 0-9). The median follow-up was 50 months (mo) [95%CI: 49-54]. At 6 mo, a 

higher PSA response (≥ 50%) in arm A (94% vs 85%, p = 0.0096) and a higher PSA 

progression (≥ 25%) in arm B (10% vs 1%, p = 0.0015) were observed. Biological PFS was 

significantly longer in arm A: 22.9 vs 12.9 mo, HR; 0.72 [95%CI: 0.57-0.91] (p = 0.005). 

Clinical PFS was increase in arm A: 23.46 vs 15.44 mo, HR: 0.75 [95CI: 0.59-0.94] 

(0.015). OS was not significantly different (median: 58.9 mo in arm A and 54.2 mo in 

arm B, HR: 1.01 [95%CI: 0.75-1.36]. The median OS for each prognostic group was 69.1 

[95%CI: 60.9-NR], 46.5 [95%CI: 37.7-NR] and 36.6 [95%CI9: 28.5-58.9] mo respectively 

in the good, intermediate, and poor prognosis groups (p = 0.001), with no difference 

between the two arms. At the cut-off time, 65% of pts from the ADT arm had received 

docetaxel since they developed castrate-resistant prostate cancer. 

Conclusion: Combining docetaxel and ADT improves PFS over ADT alone in pts 

with HSMPC. However, no difference in OS was observed between the two arms. 

Disclosure: G. Gravis: I have expert testimony to disclose: Sanofi Aventis, 

uncompensated. K. Fizazi: Participation to advisory boards and speaker for 

Sanofi-Aventis. F. Joly Lobbedez: advisory board/board of directors position: Sanofi, 

Roche, Pfizer, Novartis, Ferring; compensated consultant relationship: Roche, 

Novartis; honoraria: Sanofi, Roche, Pfizer, Novartis, Ferring, Ipsen,Takeda; travel 

remuneration: ASCO by Novartis, ESMO by Janssen. S. Oudard: I have an advisory 

relationship and honoraria to disclose: Pfizer Oncology, Bayer-Schering Pharma, 

Hoffman La Roche, Glaxo SmithKline, Novartis Pharma, Sanofi Aventis. D. Pouessel: 

Consultant role and honoraria: Sanofi, P. Beuzeboc: Presentations: Avantis, All other 


894O ASSOCIATION OF RADIOGRAPHIC PROGRESSION-FREE 

SURVIVAL (RPFS) ADAPTED FROM PROSTATE CANCER 

WORKING GROUP 2 (PCWG2) CONSENSUS CRITERIA 

(APCWG2) WITH OVERALL SURVIVAL (OS) IN PATIENTS (PTS) 

WITH METASTATIC CASTRATION-RESISTANT PROSTATE 

CANCER (MCRPC): RESULTS FROM COU-AA-302 

C.J. Ryan 1 , M. Morris 2 , A. Molina 3 , J.R. Piulats 4 , P. De Souza 5 ,J.Li 6 , T. Kheoh 3 , 

J.S. de Bono 7 , S. Larson 2 , T. Griffin 3 , S. Matheny 3 , V. Naini 3 , H.I. Scher 2 , 

E. Small 1 

1 Helen Diller Family Comprehensive Cancer Center, University of California, 

San Francisco, CA, UNITED STATES OF AMERICA, 2 Memorial Sloan-Kettering 

Cancer Center, New York, NY, UNITED STATES OF AMERICA, 3 Janssen 

Research & Development, Los Angeles, CA, UNITED STATES OF AMERICA, 

4 Institut Català d’Oncologia de l’Hospitalet, Barcelona, SPAIN, 5 St. George 

Private Hospital, Kogarah, AUSTRALIA, 6 Janssen Research & Development, 

Raritan, NJ, UNITED STATES OF AMERICA, 7 The Institute for Cancer Research 

and Royal Marsden Hospital, Sutton, UNITED KINGDOM 

Background: Imaging data have not been previously rigorously evaluated as an 

intermediate marker in mCRPC due to difficulties in interpretation and flare 

phenomenon. The APCWG2 is intended to continue treatment until clinically 

meaningful progressive disease (PD) occurs. In the prospective phase 3 study COU 

AA 302, we investigated correlation of OS with a novel rPFS endpoint using 

APCWG2 to recognize bone flare and avoid premature discontinuation (DC). 

Methods: 1088 pts were randomized 1:1 to abiraterone acetate (AA) + prednisone (P) 

or placebo (PL) + P. Scans were obtained q 8 wks during first 24 wks, q 12 wks 

thereafter. APCWG2-defined PD by bone scan (BS) required confirmation or 

persistent lesions depending on timing of first detection of PD. All scans were 

investigator reviewed (IR) and blinded central radiologist reviewed (BCRR). 

Continuing blinded study medication after radiographic PD in absence of 

unequivocal clinical PD was allowed. Association of rPFS to OS was evaluated by 

Spearman’s correlation via Clayton copula. 

Results: Positive association between rPFS and OS was observed (r = 0.71). 229 pts 

(AA 108, PL 121) showed progression (wk 8; ≥ 2 bone lesions [BL]) by BCRR. Of 

these, 166 (AA 92, PL 74) did not show PD (follow-up; +≥ 2 BL) (ie, would have 

discontinued prematurely by traditional rPFS assessment). Of these, 47 (AA 33, PL 

14) showed ↓ BL. There was high consistency between BCRR and IR at interim 

analyses (AA, 79%; PL, 76%). 

Interim Analysis 

(IA) Data Cutoff 



AA + P 

(median, 

mos) 

PL + P 

(median, 

mos) HR (95% CI) P 

RPFS 

BCRR IA1 - Dec 2010 NR 8.3 0.43 (0.35, 0.52)


in Johnson & Johnson, have served as an abiraterone consultant/advisory board 

member, and have received consulting fees/grants/travel support fees from Janssen 

Research & Development, All other authors have declared no conflicts of interest. 

895O THE IMPACT OF ABIRATERONE ACETATE (AA) THERAPY ON 

PATIENT-REPORTED PAIN AND FUNCTIONAL STATUS IN 

CHEMOTHERAPY-NAIVE PATIENTS WITH PROGRESSIVE, 

METASTATIC CASTRATION-RESISTANT PROSTATE CANCER 

(MCRPC) 

E. Basch 1 , C.J. Ryan 2 , T. Kheoh 3 , K. Fizazi 4 , C.J. Logothetis 5 , D.E. Rathkopf 6 , 

M.R. Smith 7 , P.N. Mainwaring 8 ,Y.Hao 9 ,T.Griffin 10 ,S.Li 11 , M. Meyers 12 , 

A. Molina 10 , C. Cleeland 13 

1 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, 

NY, UNITED STATES OF AMERICA, 2 Department of Medicine (Hematology/ 

Oncology), UCSF, San Francisco, CA, UNITED STATES OF AMERICA, 

3 Biostatistics, Janssen Research & Development, Los Angeles, CA, UNITED 

STATES OF AMERICA, 4 Cancer Medicine, Institut Gustave Roussy, Villejuif, 

FRANCE, 5 Department of Genitourinary Medical Oncology, The University of 

Texas M. D. Anderson Cancer Center, Houston, TX, UNITED STATES OF 

AMERICA, 6 Department of Medicine, Memorial Sloan-Kettering Cancer Center, 

New York, NY, UNITED STATES OF AMERICA, 7 Department of Genitourinary 

Medical Oncology, Massachusetts General Hospital. Boston, MA, UNITED 

STATES OF AMERICA, 8 Medical Oncology, Hematology & Oncology Clinics of 

Australia, Brisbane, AUSTRALIA, 9 Outcome Research, Janssen Global Services, 

Raritan, NJ, UNITED STATES OF AMERICA, 10 Oncology, Janssen Research & 

Development, Los Angeles, CA, UNITED STATES OF AMERICA, 11 Biostatistics, 

Janssen Research & Development, Spring House, PA, UNITED STATES OF 

AMERICA, 12 Oncology, Janssen Research & Development, Raritan, NJ, UNITED 

STATES OF AMERICA, 13 Symptom Research, MD Anderson Cancer Center, 


Background: AA is a potent, selective androgen biosynthesis inhibitor. The impact 

of AA on pain and functional status was prospectively evaluated as part of a large 

phase 3 trial in asymptomatic/mildly symptomatic, progressive, chemotherapy-naïve 

mCRPC. 

Material and methods: COU-AA-302 is an international, randomized, double-blind 

study of AA (1 g daily) + prednisone (P; 5 mg twice daily) versus placebo (PL) + P in 

chemo-naïve mCRPC patients (pts) with prior medical/surgical castration and 

anti-androgen therapy. Pain and functional status were assessed at baseline and 

throughout study treatment using the BPI-SF and FACT-P questionnaires, 

respectively. For each measure, clinically significant progression/degradation was 

evaluated using prespecified definitions. 

Results: 546 pts were randomized to AA + P and 542 to PL + P, with 

median treatment durations of 13.8 and 8.3 months, respectively. Baseline scores 

were similar between arms; at baseline, mean worst pain intensity score was 1.2 and 

mean pain interference score was 0.7 in each arm. AA + P significantly delayed 

average pain intensity progression, pain interference progression, and degradation 

in FACT-P total score and most subscales, except the social/family well-being 

subscale where there was no difference (Table). A post hoc sensitivity analysis 

using a more stringent definition of worst pain intensity progression 

(ie, a 2 point worsening at 2 consecutive study visits), showed a significant advantage 

of AA + P over PL + P at the 25th percentile (median was not reached for this 

analysis). 

Conclusions: In asymptomatic/minimally symptomatic mCRPC, AA + P delayed 

functional decline and progression of pain compared to PL + P alone. The extent of 

these benefits, coupled with improvements in other efficacy end points [Ryan et al 

ASCO 2012], suggests that AA is a suitable therapy option in this setting. 

Table: 895O 

Disclosure: T. Kheoh is an employee of Janssen R&D and holds stock options of 

Johnson & Johnson.K. Fizazi has the following conflicts of interest to disclose: 

Honoraria: Janssen Consultancy: Janssen, Cougar Biotechnology Speaker/Advisory 

Board Participation: Janssen, C.J. Logothetis has received consultancy fees and travel 

support from Ortho Biotech and research support from Johnson & Johnson, M.R. 

Smith has served as an advisor to Cougar Biotechnology and Johnson & Johnson 

and has received research funding from Cougar Biotechnology and Johnson & 

Johnson. Y. Hao is an employee of Janssen Global Services and holds stock options 

of Johnson & Johnson. T. Griffin is an employee of Janssen R&D and holds stock 

options of Johnson & Johnson. S. Li is an employee of Janssen R&D and holds stock 

options of Johnson & Johnson. M. Meyers is an employee of Janssen R&D and holds 

stock options of Johnson & Johnson. A. Molina is an employee of Janssen R&D and 

holds stock options of Johnson & Johnson. All other authors have declared no 


896O IMPACT OF ENZALUTAMIDE, AN ANDROGEN RECEPTOR 

SIGNALING INHIBITOR, ON TIME TO FIRST SKELETAL 

RELATED EVENT (SRE) AND PAIN IN THE PHASE 3 AFFIRM 

STUDY 

K. Fizazi 1 , H.I. Scher 2 , F. Saad 3 , C.N. Sternberg 4 , K. Miller 5 , P. Mulders 6 , K. Chi 7 , 

E. Basch 8 , M. Hirmand 9 , J.S. de Bono 10 

1 Department of Cancer Medicine, Institut Gustave Roussy, University of Paris 

Sud, Orsay, France, Villejuif, FRANCE, 2 Genitourinary Oncology Service, Sidney 

Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering 

Cancer Center, New York, NY, USA, New York, NY, UNITED STATES OF 

AMERICA, 3 Department of Surgery, University of Montreal Hospital Center, 

Montreal, QC, CANADA, 4 Depatment of Medical Oncology, San Camillo Forlanini 

Hospital, Rome, ITALY, 5 CC 8: Chirurgische Medizin, Klinik für Urologie, Charité - 

Universitätsmedizin Berlin, Berlin, GERMANY, 6 Department of Urology, Radboud 

University Nijmegen Medical Centre, Nijmegen, NETHERLANDS, 7 Department of 

Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, BC, 

CANADA, 8 Departmentgenitourinary Cancer, Memorial Sloan Kettering Cancer 

Center, New York, NY, UNITED STATES OF AMERICA, 9 Department of Clinical 

Development, Medivation, Inc., San Francisco, CA, UNITED STATES OF 

AMERICA, 10 Division of Clinical Studies, The Institute of Cancer Research, 

Sutton, UNITED KINGDOM 

Background: Enzalutamide-proposed INN (ENZA, MDV3100) inhibits androgen 

binding to AR, AR nuclear translocation, and AR association with DNA. The 

AFFIRM trial (NCT00974311) demonstrated that ENZA increased survival by 4.8 

mo (P

and week 13 BPI-SF Q3 scores), 28% ENZA and 39% placebo pts (P = 0.0018) had 

pain progression assessed by pt diaries (increase over baseline in mean pain score). 

Median time to pain progression (confirmed increase in FACT-P score of “I have 

pain”) was not yet reached vs 13.8 mo for ENZA and placebo (P = 0.0004, HR 0.56). 

There was a mean reduction in pain severity (average of 4 severity items of the 

BPI-SF) of 0.65 favoring ENZA (P


899PD ASSOCIATION OF BASELINE CORTICOSTEROID WITH 

OUTCOMES IN A MULTIVARIATE ANALYSIS OF THE PHASE 

3 AFFIRM STUDY OF ENZALUTAMIDE (ENZA), AN 

ANDROGEN RECEPTOR SIGNALING INHIBITOR (ARSI) 

H.I. Scher 1 , K. Fizazi 2 , F. Saad 3 , K. Chi 4 , M. Taplin 5 , C.N. Sternberg 6 , 

A.J. Armstrong 7 , M. Hirmand 8 , B. Selby 9 , J.S. de Bono 10 


New York, NY, UNITED STATES OF AMERICA, 2 Department of Cancer 

Medicine, Institut Gustave Roussy, University of Paris, Villejuif, FRANCE, 

3 Department of Surgery, University of Montreal Hospital Center, Montreal, QC, 

CANADA, 4 Oncology, Vancouver Cancer Centre, University of British Columbia, 

Vancouver, BC, CANADA, 5 Medical Oncolgy, Dana-Farber Cancer Institution, 

Boston, MA, UNITED STATES OF AMERICA, 6 Medical Oncolgy, San Camillo 

Forlanini Hospita, Department of Medical Oncology, Roma, ITALY, 7 Medical 

Oncology, Duke Comprehensive Cancer Center and the Duke Prostate Center, 

Durham, NC, UNITED STATES OF AMERICA, 8 Clinical Development, Medivation, 

San Francisco, CA, UNITED STATES OF AMERICA, 9 Department of Clinical 

Development, Medivation, Inc., San Francisco, CA, UNITED STATES OF 

AMERICA, 10 Division of Clinical Studies, Institute of Cancer Research Royal 

Marsden Hospital NHS Foundation Trust, Sutton, UNITED KINGDOM 

Background: ENZA-proposed INN (MDV3100) increased median survival by 4.8 

mo (P

Working Group (PCWG)-2 guidelines recommend time to clinical or radiographic 

event endpoints, and discouraged use of endpoints using PSA changes. We 

investigated the association of progression defined by PCWG-2 guidelines and overall 


Methods: Two trials were analyzed: CS-205, a randomized phase II trial (n = 221) 

comparing first-line docetaxel-prednisone (DP) plus AT-101 or placebo, and 

SUN-1120 (n = 873), a phase III trial comparing prednisone plus sunitinib (SP) or 

placebo (PP) following docetaxel-based chemotherapy. Both trials continued 

therapy until progression defined by PCWG-2 criteria and OS was the primary 

endpoint. OS was derived by the Kaplan-Meier method. Cox proportional hazards 

regression models were used to estimate the effect of progression on OS. Landmark 

analyses at 2-month intervals compared patients with prior progression with those 

without progression. Sub-analyses compared patients removed from trial for 

progression vs. other reasons and examined the association of type of progression 

with OS. 

Results: Patients who had previously progressed had an increased risk of death. 

In CS-205, the hazards ratio (HR) ranged from 2.31 to 3.43 between landmark 

times of 6 to 12 months and in SUN-1120 HR was 2.75 to 5.21 between 

landmark times from 2 to 8 months. Median OS was 5.5 versus 14.4 months in 

CS-205 beyond month 6 and 7.1 versus 16.1 months in SUN-1120 beyond 

month 2 for those with/without prior progression. The types of progression 

associated with OS varied between the trials. Patients removed from study due to 

progression (excluding death) had a significantly worse OS than those coming off 

for other reasons (HR: 1.90, 95% CI: 1.26-2.87 in CS-205 and HR: 1.23, 95% CI: 

1.02-1.48 in SUN-1120). 

Conclusions: Progression by PCWG-2 criteria was significantly associated with 

decreased OS in patients receiving first-line docetaxel-based chemotherapy or 

post-docetaxel therapy. Further validation will facilitate the employment of PCWG-2 

defined progression as an intermediate endpoint. 

Disclosure: G. Sonpavde: Research support to institution from Ascenta Therapeutics 

and Pfizer, Inc, B.A. Wood: Employee of Ascenta Therapeutics, S. Wang: Employee 

of Pfizer, Inc, J. Paolini: Employee of Pfizer, Inc, M. Lechuga: Employee of Pfizer, 

Inc, M.R. Smith: Research support to institution from Pfizer, Inc, M.D. Michaelson: 

Research support to institution from Pfizer, Inc, All other authors have declared no 


902P PREVALENCE OF NON-METASTATIC 

CASTRATION-RESISTANT PROSTATE CANCER IN EUROPE 

A. Liede 1 , O. Günther 2 , B. Bennett 3 , S. Wong 3 

1 24-2-A, Amgen Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA, 

2 Center for Observational Research, Amgen Ltd, Uxbridge, UNITED KINGDOM, 

3 Oncosight, Plan A, Inc., Mountain View, CA, UNITED STATES OF AMERICA 

Background: Non-metastatic (M0) castration-resistant prostate cancer (CRPC) is a 

growing public health burden that has not been adequately quantified. The increased 

incidence of prostate cancer (PC) in Europe in the last two decades is a result of 

widespread prostate-specific antigen (PSA) screening, and associated with declines in 

mortality and improved survival as more men are diagnosed with M0 disease. A 

proportion of men with M0 PC will receive medical or surgical androgen deprivation 

therapy (ADT). Many ADT-treated men eventually relapse to develop M0 CRPC, 

characterized by rising PSA without evidence of metastases while on ADT. We report 

results of a model to estimate the prevalence of M0 CRPC in key populations in 

Europe. 

Methods: The model uses age-specific incidence and survival data from 

population-based national cancer registries to estimate 5-, 10-, and 20-year limited 

duration prevalence of PC and M0 PC in each country, each year from 2008 to 2026. 

ADT rates for M0 PC by country reported by the literature and IMS Oncology 

Analyser and disease relapse and progression rates from the literature are applied 

to estimate prevalence of ADT-treated and M0 CRPC subgroups. 

Results: For EU-5 countries (France, Germany, Italy, Spain, and UK), the model 

projects that 5-year prevalence of PC will increase from approximately 1.0 million in 

2012 to 1.3 million in 2026 as a result of wider adoption of PSA testing and aging of 

the populations. M0 PC, which comprises about 85% of total PC 5-year prevalence, 

will increase from approximately 0.8 million in 2012 to 1.0 million by 2026. In 2012, 

prevalence of M0 CRPC (4-7% of total PC, depending on ADT use in the M0 

setting) in EU-5 is estimated to reach up to 70,000 with a projected increase to 

110,000 patients by 2026. 

Conclusion: This model provides the first understanding of how many men in 

Europe are living with M0 CRPC. Although M0 CRPC represents a small subset of 

the PC population, the model predicts an increase in the prevalence of M0 CRPC 

over the next 14 years. As men with M0 CRPC have an increased risk of developing 

metastases (particularly to bone) resulting in a shortened lifespan, these findings 

highlight the need for clinical trials to establish standards of care for these patients, 

and for new therapeutic options. 

Disclosure: A. Liede: Employed by and own stock in Amgen Inc. The study was 

funded by Amgen Inc.O. Günther: Employed by Amgen Ltd and own stock in 

Amgen. The study was funded by Amgen Inc. B. Bennett: Consultant at Plan A, Inc. 

S. Wong: Consultants at Plan A, Inc. 


903P IMPROVED SURVIVAL IN PATIENTS WITH METASTATIC 

CASTRATION RESISTANT PROSTATE CANCER (MCRPC) 

TREATED ON CLINICAL TRIALS 

C. Pezaro, A.G. Omlin, D. Mukherji, S. Sandhu, D. Bianchini, A. Mulick Cassidy, 

G. Maier, D. Olmos, G. Attard, J.S. de Bono 

Prostate Targeted Therapy Group, The Royal Marsden NHS Foundation Trust 

and Institute of Cancer Research ICR, Sutton, UNITED KINGDOM 

Background: Median overall survival (mOS) in patients (pts) with mCRPC was 

13-16 months (m) in the pre-docetaxel era. These data, obtained from clinical trials, 

were used to construct currently available prognostic nomograms. We hypothesise 

that these models no longer reflect survival. Pts and physicians urgently require 

updated prognostic data on which to base management decisions. 

Methods: Pts with mCRPC treated on Phase I-III and expanded access trials at our 

institution were identified and data retrospectively collected. Predicted survival by 

Halabi and Smaletz nomograms were compared to calculated survival using 

Kaplan-Maier analysis. Cox model multivariate (MV) analysis used variables at 

referral, including performance status (PS), Gleason (GS), prostate specific antigen 

(PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), hemoglobin (Hb), 

visceral disease and albumin. 

Results: Between 2003 and 2011, 442 CRPC pts were treated on clinical trials. At 

diagnosis median age was 62 years (y; 41.8 – 82.7) and 243 (55.0%) had metastatic 

disease. Median interval from diagnosis to CRPC was 2.8y (0.2 – 21.7). At referral 

259 pts (58.6%) were chemotherapy-naïve. Halabi and Smaletz models predicted 

mOS from referral in chemo-naïve pts of 21m and 17m respectively, however the 

observed mOS was 32m (95%CI 29– 38). Survival from CRPC was 43m (CI 37 – 46) 

and 39m (CI 35 - 44) in pre- and post-chemo pts, respectively. In our MV model 

using data from 225 evaluable pre-chemo patients, ALP (HR 2.65, p = 0.001), LDH 

(HR 2.66, p = 0.018), albumin (HR 0.92, p = 0.002) and PSA (HR 1.31, p = 0.046) 

were each prognostic after controlling for other variables, whereas Hb, PS, GS and 

visceral disease did not show a statistically significant effect. 

Conclusion: Our pts lived significantly longer than predicted by current nomograms. 

This is likely due to development of effective new treatments. MV analysis confirmed 

the importance of several previously identified prognostic factors. Survival data from 

this large cohort of CRPC pts should encourage men considering clinical trial 

participation. Previously developed nomograms no longer accurately predict survival. 

Disclosure: C. Pezaro: Author is an ICR employee. The ICR has a commercial 

interest in Abiraterone and PI3K and AKT inhibitors. D. Mukherji: Author is an ICR 

employee. The ICR has a commercial interest in Abiraterone and PI3K and AKT 

inhibitors. S. Sandhu: Author is an ICR employee. The ICR has a commercial 

interest in Abiraterone and PI3K and AKT inhibitors. A. Mulick Cassidy: Author is 

an ICR employee. The ICR has a commercial interest in Abiraterone and PI3K and 

AKT inhibitors. G. Maier: Author is an ICR employee. The ICR has a commercial 

interest in Abiraterone and PI3K and AKT inhibitors. D. Olmos: Author is an ICR 


inhibitors. G. Attard: Author is an ICR employee. The ICR has a commercial interest 

in Abiraterone and PI3K and AKT inhibitors. J.S. de Bono: Author is an ICR 


inhibitors. All other authors have declared no conflicts of interest. 

904P THE CHARACTERISTICS OF DIFFERENT PATTERN OF 

METASTASES IN PATIENTS WITH CASTRATE RESISTANT 

PROSTATE CANCER TREATED WITH TAXOTERE 

CHEMOTHERAPY 

S. Dixit1 , J. Tito1 , P. Afzal2 1 

Oncology, Hull & East Yorkshire NHS Trust, Hull, UNITED KINGDOM, 

2 

Oncology, Diana Princess of Wales Hospital, Grimsby, Grimsby, UNITED 

KINGDOM 

Introduction: Many new agents are being tested in patients with castrate resistant 

metastatic prostate cancer. Understanding the characteristics of different pattern of 

metastases and their responses to taxotere chemotherapy may help in stratifying the 

patients in different prognostic and predictive groups. 

Methods: Based on the metastases observed on bone scan and CT- scan, before 

starting chemotherapy, three metastatic patterns were identified. Metastases 

predominantly limited to the bones with small volume lymph node metastases (bone 

predominant), metastases limited to the bones (bones only), and metastases with 

bulky lymphadenopathy without bone metastases (lymph nodes only). Median 

survival and the distribution of known prognostic factors were analysed in these 

three groups. 

Results: Seventy eight patients with a median age of 70 (Range, 47-86) and a median 

PSA of 174 (11-3000) had a median survival of 17 months (95% C.I. 13-20). Factors 

associated with statistically significant shorter survival were symptomatic state, 

haemoglobin, PSA level, the duration of hormone response, and three metastases 

pattern. Gleason score and age were not significant. The median survival for three 

metastatic pattern, bone predominant (32), bone only (35), and lymph node only 

(11) metastases, were 12, 19 and 23 months respectively. The distributions of age, 

Gleason score, PSA level before starting chemotherapy, and PSA response were not 



significantly different in the three metastatic groups. However, patients with bone 

predominant metastatic group were symptomatic (not significant), had fewer number 

of chemotherapy cycles, and had a lower median Haemoglobin level (significant) 

compared with the bone only metastases and lymph node only metastases group. 

Conclusion: The bone predominant pattern of metastases could be biologically 

different disease than the bone only and the lymph node only (bulky) metastases. 

The trials using newer agents stratifying patients based on these metastases pattern 

may help in understanding the diverse biological behaviour of castrate resistant 

prostate cancer. 

Disclosure: S. Dixit: Sanofi- aventis has provided an educational grant to conduct 

this study. J. Tito: Sanofi aventis provided an educational grant for this study. 

P. Afzal: Sanofi -aventis provided an education grant for this study 

905P HEALTH CARE COSTS IN PROSTATE CANCER PATIENTS 

TREATED WITH DEGARELIX: LOWER COSTS IN 

HORMONE-NAïVE PATIENTS IN COMPARISON TO 

HORMONALLY PRE-TREATED PATIENTS 

J.M. Wolff 1 , M. Gedamke 2 

1 Urologische Klinik, Allgemeines Krankenhaus Viersen, Viersen, GERMANY, 

2 Urology/Uro-Oncology, Ferring Arzneimittel GmbH, Kiel, GERMANY 

Background: Degarelix is a GnRH-antagonist, which is used in the treatment of 

prostate cancer since 2009. We performed a non-interventional study (NIS) with 

prostate cancer (PCA) patients treated routinely with degarelix. This NIS focused on 

pharmaco-economic data, health-related quality of life (HRQoL) as well as efficacy 

and safety in patients receiving degarelix as first or second line therapy. 

Materials: In the interim analysis of this ongoing NIS, data from 279 out of 670 

PCA-patients treated with degarelix were included. The included cohort reflects 

advanced PCA patients (age: 72 years, PSA: 15.8 ng/ml (median)).Testosterone and 

PSA values, health-related quality of life (HRQL) and pharmaco-economic data were 

collected at baseline, 1, 3, 6, 9 and 12 months. HRQL was assessed by EORTC 

QLQ-C30. Pharmaco-economic data included costs for physicians, drugs, hospital, 

emergency treatment and others. 

Results: Treatment costs in hormone-naïve patients treated with degarelix were lower 

than in the hormonally pre-treated patients. Costs for 12 months were € 3177 for 

hormone-naïve patients treated with degarelix in contrast to € 3782 for hormonally 

pre-treated patients. As expected there was a marked difference in the PSA-decline 

between hormone-naïve patients and hormonally pre-treated patients. 

Hormone-naïve patients experienced a sharp median decrease in PSA by 80.7% 

(n = 116) at month 1. This decline remained stable in 98.7% of the patients after one 

year. Median PSA reduction was significantly different (p = 0.013) between 

hormone-naïve and pre-treated patients. Furthermore treatment with degarelix 

improved HRQL by 16% at one year in metastatic patients. Safety results mirrored 

the results of previous clinical trials, with x, y and z being the most frequent ones. 

Conclusions: First line treatment with degarelix was supported by a marked 

difference in health care costs between hormone-naïve and pre-treated prostate 

cancer patients. As expected, a pronounced difference in the PSA-decrease for 

hormone-naïve vs. pre-treated patients was seen. However a distinct health-related 

quality of life improvement was noted in all patients. 


906P A PROSTATE CANCER EXPRESSION SIGNATURE TO 

PREDICT SURVIVAL BENEFIT OF PRIMARY HORMONE 

THERAPY 

C. Li 1 , Z. Peng 2 , L. Skoog 2 , M. Hjelm-Eriksson 1 , L. Ährlund-Richter 1 , 

U. Harmenberg 1 , Y. Pawitan 3 , G. Cohn Cedermark 1 , M. Nistér 2 , S. Nilsson 1 

1 Clinical Oncology, Karolinska University Hosiptal, Stockholm, SWEDEN, 

2 Oncology-Pathology, Karolinska Instiutet, Stockholm, SWEDEN, 3 Medical 

Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SWEDEN 

Background: At the ASCO annual meeting 2012, we have presented the 

identification of an embryonic stem cell gene predictor (ESCGP) signature in a 

cohort of 189 patients with 7-21 years complete survival follow up. The expression 

signature is composed of F3, IGFBP3 and VGLL3 and can significantly improve the 

accuracy of survival prediction at the time of diagnosis. We further hypothesize that 

measuring stem cell gene expression signature in prostate cancer biopsy samples 

taken at the time of diagnosis can predict the survival benefit of hormone therapy. 

Methods: In the previous cohort, 139 of the 189 patients were primarily treated by 

hormone therapy. Of these 139 patients 65 had data of the ESCGP signature. 

Kaplan-Meier plots were used in the survival analysis of this subset of patients. 

Results: Of the 65 patients, 22 were classified as having high risk, 25 as having 

intermediate risk and 18 as having low risk subtype cancers. The obvious overall and 

cancer specific survival difference between the three subtypes was still maintained 

(Kaplan-Meier survival curve, p < 0.001 by log rank test) in these 65 patients. At 8 

years after the diagnosis, the overall survival rate was 0% in patients with the high 

risk subtype cancer, 16% in patients with the intermediate risk subtype cancer and 

55.6% in patients with the low risk subtype cancer. This obvious survival difference 

by the ESCGP classification was independent of age, PSA level, tumor grade and 

clinical stage. 

Conclusions: The expression signature of F3, IGFBP3 and VGLL3 can be accurately 

measured in prostate fine needle aspiration samples. If the finding is further 

validated in a large and independent cohort, the ESCGP expression signature can be 

used to predict the survival benefit of primary hormone treatment for patients with 

newly diagnosed prostate cancer. 

Disclosure: C. Li: Chunde Li is the major stock holder of Chundesell Medcals AB. 


907P CONFIRMATION OF THE PROGNOSTIC VALUE OF MODELED 

PSA CLEARANCE AFTER RADICAL PROSTATECTOMY: 

RESULTS OF THE VALIDATION PSAMODEL STUDY 

D. Maillet 1 , A. Ruffion 2 ,G.Freyer 3 ,M.Tod 4 , M. Wilbaux 4 , P. Perrin 2 , E. Henin 4 , 

B. You 1 

1 Medical Oncology, Lyon-Sud Hospital, Lyon, FRANCE, 2 Urology, Lyon-Sud 

Hospital, Lyon, FRANCE, 3 Medical Oncology, Centre Hospitalier Lyon Sud, 

Pierre Bénite, FRANCE, 4 EMR3738, University Lyon 01, Lyon, FRANCE 

Background: Early predictors of relapse after radical prostatectomy are needed. We 

previously showed that mathematical modeling of PSA kinetics during the first 50 

days after surgery provides a parameter, PSA clearance (CLPSA), which may be an 

independent early predictor of relapse [1](You et al; Prostate 2009;69:1325). 

Prospective validation of these outcomes was warranted. 

Methods: PSAMODEL was a prospective validation study including prostate cancer 

patients treated with radical prostatectomy. Modeled individual CLPSA was estimated 

with 4 values of PSA centrally measured during the first 50 post-operative days, 

using the bi-compartment model previously reported [1] with NONMEM program. 

The prognostic value of modeled CLPSA regarding 3-year biochemical relapse-free 

survival (3 y-bRFS) was assessed using survival univariate and multivariate analyses. 

Results: Total 119 patients were included in PSAMODEL study. Among them, 13 

patients (11%) experienced a relapse after median 6.5 months. Despite high 

inter-individual variability, individual PSA decline profiles were well fitted by the 

model. CLPSA, categorized by the 0.048 cut-off previously reported [1], was a 

significant prognostic factor of 3 y-bRFS using log-rank test (3 y-bRFS: 97% vs 66%, 

p = 0.009). Moreover it had independent significant prognostic value when adjusted 

on D’Amico score items using multivariate Cox model (p < 0.05). 

Conclusion: We confirm modeled CLPSA estimated with 4 PSA values in the first 50 

days after radical prostactectomy is a prognostic factor of relapse, independently on 

d’Amico score. The role of post-operative modeled CLPSA in adjuvant treatment 

decision will be assessed. [1] You et al; Prostate 2009;69:1325 


908P PROGNOSTIC VALUE OF FREE TESTOSTERONE (FT) LEVELS 

DURING SALVAGE CHEMOTHERAPY WITH CARBOPLATIN 

PLUS WEEKLY DOCETAXEL IN METASTATIC CASTRATION- 

AND DOCETAXEL-RESISTANT PROSTATE CANCER (MDRPC) 

C.W.M. Reuter, M.A. Morgan, M. Fenner, V. Grünwald, A. Ganser 

Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover 

Medical School, Hannover, GERMANY 

Background: Recent data suggest that carboplatin plus weekly docetaxel (DC) is an 

effective salvage therapy in DRPC. Carboplatin, docetaxel and steroids all interfere 

with testosterone biosynthesis and/or metabolism. In this study the impact of DC 

treatment on testosterone serum levels was analyzed. 

Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer 

Working Group (PCWG2 2007) criteria. Since February 2005, 71 consecutive DRPC 

pts were treated with at least two cycles of carboplatin AUC5 iv for 30 min on day 1 

every 4 weeks (q4w), docetaxel at a dose of 35 mg/m iv for one hour on days 1, 8, 

(15) plus prednisone 2x5mg/day orally after receiving informed consent until disease 

progression or occurrence of intolerable adverse effects. Efficacy measures were done 

following PCWG2 recommendations. FT was measured before (n = 44) and during 

carboplatin/docetaxel chemotherapy (n = 38). 

Results: Response of prostate-specific antigen (PSAR; ≥50% PSA) was observed in 

34/71 (47.9%) patients. At the time of the current analysis the median follow-up time 

was 14.5 months and 47/71 patients had died. Median progression-free survival 

(PFS) for all patients was 6.9 months (CI 95% 4.3, 13.6) and median overall survival 

(OS) was 18.0 months (CI 95% 10.4, 25.6). Median FT serum levels were 3.0 pmol/L 

before (n = 43) and below the RIA detection limit of

atio HR 0.39; CI 0.18, 0.83, p = 0.015) and OS (HR 0.15; CI 0.04, 0.55, p = 0.004). 

FT remained statistically prognostic in multivariable analyses. The DC regimen was 

reasonably well tolerated, with leukopenia/neutropenia as the most common 

reversible grade 3/4 toxicity (38.0/35.2%). 

Conclusion: These data demonstrate for the first time that testosterone is an 

important prognostic factor for PFS and OS in mDRPC patients receiving 


Disclosure: C.W.M. Reuter: Minor consulting fees from Sanofi Aventis, Amgen, V. 

Grünwald: Consulting fees from Novartis, All other authors have declared no 


909P PREDICTIVE AND PROGNOSTIC ROLES OF BODY MASS 

INDEX (BMI) IN DOCETAXEL(D)-TREATED 

CASTRATE-RESISTANT PROSTATE CANCER (CRPC) 

N. Rozumna-Martynyuk 1 , M.Y. Teo 1 , M.S.N. Mohd Sharial 1 , M. Doherty 1 , 

F. McDonnell 2 ,S.O’Reilly 3 , D.G. Power 3 , R. McDermott 2 

1 Dept. of Medical Oncology, AMNCH Adelaide and Meath Hospital, Dublin, 

IRELAND, 2 Department of Medical Oncology, Adelaide & Meath Hospital 

incorporating National Children’s Hospital, Dublin, IRELAND, 3 Department of 

Medical Oncology, Mercy University Hospital, Cork, IRELAND 

Introduction: Studies have suggested that overweight and obese patients with early 

stage prostate cancer present with lower PSA, higher grade disease and have poorer 

outcomes. Data remains limited on the influence of BMI on CRPC receiving D. We 

previously reported lower pretreatment PSA and rate of PSA response in obese pts 

(Teo et al, ASCO GU 2011). With an expanded cohort, we sought to examine the 

influence of BMI on PSA kinetics and CRPC survival. 

Methods: Two institutional databases were analysed to identify pts who received D for 

CRPC. Demographics and serial PSA levels were extracted. Pts were divided into Group 

A, B and C, based on BMI range of ≤25.0, 25.1-29.9 and ≥30 kg/m respectively. PSA 

responses and half life were calculated using PCWG2 guidelines. Results were compared 

with Mann-Whitney and Fisher’s exact tests. Time to PSA progression (TPP) and 

overall survival (OS) were estimated with Kaplan Meier and logrank methods. 

Results: 78 pts were identified, with median age of 66 yrs (44-80), median cycles of D 

of 7 (1-26), and median BMI of 28.5. Gleason score was evaluable in 75%, with a 

median score of 8. The number of pts in each BMI group was 21, 24 and 33, 

respectively. Pts in Gp C had significantly lower baseline PSA (table). More pts in Gp C 

were PSA non-responders compared to Gp A and B (p = .004). PSA nadir and rates of 

PSA reduction >30%, >50% and >90% at 3months were comparable in all groups. 

MMMMMedian TPP was 4.2 months in Gp A, 5.2 months in Gp B, and 4.4 months 

in Gp C (logrank p = .49). The longest median OS was observed in Gp A at 20 months, 

followed by Gp B at 19 months and Gp C at 15 months; these differences were not 

statistically significant (p = 0.38). Of 45 pts with treatment details, 24% had dose 

reduction and 44% had ≥1 infusion delays. Rates were similar across Gps A to C. 

Conclusions: Obese CRPC pts have lower pre-D PSA levels and higher rate of 

non-responsive disease. However, BMI does not appear to influence PSA kinetics, 

tolerability of D and survival. 

BMI (kg/m2) p 

≤25 25.1 - 29.9 ≥30 

n 21 24 33 NS 

Baseline PSA, median ng/mL 131.0 236.6 81.6 0.007 

PSA Reduction at 12wks, median % 34.4 47.2 41.4 NS 

PSA Nadir as % of Baseline, median 51.1 41.6 39.6 NS 

PSA Flare, % 9.5 25.0 14.8 NS 

PSA Non-Responders, % 0.0 4.2 25.9 0.004 

>30% PSA Reduction at 12wks, % 66.7 79.2 70.4 NS 



PSA Half-life, days, median 51.1 41.6 39.6 NS 


Table: 911P 

910P MOLECULAR PROFILING OF PERIPHERAL BLOOD IS 

ASSOCIATED WITH CIRCULATING TUMOR CELLS (CTCS) 

CONTENT AND SURVIVAL IN METASTATIC 

CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) 

L. Gaba Garcia 1 , M. Marín-Aguilera 1 , J.J. Lozano 2 , A. Tagliapietra 1 , V. Ortega 1 , 

P. Gascón 1 , B. Mellado 1 

1 Medical Oncology, Hospital Clinic, Barcelona, SPAIN, 2 Bioinformatics Platform, 

Ciberehd, Hospital Clinic, Barcelona, SPAIN 

Introduction: Detection of CTCs in peripheral blood has been demonstrated to 

correlate with clinical outcome in CRPC. The molecular characterization of these 

CTCs is essential for assessing genotypic features of mCRPC and should provide 

insights into the biology of tumor cell growth, invasion and metastasis. 

Objective: To analyze the molecular profiling of peripheral blood from mCRPC 

patients with known CTC content and to identify those genes that may be related to 

the number of circulating cells and/or to the clinical outcome. 

Material and methods: Peripheral blood from mCRPC patients was analyzed for 

CTC using the CellSearch System. Microarrays analysis was performed by the 

Human Gene 1.1 ST Array (Affymetrix) in samples with varing CTC content. Ten of 

the most differentially expressed genes between the < 5 and ≥ 5 CTCs groups were 

validated using reverse transcriptase PCR. 

Results: 43 patients were included. The median age was 71 years (42-88), the 

majority of patients had poor prognosis based on Gleason score (n = 22, 51.2%) and 

had recieved prior-docetaxel-based chemotherapy (n = 19, 44.2%). The median 

number of CTCs per patient sample was 59 (1-889), 23 patients (53.4%) presented < 

5 CTCs and 20 patients (46.5%) had ≥ 5 CTCs. Overall survival (OS) in patients with 

≥5 CTCs was significantly lower than those with


Conclusions: CTC enumeration by the integrated CellSearch® profile kit and LSC 

yielded improved CTC recovery compared to the standard method. CTC counts 

correlated with disease severity and support the use of CTCs as predictors of OS. We 

will present a comparison of CTC enumeration with a correlation to clinical variables. 

Disclosure: V. Melnikova: I am an employee of ApoCell. Y. Zhang: I am an 

employee of ApoCell. W. Liu: I am an employee of ApoCell. K. Anderes: I am an 

employee of ApoCell. D.W. Davis: I am an employee of ApoCell. All other authors 


912P SERUM CHROMOGRANIN A IN METASTATIC CARCINOMA 

PROSTATE - A PROGNOSTIC MARKER FOR HORMONAL 

THERAPY 

G.S. Bhattacharyya 1 , H. Malhotra 2 , P.M. Parikh 3 , J.K. Singh 4 , G.B. Kanaka 5 , 

S. Basu 6 , M. Singh 4 , J. Biswas 7 , T. Shahid 6 , A.A. Ranade 3 

1 Medical Oncology & Hemato-Oncology, FORTIS Hospital, Anandapur, Kolkata, 

INDIA, 2 Medicine & Medical Oncology, SMS Hospital, Jaipur, INDIA, 3 Medical 

Oncology & Hematology, Indian Co-operative Oncology NetworkICON ARO, 

Mumbai, INDIA, 4 Cancer Insuitute, Mahavir Cancer Sansthan, Patna, INDIA, 

5 Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, INDIA, 

6 Radiotherapy, AMRI Hospital, Kolkata, INDIA, 7 Medical Director, Chittaranjan 

National Cancer Institute, Kolkata, INDIA 

Introduction: Treatment of metastatic carcinoma prostate is hormonal manipulation. 

Response to the hormone therapy is high but duration is variable. Attempt to 

develop a marker has clinical relevance and importance to such activity. Aim 1. To 

show that Serum Chromogranin-A (CgA) at baseline can define the risk population 

of metastatic Ca Prostate 2. Baseline Serum Chromogranin-A (CgA) may be able to 

choose patient who may require early non-hormonal interventions. 

Method: Study was done in a period of 2005 to 2010. 160 patients of Metastatic Ca 

Prostate who had no chemotherapy or hormonal therapy were included. All patients 

were staged by Bone Scan, CT scan, and Trans Rectal Ultrasound. Routine 

biochemistry was done. Serum Chromogranin-A (CgA) was assayed by 

immune-fluorescence microscopy (IFM) and immuno chemiluminometer (ICMA). 

PSA was assayed by immuno chemiluminometer (ICMA). Gleason’s score was 

obtained from biopsy report. All patients were serially followed up at three monthly 

intervals. Statistical analysis, descriptive analysis for population was used. Patients 

were stratified on the basis of Gleason’s score >7 or 10 or 7 had progressed. 14 patients out of 40 with PSA

We observed tumor responses and prolonged survival. Patients had CRPC and 

were chemotherapy-naïve. They received bi-weekly GVAX for a 24 week period 

combined with monthly intravenous administrations of ipilimumab. Each cohort 

of 3 patients received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/ 

kg. In an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg 

ipilimumab. Since the teratment can be accompanied by side-effects (colitis, 

hypophysitis), we looked for lymphoid and myeloid markers as well as antibody 

formation. We observed a significantly prolonged OS for patients with high 

pre-treatment frequencies of CD4 + CTLA-4 + , CD4 + PD-1 + , or differentiated 

CD8+ T cells, or low pre-treatment frequencies of differentiated CD4+ T cells or 

CD4 + CD25hiFoxP3+ regulatory T cells. In contrast, increased frequencies of 

granulocytic Myeloid-Derived Suppressor Cells and high pre-treatment 

frequencies of monocytic CD14 + HLA-DRlo/- MDSC were associated with 

reduced OS. Antibody formation against PSMA, NRP2, and PNPO was 

associated with prolonged survival and especially when multiple antibodies were 

detected. 

Conclusions: Together these data provide an immune profile to predict clinical 

outcome; both pre-treatment CD4+ T-cells as well as antibody formation was 

associated with prolonged survival. These potentially biomarkers for patient selection 

should be validated in patients treated with ipilimumab. 

Disclosure: W.R. Gerritsen: member of advisory board of BMS, K. Hege: former 

employee of Cell Genesys, N. Sacks: former employee of Cell Genesys, I. Lowy: 

former employee of Medarex, T. Harding: former emloyee of Cell Genesys, A. 

van den Eertwegh: member advisory board BMS, T. De Gruijl: educational 

grant from Cell Genesys. All other authors have declared no conflicts of 

interest. 

916P C-MYC EXPRESSION IS MODULATED BY STATINS USE AND 

IT’S CORRELATED WITH TIME TO PROGRESSION (TTP) IN 

MEN WITH LOCALISED PROSTATE CANCER TREATED WITH 

RADICAL RADIOTHERAPY 

D. Torrejon Castro 1 , I. De Torres 2 , G. Sánchez-Ollé 3 , X. Maldonado 4 , 

R. Morales-Barrera 1 , C. Suarez 1 , C. Valverde Morales 5 , I. Nunez Hernandez 6 , 

J. Morote 7 , J. Carles 1 

1 Medical Oncology, Vall d´ Hebron University Hospital, Barcelona, SPAIN, 

2 Pathology, Hospital Vall d’Hebron, Barcelona, SPAIN, 3 Oncology, Hospital Vall 

d’Hebron, Barcelona, SPAIN, 4 Radiotherapy, Vall Hebron Univerity Hospital, 

Barcelona, SPAIN, 5 Medical Oncology, Vall Hebron Univerity Hospital, Barcelona, 

SPAIN, 6 Oncologia M, Vall d’Hebron University Hospital Institut d’Oncologia, 

Barcelona, SPAIN, 7 Urology Department, Hospital Vall d’Hebrón, Barcelona, 

SPAIN 

Background: Although statins do not affect the incidence of prostate cancer (PCa), 

its use reduces the risk of clinical progression and mortality. The mechanism by 

which statins reduce PCa progression is unknown. MYC phosphorylation is a critical 

mechanism by which the inhibition of HMG-CoA reductase by statins, thereby 

resulting in MYC dephosphorylation and inactivation, which is essential for their 

anticancer therapeutic effect. The aim of this study was to correlate statins use with 

the c-MYC levels in PCa patients treated with radical radiotherapy (RT) with 

concurrent androgen deprivation. 

Methods: A total of 85 patients with paraffin-embedded prostate tissue specimens 

were investigated immunohistochemically for c-MYC overexpression, diagnosed 

with PCa between 2000 and 2005. Clinical and pathological variables were 

compared between statin users and non-users and correlates with expression of 

c-MYC. Disease-free survival (DFS) and time to progression (TTP) were 

analysed. 

Results: Mean age was 71 (56-82) years and median follow-up was 75 months. 

Three (3.5%), 14 pts (16.5%) and 68 pts (80%) were classified as low, medium 

and high risk respectively. Of those, 20 patients (24%) were using statins, 

either during initial consultation or during follow-up. No statistical differences 

were found between treatment groups regarding median age, risk category, 

clinical T stage, Gleason score or median radiation dose. Median percentage 

value of c-MYC was 20 (5-80) of statin users vs. 35 (5-100) of non-users (p 

= 0.057) and elevated c-MYC expression was not significantly associated with 

shorterDFS(p=0.5).Atthetimeofanalysis,only13pts(15.3%)had 

biochemical relapse (1 low risk, 3 intermediate, and 9 high risk). Statins use 

(38%) was significantly associated with improved TTP (55.2 vs. 30.6 months, 

p = 0.016). 

Conclusions: In our analysis, statins use was associated with a significant 

improvement in TTP, in all risk groups. Although no differences in DFS according 

cMYC values, there is a tendency towards a lower expression in statins users. Our 

findings warrant further investigation. 



917P METFORMIN IN CHEMOTHERAPY-NAïVE CASTRATION 

RESISTANT PROSTATE CANCER (CRPC): A MULTICENTER 

PHASE II TRIAL (SAKK 08/09) 

C.A. Rothermundt 1 , R. Cathomas 2 , A. Templeton 1 , R.C. Winterhalder 3 , 

R. Strebel 4 , D. Baertschi 5 , M. Pollak 6 , L. Lui 6 , S. Crowe 7 , S. Gillessen 1 

1 Medical Oncology, Kantonsspital St. Gallen, St. Gallen, SWITZERLAND, 

2 Medical Oncology, Kantonspital Graubünden, Chur, SWITZERLAND, 3 Medical 

Oncology, Luzerner Kantonsspital, Luzern, SWITZERLAND, 4 Urology, 

Kantonsspital Chur, Chur, SWITZERLAND, 5 Trial Coordination, SAKK, Bern, 

SWITZERLAND, 6 Lady Davis Institute for Medical Research, Jewish General 

Hospital, Montreal, QC, CANADA, 7 Statistics, SAKK, Bern, SWITZERLAND 

Background: Men with prostate cancer (PC) receiving androgen deprivation therapy 

(ADT) are at risk of developing insulin resistance. Hyperinsulinemia causes 

activation of insulin-like growth factor (IGF) signalling pathways, promoting 

progression of PC. Functional loss of PTEN leads to activation of the PI3K pathway, 

including Akt kinase and mTOR, critical components of PC cell survival and 

oncogenic function of IGF-1. The biguanide metformin is an inexpensive oral drug 

used as treatment for diabetes mellitus. Metformin, an activator of AMP-activated 

protein kinase, has antiproliferative effects on PC via reduction of systemic insulin 

levels and inhibition of mTOR. 

Methods: Patients (pts) with CPRC, PSA < 114 ng/ml, PSA-doubling time 

(PSA-DT) ≥ 55 days, no prior chemotherapy, and adequate organ function were 

eligible. ADT was continued in non-surgically castrated pts. Metformin was 

administered continuously at 1000mg bd in 4 week cycles. The primary endpoint was 

progression free survival at 12 weeks (PFS12) defined as absence of progression (PSA 

increase ≥ 25% above baseline, progression of measurable disease or bone lesions, 

clinical progression) or death. Simon’s two-stage optimal design was applied. With 

5% significance level and 90% power, 44 evaluable pts were required to test if PFS12 

rate ≤ 15% (H0) vs ≥ 35% (H1). If ≥ 11 evaluable pts remain PFS12, the trial was 

deemed worth of further investigation. 

Results: 44 pts were enrolled at 10 Swiss centres between 12/2010 and 12/2011. 

Median age was 70 (range 48-87) years; median PSA-DT at registration was 89 

(range 55-438) days. In total, 186 cycles of metformin were administered; median 4 

(range 1-13) cycles. Fourteen pts (31.8%, 95% CI: 18.6%-47.6%) had PFS12. 

Confirmed PSA response was seen in 2 pts (4.5%); both of whom had 50% PSA 

response. Median PFS was 2.1 (range 0.8-12.5) months. Treatment related adverse 

events were generally mild and manageable. 

Conclusion: To our knowledge this is the first trial reporting on metformin in 

CRPC. Metformin shows activity in this disease setting and some pts have prolonged 

stabilization of disease. Analysis of insulin and C-peptide levels and correlation to 

response will be presented. 

Disclosure: S. Gillessen: Advisory boards with honorarium Millennium 

Janssen-Cilag Sanofi-Aventis. All other authors have declared no conflicts of interest. 

918P PHASE 2 RESULTS FROM A PHASE 1/2 STUDY OF TAK-700 

(ORTERONEL), AN ORAL, INVESTIGATIONAL, NONSTEROIDAL 

17,20-LYASE INHIBITOR, WITH DOCETAXEL AND 

PREDNISONE (DP) IN METASTATIC CASTRATION-RESISTANT 

PROSTATE CANCER (MCRPC) 

D.P. Petrylak 1 , J.G. Gandhi 2 , W.R. Clark 3 , E.I. Heath 4 , J. Lin 5 , W.K. Oh 6 , 

D.B. Agus 7 , B. Carthon 8 , S. Moran 9 , G. Liu 10 

1 Oncology, Columbia University Medical Center, New York, NY, UNITED STATES 

OF AMERICA, 2 Oncology and Hematology, Associates in Oncology and 

Hematology, Chattanooga, TN, UNITED STATES OF AMERICA, 3 Oncology, 

Alaska Clinical Research Center, Anchorage, AK, UNITED STATES OF AMERICA, 

4 Oncology, Karmanos Cancer Institute, Detroit, MI, UNITED STATES OF 

AMERICA, 5 Medical Oncology, Thomas Jefferson University, Philadelphia, PA, 

UNITED STATES OF AMERICA, 6 Oncology, Mt. Sinai Hospital, New York, NY, 

UNITED STATES OF AMERICA, 7 Molecular Medicine, University of Southern 

California, Keck School of Medicine, Beverly Hills, CA, UNITED STATES OF 

AMERICA, 8 Hematology, Winship Cancer Institute, Emory University, Atlanta, 

GA, UNITED STATES OF AMERICA, 9 Oncology, Millennium Pharmaceuticals, 

Inc., Cambridge, MA, UNITED STATES OF AMERICA, 10 Oncology, University of 

Wisconsin Carbone Cancer Center, Madison, WI, UNITED STATES OF 

AMERICA 

Background: The investigational agent TAK-700 (orteronel) is a selective 17,20-lyase 

inhibitor that blocks androgen production. Since DP is currently standard 

chemotherapy in mCRPC, this phase 1/2 study examined TAK-700 + DP in men 

with mCRPC. 

Methods: The primary phase 2 objective is tolerability of TAK-700 400 mg BID + D 

(75 mg/m q3w) + P (5 mg BID) in castrate men (testosterone [T]


Secondary objectives were PK, PSA response rates after 3 mo, best PSA response at 

any time, time to progression of PSA ± radiographic disease, response by RECIST 

1.1. D was started on d8 of cycle 1 (28 d); cycles ≥2 = 21 d. 

Results: 24 men were treated: median age was 66 yrs (range 53–87), ECOG PS 0/1 (88%/ 

12%). At baseline, median PSA was 47 ng/mL (4.5–813) and T was 7.2 ng/dL (3.2–13.8). 

At data cutoff, 15/24 men remained on study treatment. 22/24 men experienced a 

treatment-related AE. 3 men discontinued due to AEs (ALT increase, arthralgia, 

pneumonitis). 21 men (88%) had at least 1 Gr ≥3 AE (19 were drug-related). 

Drug-related Gr ≥3AEs≥10% were WBC decreased (29%); neutropenia (25%); 

decreased neutrophil count (25%); fatigue, and febrile neutropenia (each 13%). The most 

common drug-related SAE was febrile neutropenia (13%). As of cutoff, there were no 

on-study deaths. At 3 mo, PSA30, PSA50, and PSA90 rates in the PSA evaluable 

population were 59%, 50%, and 18%, respectively. Best PSA decline (median) was -76% 

(n = 22; -99 to +144%). Median T at 3 mo decreased to ≤0.2 ng/dL (0.3–10.6). Best ORR 

50% (n = 10; 80% CI: 27,73; partial response in 5 of 10 evaluable men). Median time to 

PSA progression was 6.1 mo (95% CI: 4.6, not reached) and median time to radiologic 

progression was not reached. The Cmax of DP + TAK-700 was similar to that of DP alone. 

Conclusions: TAK-700 400 mg BID + DP appears tolerable and shows 

androgen-lowering activity and strong PSA and partial tumor response in mCRPC. 

Plasma levels of D administered with TAK-700 + P were similar to published data on 

DP without TAK-700. 

Disclosure: D.P. Petrylak: Consultant/Advisor: Amgen, Bayer, Pfizer, Ferring, 

Millennium, Novartis, Dendreon, Johnson & Johnson, Glaxo Smith Kline Research 

funding: Celgene, Dendreon, Sanofi, Pfizer, AstraZenca, Glaxo Smith Kline, Rogosen 

institute, Boehringer Ingelheim, W.R. Clark: Investigator for BMS, Millenium, Lily, 

Watson, Roll International, Astellas, E.I. Heath: Research funding: Millennium 

Pharmaceuticals, Ltd. W.K. Oh: Advisor/consultant: Amgen, Pfizer, Sanofi, 

Dendreon, Bellicum, and Medivation, D.B. Agus: Millenium Pharmaceuticals, Inc./ 

Takeda Advisory Board, S. Moran: Employment: Millennium Pharmaceuticals, Inc. 


919P TASQUINIMOD MECHANISM OF ACTION BIOMARKERS: 

CORRELATION WITH PFS AND SURVIVAL IN MEN WITH 

METASTATIC CASTRATE RESISTANT PROSTATE CANCER 

TREATED IN A RANDOMIZED PHASE 2 TRIAL 

M. Carducci 1 , A. Armstrong 2 , M. Häggman 3 , W.M. Stadler 4 , J.R. Gingrich 5 , 

V. Assikis 6 , G. Forsberg 7 , A. Olsson 8 , Ö. Nordle 9 , R. Pili 10 

1 Kimmel Cancer Center, Baltimore, MD, UNITED STATES OF AMERICA, 

2 Divisions of Medical Oncology and Urology, Duke University, Durham, UNITED 

STATES OF AMERICA, 3 Urology, University Hospital of Uppsala, Uppsala, 

SWEDEN, 4 Medical Oncology, University of Chicago, Chicago, IL, UNITED 

STATES OF AMERICA, 5 Urology, University of Pittsburgh, Pittsburgh, PA, 

UNITED STATES OF AMERICA, 6 Oncology, Peachtree Hematology and 

Oncology, Atlanta, GA, UNITED STATES OF AMERICA, 7 BD, Active Biotech AB, 

Lund, SWEDEN, 8 Bioscience, Active Biotech, Lund, SWEDEN, 9 Development, 

Active Biotech, Lund, SWEDEN, 10 Oncology, Roswell Park Medical Centre, 

Buffalo, NY, UNITED STATES OF AMERICA 

Background: Tasquinimod (T) is an oral quinoline-3-carboxamide derivative that 

binds to S100A9 and displays immunomodulatory, anti-angiogenic and 

anti-metastatic activity. Between Dec 2007 and June 2009, 201 (134 T, 67 Placebo 

(P)) men with metastatic castrate resistant prostate cancer (CRPC) were randomized 

and received once-daily treatment with 41 P patients crossing over to T after 6 

months or disease progression. The primary endpoint to demonstrate an 

improvement in PCWG2 criteria-defined progression at 6 months was met (69 vs. 37 

% of patients (T/P) were progression free) with PFS of 7.6 vs. 3.3 months (T/P) with 

acceptable toxicity (Pili, 2011, J Clin Oncol, 20, 4022.). A trend for survival benefit 

(33.4 vs 30.4 mo) was observed and was most pronounced in the PCWG2 defined 

subpopulation (92 T, 44 P) with bone metastatic disease (34.2 vs 27.1 mo). This 

abstract provides exploratory data on biomarkers and therapeutic outcome after 

Tasquinimod therapy. 

Methods: The biomarkers PSA, LDH, Bone alkaline phosphatase (BAP), VEGF-A, 

VEGF-C, thrombospondin-1 (TSP-1), sRAGE and TGF-b were analyzed in serum or 

plasma before and during therapy in at least the subset of patients with bone 

metastatic disease. The influence of each (log2 transformed) biomarker on PFS and 

OS was estimated with Cox Regression (SAS, SAS Institute Inc, Cary, NC). 

Results: Eight weeks Tasquinimod treatment was associated with an increase (% vs 

P) in median circulating levels of VEGF-A (40 %) and TSP-1 (21%) and a decrease 

in bone alkaline phosphatase (14 %). An increased ratio (week 8/baseline) was 

associated with more rapid progression and shorter survival for TSP-1 (PFS HR = 

1.29, p = 0.052; OS HR = 1.25, p= 0.058), VEGF-C (PFS HR = 1.52, p = 0.060 OS HR 

= 1.39, p = 0.039) and TGF-b (PFS HR = 1.30, p = 0.091 OS HR = 1.27, p = 0.082). 

These changes did not correlate with changes in PSA. 

Conclusions: PFS and OS observed after Tasquinimod treatment are encouraging. 

Biomarker analysis supports an effect on both immunomodulation as well as angiogenesis. 

Changes in the levels of TGF-b, TSP-1 or VEGF-C may be markers for treatment benefit. 

A controlled phase III study is ongoing in men with bone metastatic CRPC. 

Disclosure: M. Carducci: Advisory role Active Biotech, uncompensated, 

A. Armstrong: Advisor Active Biotech and Ipsen Research Funding Active Biotech, 

M. Häggman: Advisory board Ipsen, G. Forsberg: Employed by Active Biotech 

Shareholder in Active Biotech, A. Olsson: Employed by Active Biotech Share holder 

Active Biotech, Ö. Nordle: Employed by Active Biotech Shareholder Active Biotech, 

R. Pili: Advisor Active Biotech Research funding Active Biotech, All other authors 


920P ARN-509 IN MEN WITH HIGH RISK NON-METASTATIC 

CASTRATION-RESISTANT PROSTATE CANCER 

M.R. Smith, 1 , E.S. Antonarakis 2 , C.J. Ryan 3 , W. Berry 4 , N.D. Shore 5 , G. Liu 6 , 

J. Alumkal 7 , C. Higano 8 , E. Chow-Maneval 9 , D. Rathkopf 10 

1 Genitourinary Cancer Center, Massachusetts General Hospital, Boston, MA, 

UNITED STATES OF AMERICA, 2 Sidney Kimmel Comprehensive Cancer Center, 

Johns Hopkins University, Baltimore, MD, UNITED STATES OF AMERICA, 

3 UCSF Helen Diller Family Comprehensive Cancer Center, University of 

California, San Francisco, San Francisco, CA, UNITED STATES OF AMERICA, 

4 Oncology, Cancer Centers of North Carolina, Raleigh, NC, UNITED STATES OF 

AMERICA, 5 Urology, Carolina Urologic Research Center, Myrtle Beach, SC, 

UNITED STATES OF AMERICA, 6 Oncology, University of Wisconsin Carbone 

Cancer Center, Madison, WI, UNITED STATES OF AMERICA, 7 Medicine, Oregon 

Health & Science University Knight Cancer Institute, Portland, OR, UNITED STATES 

OF AMERICA, 8 Seattle Cancer Care Alliance, University of Washington, Seattle, 

WA, UNITED STATES OF AMERICA, 9 Clinical Development, Aragon Pharmaceuticals, 

San Diego, CA, UNITED STATES OF AMERICA, 10 Medicine, Memorial 

Sloan-Kettering Cancer Center, New York, NY, UNITED STATES OF AMERICA 

Background: ARN-509 is a novel second-generation anti-androgen that binds 

directly to the ligand-binding domain of the androgen receptor, impairing nuclear 

translocation and DNA binding. The Phase II portion of a multicenter Phase I/II 

study is evaluating the activity of ARN-509 in 3 distinct patient populations of men 

with CRPC (high risk non-metastatic CRPC, metastatic treatment-naïve CRPC, and 

progressive disease after abiraterone acetate). Preliminary results for the cohort of 

patients with high-risk non-metastatic CRPC are presented here. 

Methods: All patients had CRPC, no radiographic evidence of metastases (pelvic 

lymph nodes 2 AEs and no patients 

required dose modifications. At 12 weeks, 17/19 patients (89.5%) of patients had a 

PSA response. The median decrease in PSA from baseline to week 12 was 83.3%. 

Conclusion: In men with high-risk non-metastatic CRPC, ARN-509 is safe and well 

tolerated with promising preliminary activity based on high PSA response rates. 

Disclosure: E. Chow-Maneval: As an employee of Aragon Pharmaceuticals, I have 

stock ownership in Aragon Pharmaceuticals.All other authors have declared no 


921P MLN8237 (ALISERTIB), AN INVESTIGATIONAL AURORA A 

KINASE (AAK) INHIBITOR, IN PATIENTS WITH ADVANCED 

SOLID TUMORS INCLUDING CASTRATION-RESISTANT 

PROSTATE CANCER (CRPC) RECEIVING A STANDARD 

DOCETAXEL REGIMEN: PRELIMINARY PHASE 1 RESULTS 

N.M. Hahn 1 , J. Sarantopoulos 2 , C. Higano 3 , X. Zhou 4 , B. Zhang 5 , E.J. Leonard 4 , 

E. Benaim 6 , J. Graff 7 

1 Department of Medicine, Division of Hematology/Oncology, Indiana University 

Melvin and Bren Simon Cancer Center, Indianapolis, IN, UNITED STATES OF 

AMERICA, 2 Medical Oncology, Institute for Drug Development, Cancer Therapy 

Research Center at Universtiy of Texas Health Science Center, San Antonio, TX, 

UNITED STATES OF AMERICA, 3 Seattle Cancer Care Alliance, University of 

Washington, Seattle, WA, UNITED STATES OF AMERICA, 4 Clinical 


STATES OF AMERICA, 5 Biostatistics, Millennium Pharmaceuticals, Inc., 

Cambridge, MA, UNITED STATES OF AMERICA, 6 Clinical Development, 


AMERICA, 7 Medical Oncology, Oregon Health and Science University, Portland, 

OR, UNITED STATES OF AMERICA 

Background: AAK is a key mitotic regulator overexpressed/amplified in a variety of 

tumor types including prostate cancer. MLN8237 is an oral, selective AAK inhibitor. 


Here we report emerging data from the first clinical study of MLN8237 in 

combination with docetaxel in pts with solid tumors or CRPC. 

Methods: Pts aged ≥18 y with ≤3 prior myelosuppressive chemotherapy regimens 

who were candidates for docetaxel received MLN8237 BID (days 1–5 or1–7) in 3 + 3 

dosing cohorts plus docetaxel on day 1 in 21-d cycles. Primary objectives were safety/ 

tolerability and to determine a recommended phase 2 dose/schedule (RP2D); 

secondary objectives were pharmacokinetics (PK) and antitumor activity (RECIST 

v1.1 and/or PSA response by PCWG2). 

Results: 22 pts in 5 dose cohorts received a median of 5 cycles (range 1–17); 9 pts 

remain on therapy. Median age was 63 y (36–87), 82% were male, and 14 had CRPC. 

8 pts reported dose-limiting toxicities including G4 neutropenia >7 days (n = 5) and 

G3/4 febrile neutropenia (n = 3). MTD has not yet been reached. 21 pts reported 

drug-related AEs; G ≥ 3 in 20 pts, including neutropenia (86%), leukopenia (27%), 

and febrile neutropenia (23%). 11 pts had serious AEs and 3 discontinued due to 

AEs. There were 2 on-study deaths (due to disease progression). Steady-state systemic 

exposure of MLN8237 increased in an approx. dose proportional manner over 10– 

30 mg BID when administered with docetaxel 75 mg/m (n = 18). There was no 

consistent effect of MLN8237 dose on docetaxel exposure (n = 19). Of 20 

response-evaluable pts, 3 with CRPC achieved PR plus a >50% decrease in PSA and 

7 had stable disease including 3 pts who also had a >50% decrease in PSA; 1 pt with 

bladder cancer had a PR. 

Conclusions: Myelosuppressive G ≥ 3 AEs were common, but 10 of 22 pts remained 

on study for ≥6 cycles. PK data from the expansion cohort are pending to support 

definitive conclusions regarding drug-drug interaction between docetaxel and 

MLN8237. Emerging data suggest this combination may have preliminary antitumor 

activity in pts with solid tumors/CRPC. Dose escalation/modification is ongoing to 

determine RP2D. 

Disclosure: N.M. Hahn: Research Support to institution: Merck, Dendreon, Sanofi, 

Millennium, Exelexis, Novartis, Bristol-Myers Squibb, Celgene Consultant: Sanofi, 

Celgene Speakers Bureau Honoraria: Sanofi, Janssen Biotech, C. Higano: Amgen, 

Bayer, Dendreon, GTx, MPI, AZ, Pfizer, Cell Ther., Centocor, Perceptive Inform., 

Sanofi, TEVA, BMS, Aragon, Cell Genesys, Exelixis, Genentech, GSK, ImClone, 

OncoGenex, Mediv., Clin. Care Ops, Curatio, Medscape, RBC Capital Mkts Corp., 

Cougar, Endo, X. Zhou: Employment (Millennium Pharmaceuticals, Inc.), B. Zhang: 

Employment: Millennium Pharmaceuticals, Inc., E.J. Leonard: Employment 

(Millennium Pharmaceuticals, Inc.) Ownership interest (Millennium 

Pharmaceuticals, Inc.), E. Benaim: Employment (Millennium Pharmaceuticals, Inc.). 


922P A PHASE II STUDY OF SB939 IN PATIENTS (PTS) WITH 

CASTRATION RESISTANT PROSTATE CANCER (CRPC) 

B.J. Eigl1 , S. North2 , E. Winquist3 , J. Powers4 , J. Good5 , M. Sharma6 , J. Squire5 , 

M. Cox7 , E.A. Eisenhauer8 , K. Chi9 1 2 

Oncology, Tom Baker Cancer Centre, Calgary, AB, CANADA, Oncology, Cross 

Cancer Institute, Edmonton, AB, CANADA, 3 Medical Oncology, University of 

Western Ontario London Regional Cancer Center, London, ON, CANADA, 

4 5 

Clinical Trials, NCIC Clinical Trials Group, Kingston, ON, CANADA, Pathology 

and Molecular Medicine, Queens University, Kingston, ON, CANADA, 6 Urologic 

Sciences, The Vancouver Prostate Centre, Vancouver, BC, CANADA, 7 Urologic 

Sciences, University of British Columbia, Vancouver, BC, CANADA, 8 Clinical 

Trials, Queen’s UniversityNCIC Clinical Trials Group, Kingston, ON, CANADA, 

9 

Oncology, Vancouver Cancer Centre, University of British Columbia, Vancouver, 

BC, CANADA 

Background: SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases 

(HDACs). These 3 HDAC classes are highly expressed in CRPC and associated with 

poor clinical outcomes. HDAC inhibition abrogates androgen receptor signaling via 

inactivation of HSP90, and may have particular relevance in prostate cancer with the 

TMPRSS2-ERG (T2-E) fusion. 

Methods: Pts with locally recurrent or metastatic CRPC received SB939 60mg every 

other day 3 times per week x 3 weeks on a 28-day cycle. Primary endpoints were 

PSA response rate (RR) (>50% decline from baseline for > 4 weeks) and 

progression-free survival (PFS). Secondary endpoints included objective response rate 

and duration; overall survival; circulating tumor cell (CTC) enumeration at baseline, 

6 and 12 weeks; T2-E fusion analysis; correlative analysis of archival tissue; and 

safety. In a 2-stage design, a planned maximum of 29 response evaluable patients 

were to be enrolled. 

Results: 32 pts were enrolled and have completed study treatment. Median age was 

70; 88% of pts had received no prior chemotherapy; and ECOG performance status 

was 0/1 in 44%/56%. Bone/lymph node/visceral metastases were present in 91%/75%/ 

12%. The median number of SB939 cycles administered was 3 (range 1-8). Adverse 

events were generally grade 1-2, with 5 pts experiencing one or more grade 3 events 

(fatigue (5), vomiting (1), dyspnea (1)). One pt died due to myocardial infarction. A 

confirmed PSA response was noted in 2 pts (6%), lasting 3.0 and 9.4 mo. In 16 pts 

with measurable disease, there were no objective responses, 7 pts had stable disease 

lasting 1.6 to 8.0 months. CTC response (from ≥5 at baseline to 5 at 6 weeks correlated 

with PSA progression. Correlative studies to evaluate T2-E from whole blood as well 

as T2-E fusion and PTEN deletion status on archival tissue are ongoing. 


Conclusion: SB939 is tolerable at the dose/schedule given, but does not merit further 

study as a single agent in CRPC based on PSA RR. Activity was observed in terms of 

CTC declines however. Study of SB939 with cytotoxic or AR targeted therapies may 

be warranted. Supported by grants from the Canadian Cancer Society and the 

Ontario Institute for Cancer Research. 


923P GTX-758, AN ORAL ERα AGONIST, INCREASES SEX 

HORMONE BINDING GLOBULIN, REDUCES FREE T AND 

DECREASES PSA IN PATIENTS WITH CASTRATION 

RESISTANT PROSTATE CANCER 

M.S. Steiner, R.P. Taylor, R.H. Getzenberg, M.A. Johnston, M. Hancock, J. 

T. Dalton 

Medical Affairs, GTx, Inc., Memphis, TN, UNITED STATES OF AMERICA 

Introduction & objective: GTx-758 is an oral, selective estrogen receptor α agonist, 

which induces sex hormone binding globulin (SHBG) and subsequently reduces free 

testosterone (FT) to levels below that achieved with LHRH agonists. Such agonists 

represent a distinct class of agents with the potential to impact men with advanced 

prostate cancer. Herein we report the results of a proof of concept trial of GTx-758 

in patients who developed castration resistant prostate cancer (CRPC) while on 

androgen deprivation therapy (ADT). 

Methods: Men (n = 9) receiving ADT and developed CRPC, were enrolled in a Phase 

II open label study to 2000 mg GTx-758 daily. Primary endpoint was the proportion 

of subjects with a ≥ 50% reduction in prostate specific antigen (PSA) from Day 

1. Secondary endpoints included serum FT and SHBG. SHBG, FT, and PSA were 

assessed at, Days 1, 15, 30, 60, and 90 days. 

Results: At enrollment (Day 1) values (n = 9) observed for PSA (38.7 ng/mL ± 52.8), 

FT (0.89 pg/mL ± 0.70), and SHBG (53.4± 28.6 nmol/L). Data were available from 7 

subjects with at least one on-study assessment for FT and SHBG. By Day 15, 75% (3/ 

7) and by Day 60, 100% (4/4) of patients had a ≥50% reduction in PSA. Mean 

change in FT, at last observation, was -70.4% ± 16.7%. All subjects demonstrated 

significant increases in SHBG at day 15 (251 ± 63.1 pmol/L) and end of study (266 ± 

73.0 pmol/L), with a mean change at last observation of 429% ± 158%. Although 

there were no venous thromboembolic events (VTEs) in this study, a separate study 

of GTx-758 for primary ADT in men with advanced prostate cancer was stopped 

prematurely due to an increased risk of VTEs, and consequently, this study was 

halted as well. 

Conclusions: GTx-758 is an oral selective ERα agonist that has demonstrated ability 

to increase SHBG more than 4-fold and decrease FT in men with CRPC. Coupled 

with the observation that 4/4 patients respond with a ≥50% reduction in PSA at day 

30, these results suggest that progression of disease, and the need for increasingly 

toxic therapies, may be delayed in this population. Significantly lower doses of 

GTx-758 (100 – 600mg) have also been shown to increase SHBG with a more 

favorable safety profile in previous Phase I and II GTx-758 studies. Lower doses of 

GTx-758 are being evaluated in an ongoing Phase II trial in men with CRPC. 

Disclosure: M.S. Steiner: CEO of GTx and own stock, R.P. Taylor: employee of GTx, 

Inc. and own stock in GTx, Inc., R.H. Getzenberg: employee of GTx, Inc., M.A. 

Johnston: employee of GTx and own stock, M. Hancock: employee of GTx, Inc. and 

own stock in GTx, Inc., J.T. Dalton: employee of GTx, Inc. and own stock in 

GTx, Inc. 

924P ABIRATERONE IN PATIENTS WITH METASTATIC 


PROGRESSING AFTER DOCETAXEL AND MDV3100: A 

MULTICENTRE STUDY 

D. Bianchini 1 , Y. Loriot 2 , E. Ileana 2 , S. Sandhu 1 , C. Pezaro 1 , L. Albiges 2 , 

G. Attard 1 , K. Fizazi 3 , J.S. de Bono 1 , C. Massard 3 

1 Prostate Targeted Therapy Group/ DDU, Royal Marsden Hospital, Sutton, 

UNITED KINGDOM, 2 Medical Oncology, Institut de Cancérologie Gustave 

Roussy, Villejuif, FRANCE, 3 Department of Medical Oncology, Institute Gustave 

Roussy, Villejuif, FRANCE 

Background: Androgen receptor signalling remains critically important in metastatic 

castration resistant prostate cancer (mCRPC) as confirmed by recent Phase III trials 

showing a survival advantage for abiraterone acetate and MDV3100. These novel 

inhibitors of androgen biosynthesis and androgen receptor function are anticipated 

to be broadly utilized in the near future. The antitumor activity of abiraterone in 

patients pre-treated with MDV3100 is as yet unknown. 

Methods: We investigated the activity of abiraterone acetate in patients with mCRPC 

who had progressed following treatment with docetaxel and MDV3100. Clinical 

data were retrospectively analysed for prostate-specific antigen (PSA) response, 

clinical benefit and progression-free survival (PFS). All patients received abiraterone 

1000 mg/day plus prednisone 10mg/day. 

Results: Thirty-nine patients [median age 70 years: range 52-84, median baseline 

PSA 238 ng/mL range: 2-3000, metastatic sites: bone disease in 38 patients (97%), 



lymph nodes in 15 patients (38%) and visceral disease in 10 patients (26%)] were 

included in the analyses. Three patients (8%) attained a PSA response, defined as a 

decrease of >50% in PSA, confirmed after ≥ 4 weeks. A further six patients (15%) 

had a 30% PSA decline. The median PFS was 2.7 months (95% CI: 2.2 -3.9). Six out 

of 26 evaluable patients (23%) had a symptomatic response on pain score and 

decrease of analgesic consumption. Treatment was well-tolerated. One patient 

required discontinuation of abiraterone due to oedema and hypokalemia. 

Conclusions: This study indicates that abiraterone has antitumor activity in patients 

with mCRPC pretreated with docetaxel and MDV3100. Further prospective 

evaluation of these agents administered in combination is now warranted (Richards J 

et al, Cancer Research 2012). 

Disclosure: C. Pezaro: All authors are ICR employees. The ICR has a commercial 

interest in Abiraterone, G. Attard: All authors are ICR employees. The ICR has a 

commercial interest in Abiraterone. K. Fizazi: PI and advisory board for Jansen and 

Medivation, J.S. de Bono: All authors are ICR employees. The ICR has a commercial 

interest in Abiraterone. JS de Bono has served as a paid consultant for J&J, 

Sanofi-Aventis, Medivation, Astellas, AstraZeneca, Dendreon, Genentech, Pfizer, 

GSK. All other authors have declared no conflicts of interest. 

925P CLINICAL ACTIVITY OF ABIRATERONE ACETATE (AA) AFTER 

PROGRESSION ON MDV3100 IN PATIENTS WITH 

METASTATIC CASTRATION RESISTANT PROSTATE CANCER 

(MCRPC) 

K. Noonan 1 , S. Ellard 2 , K. Chi 3 

1 Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, CANADA, 

2 Medical Oncology, BC Cancer Agency - Centre for the Southern Interior, 

Kelowna, BC, CANADA, 3 Oncology, Vancouver Cancer Centre, University of 

British Columbia, Vancouver, BC, CANADA 

Background: AA improves outcomes in patients with mCRPC through inhibition of 

CYP17 and androgen synthesis. Recently MDV3100, an androgen receptor 

antagonist has also been shown to improve overall survival from mCRPC in patients 

progressing after docetaxel. The optimal sequencing for these agents and whether 

induction of cross-resistance occurs is unknown. 

Methods: Multi-centre retrospective review of all patients with mCRPC treated with 

AA after progressing on MDV3100. 

Results: 25 patients were identified from 3 centres in Canada. Baseline characteristics 

at time of AA initiation included a median age of 72 years, metastases in bone, 

lymph nodes and lung/liver were present in 88, 44 and 28% respectively, 36% of 

patients were on opiates, median hemoglobin was 120 g/L, median alkaline 

phosphatase was 144 U/L, and LDH was elevated in 28%. 100% had prior docetaxel 

chemotherapy and 0% prior ketoconazole. Median duration of prior MDV3100 was 

34 weeks (range 8-95), with 64% (16/25) having had a >30% decline in PSA and 32% 

(8/25) having a rising PSA as best response. After AA, 21 patients were evaluable for 

response. The median duration of treatment with AA was 12 weeks (range 0-80). 

14% (3/21) had a >30% PSA decline. Of these 3 patients, 1 continues to respond at 

84 weeks of follow-up, while the other 2 had a time to PSA progression (defined as a 

25% increase from nadir and a minimum of 2ug/mL) of 18, and 21 weeks. 

Interestingly, the 2 patients with PSA responses of 18 and 21 weeks on AA did not 

respond to MDV3100. 81% (17/21) had a rising PSA as best response. No objective 

responses were observed. Median time to progression (PSA, objective or 

symptomatic) on AA was 14.6 weeks [CI 8.8-20.4] and median overall survival was 

48.7 weeks. 

Conclusions: In this study of patients progressing after MDV3100, treatment with 

AA was associated with a modest response rate; however primary resistance to 

MDV3100 may not preclude a response to AA. The clinical activity of MDV3100 

after progression on AA should also be evaluated to assist in the determination of 

the optimal sequencing of these agents. 


926P SAFETY OF ABIRATERONE ACETATE (AA) IN PATIENTS WITH 

CASTRATION RESISTANT PROSTATE CANCER (CRPC) AND 

CONCOMITANT CARDIAC RISK 

G. Procopio 1 , E. Verzoni 1 , I. Testa 1 , S. Stagni 2 , S. Villa 3 , R. Valdagni 3 

, F.G.M. De Braud 1 

1 Medical Oncology, Istituto Nazionale dei Tumori di Milano, MILAN, ITALY, 

2 Urology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, ITALY, 

3 Radiotherapy, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, ITALY 

Introduction: Abiraterone acetate (AA) is an inhibitor of extragonadal androgen 

biosynthesis that prolongs overall survival in CRPC patients who have received a 

chemotherapy including docetaxel. The most common adverse events related to AA 

therapy were fluid retention, hypertension, hypokaliemia and cardiac disorders. No 

safety data are available in patients with concomitant cardiac disease. 

Methods: Metastatic CRPC patients were enrolled in this prospective study if they 

were also suffering from a concomitant controlled cardiovascular disease. AA 1000 

mg per day and prednisone 5 mg bid were administered orally until grade 3-4 

adverse events (AE) or disease progression. The primary endpoint was the safety 

profile while the secondary endpoints were progression-free survival and PSA 

response. 

Results: From April to September 2011, 46 CRPC patients with concomitant 

cardiovascular disorders have been treated with AA. Main patients characteristics 

were: median age 71 years (range 57-81); baseline mean PSA value 40 ng/ml 

(6.32-995); the most common sites of disease were bone (33 pts, 81 %), lung (13 pts, 

33%) and liver (6 pts, 15 %). All patients were previously challenged with at least 2 

lines of hormone therapy and 1 chemotherapy regimen including docetaxel. The 

most common pre-existing cardiac disorders were hypertension 24 (66%), 

arrhythmias 4 (12 %), cardiac ischemia 4 (9 %) and conduction irregularity 2 (4 %). 

Additionally 10 patients (27 %) had metabolic disorders including dyslipidemia and 

hyperglycemia. AA was feasible without inducing grade 3-4 AE nor treatment 

modification. The most common grade 1-2 AE were asthenia (27%), hypertension 

(18%) and fluid retention (28%). After a median time of treatment of 10 months 

(range 4-12 months) no dose modifications due to toxicity were required. No efficacy 

data are still available. 

Conclusions: Treatment with AA was feasible and well tolerated also in patients 

suffering from cardiac comorbidities and risk factors for cardiovascular disease. 


927P TIME TO PROGRESSION AND SAFETY RESULTS OF A 

NONSPECIFIC CYTOCHROME-P 17 INHIBITOR AFTER 

RESPONSE/STABILIZATION TO DOCETAXEL AS A 

MAINTENANCE STRATEGY IN METASTATIC 

CASTRATATION-RESISTANT PROSTATE CANCER 

I. Gil-Bazo1 , E. Arevalo1 , A. Castillo1 , M.E. Zudaire1 , O.E. Carranza1 , J.P. Fusco1 , 

E. Castanon Alvarez1 , L. Zubiri1 , P. Martín1 , I. Gil-Aldea2 1 

Department of Oncology, Clínica Universidad de Navarra, Pamplona, SPAIN, 

2 

Centro de Investigación Biomédica, Complejo Hospitalario de Navarra, 

Pamplona, SPAIN 

Background: The first-line treatment of metastatic castration-resistant prostate 

cancer (mCRPC) consists of docetaxel-based chemotherapy. The median time to 

progression (TTP) from chemotherapy initiation is 6-8 months (mo). Ketoconazole 

is a nonspecific cytochrome-P 17 inhibitor (CYP17i) that blocks adrenal androgen 

synthesis. Low-dose ketoconazole (LDK), (200 mg, t.d.s) has shown interesting 

activity in mCRPC after progression to androgen deprivation. The role of a CYP17i 

in the maintenance setting after response/stabilization to docetaxel has never been 

studied. 

Methods: Thirty-eight mCRPC patients showing progression to luteinizing-hormone 

releasing hormone agonists (LHRHa), maintained LHRHa and received a median of 

7 cycles of front-line three-weekly docetaxel (75 mg/m2) plus daily prednisone (10 

mg). Twenty out of the thirty-eight patients showing no progression to docetaxel 

were enrolled. After docetaxel, ten patients were assigned to LDK maintenance 

treatment plus prednisone (10 mg/day) and LHRHa, and ten patients received 

LHRHa alone. TTP was the primary endpoint. 

Results: After 33 months follow-up, a median TTP from docetaxel initiation was 

11.5 months (IC95%: 6.3-16.6) for maintenance therapy and 9.2 months (IC95%: 

8.5-9.9) for the control arm p = 0.047). Maintenance treatment was well tolerated 

with only one patient experiencing a grade 4 adverse event (non-symptomatic 

pulmonary embolism). Grade 1 and 2 asthenia and hot flashes worsening were the 

most common toxicities (table). 

Conclusions: This is the first study testing a CYP17i for maintenance therapy after 

response/stabilization to docetaxel. A more than 2 months significant benefit in TTP 

with a favorable toxicity profile is observed. A further prospective analysis in a larger 

series using a CYP17i is warranted. 

Toxicity profile of maintenance therapy with a CYP17 inhibitor. 

Grade Toxicity 1 2 3 4 5 

Asthenia 3 2 - - - 

Diarrhea 1 1 - - - 

Hepatotoxicity 1 1 - - - 

Hyporexia - 1 - - - 

Cephalea 1 - - - - 

Hot flashes 1 4 - - - 

Fluid Retention 1 2 - - - 

Pulmonary embolism - - - 1 - 



928P LHRH AGONIST-INDUCED SUPPRESSION OF THE 

ANDROGEN SYNTHESIS PATHWAY IN PROSTATE CANCER 

J. Pinski, S. Xiong, Q. Wang, S.V. Liu 

Division of Medical Oncology, University of Southern California Norris 

Comprehensive Cancer Center, Los Angeles, CA, UNITED STATES OF 

AMERICA 

Background: Standard first-line therapy for advanced prostate cancer (PC) includes 

the use of a luteinizing hormone releasing hormone (LHRH) agonist. While the 

primary site of action for these agents is the pituitary-hypothalamic-gonadal axis, 

receptors fo LHRH are also present in the membrane of PC cells and mediate a 

direct anti-tumor effect. The mechanism of this effect has been largely unexplored 

and may harbor a context of vulnerability. Previously, we have demonstrated that 

luteinizing hormone (LH) increases de novo steroidogenesis in PC cells and silencing 

of the LH receptor leads to downregulation of steroidogenesis. Here, we examined 

the impact of LHRH agonists on this process at the cellular level. 

Methods: LNCaP PC cells were treated with the LHRH agonist buserelin for 8 hours 

in the presence or absence of the LHRH antagonist antide. Gene expression of LH 

and androgen synthesis enzymes was quantified by real-time polymerase chain 

reaction and protein expression was measured with Western blot. Cell proliferation 

was assessed in these cells using MTS assays. 

Results: The LHRH agonist buserelin significantly suppressed the gene expression of 

LH and the androgen synthesis enzymes AKR1C1, AKR1C2, AKR1C3, CYP11A1 

and RDH5 (p < 0.05). Protein expression of LH, AKR1C1, AKR1C3 and CYP17A1 

was also inhibited by buserelin treatment (p < 0.05). Buserelin also suppressed 

LNCaP cell proliferation in a dose-dependent manner (p < 0.05). The suppressive 

effects of buserelin on gene expression, protein expression and cell proliferation were 

mitigated by the LHRH antagonist antide. 

Conclusion: These data implicate the LHRH agonist buserelin in the direct inhibition 

of de novo tumoral steroidogenesis, which may be mediated by suppression of LH. 

The LH pathway warrants further investigation as a therapeutic target. 


929P LOW-DOSE DETHYLSTILBESTROL IN 


A. Sasse 1 , C.L. Nourani 2 , L.O. Reis 3 

1 Cevon Centre For Evidences In Oncology, UNICAMP - Universidade Estadual 

de Campinas, Campinas, BRAZIL, 2 Oncology, UNICAMP, Campinas, BRAZIL, 

3 Urology, UNICAMP, Campinas, BRAZIL 

Introduction: The role of sequential lines of hormone therapy in castration-resistant 

prostate cancer (CRPC) remains unclear. Currently, the standard treatment for 

patients with CRPC is chemotherapy. Diethylstilbestrol (DES) is a synthetic estrogen 

with anti-tumour properties, which could be effective in these patients, before 

chemotherapy. OBJECTIVE: To determine the efficacy and safety of low-dose DES in 

second-line hormonal therapy for CRPC patients in a single institution. 

Methods: Between 2007 and 2012, a total of 31 patients with metastatic CRPC 

received DES 1 mg daily. All patients had progression after central androgenic 

suppression and at least one line of androgen antagonists (bicalutamide and/or 

flutamide). Central androgenic supression with bilateral orchiectomy or a 

gonadotropin-releasing hormone agonist was maintained. Aspirin 100 mg daily was 

administered to all patients to minimize risk of thromboembolism. The data of PSA 

response (defined as a 50% reduction), progression-free survival (PFS), overall 

survival and adverse events were collected and analyzed. 

Results: The median age was 76,8 years. The PSA response rate was 55%. After a 

median follow up of 22 months, the median PFS was 12 months. Only one patient 

died at the time. The main adverse event was gynecomastia (11/31, 35.4%) and no 

thrombotic event was recorded. 

Conclusion: Low-dose DES appears to be safe and effective for metastatic CRPC 

before initiating chemotherapy. 


930P WHAT PATIENT GROUPS HAVE SPECIAL BENEFITS USING 

THE GNRH-ANTAGONIST DEGARELIX? CONCLUSIONS 

BASED ON REAL LIFE DATA FROM A GERMAN REGISTRY 

G. Geiges 1 , M. Schulze 1 , M. Gedamke 2 

1 Uro-oncology, IQUO, Berlin, GERMANY, 2 Urology/Uro-Oncology, Ferring 

Arzneimittel GmbH, Kiel, GERMANY 

Introduction and objective: The GnRH-antagonists, especially degarelix, are still 

relatively new substances in the treatment of prostate cancer. Data on advantages of 

this specific approach to ADT is accumulating. It is of interest to understand which 

patient groups have a special benefit in using degarelix. We have collected data on 

efficacy and safety of degarelix in daily practice in order to compare with data from 

clinical studies. 


Methods: Data from 421 patients with prostate cancer treated with degarelix were 

collected by 93 office based urologists. Previous treatment, concomitant medication, 

tumour stage and grade as well as alkaline phosphatase (ALP), prostate volume, 

testosterone, PSA and side-effects were documented over a period of up to 2 years or 

until completion of therapy. 

Results: Tumour stages were documented at baseline as T1 27.9%, T2 22.0%, T3 

25.1%, T4 13.1% and Tx 11.5%. Median PSA at baseline was 12.4 ng/mL. 

Testosterone was above castration level (>0.5 ng/mL) in 41.7% of patients (pts) with 

previous hormone therapy and available testosterone value at inclusion (n = 48). In 

14.5% of the pts degarelix was used intermittently. Prostate volume measured by 

transrectal ultrasound was reduced by 40.8% within 3 months compared to baseline. 

For pts in which ALP was measured (n = 61), ALP was suppressed from a median of 

639.9 (IU/L) to 108.7 (IU/L) after 2 months and was still suppressed to 78.6 (IU/L) 

at month 12. Treatment of pts with prior hormone-therapy resulted in 53.8% in a 

stable PSA after 1 year. PSA-reduction to


Has acted as a compensated consultant for Sotio and TEVA, P. Parente: Has 

participated in an advisory board for, and has received research funding from, 

Sanofi, W.R. Gerritsen: Has acted as a compensated consultant for Algaia 

Biomedical Ventures, S. Hitier: Is a Sanofi employee (biostatistician) and owns 

shares in Sanofi, A. Heidenreich: Has participated in advisory boards for Sanofi, 

Janssen Cilag and Astellas. Has received honoraria from, Sanofi, Astellas, Amgen 

and Janssen Cilag, A. Bahl: Has participated in an advisory board for, and 

received research funding from Sanofi. All other authors have declared no 


932P TOLERABILITY OF CABAZITAXEL IN SENIOR ADULTS WITH 


(MCRPC) IN EUROPE 

A. Heidenreich 1 , S. Bracarda 2 , M. Mason 3 , H. Ozen 4 , L. Sengelov 5 , 

W. Gerritsen 6 , C. Papandreou 7 , S. Fossa 8 , S. Hitier 9 , M. Climent 10 

1 Urology, RWTH Aachen University, Aachen, GERMANY, 2 Ospedale San 

Donato, Medical Oncology Arezzo, Arezzo, ITALY, 3 Institute of Cancer & 

Genetics, Cardiff University, Cardiff, UNITED KINGDOM, 4 Urology, Hacettepe 

University Medical Faculty, Ankara, TURKEY, 5 Oncology Department R, Herlev 

University Hospital, Herlev, DENMARK, 6 Medical Oncology, University Medical 

Center Nijmegen, Nijmegen, NETHERLANDS, 7 Medical Oncology, Larissa 

University Hospital, Larissa, GREECE, 8 Medical Oncology, Oslo University 

Hospital, Oslo, NORWAY, 9 Statistics, Sanofi, Paris, FRANCE, 10 Medical 

Oncology, Instituto Valenciano de Oncologia, Valencia, SPAIN 

Background: Cabazitaxel (CBZ), a novel taxane developed to overcome docetaxel 

resistance, has been shown to prolong overall survival compared with mitoxantrone 

in mCRPC patients (pts) who progressed during or after a docetaxel (D)-based 

therapy. Compassionate Use (CUP) and Early-Access (EAP) Programs are allowing 

access to the drug before its commercial availability. This interim analysis of the 

European part of the CUP/EAP focuses on the safety profile of CBZ in elderly 

population. 

Methods: As of September 1 st 2011, 746 pts (range 44-86 years; ≥70 years, n = 325; 

Disclosure: S. Oudard: Has acted as an advisor for, and received honoraria from 

Pfizer Oncology, Bayer Schering Pharma, Roche, GSK, Novartis and Sanofi, J.S. de 

Bono: Has participated in an advisory board and has acted as a consultant for Sanofi. 

Has also received honoraria and research funding from Sanofi, M. Özgüroğlu: Has 

acted as an advisor and consultant (compensated) for, and has received research 

funding from Sanofi, S. Hansen: Has participated in an advisory board for Sanofi, J. 

Machiels: Has acted as a consultant to Boehringer Ingelheim (uncompensated) and 

has received research funding from Sanofi, G. Gravis: Has acted as an 

uncompensated consultant to Sanofi, L. Shen: Is a Sanofi employee (Associate 

Director) and owns Sanofi stocks and shares, A.O. Sartor: Has acted as a consultant 

for Sanofi. Has also received honoraria and research funding from Sanofi. All other 


934P EFFICACY AND TOLERABILITY OF TAXANE-BASED 

CHEMOTHERAPY IN SENIOR ADULTS WITH METASTATIC 

CASTRATION-RESISTANT PROSTATE CANCER (MCRPC): 

A PROSPECTIVE INTERNATIONAL REGISTRY 

J. Droz 1 , E. Efstathiou 2 , A. Heidenreich 3 , A. Yildirim 4 , P. Cabrera 5 , C. Kim 6 , 

A. Horchani 7 , H. Ozen 8 , J.A. Rinck, Jr 9 

1 Medical Oncology, Centre Leon Bérard, Lyon Cedex, FRANCE, 2 Oncology, 


OF AMERICA, 3 Urology, RWTH Aachen University, Aachen, GERMANY, 

4 Oncology, SB Göztepe Training and Research Hospital, Istanbul, TURKEY, 

5 Oncology, Centro Oncologico ISSEMyM, Toluca, MEXICO, 6 Urology, Asan 

Medical Center, Seoul, KOREA, 7 Urology, La Rabta Hospital, Tunis, TUNISIA, 

8 Urology, Hacettepe University Medical Faculty, Ankara, TURKEY, 9 Medical 

Oncology, Hospital A. C. Camargo, Sao Paulo, BRAZIL 

Background: Docetaxel every 3 weeks is the standard of care in mCRPC, although 

other chemotherapy regimens may be administered. Efficacy and toxicity of taxanes 

in older men (70+ y) is poorly documented. Their enrolment in randomized trials is 

limited by exclusion criteria related to performance status (PS) and comorbidities. 

This prospective international registry evaluates taxane toxicity and efficacy in such 

men in real life practice. 

Methods: 333 men with mCRPC (median age 76 y) were evaluated. PS, grade 3-4 

comorbidities (Cumulative Illness Scoring Rate-Geriatrics), dependence (Activity 

Daily Living [ADL], Instrumental ADL [IADL]), nutritional status, primary therapy 

received and outcomes (overall survival (OS), progression-free survival (PFS), best 

clinical benefit [based on pain, analgesic consumption, PS], PSA response, toxicity) 

were collected. Follow-up under therapy was 6 months. 

Results: In all, 24.0% had PS ≥2, 13.5% grade 3-4 comorbidities, 21% were 

dependent in ≥1 IADL, 15.6% in ≥1 ADL and 12.8% had a weight loss ≥5% within 

the past 3 months. According to SIOG (International Society of Geriatric Oncology) 

algorithm, 65.2% were fit, 13.5% vulnerable, 16.8% frail and 4.5% had terminal 

illness. Most men (62.4%) had pain at enrolment. Primary therapy was a taxane in 

58% (3-weekly, 84.4%; median, 5 months) and received another therapy (hormonal 

therapy alone in 23.7%, non-taxane chemotherapy in 10.6%). Clinical characteristics 

of men treated by taxanes and other therapies were comparable at baseline. At 6 

months, 91% were still alive with taxanes vs 81% with other therapies (HR [95% CI] 

0.53 [0.30-0.93] p = 0.027). Frail patients showed the greatest benefit in OS (83% vs 

57%, HR 0.32 [0.11-0.91] p = 0.033). Taxanes also significantly increased PFS (66% 

vs 50%, HR 0.55 [0.40-0.76], p < 0.001), best clinical benefit (60% vs 36%, HR 2.05 

[1.47-2.85], p < 0.001) and PSA response ≥50% (52.5% vs 37.4%, p = 0.018), 

including in frail patients. Main grade 3-4 toxicities with taxanes were fatigue 

(17.1%), nausea/vomiting (14%), diarrhoea (8.8%), anaemia (7.8%), nail change 

(6.7%) and febrile neutropenia (2.6%). 

Conclusions: Taxanes appear the most effective first-line therapy in older men with 

mCRPC and show an acceptable and manageable toxicity, including in frail patients. 

Droz et al. BJU Int 2010; 106: 462-69 

Disclosure: J. Droz: Member of Advisory Board on Prostate Cancer- SANOFI, A. 

Heidenreich: Advisory relationship for Astellas, Janssen Cilag, Sanofi, Ipsen, Takeda 

Honoraria received from Amgen, Astellas, Glaxo, Ipsen, Jansen Cilag, Pfizer, Sanofi, 

Takeda. All other authors have declared no conflicts of interest. 

935P ORAL METRONOMIC CYCLOPHOSPHAMIDE IN PATIENTS 

WITH METASTATIC CASTRATION-RESISTANT PROSTATE 

CANCER STRATIFIED BY PRIOR DOCETAXEL THERAPY 

R. Barroso-Sousa 1 , A.C.R. Chaves 1 , L.G. Fonseca 1 , G. De Castro, Jr. 2 , C. Dzik 1 , 

P.M. Hoff 1 

1 Medical Oncology, ICESP, Sao Paulo, BRAZIL, 2 Medical Oncology, Instituto do 

Cancer do Estado de Sao Paulo, Sao Paulo, BRAZIL 

Background: Treatment options remain limited for patients (pts) with metastatic 

castration-resistant prostate cancer (mCRPC). Here we aimed to investigate the 


efficacy and safety of low-dose oral cyclophosphamide (CTX), an intermittent 

metronomic chemotherapy regimen, in pts with mCRPC, previously treated or not 

with docetaxel. 

Methods: All pts previously diagnosed with mCRPC and treated with CTX 100mg/ 

day (3 weeks on and 1 week off, every 28 days) plus prednisone 10mg/day between 

Oct/2006 and Feb/2012 at our institution were included in this retrospective analysis. 

The primary efficacy endpoint was prostate-specific antigen (PSA) decrease ≥ 50%. 

Secondary endpoints were PSA decrease ≥ 30% and toxicity. Kaplan-Meier estimates 

were calculated and plotted for time to treatment failure (TTF). Single and 

multivariate Cox proportional hazards modeling was used to estimate hazard ratios 

with 95% confidence intervals (95% CI). 

Results: 51 pts with mCRPC were identified, of which 30 (59%) had been already 

treated with docetaxel. The median age was 72 y.o. (56-86) and 27 pts (53%) 

were ECOG PS0-1 and 24 pts (47%) PS2-3. Five pts presented with visceral 

metastasis (10%) and median PSA 525 ng/dL (12-4099) before treatment. Median 

number of previous cytotoxic lines was 1 (0-2). After a median number of cycles 

CTX of 3, PSA decrease of ≥50% was achieved in 28.6% and 16.7% of 

docetaxel-naive and docetaxel-pretreated pts, respectively ( p= 0.30). Besides, PSA 

declines of ≥30% occurred in 38.1% and 30.0% of docetaxel-naive and 

docetaxel-pretreated patients, respectively (p= 0.54). Overall, the median TTF 

was estimated to be 2.4 mo. (95% CI 1.87–3.73). Previously treatment with 

docetaxel was not statistically significant to TTF, and the median TTF was 2.1 

mo. (95% CI 1.6–3.2) for docetaxel-pretreated and 3.4 mo. (95% CI 1.7–5.4) for 

docetaxel-naïve patients (HR 1.47; 95% CI 0.78 – 2.74;p=0.22).Ingeneral,oral 

CTX was safe and well tolerated and the most commonly observed G3-4 AE was 

lymphopenia (29%). 

Conclusions: Oral metronomic CTX plus prednisone seems to be active and safe in 

mCRPC, even in pts previously treated with docetaxel. Its convenient oral 

administration, low cost, and acceptable toxicity profile may justify future 

investigations of this classic alkylating agent in mCRPC. 


936P SAFETY OF CYTOTOXIC CHEMOTHERAPY FOLLOWING 

RADIUM-223 CHLORIDE (RA-223) THERAPY IN THE PHASE 3 

ALSYMPCA STUDY IN PATIENTS WITH 

CASTRATION-RESISTANT PROSTATE CANCER (CRPC) WITH 

BONE METASTASES 

O. Sartor 1 , R.E. Coleman 2 , S. Nilsson 3 , N. Vogelzang 4 , A. Cross 5 ,C. 

G. O’Bryan-Tear 6 , K. Staudacher 6 , J.E. Garcia-Vargas 7 ,J.Zou 8 , C. Parker 9 

1 Department of Medicine: Section of Hematology & Medical Oncology and 

Department of Urology, Tulane Cancer Center, New Orleans, LA, UNITED 

STATES OF AMERICA, 2 Academic Unit of Clinical Oncology, Weston Park 

Hospital, Sheffield, UNITED KINGDOM, 3 Radiumhemmet, Karolinska University 

Hospital, Stockholm, SWEDEN, 4 Developmental Therapeutics, Comprehensive 

Cancer Centers of Nevada, Las Vegas, NV, UNITED STATES OF AMERICA, 

5 Biostatistics, PharmaNet, Hemel Hempstead, UNITED KINGDOM, 6 Medical, 

Algeta ASA, Oslo, NORWAY, 7 Oncology Global Clinical Programs, Bayer 

HealthCare Pharmaceuticals, Montville, NJ, UNITED STATES OF AMERICA, 

8 Global Medical Affairs, Bayer HealthCare Pharmaceuticals, Montville, NJ, 

UNITED STATES OF AMERICA, 9 Academic Urology, The Royal Marsden NHS 

Foundation Trust, Sutton, UNITED KINGDOM 

Introduction: Ra-223 is a first-in-class alpha-emitter pharmaceutical that 

targets bone metastases with high-energy, extremely short range (


deaths occurred. Prospective studies to evaluate Chemo following Ra-223 are 

warranted. 

Ra-223 + BSC Placebo + BSC 

Parameter 

(n = 90) 

(n = 54) 

Median time to Chemo; days (range) 79.0 (2–667) 64.5 (2–448) 

Median duration Chemo; days 

(range) 

117.5 (1–809) 112.5 (1–863) 

Chemo = docetaxel; n (%) 63 (70.0) 39 (72.2) 

Docetaxel daily dose (mg); n 22 17 

Mean (SD) 97.8 (41.6) 102.7 (46.3) 

Median (min-max) 92.5 (35-150) 120.0 (30-165) 

Deaths on Chemo; n (%) 13 (14.4) 8 (14.8) 

Cause: PC and skeletal mets (± other 

mets) 

9 (10.0) 7 (13.0) 

PC with other mets (or mets not 

specified) 

3 (3.3) 0 (0) 

Cerebral hemorrhage due to trauma 

Cardiopulmonary failure 

1 (1.1) 0 (0) 0 (0) 1 (1.1) 

Deaths within 30 days post Chemo; 

n (%) 

5 (5.6) 2 (3.7) 

Cause: PC and skeletal mets 

(± other mets) 

3 (3.3) 2 (3.7) 

Bronchopneumonia Respiratory 

failure + pulmonary edema 

1 (1.1) 1 (1.1) 0 (0) 0 (0) 

Neutrophils; (Absolute) (x10^9/L) 88 3.6 (0.9-26.0) 47 49 4.6 (1.9-16.4) 30 

Baseline, n Median (min-max) 4.4 (0.5-24.4) 41 5.7 (1.6-13.1) 19 

Month 2, n Median (min-max) 3.8 (1.3-10.8) 23 4.6 (1.1-8.9) 12 

Month 4, n Median (min-max) 3.5 (0.5-6.3) 12 4.7 (1.5-12.2) 7 

Month 6, n Median (min-max) 3.5 (1.9-9.4) 13 3.9 (3.0-6.4) 8 4.6 

Month 8, n Median (min-max) 3.6 (1.1-8.9) 8 (3.0-8.5) 6 5.6 

Month 10, n Median (min-max) 

Month 12, n Median (min-max) 

5.0 (2.5-7.1) (2.8-8.9) 

BSC, best standard of care; Chemo, cytotoxic chemotherapy; mets, metastases; PC, 

prostate cancer 

Disclosure: O. Sartor: O. Sartor has served in a consultant or advisory role for Algeta 

ASA and Bayer. S. Nilsson: S. Nilsson has served in a consultant or advisory role for 

Algeta ASA. N. Vogelzang: N. Vogelzang has served in a consultant or advisory role 

for and has received grant/research support from Algeta ASA and Bayer. C.G. 

O’Bryan-Tear: C.G. O’Bryan-Tear is employed by and has an ownership interest in 

Algeta ASA. K. Staudacher: K. Staudacher is employed by and has an ownership 

interest in Algeta ASA. J.E. Garcia-Vargas: J. Garcia-Vargas is employed by Bayer 

HealthCare Pharmaceuticals. J. Zou: J. Zou is employed by Bayer HealthCare 

Pharmaceuticals. C. Parker: C. Parker has served in a consultant or advisory role for 

Algeta ASA (uncompensated) and Bayer. All other authors have declared no conflicts 

of interest. 

937P DENOSUMAB IN PATIENTS WITH METASTATIC PROSTATE 

CANCER PREVIOUSLY TREATED WITH DENOSUMAB OR 

ZOLEDRONIC ACID: 2-YEAR OPEN-LABEL EXTENSION 

PHASE RESULTS FROM THE PIVOTAL PHASE 3 STUDY 

K. Fizazi 1 , J.E. Brown 2 , M. Carducci 3 , N.D. Shore 4 , P. Sieber 5 , F. Kueppers 6 , 

L. Karsh 7 ,R.Wei 8 , C. Goessl 9 

1 Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, 

FRANCE, 2 Medical Oncology, Cancer Research UK Clinical Centre, Universities 

of Leeds/Sheffield, Leeds, UNITED KINGDOM, 3 Kimmel Cancer Center, Sidney 

Kimmel Comprehensive Cancer Center, Baltimore, MD, UNITED STATES OF 

AMERICA, 4 Urology, Carolina Urologic Research Center, Myrtle Beach, SC, 

UNITED STATES OF AMERICA, 5 Urology and Urological Surgery, Urological 

Associates of Lancaster, Ltd., Lancaster, PA, UNITED STATES OF AMERICA, 

6 Urology, Urology Associates, Christchurch, NEW ZEALAND, 7 Clinical Research 

Department, The Urology Center of Colorado, Denver, CO, UNITED STATES OF 

AMERICA, 8 Global Biostatistical Science, Amgen Inc., Thousand Oaks, CA, 

UNITED STATES OF AMERICA, 9 Clinical Development, Amgen Inc., Thousand 

Oaks, CA, UNITED STATES OF AMERICA 

Background: In a phase 3, randomized, double-blinded (DB) trial (NCT00321620), 

subcutaneous (SC) denosumab prevented skeletal-related events (SRE) more 

effectively compared with intravenous (IV) zoledronic acid (ZA) in men with 

castration-resistant prostate cancer (CRPC) and bone metastases (Fizazi K et al., 

Lancet 2011). As a result, all patients (pts) remaining on study were offered 

open-label (OL) denosumab in a pre-specified 2-year extension phase. 

Materials and methods: Pts (n = 1901) with CRPC metastatic to bone received either 

SC denosumab 120 mg and IV placebo or IV ZA 4 mg (adjusted for renal function) 

and SC placebo Q4W in the DB treatment phase. OL denosumab Q4W was offered 

for up to 2 years to pts remaining on study. Pts declining OL treatment were 

followed for survival for up to 2 years after their last dose of investigational product 

in the DB treatment phase. 

Results: Of 323 pts completing the DB phase, 153 (87.4%) who were randomized to 

denosumab (here referred to as DD pts) and 128 (86.5%) randomized to ZA (here 

referred to as ZD pts) continued in the OL phase. Demographics were balanced 

between groups. Cumulative median (Q1, Q3) denosumab exposure over the entire 

study for DD pts was 12.0 (5.6, 21.3) months (range: 0.1 to 67.2 months). Overall, 

adverse events (AEs) were comparable between groups (n = 138/147 [93.9%] DD pts; 

n = 105/118 [89.0%] ZD pts). Twelve pts in the DD group and 7 pts in the ZD group 

developed osteonecrosis of the jaw (ONJ) in the OL phase, resulting in a cumulative 

ONJ incidence for the entire study of 3.8% for DD pts and 2.2% for ZD pts. 

Hypocalcemia AEs during the OL phase were balanced between groups (n = 8 DD 

pts; n = 5 ZD pts). Serious AEs were reported in 78 (53.1%) DD pts and 63 (53.4%) 

ZD pts. Median (95% CI) overall survival over the entire study was similar 

between groups: 19.4 months (17.8 to 21.0) for DD pts, 19.3 months (18.0 to 20.6) 

for ZD pts. 

Conclusion: This two-year OL extension treatment phase confirmed the 

long-term safety profile of denosumab in pts with prostate cancer metastatic to bone 

who received denosumab for up to 5.6 years or who switched from ZA to 

denosumab. 

Disclosure: K. Fizazi: Consultant/advisor: Amgen, Novartis, J.E. Brown: Advisory 

Board Member: Amgen, Novartis, Bristol Myers Squibb Corporate Sponsored 

Research: Novartis Other Substantive Relationships: Consultant, Amgen, M. 

Carducci: Consultant/advisor: Amgen, N.D. Shore: Consultant/Advisor: Amgen, 

Astellas, Bayer, Dendreon, Janssen, Medivation, Sanofi Corporate Sponsored 

Research: Amgen, Astellas, Bayer, Dendreon, Janssen, Medivation, Sanofi, Active 

Biotech, BMS, Millenium, Oncogenix, Progenics, BN Immunotherapeutics, P. Sieber: 

Other substantive relationships: consultant, speaker: Amgen, R. Wei: Employee and 

stockholder: Amgen, C. Goessl: Employee and stockholder: Amgen. All other authors 


938P ANDROGEN DEPRIVATION AND RADIATION WITH HELICAL 

TOMOTHERAPY TO METASTASES IN PATIENTS WITH 

OLIGOMETASTATIC HORMONE - SENSITIVE PROSTATE 

CANCER 

P. Twardowski 1 ,W.Ye 2 ,S.Pal 1 , C. Arbayo 2 , M. Junqueira 1 , P. Tryon 1 , J. Wong 3 

1 Medical Oncology and Experimental Therapuetics, City of Hope Cancer Center, 

Duarte, CA, UNITED STATES OF AMERICA, 2 Biostatistics, City of Hope Cancer 

Center, Duarte, CA, UNITED STATES OF AMERICA, 3 Radiation Oncology, City of 

Hope Cancer Center, Duarte, CA, UNITED STATES OF AMERICA 

Background: Metastatic prostate cancer (PC) is treated with androgen deprivation 

therapy (ADT) and subsequent treatments are employed only after the development 

of castration resistance. We hypothesized that treatment of oligometastases with 

external beam radiation therapy (EBRT) concurrent with ADT will be feasible and 

safe and may provide therapeutic benefit by more effective reduction in the tumor 

burden. 

Methods: Patients (pts) with hormone sensitive PC (HSPC) and 1-5 metastases 

(mts) detected by bone scan and CT scan were treated with 36 weeks of LHRH 

agonist combined with bicalutamide and EBRT up to 45 Gy to all visible metastatic 

sites. Seventeen pts (59%) who had no prior therapy of the primary tumor, also 

received up to 78 Gy to the prostate. Primary objectives were time to treatment 

failure (TTF) and toxicity. TTF was calculated from the end of therapy until PSA 

reached pre-treatment level or 10 (whichever was lower) or radiographic progression 

or until ADT was restarted. 

Results: Twenty nine pts were treated. Median number of mts was 1. Median 

Gleason score was 8 (range 5-10). Median baseline PSA was 11.4 (range 1-74.5). 

Twenty one pts (72%) had bone mts, 13 pts (45%) had lymph node (LN) mts and 8 

pts (28%) had mts limited to pelvic LNs. Median follow up was 25.7 months (range 

13.4-61.4). Grade 3 toxicities included diarrhea (7%), urinary frequency (3%), renal 

insufficiency (3%). Twenty five pts (86%) reached PSA nadir of

939P NEOADJUVANT SIPULEUCEL-T IN LOCALIZED PROSTATE 

CANCER: EFFECTS ON IMMUNE CELLS WITHIN THE 

PROSTATE TUMOR MICROENVIRONMENT 

L. Fong1 , V. Weinberg1 , S. Chan1 , J. Corman2 , C. Amling3 , R.A. Stephenson4 , 

J. Simko1 , R.B. Sims5 , P. Carroll1 , E.J. Small1 1 

Comprehensive Cancer Center, University of California, San Francisco, 

San Francisco, CA, UNITED STATES OF AMERICA, 2 Surgery, Virginia Mason 

Medical Center, Seattle, WA, UNITED STATES OF AMERICA, 3 Urology, Oregon 

Health & Science University, Portland, OR, UNITED STATES OF AMERICA, 

4 

Urology, University of Utah, Salt Lake City, UT, UNITED STATES OF AMERICA, 

5 

Clinical Affairs, Dendreon Corporation, Seattle, WA, UNITED STATES OF 

AMERICA 

Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy 

for patients with asymptomatic or minimally symptomatic metastatic castrate 

resistant prostate cancer (mCRPC). To date, studies of sipuleucel-T in patients with 

mCRPC have studied immune response in peripheral blood. The immune effects of 

sipuleucel-T in prostatic cancer tissue are unknown. 

Methods: NeoACT (P07-1; NCT00715104) is an open-label, Phase 2 study of 

patients with localized prostate cancer who received sipuleucel-T prior to radical 

prostatectomy (RP) to examine the immunologic effects of treatment on prostate 

tissue. Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals, 

beginning 6-7 weeks prior to RP, and post-RP are being followed for immune 

response. The primary endpoint was the change in the frequency of lymphocytes 

between prostate biopsies (pre-treatment) and RP tissue (post-treatment), as assessed 

by immunohistochemistry (IHC). 

Results: Of the 42 enrolled patients (median age 61 years, all ECOG = 0, Gleason 

Sum: ≤6 = 24%, 7 = 43%, ≥8 = 33%), 38 received all 3 pre-RP sipuleucel-T infusions 

and were evaluable by IHC. Treatment-related AEs were manageable and transient. 

Sipuleucel-T did not appear to affect operative complications, procedure time, or 

estimated blood loss. Frequent events (>10% of patients) that occurred ≤1 day after 

infusion were fatigue, headache, and myalgia. Significant increases (>3 fold) in 

infiltrating CD3 + , CD3 + /CD4 + , and CD3 + /CD8+ T cell populations were 

observed at the tumor rim (where benign and malignant glands interface), compared 

with the pretreatment biopsy (all p = 0.0001). CD3 + /CD4 + /FoxP3+ cells were also 

increased at the tumor rim (∼2-fold; P = 0.005), but represented a small proportion 

of the observed T cells. This level of T cell infiltration was not seen in a cohort of 12 

concurrent cases that did not receive neoadjuvant treatment. 

Conclusions: Neoadjuvant sipuleucel-T treatment is associated with an increased 

frequency of T cells in the prostate at the interface of the benign and malignant 

glands. These data demonstrate that sipuleucel-T can modulate the presence of 

lymphocytes at prostate cancer tissue in vivo. 

Disclosure: L. Fong: Research funding from Dendreon. R.B. Sims: Employee and 

stockholder of Dendreon. P. Carroll: Honoraria from Takeda. Research funding from 

Myriad and Abbot, E.J. Small: Honoraria from Dendreon. All other authors have 


940P OVERALL SURVIVAL BENEFIT WITH SIPULEUCEL-T BY 

BASELINE PROSTATE-SPECIFIC ANTIGEN (PSA): AN 

EXPLORATORY ANALYSIS FROM THREE PHASE 3 TRIALS 

P. Kantoff 1 , G. Chodak 2 , R.B. Sims 3 , J.B. Whitmore 4 , P. Schellhammer 5 

1 Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, UNITED STATES 

OF AMERICA, 2 Oncology, Weiss Memorial Hospital, Chicago, IL, UNITED 

STATES OF AMERICA, 3 Clinical Affairs, Dendreon Corporation, Seattle, WA, 

UNITED STATES OF AMERICA, 4 Biometrics, Dendreon, Seattle, WA, UNITED 

STATES OF AMERICA, 5 Urology, Eastern Virginia Medical School / Urology of 

Virginia, Virginia, VA, UNITED STATES OF AMERICA 

Introduction and objective: Sipuleucel-T is an autologous cellular immunotherapy 

approved for the treatment of asymptomatic or minimally symptomatic metastatic 

castrate-resistant prostate cancer (mCRPC) based on improved overall survival (OS) 

in the pivotal phase 3 IMPACT trial (NCT00065442). In a subgroup analysis of 

pooled data from three Phase 3 trials of sipuleucel-T in mCRPC, baseline PSA was 

found to be the most significant predictive factor for OS. To further investigate the 

impact of baseline PSA levels on outcomes following sipuleucel-T, we conducted an 

exploratory analysis of patients (pts) from three Phase 3 trials. 

Methods: The analysis included all 737 randomized pts from three Phase 3 trials 

(D9901, D9902A and IMPACT). Pts were categorized by baseline PSA quartile 

(Table), as well as by ECOG PS, and median for other baseline prognostic variables 

(i.e. lactate dehydrogenase [LDH], alkaline phosphatase [ALP], and hemoglobin 

[Hgb]). Median OS and hazard ratio (HR) were estimated using Kaplan-Meier and 

Cox models, respectively. 

Results: HR values suggest consistent treatment effect in all subsets, although there is 

inadequate power to show statistical significance within each quartile. There was a 

trend toward an increased magnitude of treatment benefit in pts with a lower 

baseline PSA (Table). Results for other baseline prognostic variables also suggest a 

trend toward greater benefit with better prognostic features. However, results for 

baseline Hgb indicated an opposite trend 

Conclusions: Although not powered for statistical significance, this analysis supports 

a consistent OS benefit with sipuleucel-T across PSA quartiles in patients enrolled in 

Phase 3 trials. The greater benefit with lower baseline PSA suggests that pts with less 

advanced disease may benefit more from sipuleucel-T. 

Baseline PSA (ng/mL) 

≤22.3 >22.3– ≤ 49.9 >49.9– ≤ 137.8 >137.8 

n 

Median OS, mos 

184 184 184 183 

Sipuleucel-T 41.2 25.9 20.6 15.1 

Control 26.7 22.0 14.8 13.5 

Difference 14.5 3.9 5.8 1.6 

HR; 95% CI 0.48; 

0.32–0.73 

0.76; 

0.53–1.11 


0.67; 

0.47–0.95 

0.88; 

0.62–1.25 

Disclosure: P. Kantoff: Advisory boards for Dendreon Corporation G. Chodak: Stock 

ownership in Amgen; Advisory boards for Dendreon Corporation and Janssen; 

Honoraria for Dendreon Corporation and Amgen. R.B. Sims: Stock ownership and 

employee of Dendreon Corporation. J.B. Whitmore: Employee of Dendreon 

Corporation; Stock ownership in Dendreon Corporation and Amgen, P. 

Schellhammer: Honoraria for Dendreon Corporation 

941P IMPACT OF SALVAGE THERAPY WITH APC8015F ON THE 

OVERALL SURVIVAL (OS) BENEFIT ACHIEVED WITH 

SIPULEUCEL-T IN THREE PHASE 3 STUDIES OF 

METASTATIC CASTRATE-RESISTANT PROSTATE CANCER 

(MCRPC) 

D.J. George 1 , L.G. Gomella 2 , T. Devries 3 , J.B. Whitmore 3 , M.W. Frohlich 4 , 

C. Nabhan 5 

1 Medicine, Duke University, Durham, NC, UNITED STATES OF AMERICA, 

2 Urology, Thomas Jefferson University, Philadelphia, PA, UNITED STATES OF 

AMERICA, 3 Biometrics, Dendreon, Seattle, WA, UNITED STATES OF AMERICA, 

4 Clinical Affairs, Dendreon Corporation, Seattle, WA, UNITED STATES OF 

AMERICA, 5 Hematology and Medical Oncolgoy, Advocate Lutheran General 

Hospital, Park Ridge, IL, UNITED STATES OF AMERICA 

Background: Sipuleucel-T is an autologous cellular immunotherapy approved for 

asymptomatic or minimally symptomatic mCRPC. Three Phase 3 sipuleucel-T trials 

(D9901, D9902A, IMPACT) allowed control patients (pts) to receive salvage 

treatment with an autologous product derived from previously frozen cells 

(APC8015F). We previously reported that APC8015F demonstrated no deleterious 

effect. Control pts who received APC8015F had more favorable baseline prognostic 

features; however, after adjusting for these imbalances, APC8015F appears to have 

prolonged OS in control pts, potentially reducing the observed sipuleucel-T 

treatment effect. This exploratory integrated analysis estimates the OS benefit 

conferred by sipuleucel-T, adjusting for APC8015F in control pts. 

Methods: A rank-preserving structural failure time (RPSFT) model was used to 

estimate control arm OS if treatment with APC8015F had not occurred. This allows 

estimation of the treatment effect of sipuleucel-T, adjusting for salvage effect. 

Results: Median OS from randomization in the three pooled trials was 25.4 months 

with sipuleucel-T (n = 488) and 21.5 months with control (n = 249). Of the control 

arm pts, 165 (66.3%) subsequently received APC8015F. Median OS from 

randomization in the control population was 23.6 months for pts receiving 

APC8015F and 12.7 months for those who did not. Using the RPSFT model, and 

assuming APC8015F was as effective as sipuleucel-T, the estimate of median OS for 

control pts was 17.3 months, representing an 8.1 month median increase in OS with 

sipuleucel-T. Results from extensions of the RPSFT model, where APC8015F is 

assumed to have less treatment effect than sipuleucel-T, will be presented. 

Conclusions: These analyses estimate a median OS benefit for sipuleucel-T between 

3.9 and 8.1 months, assuming that APC8015F had either no efficacy or comparable 

efficacy to sipuleucel-T, respectively. These results suggest a possible greater 

treatment effect of sipuleucel-T than was reported in the three Phase 3 studies. 

Future studies should account for potential crossover treatment bias as this may 

diminish estimates of OS benefit. 

Disclosure: D.J. George: Consultant, Investigator, or Lecturer for the following 

companies: Astellas, Bayer, BMS, Dendreon, Exelixis, Genentech/Roche, GSK, Ipsen, 

Jansen, Medivation, Novartis, Pfizer, Sanofi, Viamet, L.G. Gomella: Consultant/ 

Advisor and Clinical Trials for Dendreon, T. Devries: Employee and Stockholder of 

Dendreon. J.B. Whitmore: Employee and Stockholder of Dendreon. M.W. Frohlich: 

Employee and Stockholder of Dendreon. C. Nabhan: I am on the speakers bureau of 

Dendreon and have received honoraria for speaking engagements. 



942P ANTIGEN PRESENTING CELL (APC) ACTIVATION IN 

SIPULEUCEL-T: IS ACTIVATION INCREASED IN EARLIER 

PROSTATE CANCER DISEASE STATES? 

E.J. Small1 , J.D. Wesley2 , D.I. Quinn3 , C. Higano4 , D. Lin5 , H. Haynes2 , 

F. Stewart6 , J.B. Trager2 , N. Sheikh7 1 

Medicine/urology, University of California, San Francisco, San Francisco, CA, 

UNITED STATES OF AMERICA, 2 Clinical Immunology, Dendreon, Seattle, WA, 

UNITED STATES OF AMERICA, 3 USC Norris Comprehensive Cancer Center, 

University of Southern California, Keck School of Medicine, Los Angeles, CA, 

UNITED STATES OF AMERICA, 4 Seattle Cancer Care Alliance, University of 

Washington, Seattle, WA, UNITED STATES OF AMERICA, 5 School of Medicine, 

University of Washington, Seattle, WA, UNITED STATES OF AMERICA, 

6 

Biometrics, Dendreon Corporation, Seattle, WA, UNITED STATES OF AMERICA, 

7 

Clinical Immunology, Dendreon Corporation, Seattle, WA, UNITED STATES OF 

AMERICA 

Background: Sipuleucel-T is an autologous cellular immunotherapy approved by the 

US FDA for the treatment of asymptomatic or minimally symptomatic metastatic 

castrate resistant prostate cancer (mCRPC). In the Phase 3 mCRPC trials, APC 

activation in the sipuleucel-T product correlated with overall survival. In this analysis, 

sipuleucel-T product characteristics were compared across a range of disease states. 

Methods: Sipuleucel-T product parameters were assessed in 4 trials of the following 

treatment settings: neoadjuvant, n = 42; serologic progression following local therapy, 

n = 12; asymptomatic or minimally symptomatic mCRPC, n = 341; and mCRPC 

(asymptomatic and symptomatic), n = 104. Cellular composition and APC activation 

(CD54 upregulation) were evaluated for all 3 sipuleucel-T doses; cumulative CD54 

upregulation was calculated for each patient. In some studies, cytokines and T cell 

and B cell activation markers were assessed during sipuleucel-T manufacture. 

Results: Baseline demographics were generally representative of each disease state: 

patients in the neoadjuvant setting were younger with lower disease burden; those 

with mCRPC had the highest disease burden and more patients had received prior 

chemotherapy. APC activation patterns were similar among trials, with increased 

CD54 upregulation at the second and third treatment. The median cumulative fold 

increase in CD54 upregulation in patients with earlier disease (neoadjuvant: 35.5, 

serological progression: 43.5) was significantly greater than in patients with 

asymptomatic or minimally symptomatic mCRPC (28.7) and mCRPC (21.8) (p < 

0.0001). During sipuleucel-T manufacture, lymphocyte activation and cytokine 

profiles were similar across disease states, with consistently enhanced expression at 

the second and third doses. 

Conclusion: The process of manufacturing sipuleucel-T activates APCs in both early 

and late disease states, and generates similar T and B cell activation and cytokine 

profiles consistent with immunological prime-boost. However, APC activation was 

more robust in earlier disease states, raising the possibility that patients with less 

advanced disease may derive greater benefit. 

Disclosure: E.J. Small: Honoraria from Dendreon. J.D. Wesley: Employee and 

Stockholder of Dendreon. D.I. Quinn: Consultant/Advisor to Dendreon, Pfizer, 

Bayer, Novartis, Genentech, C. Higano: Consultant/advisory role, honoraria, and 

research funding from Dendreon, D. Lin: Honoraria from Dendreon. H. Haynes: 

Employee and Stockholder of Dendreon. F. Stewart: Employee and Stockholder of 

Dendreon. J.B. Trager: Employee and Stockholder of Dendreon. N. Sheikh: Employee 

and Stockholder of Dendreon. 

943P OPENACT: PHASE 2, OPEN-LABEL STUDY OF SIPULEUCEL-T 

IN METASTATIC CASTRATE-RESISTANT PROSTATE CANCER 

(MCRPC) 

J. Corman 1 , N. Dawson 2 , S. Hall 3 , C. Nabhan 4 , A. Ferrari 5 , A.J. Armstrong 6 , 

M.I. Murdock 7 , F. Stewart 8 , N. Sheikh 9 , D.P. Petrylak 10 

1 Surgery, Virginia Mason Medical Center, Seattle, WA, UNITED STATES OF 

AMERICA, 2 Medical Oncology, Georgetown University, Washington, WA, 

UNITED STATES OF AMERICA, 3 Urology, Mount Sinai School of Medicine, 

New York, NY, UNITED STATES OF AMERICA, 4 Hematology and Medical 

Oncolgoy, Advocate Lutheran General Hospital, Park Ridge, IL, UNITED STATES 

OF AMERICA, 5 Medicine, New York University Cancer Center, New York, NY, 

UNITED STATES OF AMERICA, 6 Medical Oncology, Duke Cancer Institute, Duke 

University, Durham, NC, UNITED STATES OF AMERICA, 7 Urology, Murdock 

Urology Associates, Greenbelt, MD, UNITED STATES OF AMERICA, 

8 Biometrics, Dendreon Corporation, Seattle, WA, UNITED STATES OF AMERICA, 

9 Clinical Immunology, Dendreon Corporation, Seattle, WA, UNITED STATES OF 

AMERICA, 10 Medical Oncology, Columbia University Medical Center, New York, 

NY, UNITED STATES OF AMERICA 

Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy 

for the treatment of asymptomatic or minimally symptomatic mCRPC. In the Phase 

3 IMPACT trial, sipuleucel-T showed a 22% reduction in risk of death (p = 0.032) 

and a 4.1-month median OS improvement (25.8 vs 21.7 months) compared with 

control. OpenACT (P09-1; NCT00901342) is a Phase 2 open-label study to further 

evaluate the safety and immune responses of sipuleucel-T in patients (pts) with 

mCRPC. 

Methods: Pts received sipuleucel-T at 2-week (wk) intervals for a total of 3 infusions. 

Sipuleucel-T is manufactured from autologous PBMCs isolated by leukapheresis at 

wks 0, 2 and 4, and activated with PA2024 (a recombinant fusion protein composed 

of prostatic acid phosphatase [PAP] linked to GM-CSF). Cell activation is measured 

by upregulation of the costimulatory molecule CD54. The primary endpoint was to 

evaluate the magnitude of immune responses to sipuleucel-T treatment. 

Results: From October 2009–June 2010, 104 pts were enrolled; 101 pts received ≥1 

leukapheresis and 98 pts received ≥1 infusion (safety population). Pts who had 

received prior docetaxel (D; 29.3% of enrolled pts) had a higher baseline 

prostate-specific antigen (90 vs 40ng/mL) and a greater proportion with a time from 

diagnosis of ≥6 years (93.5% vs 68.7%) compared with pts with no prior D exposure. 

Consistent with previous studies, CD54 upregulation and post-culture cytokine levels 

were significantly greater at wk2 and wk4 compared with wk0 (p < 0.05). At wk 6, 

PAP2024 and PAP-specific humoral and T cell proliferative responses were 

significantly increased from baseline. Pts without prior exposure to D had higher 

CD54 cell counts and total nucleated cell count (TNC) than pts who had received 

prior D. The most common AEs were infusion-related: fatigue (30.6%), nausea 

(18.4%) and chills (17.3%). 

Discussion: Sipuleucel-T generates antigen-specific immune responses in patients 

with and without prior D exposure. However, product characteristics suggest that 

patients without prior D may generate sip-T products with higher TNC, which has 

previously been shown to correlate with prolonged survival, supporting earlier use in 

the mCRPC treatment paradigm. 

Disclosure: J. Corman: On the Board of Directors for Benaroya Research Institute 

and employee of Virginia Mason Medical Center, N. Dawson: Corporate sponsored 

research for Dendreon Corporation, and participation in Speakers Bureau also for 

Dendreon Corporation, S. Hall: Corporate sponsored research for Dendreon and 

Medivation, C. Nabhan: Participation in corporate sponsored research and speakers 

bureau, A. Ferrari: Participation in advisory boards, A.J. Armstrong: Advisory boards 

for Bristol Myers Squibb, Bayer, Amgen; sponsored research for Dendreon, Sanofi 

Aventis, Medivation, Eli Lilly, Pfizer, Novartis, Janssen Biotech, Kanglaite Active 

Biotech/Ipsen; speaker for Dendreon, Sanofi Aventis, Amgen, Pfizer, F. Stewart: 

Employee and stock ownership in Dendreon Corporation, N. Sheikh: Employee of 

and stock ownership in Dendreon Corporation, D.P. Petrylak: Advisory boards for 

Amgen, Bayer, Pfizer, Ferring, Millenium, Novartis, Dendreon, Johnson and 

Johnson, GlaxoSmithKline; sponsored research Celgene, Dendreon, Sanofi, Pfizer, 

AstraZeneca, GlaxoSmithKline, Rogesen Institute, Boheringer Ingelheim, All other 


944P COMPARATIVE EVALUATION OF RADIATION-INDUCED 

DAMAGES IN PROSTATE CANCER PATIENTS AFTER 

INTRATISSUE RADIATION THERAPY USING I-125 SEEDS 

AND EXTERNAL BEAM RADIATION THERAPY 

I.N. Boyko, A. Ulyanov, V. Pasov, O. Terekhov 

Radiation-Induced Damages, Medical Radiological Research Center of the RF 

Health and Social Development Ministry, Obninsk, RUSSIAN FEDERATION 

Purpose: To compare complications of external beam radiation therapy (EBRT) and 

brachytherapy for prostate cancer. 

Materials and methods: We performed a comparative evaluation of 

radiation-induced damages of the small pelvis organs in 46 patients with prostate 

cancer. The first group consisted of 24 patients who received EBRT to a total tumor 

dose of 65-72 Gy. In the second group (22 patients), standard brachytherapy 

procedures were carried out. 

Results: The patients were distributed according to the type of radiation-induced 

complications (Table 1). Table 1 Distribution of patients according to the type of 

radiation-induced complications. 

Group No. Cystitis 

Bladder 

ulcer Rectitis 

Rectal 

ulcer 

Combined damages 

(rectitis, rectal 

ulcer) 

Group 1 (24) 8 (33.3%) 2 (8.3%) 7 (29.2%) 3 (12.5%) 4 (16.7%) 

Group 2 (22) 4 (18.2%) 0 13 (59%) 2 (9.1%) 3 (13.7%) 

Thus, the rate of rectal complications was higher in the brachytherapy group 

compared with the EBRT group. Radiation cystitis occurred more frequently in 

patients with bladder lesions of group 1. It is worth noting that the severity of 

radiation-induced damage appeared to be more marked in group 

2. Radiation-induced strictures of the posterior urethra were detected in 2 (8.3%) 

patients of group 1 and in 5 (22.7%) patients of group 2. More serious complications 

associated with functional disturbances of organs (microcystitis, rectovesical fistula, 

rectal stricture) occurred only in patients who had undergone external beam 

radiation therapy. 

Conclusions: Our study suggests that radiation-induced damages of the rectum and 

posterior urethra occur more often after brachytherapy. EBRT can result in radiation 

cystitis. It should be pointed out that EBRT can produce more severe lesions of the 

pelvic organs including complications associated with physical disability. 



945 BONE TURNOVER MARKERS AND POTENTIAL CORRELATION 

WITH OUTCOMES IN PATIENTS WITH GENITOURINARY 

CANCER (PROSTATE) AND BONE METASTASIS (RESULTS OF 

TUGAMO STUDY) 

J. Bellmunt 1 , C. De La Piedra 2 ,A.Gómez Caamaño 3 , M.J. Ribal 4 , F. Vázquez 5 , 

U. Anido 6 , E. Solsona 7 , P. Samper 8 , E. Esteban 9 , J. Morote 10 

1 Medical Oncology Department, Hospital del Mar, Barcelona, SPAIN, 2 Clinical 

Biochemistry Department, Instituto de Investigación Sanitaria Fundación Jiménez 

Díaz, Madrid, SPAIN, 3 Radiation Oncology Department, Complexo Hospitalario 

Universitario de Santiago de Compostela, A Coruña, SPAIN, 4 Urology 

Department, Hospital Clínic, Barcelona, SPAIN, 5 Urology Department, Hospital 

Universitario Virgen de las Nieves, Granada, SPAIN, 6 Oncology Department, 

Complexo Hospitalario Universitario de Santiago de Compostela, A Coruña, 

SPAIN, 7 Urology Department, Instituto Valenciano de Oncología, Valencia, 

SPAIN, 8 Urology Department, Hospital Central de la Defensa Gómez Ulla, 

Madrid, SPAIN, 9 Medical Oncology Department, Hospital Universitario Central de 

Asturias, Oviedo, SPAIN, 10 Urology Department, Hospital Vall d’Hebrón, 


Background: Levels of bone turnover markers (BTM) might be correlated with 

outcome in terms of skeletal related events (SRE), disease progression and death. The 

aim of this study was to determine the possible correlation between BTM, disease 

progression, SREs and death in patients with genitourinary cancer and bone 

metastases (BM) treated with zoledronic acid (ZA). 

Methods: Observational, prospective, multicenter study. Patients with genitourinary 

cancer (prostate, renal, bladder) and BM were included. BTM determined were: 

carboxiterminal telopeptide of type I collagen (β-CTX) and bone specific alkaline 

phosphatase (BALP) by ELISA (immunoenzymatic assay, IDS UK), and 

aminoterminal propeptide of type I collagen (P1NP) by automatised assays (Elecsys, 

Roche). All BTM were determined at baseline (V0) and every 3 mo of treatment 

until Month 18 (V6). All patients started treatment with ZA 4 mg IV every 3-4 

weeks at the beginning of the study. 

Results: Data of 168 patients with genitourinary cancer were analyzed. In this work 

data of prostate cancer patients (n = 95) are presented. Population basal 

characteristics [35 new, without previous treatment (N) / 60 pre-treated, with 

anti-hormonal treatment (P)]: mean age (years): 72.1; median time from tumor 

diagnosis (months): 7.6 (N) / 11.6 (P); ECOG 0-1: 90% (N) / 87.5% (P). Patients 

with pathologic baseline levels were: 47.1% β-CTX, 64.7% BALP and 57.1% P1NP 

(N) and 48.3% β-CTX, 80.7% BALP and 60% P1NP (P). After 6 mo.: 28%, 48% and 

32% (N) and 32%, 59.4% and 31.3% (P) presented pathologic values of β-CTX, 

BALP and P1NP respectively. Normalized levels remained steady throughout 18 mo 

follow-up. Reductions from baseline to month 3 in BALP levels correlated with lower 

risk of death (p = 0.0219) (Cox regression analysis). 

Conclusions: Elevation of baseline BTM levels is frequently present in advanced 

prostate cancer with bone metastasis. Addition of AZ to standard systemic therapy 

reduces BTM levels, even though in those highly hormone sensitive ones. A 

significant association was observed between elevated levels of BALP and death 

throughout follow-up. 


946 CABAZITAXEL (CBZ) SHOWS SUPERIOR ANTITUMOR 

EFFICACY OVER DOCETAXEL IN A HORMONE-RESISTANT 

PROSTATE TUMOR XENOGRAFT MODEL (HID28) 

L. Bourré 1 , D. Nicolle 1 , M. Legrier 2 , V. Yvonnet 3 , J. Charpentier 3 , M. Poupon 4 , 

P. Vrignaud 5 , S. Oudard 6 , J-G. Judde 3 

1 Contract Research Department, XenTech, Evry, FRANCE, 2 R & D, XenTech, 

Evry, FRANCE, 3 XenTech, Evry, FRANCE, 4 Scientific Advisory Board, XenTech, 

Fresnes, FRANCE, 5 Translational and Experimental Medicine, Sanofi Oncology, 

Vitry-sur-Seine, FRANCE, 6 Medical Oncology Department, Hopital Europeen 

Georges Pompidou, Paris, FRANCE 

Background: Docetaxel (D) was the first cytotoxic treatment demonstrating a 

survival benefit in metastatic castration-resistant prostate cancer (mCRPC) patients. 

Recently, the novel taxane cabazitaxel and the CYP17 inhibitor abiraterone acetate 

have demonstrated a significant survival benefit in mCRPC patients progressing after 

receiving a D-containing regimen. Here we compare the antitumour efficacy of D, 

cabazitaxel and abiraterone acetate in the HID28 hormone-resistant human prostate 

carcinoma xenograft. 

Methods: HID28 tumour-bearing nude mice received 20 mg/kg of D (IP, Q3W x 2), 

cabazitaxel at 15 and 20 mg/kg (IP, Q3W x 2) and abiraterone acetate at 50 mg/kg 

(PO, QD x 21). Median tumour growth inhibition (T/C%) was evaluated, as well as 

time-course androgen receptor expression (4, 8 and 24 h post-dosing) by western 

blot analysis. 

Results: D inhibited tumour growth with a T/C% = 16.7% at day 35, 2 partial (PR) 

and 1 complete (CR) tumour regressions, and with relapse of all tumours (3/3) 

observed at day 42. Cabazitaxel demonstrated dose-dependent efficacy at day 35 with 

T/C% = 10.8% and 1.4% for 15 and 20 mg/kg doses, respectively. At a cabazitaxel 

dose of 15 mg/kg, 4/10 PR and 3/10 CR were observed, whereas 4/10 PR and 6/10 


CR were observed at 20 mg/kg. At day 42, 6/6 tumour relapses were observed at 15 

mg/kg, whereas only 3/6 relapses were observed at 20 mg/kg. No anti-tumour activity 

was demonstrated with abiraterone acetate as well as no significant decreases in 

testosterone levels compared with the vehicle group. Tolerability was good for all 

treatment groups, with a transitory maximum mean body weight loss of 12%, 6 days 

after treatments.Androgen receptor western blot expression analysis after 4, 8 and 24 

h post-dosing demonstrated no significant difference between groups and over time. 

Conclusions: Cabazitaxel demonstrated superior antitumour efficacy and a similar 

tolerability compared with D at equivalent dosing in the HID28 hormone-resistant 

tumour model. The model did not respond to abiraterone. These results support the 

clinical development of cabazitaxel in first-line treatment of mCRPC patients.This 

research was funded by Sanofi. 

Disclosure: L. Bourré: Is a Xentech employee, D. Nicolle: Is a Xentech employee, 

M. Legrier: Is a Xentech employee, V. Yvonnet: Is a Xentech employee, J. 

Charpentier: Is a Xentech employee, M. Poupon: Has acted as an uncompensated 

consultant and has provided expert testimony. Is a Xentech employee, P. Vrignaud: 

Is a Sanofi employee (Research Investigator) and owns Sanofi stocks and shares, S. 

Oudard: Has acted as an advisor for, and received honoraria from Pfizer Oncology, 

Bayer Schering Pharma, Roche, GSK, Novartis and Sanofi, J-G. Judde: Is a Xentech 

employee. 

947 AUGMENTATION OF THE CYTOTOXICITY OF IBANDRONATE 

BY Y-27632 IN PROSTATE CANCER CELL LINES 

A. Ata 1 , A. Özçimen 2 , H. Kurt 3 , N. Tiftik 4 ,A.Arıcan 5 , K. Büyükafs¸ar 4 

1 Dept of Medical Oncology, Mersin State Hospital, Mersin, TURKEY, 2 Biology, 

Mersin University Science and Art Faculty, Mersin, TURKEY, 3 Dept of 

Pharmacology, Mersin University School of Medicine, Mersin, TURKEY, 4 Dept of 

Pharmacology, Mersin University School of Medicine, Mersin, TURKEY, 5 Dept. of 

Medical Oncology, Mersin University School of Medicine, Mersin, TURKEY 

Background: Bisphosphonates, which have been used for the treatment of the 

metastatic bone disease and malignant hypercalcemia due many cancers. These 

drugs also inhibit mevalonate pathway that results in the reduction of Ras 

prenylation, which eventually inhibits tumor growth. Rho/Rho kinase signaling has 

a fundamental role in cancer cell proliferation, migration and metastasis. In this 

study, we aimed to investigate the effects of y-27632 (a Rho-kinase inhibitor) and 

ibandronate (a bisphosphonate) and their combination on cell proliferation in 

prostate cell lines. 

Methods: The adherent prostate cell line, PC-3, was grown in RPMI-1640 

supplemented with 10% fetal bovine serum, 1% L-glutamine, 1% penicillin 

(10.000U/ml) and streptomycin (10.000 mg/ml) in a humidified atmosphere 

of 5% CO2 at 37 o C for confluency. The cells were seeded in the wells of E-plates 

(24,000 cells/well) that allowed a real-time-monitoring of the cell index reflected 

cell growth and proliferation (xCELLigence, Roche). The cell index was evaluated at 

the different points of time (post-treatment 12, 24, 36, 48, 60 and 72 h) in the 

groups of, y-27632, ibandronate, the combination of these drugs and time-course 

control. 

Results: Both ibandronate alone (10-100 mM) and y-27632 alone (50-100 mM) 

markedly decreased cell index. But the combination of ibandronate with y-27632 

(in differrent concentrations but especially in higher concentrations) resulted in 

potentiation of cytotoxicity in prostate cell line. 

Conclusions: Rho kinase inhibitors, bisphosphonates and their combinations may be 

used for the treatment of prostate cancer in the future, according to the possible 

beneficial results of clinical trials. 


948 ANALYSIS OF THE USA POSTMARKETING SAFETY PROFILE 

OF CABAZITAXEL IN THE TREATMENT OF METASTATIC 

CASTRATE-RESISTANT PROSTATE CANCER (MCRPC) 

PREVIOUSLY TREATED WITH A DOCETAXEL-CONTAINING 

TREATMENT REGIMEN 

L. Nicacio 1 , P. Raina 2 , R. Sands 3 , S. Neibart 4 

1 NA Oncology, Sanofi-Aventis U.S. LLC, Inc., a Sanofi Company, Bridgewater, 

NJ, UNITED STATES OF AMERICA, 2 US Pharmacovigilance, sanofi-aventis U.S. 

LLC, Inc., a Sanofi Company, Bridgewater, NJ, UNITED STATES OF AMERICA, 

3 Global Oncology, sanofi-aventis U.S. LLC, Inc., a Sanofi Company, Cambridge, 

MA, UNITED STATES OF AMERICA, 4 Global Pharmacovigilance, sanofi-aventis 

U.S. LLC, Inc., a Sanofi Company, Bridgewater, NJ, UNITED STATES OF 

AMERICA 

Background: Cabazitaxel (Jevtana®) in combination with prednisone was licensed in 

the United States (USA) in June 2010 for the treatment of mCRPC in patients (pts) 

previously treated with a docetaxel-containing treatment regimen. We estimate that 

over 13,000 patients have since been treated in the US. This research analyzes the 

post-marketing safety profile of cabazitaxel based on spontaneously reported 

pharmacovigilance (PV) Adverse Events (AEs) in the USA. As such reports depend 



on voluntary reporting, only a qualitative comparison to the safety profile observed 

in the clinical trial setting is possible. 

Methods: Safety information spontaneously reported to Sanofi US PV from June 17, 

2010 - March 31, 2012 was reviewed. The most frequently reported AEs are 

presented, using MedDRA preferred terms and compared with the safety profile 

observed in clinical trials. 

Results: A total of 692 spontaneously reported AEs were received for 373 US men in 

the time period indicated, 312 (45%) serious (SAEs) and 380 (55%) non-serious. The 

pts were 45 to 88 years old (mean ± SD: 68.6 ± 12) and virtually all with mCRPC. 

The most frequently reported hematologic AEs were neutropenia [n = 27; 16 SAEs], 

febrile neutropenia [n = 18; 17 SAEs], anemia [n = 9; 4 SAEs] and thrombocytopenia 

[n = 7; 3 SAEs]. The most frequently reported non-hematologic AEs included 

diarrhea [n = 32; 8 SAEs], fatigue [n = 28; 1 SAEs], hematuria [n = 15; 5 SAEs], 

nausea [n = 14; 1 SAEs], vomiting [n = 9; 2 SAEs] and pyrexia [n = 3; 0 SAEs]. 

Concomitant therapies and co-morbidities were associated with most of the cases. 

Disease progression was reported as an event in 68 pts with 38 pts reporting 

increased PSA levels. A total of 57 deaths were reported: 9 due to disease 

progression; 3 pulmonary embolism; 2 chronic obstructive pulmonary disease; 2 

febrile neutropenia; 2 sepsis; 2 septic shock; 12 other causes; and, 25 cause not 

specified. 

Conclusion: Although subject to the limitations of the post-marketing voluntary 

adverse event reporting system, the emerging safety profile of Jevtana is consistent 

with that observed in the clinical trial setting. 

Disclosure: L. Nicacio: I am an employee of Sanofi and own Sanofi stock. P. Raina: 

I am an employee of Sanofi and own Sanofi stock. R. Sands: I am an employee of 

Sanofi and own Sanofi stock. S. Neibart: I am an employee of Sanofi and own 

Sanofi stock. 

949 PARAMETRIC EFFECT SIZE ESTIMATES FROM SIPULEUCEL-T 

RANDOMIZED TRIALS 

B.A. Blumenstein 

Trial Architecture Consulting, Washington, DC, UNITED STATES OF AMERICA 

Introduction: Median overall survival (OS) difference is frequently used as a 

measure of effect size because it is easily understood. Other effect size estimates can 

more fully represent the OS distribution, and are less subject to local variations. 

Analysis of the sipuleucel-T D9901 and IMPACT trials using non-parametric 

(median) or semi-parametric (hazard ratio [HR]) methods provide 4.5- and 

4.1-month estimated median OS differences, respectively, with HRs of 0.586 and 

0.752 (not stratified or adjusted). The OS curves from these trials exhibit delayed 

separation, suggesting a delayed treatment effect consistent with that shown for 

other immunotherapies. In this research, parametric statistical models are used 

to account for delayed effect and obtain alternative effect size estimates from D9901 

and IMPACT. 

Methods: Parametric models based on the Weibull distribution and a modification 

of the Weibull distribution that allows for delay of effect were applied. These models 

require specification of the general shape of the hazard function. 

Results: The table shows the original OS and HR estimates in comparison to those 

obtained through parametric modeling. D9901 estimates from the Weibull model 

suggested a larger median OS difference vs the original estimates. The OS difference 

and the HR estimate using the delayed effect Weibull model were both indicative of 

greater sipuleucel-T effect. For IMPACT, the OS difference and HR estimates from 

the Weibull model indicated greater effect, but to a lesser degree than in D9901. The 

delayed effect modified Weibull model for IMPACT did not support a delayed effect. 

Discussion: This statistical modeling illustrates alternative methods of obtaining 

effect size estimates that may be particularly applicable to clinical trials of cancer 

immunotherapies. For the sipuleucel-T trials, these models suggest a greater 

sipuleucel-T effect than obtained from non-parametric or semi-parametric methods. 

Study Estimate Type 

D9901 Non-parametric/semi-parametric 

Weibull Modified Weibull 

IMPACT Non-parametric/semi-parametric 

Weibull Modified Weibull 

NS, delayed effect not supported *Applicable after delayed efffect 


Median 

Difference 

(mos) Hazard Ratio 

4.5 10.3 6.6 0.586 0.585 0.486* 

4.1 4.7 NS 0.752 0.749 NS 

950 THE EFFECT OF NEUTROPHIL TO LYMPHOCYTE RATIO (NLR) 

PRIOR TO TAXOTERE-BASED CHEMOTHERAPY IN PATIENTS 

(PT’S) WITH METASTATIC CASTRATION RESISTANT 

PROSTATE CANCER (MCRPC) 

A. Sella 1 , T. Sella 2 ,S.Kovel 1 

1 Oncology, Asaf Harofeh Medical Center, Beer Jacob, ISRAEL, 2 Oncology, 

Sheba Medical Center, Ramat Gan, ISRAEL 

Introduction: Increasing evidence supports the involvement of systemic 

inflammation in cancer development and progression. Neutrophiles/lymphocytes 

ration (NLR), a marker of inflammatory response which is associated with poor 

outcome in colorectal, gastric, pancreas, hepatocellular, breast, lung and renal cancer 

cases. The improved survival with immunotherapy (Provenge) in mCRPC and the 

recent report that high NLR in associated with poor outcome in mCRPC treated with 

ketoconazole prompted the evaluation of NLR in such pt’s treated with 

Taxotere-based chemotherapy. 

Methods: During the last decade we treated 62 mCRPC pt’s with Taxotere-based 

chemotherapy. Blood counts up to 2 month prior to therapy without infection or 

steroid treatment are available in 31 pt’s. Statistical analysis was performed with 

SPSS17, survival curve was measured with Kaplan-Meyer curve. 

Results: Patient’s characteristics: median age-70 (55-82) years, median PSA-95.2 

(1.6-2316), median alkaline phosphatase- 123(10.8-1795)U/ml was elevated (> 115 

U/ml) in 18 pt’s (58%) and median hemoglobin-12.1(8.4-15.4) with anemia (< 12 gr/ 

%) in 15 pt’s (48%). Median survival was 15.8 + 2.2 months (mo.) while PSA 

response (> 50% decline) occurred in 14 pt’s (45.1%). Eighteen pts (58%) had NLR > 

3.0. The two groups were similar in PSA, alkaline phosphatase elevated levels and 

PSA response. We observed no difference in survival nor PFS between the pt’s with 

NLR> 3.0 and NLR < 3.0; 17.1 v.s 13.7 mo. and 5.4 v.s 4.5 mo. respectively. Analysis 

according to alkaline phosphatase, hemoglobin levels, elevated PSA and alkaline 

phosphatase or PSA response was non-significant. 

Conclusions: Unlike other cancers, elevated NLR in mCRPC treated with 

Taxotere-based chemotherapy does not predict worse outcome. 


951 REPONSE TO CABAZITAXEL IN THE POSTCHEMOTHERAPY 

SETTING IN CRPC PATIENTS PREVIOUSLY TREATED WITH 

DOCETAXEL AND ABIRATERONE ACETATE 

L. Albiges 1 , S. Le Moulec 2 , Y. Loriot 1 , M. Gross Goupil 3 , T. De La Motte Rouge 4 , 

A. Guillot 5 , K. Fizazi 6 , C. Massard 7 

1 Medical Oncology, Institut de cancérologie Gustave Roussy, Villejuif, FRANCE, 

2 Oncologie Medicale, Hopital du Val de Grace Val de Grace, Paris Cedex, 

FRANCE, 3 Medical Oncology, Hôpital Saint-André, CHU bordeaux, Bordeaux, 

FRANCE, 4 Medical Oncology, Salpétrière Hospital, Paris, FRANCE, 5 Medical 

Oncology, Institut de Cancérologie de la Loire, Saint Priest en Jarez Cedex, 

FRANCE, 6 Department of Medical Oncology, Institute Gustave Roussy, Villejuif, 

FRANCE, 7 SITEP, Institut de Cancérologie Gustave Roussy, Villejuif Cedex, 

FRANCE 

Background: Cabazitaxel (a tubulin-binding taxane chemotherapy) and Abiraterone 

acetate (AA) have recently been approved for patients with metastatic castration 

resistant prostate cancer (CRPC) following docetaxel chemotherapy. Recent studies 

suggest that taxane also impact AR signalling such as AA, and could explain 

cross-resistance between new hormonal manipulations and taxane chemotherapy. 

The aim of this study is to evaluate the antitumor activity of cabazitaxel in patients 

whose disease progresses on AA. 

Patients and methods: Eligible pts had metastatic CRPC and progression disease 

after docetaxel and AA. All the patients received cabazitaxel 20 mg/m2 every 3 

weeks + prednisone 5 mg BID. Radiological response by RECIST, PSA response by 

PSAWG2 criteria and symptomatic benefit were evaluated. 

Results: In the 38 pts treated with cabazitaxel, baseline median age was 69 years 

(48-81), ECOG PS 0 or 1 in 90% of pts, and median PSA 350 ng/ml (3,75-9150). 

Bone, lymph nodes and visceral metastases were present in 30 pts (90%), 5 pts 

(15%), and 5 pts (15%) respectively. An average of 4 cycles of cabazitaxel (range 1-9) 

were given, 85% patients received granulocyte-colony stimulating factor prophylaxis 

from cycle 1, and 15 pts (39%) continue on cabazitaxel at the time of safety analysis. 

Out of 38 patients, 16 patients stopped before completing the full course, 15 of these 

patients were due to disease progression. No major toxicities were noticed. Of 32 

patients with PSA data available, 18 (56%) pts have had a 50% or greater PSA 

decline, 5 pts (15%) have had a partial response. 

Conclusion: Cabazitaxel appears active and well tolerated in pts with metastatic 

CRPC who are resistant to AA. Our data do not provide any evidence for 

cross-resistance between these two agents. Final results will be reported. 



952 SEQUENTIAL ANDROGEN DEPRIVATION AND 

CHEMOTHERAPY IN METASTATIC PROSTATE CANCER: 

DISCORDANT RESPONSES IN PILOT STUDY SUGGEST AN 

OPPORTUNITY FOR INDIVIDUALIZED THERAPY 

R. Tang 1 , C. Piatek 1 , J. Pinski 2 , F. Acosta 1 , C. Korn 1 , D. Raghavan 3 , T.B. Dorff 2 , 

D.I. Quinn 2 

1 Medicine, University of Southern California, Los Angeles, CA, UNITED STATES 

OF AMERICA, 2 USC Norris Comprehensive Cancer Center, University of 

Southern California, Keck School of Medicine, Los Angeles, CA, UNITED 

STATES OF AMERICA, 3 Carolinas Healthcare, Levine Cancer Institute, Charlotte, 

NC, UNITED STATES OF AMERICA 

Background: CRPC is fatal but with recent better survival based on new agents. 

Optimal sequential therapy remains a challenge. We undertook a phase II pilot study 

of Mitoxantrone (MTX) followed by docetaxel, estramustine, carboplatin (DEC). 

Methods: CRPC pts who progressed on/after MTX were given estramustine 280mg 

TID x 5d, docetaxel 60mg/m2, carboplatin AUC = 5 q28 days; ASA & warfarin daily, 

max 8 cycles. Endpoints: RR >30% with PSA fall >30% & 30% drop in PSA to MTX or DEC & median OS were: responders to MTX only (n 

= 4; 20.3 mos (18.4-25.4)); to docetaxel only (n = 10; 14.6 mos (9.1-43.7); both (n = 5; 

28.9 mos (22.7-40.3); neither (n = 1; 12.3 mos (Fisher’s exact p = 0.3 for response 

MTX vs DEC, logrank p = 0.028 for OS). Based on pts ADT PSAn, we found longer 

PFS for DEC and MTX with higher PSAn (log-rank p = 0.048 & 0.019) & trend to 

better OS on MTX/DEC sequence with PSAn >4 (p = -0.14, med OS 20.1 vs 25.8 

months). Fall in Hgb between ADT & start of DEC associated with shorter PFS on 

DEC (p = 0.05) with a trend to shorter OS (p = 0.08). 

Conclusions: DEC was effective in patients with CRPC given MTX. Pts benefited if 

they responded to either or both agents but there was limited overlap in response 

(25%). High PSA nadir on ADT maybe associated with a longer PFS & OS to 

chemotherapy. Biomarkers linked to hormonal & chemotherapy effect for individual 

agents in PC could have significant utility. Study with larger cohorts of sequential 

therapy is ongoing 


953 CABAZITAXEL IN PATIENTS WITH ADVANCED CRPC AFTER 

DOCETAXEL-FAILURE. RESULTS OF EXPANDED PROGRAM 

ACCESS (EAP) IN SPAIN: SAFETY AND EFFICACY 

D.E. Castellano 1 , L.M. Anton Aparicio 2 , E. Esteban 3 , G. Velasco 1 , Q. Perez 4 , 

A. Sanchez 5 , B. Pérez-Valderrama 6 , N. Batista 7 

1 Medical Oncology Department, University Hospital 12 de Octubre, Madrid, 

SPAIN, 2 Medical Oncology Department, Complejo Hospitalario A Coruña, A 

Coruña, SPAIN, 3 Medical Oncology Department, Hospital Universitario Central 

de Asturias, Oviedo, SPAIN, 4 Medical Oncology, Hospital Universitario Central de 

Asturias, Oviedo, SPAIN, 5 Medical Oncology Department, Hospital Provincial de 

Castellon, Castellon, SPAIN, 6 Medical Oncology, Hospital Virgen del Rocío, 

Seville, SPAIN, 7 Medical Oncology Department, Hospital Universitario de 

Canarias, Las Palmas, SPAIN 

Background: Cabazitaxel is the new chemotherapy standard in second line treatment 

of metastatic castrate resistant prostate cancer (CPRC) [TROPIC Trial, Lancet 2010]. 

The aim of this study was to analyze the baseline characteristics and outcomes of a 

cohort of patients from six Spanish hospitals enrolled in a EAP. (total nº of pts: 138) 

Methods: Between 3-2011 and 12-2012, 65 mCRPC pts who have progressed on or 

after docetaxel-based chemotherapy were treated with Cabazitaxel (25 mg/m2 IV 

q3wks plus oral prednisone 10mg daily. All pts had proven histology confirmation of 

prostate adenocarcinoma and progressive disease (radiologic and/or rising PSA) at 

the beginning of the treatment. 

Results: Median age was 63 years (range 45-83) and ECOG 0-1 in 25%-68% 

respectively. Median PSA at baseline was 864 ng/ml. Seventy-eight percent had bone 

metastases, 33% lymph nodes metastases and 14% visceral metastases. Previous 

therapy was: hormonal, (median 2 lines) and chemotherapy (median 1.6 lines). 

Thirty percent (20 pts) had received ketoconazole. Median previous docetaxel dose 

was 1029 mg/m2(50-3750). Seventy percent of pts received G-CSF as primary 

prophylaxis in any cycle, 24% (16pts) had grade >3 neutropenia and 9% (6 pts) had 

febrile neutropenia. Other grade 3 toxicities were: anemia 3pts (4,6%), asthenia 5pts 

(7,7%), diarrhea 1 pt (1,5%). No toxic death was reported. The PSA decrease ≥50% 


was observed in 64% (31pts) and the median number of cycles administered was 6 at 

last check. Median progression free survival was 4.4 months (2.7-6.1). 

Conclusions: Results of this Spanish EAP confirm the efficacy and manageable safety 

of Cabazitaxel in daily practice. (CGR I would not comment on GCSF as many 

countries do not use prophylactic GCSF) 


954 QUALITY OF LIFE OF PATIENTS WITH METASTATIC 

CASTRATION-RESISTANT PROSTATE CANCER: RESULTS 

FROM AN OBSERVATIONAL STUDY IN 6 EUROPEAN 

COUNTRIES 

R.N. Dass 1 , P. Hamberg 2 , M. Spencer 1 , P. Wheatley Price 1 

1 Hemar (Health Economics, Market Access and Reimbursement), Janssen-Cilag 

Ltd, London, UNITED KINGDOM, 2 Internal Medicine, St Franciscus Gasthuis, 

Rotterdam, NETHERLANDS 

Background: Despite advances in prostate cancer (PC) therapy, treatment options 

for metastatic castration-resistant prostate cancer (mCRPC) are limited. However, 

studies on health-related quality of life (HRQoL) for mCRPC patients are rare and 

although HRQoL is considered as a key outcome of mCRPC treatments, patient 

utilities are not measured routinely. 

Objective: To assess QoL outcomes in mCRPC patients. Methodology Observational, 

cross-sectional, prospective year-long study conducted in 47 centres specialised in PC 

treatment in 6 countries: Belgium, France, Germany, Sweden, the Netherlands, and 

the United Kingdom. Patients with confirmed diagnosis of PC, presenting with 

metastatic castration-resistant disease were eligible. At inclusion, clinical and 

therapeutic data were collected by physicians, and EQ-5D and FACT-P 

questionnaires were completed by patients. Interim results based on 200 patients, of 

a target of 900, are presented below. 

Results: Mean age was 72.8 years. Mean time since diagnosis of PC was 6.6 years. At 

diagnosis, 34.5% of patients had metastases, and 79.2% had a Gleason score ≥ 7. At 

inclusion, 34.2% of the patients had never been treated with any prior cytotoxic 

chemotherapy (CT), 35.3% had been treated with CT in the past and 30.5% were 

undergoing CT (respective mean times since PC diagnosis: 7.3, 6.4 and 5.7 years). 

Mean (SD) EQ-5D single index utility score was 0.7 (0.3). 65.3% of patients had 

moderate or extreme pain or discomfort, 53.2% had problems performing daily 

activities and 51,3% had mobility problems. Mean (SD) EQ-5D VAS score was 55.7 

(22.7). Although not statistically significant (NS), a trend for patients without any 

prior CT to have higher mean EQ-5D single index utility and VAS scores, was 

observed. Mean (SD) FACT-P total score was 102.8 (24.1) and 107.2 (25.8), 103.2 

(23.7) and 98.1 (21.9) respectively in patients without any prior CT, undergoing CT 

and treated with CT in the past (NS). Subscale scores were: physical well being: 20.3 

(6.1), social/family well being: 20.4 (5.4), emotional well being: 16.9 (4.7), functional 

well being: 16.0 (6.3) and PC subscale: 29.4 (8.3). 

Conclusion: The interim analysis was insufficiently powered to detect a significant 

impact of CT on HRQoL in mCRPC patients. The final analysis is expected to 

adequately highlight determinants of HRQoL. 

Disclosure: R.N. Dass: Janssen Cilag employee, P. Hamberg: Study investigator, M. 

Spencer: Janssen Cilag employee, P. Wheatley Price: Janssen Cilag employee 

955 SAFETY DATA OF CABAZITAXEL (JEVTANA®) IN PATIENTS 

TREATED FOR METASTATIC CASTRATION RESISTANT 

PROSTATE CANCER AFTER DOCETAXEL TREATMENT: 

RESULTS OF A COHORT OF PATIENTS DURING THE 

TEMPORARY AUTHORIZATION FOR USE IN FRANCE (ATU) 

N. Houede 1 , J. Eymard 2 , T. Zoubir 3 

1 Medical Oncology, Institut Bergonié, Bordeaux, FRANCE, 2 Medical Oncology, 

Institut Jean Godinot, Reims Cedex, FRANCE, 3 Médical Oncologie, Sanofi, Paris, 

FRANCE 

Background: The TROPIC 1 study demonstrated that cabazitaxel (a novel 

tubulin-binding taxane drug) improves overall survival of patients (pts) with 

metastatic castration resistant prostate cancer (mCRPC) who progressed during or 

after docetaxel-based chemotherapy, with a median survival of 15.1 months. Based 

on this result, a compassionate-use program has been established to provide pts with 

mCRPC with the opportunity to receive treatment with cabazitaxel, before licensing 

of the drug. 

Methodology: Temporary Authorization for Use (ATU) of cabazitaxel in France has 

been granted before its marketing authorization; all safety data from pts treated 

during this period were collected following a specific therapeutic use protocol. All 

participating physicians were instructed about the molecule and its administration by 

a company physician and contacted before the first treatment, on day 15 and at the 

end of treatment of each patient to make sure that all G3/4 and serious adverse 

events were collected. 

Results: We report baseline characteristics and safety data from the 184 pts treated in 

92 French centers. The median age was 67.2 years (46 - 92), ECOG performance 



status was 0-1 for 85% of pts, 88% had bone metastases and 21% had visceral 

metastases. All the pts had received prior docetaxel, 55% had discontinued for 

disease progression; 85% of the patients received 1-2 lines of chemotherapy before 

cabazitaxel. Patients received a median of 3 cycles of cabazitaxel (1-6). Rates of grade 

3-4 hematological toxicities were: neutropenia grade≥ 3 (4%), febrile neutropenia 

(3%), all resolved. All grade non-hematological toxicities were: nausea (0.5%), 

diarrhea (2.7%) and fatigue (0.5%). No treatment-related death was reported. 

Conclusion: The ATU program provides additional safety information on cabazitaxel 

in the real-life setting; they are consistent with the TROPIC study safety results. The 

incidence of neutropenia grade≥ 3 (4%) and febrile neutropenia (3%) appears to be 

lower than expected from the TROPIC trial. Therapeutic use protocols such as these 

can be helpful for physicians and pharmacists when new therapies become available. 

Proactive education of healthcare givers on AEs management could be considered 

when new treatments are introduced. 1 Johann Sebastien de Bono et al; Lancet Vol 

376 October 2, 2010. 

Disclosure: T. Zoubir: Medical Director of Sanofi France. All other authors have 


956 HEALTH-RELATED QUALITY OF LIFE (QOL) IN PATIENTS WITH 


(MCRPC): CABAZITAXEL EARLY ACCESS PROGRAM (EAP) 

INTERIM RESULTS FROM CANADA 

F. Saad 1 , E. Winquist 2 , M. Girard 3 , S.S. Sridhar 4 

1 Medical Oncology, CHUM, Notre-Dame Hospital, Montreal, QC, CANADA, 

2 Medical Oncology, University of Western OntarioLondon Regional Cancer 

Center, London, ON, CANADA, 3 Biostatistics, Sanofi Canada, Montreal, QC, 

CANADA, 4 Medical Oncology, Princess Margaret Hospital, Toronto, ON, 

CANADA 

Background: QoL and preference/utility data have not been extensively collected in 

post-docetaxel (D) mCRPC. Canada collected EQ-5D-3L data in this setting as part 

of the single-arm multicenter EAP for Cabazitaxel. 

Methods: Between May 2011 and February 2012, 61 evaluable patients (pts) were 

enrolled at 9 centers. EQ–5D-3L data was collected and analyzed at baseline and 

after every cycle. EQ-5D health state index (HIS) and visual analog scale (VAS) data 

were collected. HIS data were converted into utility values using the UK tariff from 

Dolan 1997. The relationship between baseline ECOG performance status (PS) and 

EQ-5D values (HIS and VAS) across visits was examined. 

Results: At time of abstract submission, baseline characteristics and EQ-5D data were 

available for 58 pts: median age 65 years, 94% of pts ECOG PS 0 or 1, 85% had bone 

metastases, and 45% received at least 6 cycles of cabazitaxel. Significant 

improvements (p < 0.05) were noted in the EQ-5D pain/discomfort (Pain) domain. 

From baseline to cycle 6, the percentage of pts reporting “no problem” in Pain 

improved from 17% to 30%. Other EQ-5D dimensions (anxiety/depression, mobility, 

self-care and usual activities) remained stable over the course of treatment. Utility 

values (HIS and VAS) remained unchanged during treatment, even after stratifying 

by baseline PS. However, stratifying by baseline ECOG PS of 0 or 1, 45% and 36% of 

pts improved by a minimally important difference (MID) (Pickard 2007) on the 

EQ-5D VAS and HIS by cycle 6, respectively. 

Conclusions: Improvements were seen on the EQ-5D in the Pain domain, with more 

than a third of pts reaching a MID on the EQ-5D by cycle 6. Improvements in pain, 

a common symptom in mCRPC, directly impact pts’ experience of their disease. The 

poster will present updated data. 

Disclosure: F. Saad: Dr Fred Saad sits on the advisory board for Sanofi Canada and 

has received consultant’s honoraria from Sanofi Canada. He is involved in research 

projects with Sanofi Canada. E. Winquist: Dr Eric Winquist has received travel 

funding and consultant’s honoraria from Sanofi Canada. He is involved in research 

projects with Sanofi Canada, M. Girard: Employee with Sanofi Canada, S.S. Sridhar: 

Dr S.S. Sridhar sits on Advisory Boards and receives Research Funding from 

Sanofi Canada. 

957 WHAT CLINICAL AND NON-CLINICAL FACTORS INFLUENCE 

PROSTATE CANCER TREATMENT DECISIONS? A NATIONAL 

CLINICAL SURVEY 

J.M. Fitzpatrick 1 , L. Sharp 2 , M. De Camargo Cancela 3 , H. Comber 4 

1 Surgical Professorial Unit, Mater Misericordiae University HospitalUniversity 

College Dublin, Dublin, IRELAND, 2 Research Department, National Cancer 

Registry, Ireland, Cork, IRELAND, 3 Reseach Department, National Cancer 

Registry, Ireland, Cork, IRELAND, 4 National Cancer Registry, Ireland, Cork, 

IRELAND 

Background: Prostate cancer treatment remains controversial. Several 

population-based studies have revealed strikingly different treatment trends by 

patient age, suggesting treatment decisions may be influenced heavily by non-clinical 

considerations. To investigate factors considered important by clinicians we surveyed 

radiotherapists and urologists in Ireland. 

Materials and methods: All radiotherapists and urologists were asked to complete a 

postal questionnaire involving patients scenarios rating 68 comorbid conditions 

(from ACE-27) in terms of their impact on treatment recommendations regarding 

radical prostatectomy (RP; urologists), radiotherapy (RT; radiotherapists) and 

androgen deprivation therapy (both). Respondents indicated which of 13 

non-medical issues impacted on treatment. 

Results: 24 urologists (56%) and 12 radiotherapists (46%) responded. Performance 

assessment tools were used by more radiotherapists than urologists (92% vs 20%). 

All urologists and 10 radiotherapists prescribed ADT. Conditions rated as having 

the greatest impact on RP or RT treatment decisions were similar: severe 

dementia, acute stroke and recent bypass or amputation for gangrene. Non-clinical 

factors with the greatest impact were: life expectancy (urologists: 100%; 

radiotherapists: 100%) and patient’s preference (100%, 92%), followed by age for 

urologists (96%) and patient quality-of-life for radiotherapists (83%). Conditions 

impacting on ADT recommendations were: recent pulmonary embolia, acute stroke 

and cirrhosis. 

Conclusions: Radiotherapists were more heterogeneous than urologists in their views 

on which clinical factors influence treatment decisions. Many conditions which 

strongly influence treatment are uncommon in patients, therefore unlikely to explain 

treatment variations. Our findings confirm clinicians consider non-clinical factors 

important, suggesting these may influence treatment independently of comorbid 

status or fitness for treatment. 

Disclosure: J.M. Fitzpatrick: This study was funded by Sanofi-Aventis, L. Sharp: 

This study was funded by Sanofi-Aventis, M. De Camargo Cancela: This study was 

funded by Sanofi-Aventis, H. Comber: This study ws funded by Sanofi-Aventis 

958 OBSERVATIONAL CROSSOVER STUDY OF CABAZITAXEL AND 

ABIRATERONE ACETATE IN METASTATIC 

DOCETAXEL-REFRACTORY CASTRATION-RESISTANT 

PROSTATE CANCER (MDR-CRPC) 

S. Bracarda 1 , M. Sisani 2 , A. Hamzaj 2 , F. Marrocolo 1 , S. Del Buono 1 

, V. De Angelis 3 

1 Department of Oncology, Ospedale San Donato and U.O.C. of Medical 

Oncology, Arezzo, ITALY, 2 Oncology, U.O.C. Medical Oncology, Arezzo, ITALY, 

3 Haematology-Oncology, S.C. Medical Oncology. Ospedale S.Maria della 

Misericordia, Perugia, ITALY 

Purpose: In recent years both cabazitaxel (Cbz) and abiraterone acetate (AA) showed 

to be efficacious treatment options for patients with mDR-CRPC. However, no data 

exist for patients treated with both these drugs. Aim of our study was to analyze 

these data in a real world scenario. 

Material and methods: Intention-to-treat (ITT) analysis of activity data deriving 

from all consecutive patients with mDR-CRPC treated in our unit with prednisone 

plus Cbz, AA or both. Primary end point of the study was median Progression Free 

Survival (mPFS), evaluated according to Prostate Cancer Working Group 2 

(PCWG2) criteria. 

Results: Here we report characteristics and activity data of 42 patients, 8 treated with 

Cbz, 24 with AA and 10 with both drugs. The median age of our study population 

was 70.5 years (range, 55-82), median Gleason Score 8 (4-9) and median ECOG PS 0 

(0–3); visceral disease was present in 28 cases (66.7%). The mPFS, according to 

Kaplan Meier method (KM), was 4.7 months (m) for patients treated with Cbz, not 

reached for cases treated with AA and 6.7 m for cases treated with both agents. Of 

the 10 patients treated with both drugs, 6 received a sequence Cbz-AA and 4 a 

sequence AA-Cbz for an overall median PFS of, respectively, 6.7 and 4.6 m. 

Conclusions: In our limited experience, both Cbz and AA confirmed an intriguing 

activity in the mDR-CRPC setting. Moreover, both drugs seems to be active also in a 

sequential use. These data should be verified in large size prospective studies to avoid 

potential selection biases. 

Disclosure: S. Bracarda: Advisory Board Member for Sanofi-Aventis, Jannsen & 

Jannsen. Honoraria (Talks) from Sanofi-Aventis. All other authors have declared no 


959 PROSTATE CANCER PATIENTS MANAGED BY A 

MULTIDISCIPLINARY, MULTIPROFESSIONAL TEAM: IS IT 

REALLY FEASIBLE AND EFFECTIVE? 

T. Magnani 1 , R. Salvioni 2 , S. Villa 3 , L. Bellardita 1 , N. Nicolai 2 , G. Procopio 4 , 

E. Verzoni 4 , N. Bedini 3 , S. Donegani 1 , R. Valdagni 3 

1 Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, 

Milan, ITALY, 2 Urologic Surgery Unit, Fondazione IRCCS Istituto Nazionale dei 

Tumori, Milan, ITALY, 3 Radiotherapy 1, Fondazione IRCCS Istituto Nazionale dei 

Tumori, Milan, ITALY, 4 Medical Oncology, Fondazione IRCCS Istituto Nazionale 

dei Tumori, Milano, ITALY 

The aim of this abstract is to describe the multidisciplinary, multiprofessional 

management of prostate cancer (PC) patients activated by the Prostate Cancer 

Programme at Istituto Nazionale dei Tumori, Milan. PC patients should be better 


managed in a multidisciplinary (MD) setting since they have multiple therapeutic 

and observational options, depending on the risk class. The PC Programme was 

established in 2004 as a translational project. A MD team with urologists, radiation 

oncologists, medical oncologists, psychologists, palliative care experts, uropathologists 

and radiologists was built, diagnostic and therapeutic guidelines were shared and 

adopted, a MD clinic was started in March 2005 organized in: Friday clinic: 

urologist, radiation oncologist and psychologist (medical oncologist on demand) 

examine PC patients synchronously Monday case discussion (CC) to share the cases, 

check quality and application of guidelines, discuss problematic cases on observation 

and complex cases seen monodisciplinarily The MD team became multiprofessional 

by including a project manager, a secretary, a data manager and a nurse. Results 

2760 MD clinics from March 2005 to March 2012. The organizational model was 

modified to better the service. Considering the % of low risk PC patients referring to 

the MD clinic (61% in 2009) and on active surveillance protocols (342 patients in 

Feb 2012), we increased resources to better manage this sub-population. The % of 

advanced and metastatic PC patients (5% in 2011) induced to organize the lists 

according to the risk class (medical oncologist on demand). Efficacy of the MD clinic 

is demonstrated in the drug therapies prescribed outside our Institution and 

terminated by the MD team (11%). Efficacy of the CC is demonstrated in the % of 

indications formulated in the MD clinics, changed in the following CC (6%) 

resulting from quality checks of our own performance. 

Conclusions: The MD approach is proving successful. Strategies are agreed on, cases 

managed multidisciplinarily, critical issues shared. Psychologists help evaluate 

education-related and cultural factors in patients’ decisions. The CC discussion is 

fundamental to learn the MD working, create a shared know how and approach the 

patient as a subject of care rather than disease to cure. Thanks to Pro ADAMO and 

Fond. Monzino for the support 


960 CABAZITAXEL EARLY ACCESS PROGRAM (EAP) - CANADIAN 

INTERIM Results: SAFETY, QOL, AND UTILITY VALUES IN 

METASTATIC CASTRATION RESISTANT PROSTATE CANCER 

(MCRPC) 

S.S. Sridhar 1 , E. Winquist 2 , S. Hubay 3 , C. St.-Laurent Thibault 4 , H. Assi 5 , 

S. Berry 6 , E. Levesque 7 , N. Aucoin 8 , P. Czaykowski 9 , F. Saad 10 

1 Medical Oncology, Princess Margaret Hospital, Toronto, ON, CANADA, 

2 Medical Oncology, University of Western OntarioLondon Regional Cancer 

Center, London, ON, CANADA, 3 Medical Oncology, Grand River Regional 

Cancer Centre, Kitchener, ON, CANADA, 4 Oncology, Sanofi Inc. Canada, 

Montreal, QC, CANADA, 5 Medical Oncology, The Moncton Hospital, Moncton, 

NB, CANADA, 6 Medical Oncology, Odette Cancer Centre, Toronto, CANADA, 

7 Medical Oncology, CHUQ-L’Hotel-Dieu de Quebec, Quebec City, QC, 

CANADA, 8 Medical Oncology, Cité-de-la-Santé Hospital, Laval, QC, CANADA, 

9 Medical Oncology, Cancer Care Manitoba, Winnipeg, MB, CANADA, 10 Surgery, 

CHUM, Notre-Dame Hospital, Montreal, QC, CANADA 

Background: Cabazitaxel/Prednisone (CbzP) improves survival in docetaxel resistant 

mCRPC. Canadian investigators collected safety and QoL data for patients (pts) 

participating in a global single-arm multicenter EAP. 

Methods: Between May 2011 and Feb 2012, 61 evaluable pts were enrolled at 9 

centers. Safety and QoL data were collected at baseline and at each cycle. QoL was 

assessed using the FACT-P and its subscales, EQ 5D-3L, and ESAS questionnaires. 

Utility values were derived from the EQ 5D-3L. Present pain intensity (PPI) and 

analgesic scores were assessed using the McGill-Melzack questionnaire. The change 

from baseline QoL in individual patients was analyzed. 

Results: At the time of analysis, baseline characteristics and safety data were available 

for the first 33 pts. Median age was 65; 94% were ECOG 0/1; 85% had bone 

metastases; and 76% had progressed within 3 months of prior docetaxel. Over half 

(56%) received at least 5 cycles of CbzP. Main grade 3+ toxicities were anemia 3%, 

leukopenia 3%, and febrile neutropenia 3% (prophylactic and therapeutic G-CSF use 

was permitted). Incidence of diarrhea (all grades) was 52%, and grade 3+ diarrhea 

was 3%. No treatment related deaths were reported. Preliminary analyses showed 

stable QoL and derived utility values over time. A pain subscale of FACT-P, showed 

improvements in the first 4 cycles; PPI scores improved despite stable analgesic use. 

Conclusions: In this EAP, reflecting routine clinical practice, the main toxicities of 

CbzP were similar to the TROPIC trial (neutropenia and diarrhea) emphasizing the 

need for close toxicity monitoring. Preliminary QoL and PPI data support a palliative 

benefit of CbzP not reported in TROPIC. Updated data with all evaluable pts and 

percentages of pts meeting important response thresholds will be presented. 

Disclosure: S.S. Sridhar: Dr. Sridhar has served on the advisory board for and is 

involved in research projects with Sanofi Aventis Canada. E. Winquist: Dr Winquist 

has received travel funding and consultant’s honoraria from Sanofi Canada. He is 

involved in research projects with Sanofi Canada. C. St.-Laurent Thibault: Catherine 

Saint-Laurent Thibault is an employee of Sanofi Canada Inc. H. Assi: Membership 

on an Advisory board, S. Berry: Membership on an advisory board, N. Aucoin: 

Membership on an advisory board, F. Saad: Dr Fred Saad sits on the advisory board 


for Sanofi Aventis Canada and has received consultant\\’s honoraria from Sanofi 

Canada. He is involved in research projects with Sanofi Canada. All other authors 


961 UPDATED ANALYSIS OF A COMBINATION HERBAL 

SUPPLEMENT TRIAL IN BIOCHEMICALLY RECURRENT 

PROSTATE CANCER 

J. Pinski 1 , T.B. Dorff 1 ,D.Hawes 1 , D. Tsao-Wei 1 , D.I. Quinn 1 , A. Goldkorn 1 , 

G. Liskovsky 1 , N. Vogelzang 2 , S. Groshen 3 ,L.Ji 1 

1 USC Norris Comprehensive Cancer Center, University of Southern California, 

Keck School of Medicine, Los Angeles, CA, UNITED STATES OF AMERICA, 

2 Oncology, US Oncology Nevada, Las Vegas, NV, UNITED STATES OF 

AMERICA, 3 Biostatistics, USC Norris Comprehensive Cancer Center, 

Los Angeles, CA, UNITED STATES OF AMERICA 

Background: After curative local therapy, thousands of men will experience rising 

PSA as an early indicator of recurrent prostate cancer. For these men no standard of 

care exists, and concern over serious side effects of androgen deprivation (ADT) 

makes delaying ADT common. We tested Prostate Health Cocktail (PHC), which 

contains vitamins D & E, saw palmetto, lycopene, green tea and soy extracts, in this 

population, to see whether it could induce PSA declines. 

Methods: Eligible men had a rising PSA with doubling time (DT) between 3 and 36 

months, with no evidence of metastases on CT and bone scan. Treatment included 

PHC 3 capsules PO daily for 4 week cycles for a maximum of 1 year. PSA was 

repeated after 1 cycle and then every 2 cycles thereafter with imaging only as 

clinically indicated; the primary endpoint was PSA decline at 12 weeks. PSA 

progression was defined as 25% increase above baseline/nadir and absolute increase 

of 5 ng/mL or return to baseline. Circulating tumor cells (CTCs) were measured at 

baseline and after 3 cycles using parylene membrane filters. 

Results: A total of 36 patients were enrolled as of January 31, 2012; 3 were 

retrospectively classified as ineligible and were excluded from all analyses except for 

toxicity. The median age was 67 (range 54-85) and baseline PSA was 2.9 ng/mL 

(1.1-53.2). The median number of cycles was 8 (1-13). Stable PSA was the best 

response for 25/27 men assessable at 12 weeks (93%) and 11/33 men (33%) had a 

PSA decline (1.1%-49.0% decrease). There was no significant change in testosterone 

or DHT during treatment. Circulating tumor cells were detected in some of the 

subjects. One patient had grade 3 transaminitis in the setting of alcohol 

consumption, otherwise the toxicities were limited to grade 1 or 2 and related to the 

gastrointestinal and metabolic/laboratory systems. 

Conclusion: PHC demonstrated activity in men with biochemical recurrence, 

resulting in PSA declines in about a third of cases, and was not associated with 

changes in serum androgens or significant toxicities. For the first time, we are 

reporting that circulating tumor cells can be detected in men with biochemical 

recurrence using filter technology. 

Disclosure: J. Pinski: I am a co-owner of OncoNatural Solutions Inc, the company 

which produces the Prostate Heath Coctail (PHC). All other authors have declared 


962TiP CABAZITAXEL PLUS PREDNISONE (CBZP) IN METASTATIC 

CASTRATION-RESISTANT PROSTATE CANCER (MCRPC) 

PATIENTS PREVIOUSLY TREATED WITH DOCETAXEL (D): 

EFFICACY AND SAFETY RESULTS FROM EARLY-ACCESS 

PROGRAM (EAP) SINGLE SITE EXPERIENCE 

P. Rescigno 1 ,C.D’Aniello 1 , P. Federico 1 , L. Puglia 1 , A. Petremolo 1 , 

C. Cavaliere 1 , C. Buonerba 1 , S. De Placido 2 , G. Di Lorenzo 1 

1 Genitourinary Cancer Section and Rare-cancer Center, University Federico II, 

Naples, ITALY, 2 Medical Oncology Department, University Federico II, Naples, 

ITALY 

Background: In the phase 3 TROPIC trial, mCRPC pts previously treated with D 

had a significant survival and clinical benefit with CbzP, a new tubulin-binding 

taxane, compared with mitoxantrone plus prednisone. The clinical benefits observed 

supported a global EAP, allowing pts with mCRPC to have access to Cbz prior to its 

commercial availability and providing safety and efficacy data in the real life 

population. We report the safety and efficacy results of 32 consecutive pts treated 

with CbzP in a single Italian centre. 

Methods: Pts recruited from a single centre between March and December 2011 

received Cbz 25mg/m2 IV q21 and prednisone 10 mg daily until disease progression, 

unacceptable toxicity, physician/pt decision or death. Biochemical and Tumour 

response were assessed before cycle 6 and 12. Pain response was assessed in 

symptomatic Pts before each cycle. 

Results: 32 pts were analyzed; median age was 67 years (≥ 75 years, 18%); 68.8% of 

pts had one previous D regimen and 31.2% ≥ 2 regimens, 93.8% had ECOG PS 0-1; 

Median number of CbzP cycles was 8; 43.7% had pain at treatment initiation with a 

median PSA value of 85 ng/mL. All pts had bone mets, 68% had visceral disease 



(visceral and nodes). The most common Grade 3/4 adverse events (AEs) were 

neutropenia (64.5%, 20 Pts) leukopenia (45.2%, 14 Pts), and febrile neutropenia 

(9.7%, 3 Pts). G3/4 diarrhoea was reported 3.2%, 1 pt. Pain response was 64.3%. 

PSA response 6 cycles (32 Pts) 

decline ≥50% 

PSA response by Gleason (decline >50%) 

53% 

GS 4-6 ( 9 Pts) 44% 

GS 7 (10 Pts) 60% 

GS 8-10 (13 Pts) 

PSA response by previous D regimen 

54% 

1 (17 Pts) 12 (71%) 

>1 (15 Pts) 5 (33%) 

Tumor Response (RECIST) 22 Pts 

PR + SD 19 (86.4%) 

PD 3 (13.6%) 

Conclusions: Our results indicate a high activity of cabazitaxel in terms of PSA, 

tumor and pain responses in all subgroups of pts analysed; cabazitaxel shows globally 

a clinically manageable safety profile in daily clinical practice. 


963TiP PHASE I TRIAL OF ASG-5ME IN METASTATIC CASTRATION 

RESISTANT PROSTATE CANCER (CRPC) 

M. Morris 1 , J. Bruce 2 , L. Reyno 3 , B. Anand 3 , A. Hartford 3 , K. Jelaca-Maxwell 3 , 

J. Lackey 3 , M. Eisenberger 4 

1 Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, UNITED 

STATES OF AMERICA, 2 Medicine, University of Wisconsin Center for Health 

Sciences Medical School UW Carbone Cancer Center, Madison, WI, UNITED 

STATES OF AMERICA, 3 Development, Agensys, Santa Monica, CA, UNITED 

STATES OF AMERICA, 4 Medicine, Sidney Kimmel Comprehensive Cancer 

Center at Johns Hopkins Medical Center, Baltimore, MD, UNITED STATES OF 

AMERICA 

Background: SLC44A4 is a 710 amino acid protein expressed on prostate, pancreas 

and other cancers. SLC44A4 is found in 95% of primary prostate tumors (75% 

express moderate to high levels). ASG-5ME is an antibody drug conjugate (ADC) 

comprised of a fully human antibody against SLC44A4, conjugated to the 

microtubule-disrupting agent monomethyl auristatin E. ASG-5ME has 

dose-dependent cytotoxic effects in vitro and significant anti-tumor activity in 

xenograft models. We report results of a phase I study of ASG-5ME for CRPC, 

conducted by the Prostate Cancer Clinical Trials Consortium. 

Methods: Patients (pts) had progressive metastatic CRPC. Prior chemotherapy was 

allowed. Treatment cohorts were 0.3, 0.6, 1.2, 1.8, 2.4, 2.7 and 3.0 mg/kg. ASG-5ME 

was given IV q3 weeks. Safety, pharmacokinetic properties, anti-tumor effects, 

circulating tumor cell (CTC) enumeration, and CTC molecular profiles were assessed. 

Pts were treated until disease progression or unacceptable toxicity. Dose limiting 

toxicity (DLT) was defined by cycle 1 toxicity. 

Results: 26 pts have been treated (3, 3, 3, 3, 6, 6, and 2 pts per respective cohort). 

Mean age was 69.5 (range 56-87), median Gleason score 8 (6-10), mean baseline PSA 

82.25 (4.4-1987). Pts received a mean of 3.8 doses (1-12). A DLT occurred at 2.7 mg/ 

kg: Grade (Gr) 4 neutropenia, Gr 3 constipation and diarrhea. 2 DLTs occurred at 3 

mg/kg: one with Gr 3 troponin elevation and the second with Gr 3 maculopapular 

rash, hypoxia, constipation, and Gr 4 neutropenia. Common Gr 1 and 2 adverse 

events included fatigue, anorexia, peripheral neuropathy, dyspnea and nausea. Gr 3 

events included: fatigue (2 pts), peripheral neuropathy (1), dyspnea (1) and nausea 

(1). Serum concentrations of ASG-5ME decreased multi-exponentially and the 

exposure was dose-proportional. The half-life of the ADC was 7.01 days 

(range-3.93-15.9, n = 17) after the first dose and 11.2 days (range-7.75-19.1 days, n = 

10) after the last dose. PSA declines of >50% were seen in 3/8 pts treated in the last 3 

cohorts and one >50% decrease in retroperitoneal nodes. 

Conclusions: The maximum tolerated dose (MTD) was exceeded at 3 mg/kg. The 

drug appears to have anti-cancer activity above 2.4 mg/kg. 

Disclosure: L. Reyno: The author is the CMO and Sr Vice President of Agensys, Inc, 

B. Anand: The author is a director of Agensys, IncA. Hartford: The author is a 

director of Agensys, Inc, K. Jelaca-Maxwell: The author is a paid safety consultant of 

Agensys, Inc, J. Lackey: The author is a director of Agensys, Inc. All other authors 


964TiP ARN-509 IN MEN WITH METASTATIC 

CASTRATION-RESISTANT PROSTATE CANCER (CRPC) 

D. Rathkopf 1 , E.S. Antonarakis 2 , N.D. Shore 3 , R. Tutrone 4 , J. Alumkal 5 , 

C.J. Ryan 6 , M. Saleh 7 , R. Hauke 8 , E. Chow-Maneval 9 , H.I. Scher 1 

1 Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, UNITED 

STATES OF AMERICA, 2 Sidney Kimmel Comprehensive Cancer Center, Johns 

Hopkins University, Baltimore, MD, UNITED STATES OF AMERICA, 3 Urology, 

Carolina Urologic Research Center, Myrtle Beach, SC, UNITED STATES OF 

AMERICA, 4 Urology, Chesapeake Urology Research Associates, Baltimore, MD, 

UNITED STATES OF AMERICA, 5 Medicine, Oregon Health & Science University 

Knight Cancer Institute, Portland, OR, UNITED STATES OF AMERICA, 6 Ucsf 

Helen Diller Family Comprehensive Cancer Center, University of California, 

San Francisco, San Francisco, CA, UNITED STATES OF AMERICA, 7 Medicine, 

Georgia Cancer Specialists, Atlanta, GA, UNITED STATES OF AMERICA, 

8 Medicine, Nebraska Cancer Specialists, Omaha, NE, UNITED STATES OF 

AMERICA, 9 Clinical Development, Aragon Pharmaceuticals, San Diego, CA, 


Background: ARN-509 is a novel second-generation anti-androgen that binds 

directly to the ligand-binding domain of the androgen receptor, impairing nuclear 

translocation and DNA binding. The Phase II portion of a multicenter Phase I/II 

study is evaluating the activity of ARN-509 in 3 distinct patient populations of men 

with CRPC: 1) non-metastatic treatment-naïve CRPC; 2) mCRPC treatment-naïve 

(tx-naïve); and 3) mCRPC abiraterone acetate pre-treated (AA). Preliminary results 

for the 2 cohorts of patients with metastatic CRPC are presented here. 

Methods: All patients had metastatic CRPC with progressive disease based on rising 

PSA and/or imaging. No prior chemotherapy for metastatic prostate cancer was 

allowed. Patients on the AA pre-treated cohort had to have been treated with AA for 

at least 6 months. All patients received ARN-509 at the recommended Phase II dose 

of 240 mg/day (Rathkopf et al, GU ASCO 2012). The primary endpoint was PSA 

response rate at 12 weeks according to the Prostate Cancer Working Group 2 Criteria 

in each of the treatment groups. Secondary endpoints included safety, time to PSA 

progression and objective response rates. PSA assessments were collected every 4 

weeks and tumor imaging was performed every 16 weeks. 

Results: To date, 32 patients have been enrolled: 25 on the tx-naïve and 7 on the 

post-AA cohorts, respectively. The combined median age was 67 (range 51-91) and at 

baseline, patients presented with ECOG performance status 0 (55%), Gleason Score 8-10 

(54%), and median PSA of 14.7 (tx-naïve) and 69.6 (post-AA) ng/mL. All patients 

received prior treatment with a LHRH analog with or without a first-generation 

anti-androgen. At a median treatment duration of 16 weeks, 4 patients discontinued the 

study due to disease progression, 2 in each cohort. The most common treatment-related 

adverse events (AE) were abdominal pain (36%), diarrhea (19%), nausea (16%) and 

fatigue (10%). There was only 1 treatment-related Grade 3 AE of abdominal pain. At 12 

weeks, the PSA response was 91% (tx-naïve) and 60% (post-AA), respectively. 

Conclusion: In men with CRPC, ARN-509 is safe and well tolerated with promising 

preliminary activity in metastatic, chemo-naïve patients both before and after 

treatment with abiraterone. 

Disclosure: E. Chow-Maneval: Dr. Chow Maneval is an employee of Aragon and 

holds stock in the company. All other authors have declared no conflicts of interest. 

965TiP A PHASE II STUDY (PERSEUS) OF TWO DOSES OF EMD 

525797 (DI17E6) IN PATIENTS (PTS) WITH ASYMPTOMATIC 

OR MILDLY SYMPTOMATIC METASTATIC 

CASTRATE-RESISTANT PROSTATE CANCER (MCRPC) 

K. Miller 1,* , M. Hussain 2,* , G. Mordenti 3 , H. Lannert 4 

1 Charité, Department of Urology, Berlin, GERMANY, 2 University of Michigan, 

Comprehensive Cancer Center, Ann Arbor, MI, UNITED STATES OF AMERICA, 

3 Merck Serono S.A., Global Biostatistics, Geneva, SWITZERLAND, 4 Merck 

KGaA, Global Clinical Development Unit Oncology, Darmstadt, GERMANY, * on 

behalf of the PERSEUS Study Group 

Purpose: Expression and function of αv-integrins are deregulated in prostate cancer, 

and αv-integrins are thought to play an important role in prostate cancer metastasis. 

EMD 525797 (DI17E6) is a humanized monoclonal IgG2 antibody specifically 

directed against αv integrin receptors (αvß1, αvß3, αvß5, αvß6, and αvß8). It has 

been shown to target tumor cells, the tumor’s environment (e.g. osteoclasts and 

osteoblasts), as well as angiogenic blood vessels. Previous studies with EMD 525797 

have shown a favorable tolerability profile in healthy volunteers and in mCRPC pts. 

A phase II trial is investigating the anticancer activity of 2 dose levels of EMD 

525797 in asymptomatic or mildly symptomatic mCRPC pts. 

Methods: Adult pts with CRPC who show radiologic progression of bone lesions 

with/without soft tissue lesions within 28 days prior to randomization are eligible for 

inclusion. Exclusion criteria are: acute pathologic fracture, spinal cord compression, 


or hypercalcemia at screening; prior chemotherapy, biologic, or experimental therapy 

for mCRPC; or radiotherapy to bone lesions and/or orthopedic surgery for 

pathologic fractures. A total of 216 pts receiving standard of care (luteinizing 

hormone-releasing hormone [LHRH] antagonists) and bisphosphonate therapy will 

be randomized 1:1:1 to receive in a blinded manner placebo, 1500 mg or 750 mg 

EMD 525797 (all 1-h intravenous [IV] infusions) on day 1 of every 3-week cycle 

until radiographic disease progression (PD). At progression, therapy will be 

unblinded and pts in the placebo group who show asymptomatic or mildly 

symptomatic radiographic confirmed PD can receive open-label therapy with 1500 

mg EMD 525797. The primary endpoint is composite progression-free survival, 

defined as the time (months) from randomization date to first documented sign of 


objective radiographic PD or death from any cause. Secondary endpoints include 

efficacy (e.g. overall survival and time to progression), safety, the pharmacokinetic 

profile of EMD 525797, and the exploration of a relationship between the number of 

circulating tumor cells and clinical outcomes. As of April 2012, 106 pts have entered 

the trial. 

Disclosure: K. Miller: Membership on an advisory board for Merck KGaA, 

Darmstadt, Germany, G. Mordenti: Employee of Merck KGaA, Darmstadt, 

Germany, H. Lannert: Employee of Merck KGaA, Darmstadt, Germany. All other 



gynecological cancers 

966O BRIVANIB (B) IN ADVANCED OVARIAN CANCER (OC): SUBSET 

RESULTS OF A PHASE 2 RANDOMIZED DISCONTINUATION 

TRIAL (RDT) 

S.B. Kaye 1 , L.L. Siu 2 , J. Jassem 3 , J. Medioni 4 , P. M.M.B. Soetekouw 5 , 

S. Slater 6 , C. M. Rudin 7 , G.K. Schwartz 8 , M. De Jonge 9 ,P.O’Dwyer 10 , 

C. Baudelet 11 , A. Chen 12 , M. J. Ratain 13 

1 Royal Marsden Hospital and Institute of Cancer Research, Sutton, UNITED 

KINGDOM, 2 Department of Medical Oncology, Princess Margaret Hospital, 

Toronto, CANADA, 3 Oncology and Radiotherapy, Medical University of Gdansk, 

Gdansk, POLAND, 4 Département d’Oncologie Médicale, Hôpital Européen 

Georges Pompidou, Paris, FRANCE, 5 Division of Medical Oncology, Maastricht 

University Medical Center, Maastricht, NETHERLANDS, 6 Department of Medical 

Oncology, Beatson West of Scotland Cancer Center, Glasgow, UNITED 

KINGDOM, 7 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins 

University, Baltimore, MD, UNITED STATES OF AMERICA, 8 Melanoma and 

Sarcoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY, 

UNITED STATES OF AMERICA, 9 Department of Medical Oncology, Erasmus 

University Medical Center, Rotterdam, NETHERLANDS, 10 Abramson Cancer 

Center, University of Pennsylvania, Philadelphia, PA, UNITED STATES OF 

AMERICA, 11 Research and Development, Brstol-Myers Squibb, Braine-l’Alleud, 

BELGIUM, 12 Research and Development, Bristol-Myers Squibb, Wallingford, CT, 

UNITED STATES OF AMERICA, 13 Department of Medicine, University of 

Chicago, Chicago, IL, UNITED STATES OF AMERICA 

Background: Brivanib (B) is an oral once daily selective dual inhibitor of FGF 

and VEGF signaling with preclinical activity against various tumor types. An 

RDT assessed B in pts with advanced solid tumors; data showing activity in 

sarcoma pts were reported previously, and data for the OC pts are presented 

here. 

Methods: OC pts progressing after previous treatment received open-label B 800 mg 

QD for a 12-wk lead-in period and were assessed by CT/MRI. Pts with complete 

(CR) or partial response (PR) continued on open-label B, those with progressive 

disease (PD) went off study. Pts with stable disease (SD) were randomized 1:1 to B 

or placebo (P) until PD or intolerance. Pts with PD on P could crossover to 

open-label B. Endpoints included progression-free survival (PFS) in randomized 

pts, objective response rate (ORR), disease control rate (DCR = ORR + SD), and 

safety. 

Results: One hundred twenty-six pts (63% with >3 prior systemic regimens; 88% 

FGF2 + by IHC) entered 12-wk lead-in and received B. At wk 12, 12 pts had PR and 

43 pts had SD (ORR 10%; DCR 44%). Three of 18 pts pretreated with bevacizumab 

(BEV) achieved PR at wk 12. After 12 wks, 49 continued on the study, 10 with PR 

remained on open-label B; and 39 were randomized to either B (n = 19) or P (n = 

20). Two pts with PR were randomized in error. Among randomized pts (n = 39), 

median PFS was 4 mo for B vs 2 mo for P with HR of 0.54 (90% CI: 0.28-1.03; 

p = 0.11). Among randomized FGF2 + pts (n = 36), HR was 0.56 (90% CI: 

0.29-1.07; p = 0.14). In the randomized phase, 3 additional pts achieved PR 

(overall population: 15 PRs; ORR 12%). The most common (≥5%) grade ≥3 AEs 

were increased ALT (20%) and AST (14%), fatigue (12%), hyponatremia (9%), 

asthenia (7%), diarrhea (7%), hypertension (7%), abdominal pain (6%), and 

decreased appetite (6%). Discontinuation due to treatment-related AE occurred in 

13% of pts. 

Conclusions: The observed PFS prolongation with B vs P, ORR and DCR in this 

RDT indicate clinical activity of B in pts with heavily pretreated OC, including those 

with prior BEV. The high frequency of FGF2 + pts precluded the assessment of FGF2 

as a predictive biomarker. The safety profile was acceptable. These results support 

further investigation of B in OC, potentially in pts with prior BEV. 

Disclosure: S.B. Kaye: Consultant for Astra Zeneca, Clovis, GSK, J&J, Pfizer Roche 

advisory boards Received payment from Roche for development of educational 

presentations L. Siu: Received research funding from Bristol-Myers Squibb J. 

Jassem: Advisory Board Member for Bristol-Myers Squibb C.M. Rudin: 

Consultancy for Oncothyreon P.J. O’Dwyer: Research funding and honorarium 

from Bristol-Myers Squibb Company. C. Baudelet: Employment and stock 

ownership of Bristol-Myers Squibb Company. A. Chen: Employment and stock 

ownership of Bristol-Myers Squibb Company. M.J. Ratain: Research funding 

from Bristol-Myers Squibb Company All other authors have declared no 




967O UPDATED OVERALL SURVIVAL ANALYSIS IN OCEANS, A 

RANDOMIZED PHASE 3 TRIAL OF GEMCITABINE (G) + 

CARBOPLATIN (C) AND BEVACIZUMAB (BV) OR PLACEBO (PL) 

FOLLOWED BY BV OR PL IN PLATINUM-SENSITIVE 

RECURRENT EPITHELIAL OVARIAN (ROC), PRIMARY 

PERITONEAL (PPC), OR FALLOPIAN TUBE CANCER (FTC) 

C. Aghajanian 1 , L.R. Nycum 2 , B. Goff 3 , H. Nguyen 4 , A. Husain 5 , S.V. Blank 6 

1 Gynecologic Medical Oncology Service Memorial Sloan-Kettering Cancer 

Center New York NY UNITED STATES OF AMERICA, 2 Department of Obstetrics 

Gynecology Forsyth Regional Cancer Center Winston-Salem NC UNITED 

STATES OF AMERICA, 3 Department of Obstetrics Gynecology University of 

Washington School of Medicine Seattle WA UNITED STATES OF AMERICA, 

4 Biostatistics Genentech Inc. South San Francisco CA UNITED STATES OF 

AMERICA, 5 Avastin Ovarian Cancer Program Genentech Inc. South 

San Francisco CA UNITED STATES OF AMERICA, 6 Division of Gynecologic 

Oncology NYU School of Medicine New York NY UNITED STATES OF AMERICA 

Background: In OCEANS, BV in combination with GC resulted in a statistically 

significant and clinically meaningful improvement in PFS in patients (pts) with 

platinum-sensitive (Plat-S) ROC (median PFS, 12.4 vs 8.4 months; HR = 0.484; 

P < .0001). These results were supported by the overall response rate (ORR), duration 

of response (DOR), and independent review committee (IRC) analyses. At the time 

of the final PFS analysis, the OS data were still not mature. Additional OS updates 

have been performed; here we present the 3rd interim OS analysis. 

Methods: Eligibility criteria included first recurrence of Plat-S OC, PPC, or FTC with 

an ECOG PS of 0 or 1, no prior BV or chemotherapy for ROC, and measurable 

disease. Pts were randomized 1:1 to arm A: GC (G [1000 mg/m2, days 1 and 8] and 

C [AUC 4, day 1], q3w for 6–10 cycles) + concurrent PL (q3w), followed by PL until 

disease progression (PD) or unacceptable toxicity; or arm B: GC + concurrent BV 

(15 mg/kg q3w), followed by BV until PD or unacceptable toxicity. The primary end 

point was investigator-assessed PFS by RECIST. Secondary end points included ORR, 

OS, DOR, and safety. The 3rd interim OS analysis was conducted with a data cutoff 

date of March 30, 2012. 

Results: As of the data cutoff date, 286 events (59% of pts) had occurred. There was no 

difference in OS between the arms, with an HR of 0.960 (95% CI, 0.760–1.214; log-rank 

P = 0.736). With a median follow-up of 42 months, median OS was 33.7 months in the 

GC + PL arm and 33.4 months in the GC + BV arm. There was no difference in the 

number of grade 5 treatment-emergent adverse events between arms (1 in each), the 

number of deaths was balanced between arms, and the cause of death in the majority of 

cases was PD in both arms. 89% and 86% of pts received subsequent therapy (including 

BV in 39% and 22%) in the PL and BV arms, respectively. 

Conclusions: These data provide assurance that there is no detriment to OS with 

the addition of BV in this setting, and supports the positive benefit:risk ratio of the 

GC + BV regimen in significantly improving PFS in patients with platinum-sensitive 

ROC. 

Disclosure: L.R. Nycum: Dr. Nycuum was a member of the Avastin-Ovary advisory 

board for Genentech for a contract of 1 year. The contract ended the end of March 

2012. H. Nguyen: Hoa Nguyen is an employee of Genentech and owns stock in 

Roche. A. Husain: Dr. Husain is an employee of Genentech and holds stock 

ownership (Roche). All other authors have declared no conflicts of interest. 

969PD NATURAL HISTORY OF SEROUS OVARIAN CARCINOMA: 

HIGH GRADE VERSUS LOW GRADE AND CARCINOMAS 

WITH BRCA MUTATIONS 

S. Ayers 1 , T.T. Tun 1 , N. Mescallado 1 , A. Wright 1 , D.G.R. Evans 2 , A. Clamp 1 , 

G.C. Jayson 1 , J. Hasan 1 


KINGDOM, 2 Regional Genetic Service, St Mary’s Hospital, Manchester, UNITED 

KINGDOM 

Serous carcinomas are the commonest histological subtype of epithelial ovarian 

cancer (EOC) and associated with BRCA mutations. In this study we analysed 

presentation and treatment-related outcomes of patients with high-grade(HGSC) and 

low-grade serous carcinomas (LGSC) and their relationship with BRCA mutations. 

Study design: A retrospective cohort study was carried out. Patients diagnosed with 

serous ovarian carcinoma from 2005-2010 were identified. A separate database was 

accessed to identify BRCA carriers ever treated at the Christie Hospital, UK. 

Individual patient data was analysed. 

Results: 391 patients were identified including 151 with BRCA mutations. 

Preliminary data on 303 cases is discussed. Mature data will be presented at the 



abstracts

meeting. The prevalence of LGSC is low. They present a decade earlier than HGSC 

(median age 50 vs 64) and fewer patients have advanced disease at first presentation 

(50%). The relapse rate is significantly less than with HGSC (23% vs 64%). Fewer 

patients with LGSC maintained platinum-sensitivity at first (15% vs 45%) and 

subsequent relapse (4% vs 20%). The median age of ovarian cancer patients with 

BRCA mutations was 54. 66% were BRCA1 carriers. The predominant histological 

subtype was serous (50%). 25% were poorly differentiated carcinomas. 53% had 

FIGO III/IV disease at presentation. At the time of analysis over half of patients with 

BRCA mutations and HGSC had died compared to 30% with LGSC. BRCA carriers 

maintained platinum-sensitivity for a greater period of time and lived longer 

compared to patients with sporadic HGSC or LGSC. The median times to 

development of platinum-resistance for BRCA carriers, HGSC and LGSC were 139, 

79 and 113 weeks respectively. The median overall survival times for the three groups 

were 367, 159 and 182 weeks respectively. BRCA2 carriers did better than BRCA1 

patients. None of the LGSC were associated with BRCA mutations. 

Conclusion: The presentation and natural history of LGSC is distinct to that of 

HGSC. BRCA carriers present at an earlier age and have better survival outcomes 

when compared to patients with sporadic serous ovarian carcinoma. 


970PD ANALYSIS OF GENE DOSAGE ABERRATIONS OF ERBB 

ONCOGENE FAMILY IN ENDOMETRIAL CANCER 

A.M. Supernat 1 , Z. Urban 1 , S. Lapinska-Szumczyk 2 , S. Sawicki 2 , D. Wydra 2 ,A. 

J. Zaczek 1 

1 Department of Medical Biotechnology, Medical University of Gdansk, Gdansk, 

POLAND, 2 Department of Gynaecology, Gynaecological Oncology and 

Gynaecological Endocrinology, Medical University of Gdansk, Gdansk, POLAND 

Introduction: ERBB (EGFR, epidermal growth factor receptor) family consists of 

four tyrosine kinase receptors: ERBB1, ERBB2, ERBB3 and ERBB4, which form a 

complex network of interacting signal transduction pathways. Excessive activation of the 

ERBB network, often found in tumors, is associated with rapid growth, proliferation, 

cell survival and also poor patient prognosis. Data about the importance of ERBB 

network in endometrial cancer is scarce. The purpose of this study was to determine 

the gene dosages of all the ERBB genes in endometrial cancer in the context of mutual 

dependence as well as clinicopathological parameters. 

Materials and methods: The study group included 144 premenopausal and 

postmenopausal endometrial cancer patients, staged I-IV. Fresh frozen specimens, 

derived from primary tumors, were used as material for molecular analysis. Relative 

gene dosages of ERBB1, ERBB2, ERBB3 and ERBB4 were assessed by SYBR 

Green-based quantitative PCR, using ΔΔCt method. 

Results: Gene dosages of individual ERBB genes correlated with each other. 

Particularly strong correlation occurred in case of ERBB2 and ERBB3 (p = 0.002), 

ERBB2 and ERBB4 (p T single nucleotide 

polymorphism (SNP) within the promoter of HMOX1 gene. 

Methods: The study included 135 patients (median age, 54 years; 95% CI, 39-69) 

with stage I-IV epithelial ovarian cancer who underwent cytoreductive surgery 

followed by standard paclitaxel/platinum analogue chemotherapy. Patients DNA was 

routinely isolated from the peripheral blood and -413A > T SNP was genotyped using 

specific SNP Genotyping Assay (Applied Biosystems). 

Results: The respective frequencies of -413A > T SNP AA, AT and TT genotypes 

within the patients’ group were 34.1% (46/135), 46.7% (63/135) and 19.3% (26/135) 


and were similar to distribution within the general population control group. 

Kaplan-Meier analysis has revealed that AA genotype was associated with significantly 

longer progression free survival time. The median progression free survival time was 

22.2 months in AA harboring patients and 14.5 months in patients with AT + TT 

genotype (p = 0.033 by log-rank test). AA genotype was also significantly associated 

with longer overall survival time. Three-year overall survival in AA and AT + TT group 

was 77.9% and 52.5%, respectively (p = 0.014). 

Conclusions: The results of our study show for the first time that response to the 

first line treatment and clinical outcome of ovarian cancer patients with standard 

paclitaxel/platinum analogue chemotherapy might be associated with functional 

-413A > T SNP in the HMOX1 gene. This finding may be of practical importance for 

prognostication and may suggest that HMOX-1 is a potential target for a supportive 

clinical intervention. 


972PD EFFICACY OF PLATINUM PLUS GEMCITABINE (G) IN 

PLATINUM-RESISTANT (R) COMPARED TO 

PLATINUM-SENSITIVE (S) OVARIAN CANCER: THE ROYAL 

MARSDEN EXPERIENCE 

A. George 1 , N. Tunariu 2 , N. Wilkinson 3 , S. Gupta 4 , M.E. Gore 5 , S.B. Kaye 6 , 

S. Banerjee 7 

1 Dept of Medicine, Royal Marsden NHS Foundation Trust and Institute of Cancer 

Research ICR, Sutton, UNITED KINGDOM, 2 Radiology Department, Royal 

Marsden NHS Foundation Trust and the Institute of Cancer Research ICR, 

Sutton, UNITED KINGDOM, 3 Gynaecology Unit, Royal Marsden NHS Foundation 

Trust and Institute of Cancer Research ICR, Sutton, UNITED KINGDOM, 

4 Statistics Department, Royal Marsden NHS Foundation Trust, London, UNITED 

KINGDOM, 5 Department of Medicine, Royal Marsden Hospital NHS Foundation 

Trust, London, UNITED KINGDOM, 6 Dept. of Medicine, Institute of Cancer 

Research, Sutton, UNITED KINGDOM, 7 Department of Medicine, Royal Marsden 

HospitalNHS Foundation Trust, London, UNITED KINGDOM 

Background: Carboplatin plus gemcitabine (GC) is approved in S relapsed ovarian 

cancer. The likelihood of response to platinum in R relapse (< 6months treatment free 

interval) is perceived to be low. Rechallenge with platinum-based chemotherapy is not 

routinely used in this setting. However, recent experience suggests that GC should be 

considered. Our aims were to assess the efficacy of GC in R patients, compare this with 

S patients and explore potential factors predicting clinical outcome. 

Method: Patients who started GC (C AUC 4 D1, G 800-1000 mg/m 2 D1, D8 q3wk) 

for relapsed ovarian, peritoneal or fallopian tube carcinoma between 01/01/10 and 

01/04/12 were analysed retrospectively. The primary endpoint was response rate 

(RR). Secondary endpoints included GCIG CA125 response and time to progression. 

The time between last platinum and first dose of GC (LPGCI) was assessed as a 

predictor of response to treatment. 

Results: 63 patients (33 S; 29 R; 1 platinum-refractory) were evaluable: age (median, 

range) S 57 (34-74), R 58 (34-79); prior lines of chemotherapy (median, range) S 1.5 

(1-12), R 3.5 (1-6); 83% high grade serous; 22% BRCA 1/2 germline mutation; 19% 

prior PARP inhibitor, 11% received cisplatin due to carboplatin hypersensitivity. The 

LPGCIs were (median, range) S 12.3 months (7.0-138), R 11.2 months (2.3-40). The 

differences in RR between S and R patients were not statistically significant (RECIST 

RR S 74%, R 57% p = 0.17; GCIG CA125 S 79% R 67% p = 0.31). Treatment was 

generally well tolerated. However, omission of D8 G on ≥2 cycles was required in 

16% due to toxicity (myelosuppression and fatigue). At the time of analysis, 78% had 

no evidence of disease progression. LPGCI was not predictive of response (p = 0.60, 

95% CI 0.97 – 1.04). 

Conclusions: The level of activity of GC in R patients is equivalent to that expected 

in S patients. This may relate to the potential for G to overcome platinum resistance. 

The relevance of LPGCI needs to be explored further. Further clinical outcome 

analyses and data on potential predictive factors will be presented. GC should now 

be considered a valid option for patients with platinum-resistant ovarian cancer. 


973PD DOSE-DENSE WEEKLY PACLITAXEL AND CARBOPLATIN IS 

MORE COST-EFFECTIVE THAN BEVACIZUMAB PLUS 

TRIWEEKLY PACLITAXEL AND CARBOPLATIN FOR THE 

PRIMARY TREATMENT OF ADVANCED OVARIAN CANCER 

K. Harano 1 , T. Shiroiwa 2 , M. Watanabe 3 , K. Suzuki 3 , T. Fukuda 4 , S. Watanabe 3 , 

N. Katsumata 1 

1 Department of Medical Oncology, Nippon Medical School Musashikosugi 

Hospital, Kawasaki city, JAPAN, 2 Department of Hygiene and Public Health, 

Teikyo University School of Medicine, Tokyo, JAPAN, 3 Consulting Division, 

Global Health Consulting Japan, Tokyo, JAPAN, 4 Center for Public Health 

Informatics, National Institute of Public Health, Saitama, JAPAN 

Purpose: To determine whether dose-dense weekly paclitaxel and carboplatin (ddPC) 

is cost effective compared to bevacizumab plus triweekly paclitaxel and carboplatin 

(PCB) for the primary treatment of advanced ovarian cancer. 



Methods: A cost-effectiveness analysis compared three treatments: 6 cycles of 

paclitaxel and carboplatin (PC), 6 cycles of PC plus bevacizumab followed by 12 

cycles of maintenance bevacizumab (PCB), and 6 cycles of dose-dense weekly 

paclitaxel and carboplatin (ddPC). Data were taken from reported results of ICON7 

(PC and PCB) and JGOG3016 (ddPC). Actual and estimated costs of treatment plus 

costs of complications were established for each regimen. Progression-free survival and 

rates of complications were estimated based on the results of clinical trials. Incremental 

cost-effective ratios (ICER) per progression-free life-year saved (PFLYS) were estimated. 

Results: The ICER for ddPC was $5,000 per PFLYS compared to PC. For PCB 

compared to PC, the ICER was $285,000 per PFLYS. When compared 

simultaneously, PCB was more costly and less effective than ddPC. 

Conclusions: In this model, dose-dense weekly paclitaxel and carboplatin is more 

cost effective than PCB for the treatment of advanced ovarian cancer. 


974PD A PHASE 1 STUDY OF THE ANTI-ERBB3 ANTIBODY MM-121 

IN COMBINATION WITH WEEKLY PACLITAXEL IN PATIENTS 

WITH ADVANCED GYNECOLOGICAL AND BREAST CANCERS 

J. Liu 1 , R. Patel 2 ,G.Kato 3 , U. Matulonis 1 , V. Moyo 4 , K. Riahi 4 , J. Pearlberg 5 , 

A. Czibere 4 , S. Isakoff 6 

1 Gynecology, Dana Farber Cancer Institute, Boston, MA, UNITED STATES OF 

AMERICA, 2 Research Department, Comprehensive Blood and Cancer Center, 

Bakersfield, CA, UNITED STATES OF AMERICA, 3 Research, Pinnacle Oncology 

Hematology, Scottsdale, AZ, UNITED STATES OF AMERICA, 4 Clinical 

Development, Merrimack Pharmaceuticals, Cambridge, MA, UNITED STATES 

OF AMERICA, 5 Sanofi Oncology, Sanofi, Cambridge, MA, UNITED STATES OF 

AMERICA, 6 Department of Hematology and Medical Oncology, Massachusetts 

General Hospital, Boston, MA, UNITED STATES OF AMERICA 

Background: MM-121 is a fully human monoclonal antibody targeting the 

epidermal growth factor receptor family member ErbB3. ErbB3 has been widely 

implicated in driving cancer growth and in the development of resistance to 

conventional chemotherapies and targeted agents across multiple malignancies. 

Single agent weekly paclitaxel is a standard regimen for patients with advanced 

gynecological and metastatic breast cancers. Here we present results from an 

ongoing Phase 1 study evaluating the combination of MM-121 and weekly 

paclitaxel. 

Methods: A total of 24 patients with either platinum resistant ovarian cancer, 

metastatic endometrial cancer, or HER2 negative metastatic breast cancer, were 

treated in a dose escalation (12 pts) or expansion cohort (12 pts). Patients were 

treated until disease progression or intolerable toxicity. Response was assessed every 

eight (8) weeks according to RECIST 1.1. In the dose-expansion cohorts, pre- and 

post-treatment fresh tumor biopsies were obtained from 12 patients to assess ErbB3 

signaling status and its potential as a predictive marker for MM-121 response. 

Results: To date, 24 patients have been treated with a median follow up of 5.5 

months (range 0.8 – 13.1). The median age was 58 years (range 38 – 72), and 

patients had received a median of four (range 1 – 11) prior lines of therapy. 

Common (>20%) adverse events of any grade included fatigue (62%), peripheral 

neuropathy (58%), diarrhea (46%), neutropenia (46%) and rash (38%). Grade 3/4 

toxicities included fatigue (17%), peripheral neuropathy (8%), diarrhea (12%), 

neutropenia (16%), anemia (4%), abdominal pain (8%), and hypokalemia (4%). 17 

(71%) patients were evaluable for response and the overall clinical benefit rate, defined 

as PR or SD lasting for >4 months, was 71%. 47% achieved a PR and 35% a confirmed 

PR with a median duration of response of 4.6 months (range1.7 – 9.6) and 24% had 

SD >4 months with a median duration of SD of 5.6 months (range 4.2-12.6). 17% 

patients had PD at first assessment and 38% remain on study with a median on-study 

time of 10.2 months (range 1.4 – 13.1). Translational analyses exploiting tissue analysis 

in combination with in silico modeling are ongoing. 

Conclusion: The combination of MM121 and paclitaxel showed activity in metastatic 

ovarian and breast cancers. 

Disclosure: J. Liu: Joyce Liu is an investigator participating in the corporatesponsored 

study which is the subject of the abstract. R. Patel: Ravi Patel is an 

investigator participating in the corporate-sponsored study which is the subject of 

the abstract. G. Kato: Giraldo Kato is an investigator participating in the 

corporate-sponsored study which is the subject of the abstract. U. Matulonis: Ursula 

Matulonis is an investigator participating in the corporate-sponsored study which is the 

subject of the abstract. V. Moyo: Victor Moyo is employed by and owns stock in the 

corporate sponsor of this reserach. K. Riahi: Kaveh Riahi is employed by and owns stock 

in the corporate sponsor of this research. J. Pearlberg: Joseph Pearlberg is employed by 

and owns stock in a corporate sponsor of this research. A. Czibere: Akos Czibere is 

employed by and owns stock in the corporate sponsor of this research. S. Isakoff: Steven 

Isakoff is an investigator participating in the corporate-sponsored study which is the 

subject of the abstract. He has also served as a consulant to Merrimack Pharmaceuticals. 

975PD A PHASE 1B STUDY OF AMG 386 PLUS PACLITAXEL AND 

CARBOPLATIN IN OVARIAN CANCER PATIENTS 

UNDERGOING PRIMARY OR INTERVAL DEBULKING 

SURGERY 

I.B. Vergote 1 , A. Oaknin Benzaquen 2 , J. Baurain 3 , S. Ananda 4 , S. Wong 5 , 

X. Yang 6 ,B.Wu 7 , Z. Zhong 8 , M. Puhlmann 9 , A. Casado 10 

1 Gynecologic Oncology, University Hospital Leuven, Leuven Cancer Institute, 

Leuven, BELGIUM, 2 Medical Oncology, Vall d’Habron University Hospital, 

Barcelona, SPAIN, 3 Service d’Oncologie Medicale, Universite Catholique de 

Louvain, Bruxelles, BELGIUM, 4 Oncology Unit, Royal Women’s Hospital, 

Parkville, VIC, AUSTRALIA, 5 Medical Oncology, Western Hospital, Footscray, 

VIC, AUSTRALIA, 6 Department of Biostatistics, Amgen Inc., Thousand Oaks, 

CA, UNITED STATES OF AMERICA, 7 Department of Pharmacokinetics and Drug 

Metabolism, Amgen Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA, 

8 Department of Clinical Immunology and Biological Sample Management, 

Amgen Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA, 9 Department 

of Clinical Development, Amgen Inc., Thousand Oaks, CA, UNITED STATES OF 

AMERICA, 10 Medical Oncology, Hospital Clínico San Carlos, Madrid, SPAIN 

Background: AMG 386, an investigational peptibody, blocks the interaction of 

angiopoietin-1 and -2 with the Tie2 receptor, thereby inhibiting tumor angiogenesis. 

We evaluated the tolerability of AMG 386 plus paclitaxel and carboplatin in ovarian 

cancer patients who had primary or interval debulking surgery (PDS or IDS, 


Methods: Women (≥ 18 yrs, GOG ≤ 1) with high-risk stage I (grade 3 or aneuploid 

grade 1 or 2) or II-IV ovarian cancer received 6 cycles of the combination AMG 386 

(15 mg/kg IV QW) plus paclitaxel (175 mg/m 2 IV Q3W) and carboplatin (AUC 6 IV 

Q3W) followed by AMG 386 maintenance monotherapy up to 18 months. Patients 

had PDS; patients with disease stage IIIC or IV had the option of planned IDS. 

AMG 386 dosing was withheld for > 4 weeks after PDS or before IDS. The primary 

endpoint was the incidence of dose-limiting toxicities (DLTs), which determined 

cohort expansion to n = 25; secondary endpoints included the patient incidence of 

adverse events (AEs), the incidence of anti-AMG 386 antibody formation, and 

pharmacokinetics (PK). The current report presents results from the study’s 

combination therapy phase. 

Results: At interim analysis, 27 patients (14 PDS, 13 IDS) were enrolled and 

received ≥ 1 dose of AMG 386 plus paclitaxel and carboplatin. No patients 

experienced DLTs. The patient incidence of AEs is summarized in the table below. 4 

of 24 patients developed non-neutralizing binding antibodies; 1 of 26 patients had 

pre-existing, non-neutralizing binding antibodies. Coadministration of AMG 386 did 

not alter the PK of paclitaxel or carboplatin. 

AMG 386 + 

paclitaxel and carboplatin (n = 27) 

Patient incidence of 

AEs – n (%) 

PDS (n = 14; 52%) IDS (n = 13; 48%) 

Patients with any 

adverse event 

14 (100) 12 (92) 

Worst grade ≥ 3 7 (50) 5 (38) 

Worst grade ≥ 4 3 (21)* 2 (15)** 

Worst grade 5 0 (0) 0 (0) 

In ≥ 20% of patients Any Worst grade ≥ 3 Any Worst grade ≥ 3 

who had PDS or 

IDS 

grade 

grade 

Localized edema 8 (57) 0 (0) 3 (23) 0 (0) 

Diarrhea 7 (50) 0 (0) 5 (38) 0 (0) 

Nausea 7 (50) 0 (0) 6 (46) 0 (0) 

Fatigue 7 (50) 0 (0) 5 (38) 0 (0) 

Thrombocytopenia 3 (21) 1 (7) 6 (46) 2 (15) 

Decreased appetite 2 (14) 0 (0) 6 (46) 0 (0) 

Asthenia 6 (43) 0 (0) 4 (31) 0 (0) 

Neutropenia 5 (36) 4 (29) 3 (23) 2 (15) 

Nasopharyngitis 5 (36) 0 (0) 0 (0) 0 (0) 

Alopecia 5 (36) 0 (0) 0 (0) 0 (0) 

Abdominal 

distension 

1 (7) 0 (0) 4 (31) 0 (0) 

Abdominal pain 2 (14) 0 (0) 4 (31) 0 (0) 

Constipation 4 (29) 0 (0) 4 (31) 0 (0) 

Peripheral sensory 

neuropathy 

4 (29) 0 (0) 4 (31) 0 (0) 

Hypokalemia 0 (0) 0 (0) 4 (31) 1 (8) 

Peripheral 

neuropathy 

4 (29) 0 (0) 0 (0) 0 (0) 

Continued 


Table: 975PD Continued 

AMG 386 + 

paclitaxel and carboplatin (n = 27) 

Parasthesia 4 (29) 0 (0) 1 (8) 0 (0) 

Vomiting 2 (14) 0 (0) 3 (23) 0 (0) 

Musculoskeletal pain 2 (14) 0 (0) 3 (23) 0 (0) 

Anemia 3 (21) 0 (0) 3 (23) 1 (8) 

Mucosal 

3 (21) 0 (0) 1 (8) 0 (0) 

inflammation 

Myalgia 3 (21) 0 (0) 1 (8) 0 (0) 

Dizziness 3 (21) 0 (0) 2 (15) 0 (0) 

Dysgeusia 

Of specific interest 

Edema 

3 (21) 0 (0) 1 (8) 0 (0) 

Generalized 2 (14) 0 (0) 0 (0) 0 (0) 

Lymphedema 2 (14) 1 (7) 1 (8) 0 (0) 

Female genital tract 

fistula 

0 (0) 0 (0) 1 (8) 0 (0) 

Wound 0 (0) 0 (0) 1 (8) 0 (0) 

*Grade 4 AEs were neutropenia (n = 3). 

** Grade 4 AEs were neutropenia (n = 1) and thrombocytopenia (n = 1). 

Conclusions: Interim results from this Phase 1b study of ovarian cancer patients 

undergoing PDS or IDS suggest that AMG 386 at 15 mg/kg IV QW plus paclitaxel 

and carboplatin was tolerable. No PK interactions were observed between AMG 386 

and paclitaxel or carboplatin. 

Disclosure: I.B. Vergote: As is relevant for the current drug, I am an advisory board 

member for and received funding from Amgen. However, I am also an advisory board 

member and received funding from other companies. J. Baurain: Corporate-sponsored 

research: Academic clinical trial run with an Amgen product in squamous skin cancer. 

X. Yang: Stock ownership: Amgen I am an employee with Amgen. B. Wu: Stock 

ownership: Amgen I am an employee at Amgen. Z. Zhong: Stock ownership: Amgen I 

am an employee at Amgen. M. Puhlmann: Stock ownership: Amgen I am an employee 

at Amgen. All other authors have declared no conflicts of interest. 

976P A SEMI-PROSPECTIVE TRIAL TO DETERMINE THE OUTCOME 

OF BORDERLINE OVARIAN TUMOR PATIENTS. RESULTS OF 

ROBOT, A STUDY OF THE AGO STUDY GROUP 

H. Lueck 1 , N. Ewald-Riegler 2 , N. De Gregorio 3 , A. Reuss 4 , S. Mahner 5 , 

C. Fotopoulou 6 , F. Kommoss 7 , B. Schmalfeldt 8 , S. Hauptmann 9 , 

A. Du Bois 10 

1 Gyn Oncol, Gynäkologisch-Onkologische Schwerpunktpraxis Hannover, 

Hannover, GERMANY, 2 Klinik für Gynäkologie U. Gynäkologische Onkologie, 

HSK Wiesbaden, Wiesbaden, GERMANY, 3 Frauenklinik, Universitätsklinikum Ulm, 

Ulm, GERMANY, 4 Studienzentren, Koordinierungszentrum für Klinische Studien, 

Marburg, GERMANY, 5 Dept of Gynecology and Gynecologic Oncology, 

University Medical Center Hamburg-Eppendorf, Hamburg, GERMANY, 

6 Frauenklinik, Charité, Campus Virchow Klinikum, Berlin, GERMANY, 7 Gyn 

Tumors, Institut für Pathologie, Mannheim, GERMANY, 8 Frauen- und Poliklinik, 

Klinikum rechts der Isar der Technischen Universität, München, GERMANY, 9 Gyn 

Tumors, Institut für Pathologie Allgäu-Oberschwaben, Wangen, GERMANY, 

10 Klinik für Gynäkologische Onkologie, Kliniken Essen-Mitte, Essen, GERMANY 

Background: Borderline ovarian tumors (BOT) are a rare entity, current standard of 

care is based on the available data of predominantly small retrospective trials. 

Therefore we performed a pattern of care study including central pathology review. 

Methods: All consecutive patients diagnosed with BOT 1998-2008 in 24 German 

institutions were included. Tumor samples were sent for central histopathological 

review to experienced pathologists, clinical data were collected and patient follow-up 

was updated. 

Results: Pathological review was obtained in 1,042 of 1,236 pts resulting in 950 

confirmed BOT cases analyzed here. Under- and overdiagnosis occurred in 5.0% and 

6.2% of cases. Median age was 49 years; 82% of patients had FIGO stage I disease; 

serous type (S-BOT) was diagnosed in 68% and mucinous type (M-BOT) in 31%. 

Primary/re-staging surgery led to complete debulking in 92% of pts (residual disease 

1.3%, unknown 6.4%). Adjuvant chemotherapy was given to 33 (3.5%) pts only. 166 

(17%) underwent fertility preserving surgery and 31 (19%) of these patients had 

documented pregnancies thereafter. Overall, 74 (7.8%) pts experienced relapse and 43 

(4.5%) died, transformation to invasive carcinoma occurred in 30% of the relapses. 

Inadequate surgical staging, residual tumor, fertility sparing surgery and higher FIGO 

stage were associated with shorter progression-free survival. No differences were observed 

for laparatomy vs. laparoscopy as initial surgical approach or adjuvant chemotherapy. 

Conclusions: To this day, this is the largest data set available for this entity. 

Prognosis of BOT is good even without adjuvant therapy if correct surgical staging is 

performed. Both tumor characteristics and treatment variables had a significant 

impact on relapse rate and outcome. In contrast to previous data, transformation to 

invasive carcinoma occurred in a significant amount of relapse cases. 



977P PROGNOSTIC FACTORS AFTER CONSERVATIVE TREATMENT 

OF A LARGE SERIES OF "STAGE I" SEROUS BORDERLINE 

OVARIAN TUMORS 

P. Morice 1 , A. Kane 1 , E. Muller 1 , R. Fauvet 2 , S. Gouy 1 , P. Pautier 3 , C. Lhomme 3 , 

E. Darai 4 , P. Duvillard 1 , C. Uzan 1 

1 Surgery, Institut Gustave Roussy, Villejuif, FRANCE, 2 Obstetrics Gynecology, 

CHU, Amiens, FRANCE, 3 Consultation de Gyn, Institut de Canc, Villejuif Cedex, 

FRANCE, 4 Obstetrics & Gynecology, Hopital Tenon, Paris, FRANCE 

Objectives: The aim of this study was to evaluate the prognostic factors of recurrence 

after conservative treatment of a large series of “apparent” stage I serous borderline 

ovarian tumors (SBOT). 

Methods: A review of 119 patients treated conservatively between 2000 and 2010 

with data on the follow-up. All pathological slides were reviewed by the same expert 

pathologist. Prognostic factors of recurrences were studied (age, histologic subtypes, 

surgical procedures used … ). 

Results: Conservative procedures were: unilateral cystectomy/UC (n = 43; 36%); 

unilateral salpingo-oophorectomy/USO (n = 50; 42%); bilateral cystectomy (n = 11; 

9%) and USO + CC (n = 15; 13%). Fourteen patients underwent complete peritoneal 

staging. Stages distributions were: IA (n = 80; 67%); IB (n = 18; 15%) & IC (n = 21; 

18%). Twenty-six patients had bilateral tumors. Respectively 21 (18%) & 13 (11%) 

had stromal microinvasion and/or micropapillary pattern. With a median follow-up 

of 45 months, 40 (33%) patients recurred (in whom 10 had peritoneal recurrence 

under the form of non invasive implants during the 1 st recurrence). Two of these 40 

recurrent patients had evolution in the form of invasive recurrence (during the 2 nd or 

3 rd recurrence): 1 in remaining ovary & 1 in the peritoneum. None patient died from 

disease. Only 2 prognostic factors of recurrence were identified in multivariate 

analysis: the young age of the patients (< 30 years old) & the bilaterality of the 

tumours. None of the others factors studied had impact on the rate of recurrence. 

Conclusions: In this series (representing the largest series reported of conservative 

management of stage I SBOT), the risk of recurrence is not related to the histologic 

patterns of the tumor (micropapillary, stromal microinvasion) nor to the surgical 

procedures used (type of conservative approach, the use of staging surgery, the use of 

laparoscopic approach). The rate of invasive recurrence is very rare in stage I SBOT (2 

cases in this series). Young age (< 30 years old) and bilaterality of the tumors are risk 

factors of recurrence suggesting that improvement of the fertility management (before 

potential recurrence) should be improved particularly in theses subgroup of patients. 


978P ROSIA: A SINGLE-ARM STUDY IN MORE THAN 1000 

PATIENTS (PTS) RECEIVING FRONT-LINE BEVACIZUMAB 

(BEV) + CHEMOTHERAPY (CT) FOR OVARIAN CANCER (OC) 

C. Mendiola 1 , I. Davidenko 2 , N. Colombo 3 , J. Korach 4 , F. Selle 5 , P. Gocze 6 , 

E. Chmielowska 7 , P. Pautier 8 , D. Bollag 9 , A.M. Oza 10 

1 Medical Oncology Service, University Hosptial 12 De Octubre Medical 

Oncology, Madrid, SPAIN, 2 Oncology Dispensary, Krasnodar Regional Clinical 

Oncology Center, Krasnodar, RUSSIAN FEDERATION, 3 Gynecologic Oncology 

Division, European Institute of Oncology, Milan, ITALY, 4 Gynecology Oncology, 

The Chaim Sheba Medical Center, Tel Hashomer, ISRAEL, 5 Medical Oncology, 

Hôpital Tenon, Paris, FRANCE, 6 Department of Obstetrics and Gynaecology, 

University of Pecs, Pecs, HUNGARY, 7 Oddzial Onkologii, SPZOZ Centrum 

Onkologii im. Prof.Lukaszczyka, Bydgoszcz, NAP, POLAND, 8 Hopital de Jour de 

Medecine, Institut Gustave Roussy, Villejuif, FRANCE, 9 GPS, F. Hoffmann- La 

Roche AG, Basel, SWITZERLAND, 10 Dept. of Medicine, Princess Margaret 

Hospital, Toronto, ON, CANADA 

Background: BEV significantly improved the efficacy of front-line CT for OC in the 

ICON7 and GOG-0218 phase III trials. The global single-arm ROSiA study was 

designed to assess the safety of BEV-containing therapy, given until progression or 

for up to 36 cycles, in the context of routine oncology practice. 

Methods: Eligible pts have FIGO stage IIb–IV or grade 3 stage I–IIa epithelial 

ovarian, fallopian tube or primary peritoneal carcinoma, have received no prior 

post-surgical therapy for OC, are aged ≥18 years and have ECOG PS 0–2. Prior 

neoadjuvant CT is permitted. Pts with uncontrolled hypertension, clinical signs/ 

symptoms of GI obstruction, or a history of abdominal fistula, GI perforation or 

intra-abdominal abscess within the preceding 6 months are ineligible. After definitive 

surgery, pts receive BEV 15 mg/kg q3w (or 7.5 mg/kg at the investigator’s discretion) 

in combination with 4–8 cycles of CT (paclitaxel [175 mg/m 2 d1 q3w or 80 mg/m 2 

qw) + q3w carboplatin [AUC 5 or 6]). BEV is continued at the same dose as a single 

agent until disease progression (PD), unacceptable toxicity or for up to 36 cycles. 

The primary objective is to assess safety (CTCAE v4.03). Secondary endpoints 

include progression-free survival, overall response rate by RECIST and/or CA-125 

response criteria, duration of response and overall survival. The study includes 

exploration of potential correlations of plasma, tumour and genetic biomarkers with 

BEV efficacy and toxicity. 



Results: Between Dec 2010 and Apr 2012, ∼1000 pts were enrolled from 35 

countries, predominantly Spain (n = 180), Italy (n = 110) and France (n = 101). 

Baseline characteristics were available from 677 pts as of 30 Jan 2012. Most pts had 

stage III/IV OC (stage I/II/III/IV: 7%/11%/60%/18%). The majority (93%) received 

paclitaxel q3w and 94% received BEV at a dose of 15 mg/kg; 14% had received prior 

neoadjuvant CT. Baseline characteristics from the entire population of ∼1000 pts will 

be reported, together with details of CT and BEV schedules selected. 

Conclusions: ROSiA should provide valuable new information on the safety of BEV 

for up to 36 cycles and in pts who have received neoadjuvant CT, as well as enabling 

extensive translational research. 

Disclosure: N. Colombo: NC has received honoraria for advisory boards and speaker 

engagements from Roche. F. Selle: FS acts as a Consultant for Roche and PharmaMar. 

P. Pautier: PP has served on Advisory Boards for Roche and Ipsen. D. Bollag: DB is an 

employee and holds stocks in F Hoffmann-La Roche Ltd. A.M. Oza: AO has received 

research funding from Roche. All other authors have declared no conflicts of interest. 

979P PREDICTIVE AND PROGNOSTIC ROLE OF SURVIVIN AND P53 

EXPRESSION IN PATIENTS WITH ADVANCED OVARIAN 

CANCER TREATED WITH NEOADJUVANT CHEMOTHERAPY 

A. Ga˛ sowska- Bodnar 1 , L. Bodnar 2 , M. Jerzak 3 , G. Wcisło 2 , M. Cichowicz 4 , 

A. Da˛ bek 4 , W. Kozłowski 4 , C. Szczylik 2 , W. Baranowski 1 

1 Department of Gynecology and Gyneacology Oncology, MIlitary Institute of 

Medicine, Warsaw, POLAND, 2 Department of Oncology, Military Institute of 

Medicine, Warsaw, POLAND, 3 Department of Gyneacology and Gyneacology 

Oncology, MIlitary Institute of Medicine, Warsaw, POLAND, 4 Department of 

Pathology, Military Institute of Medicine, Warsaw, POLAND 

Background: Qualification of patients with advanced ovarian cancer (AOC) to 

treatment with primary or interval debulking surgery (IDS) is the subject of 

controversy. The aim of this study was to assess the expressions of selected proteins of 

apoptosis to the effects of neoadjuvant chemotherapy (NAC) in patients with AOC. 

Material and methods: We evaluated 60 consecutive patients with AOS (FIGO stage 

IIIC-IV) treated with NAC, retrospectively. Formalin-fixed, paraffin-embedded tissue 

specimens were immunohistochemically stained for expression of p53 and survivin in 

patients given platinum-based NAC undergoing IDS. The expression of survivin was 

adopted dichotomization by the median expression of the protein found total score 

(TS) equals 2. For low expression of survivin was TS ≤ 2, while high total score TS> 2 

The positive and negative expression of p53 were used to dichotomization study group. 

Results: Median age of 60 patients was 60 years. The optimal IDS was achieved in 

69.1% (38/55). We observed significant difference in the percentage of stained nuclei 

(PS, p = 0.0002), the intensity of staining (IS, p = 0.0003) and TS (p = 0.0001) by 

comparing the expression of survivin in tumor tissue taken before and after NAC. The 

expression of p53 in tumor tissue before and after NAC was observed and significant 

difference was in PS, (p = 0.0424). There were no statistically significant difference in 

IS and the TS. Expression of survivin and p53 was not related to the results of IDS. 

Survivin expression was a prognostic factor in AOC patients treated with NAC (p = 

0.0484). Expression of survivin and p53 proteins was not a predictor factor in AOC 

patients. Adverse factors affecting the PFS for AOC patients treated with NAC were: 

lack of optimal IDS and the lack of an objective response by RECIST criteria 

(respectively HR was 3.93 (95% CI, 2.07-7.46, p

physicians in the U.S. and Europe. Using historical data, we analyzed projection estimates 

up to 2020 across US and EU5 countries by line of therapy and platinum response status. 

Results: Projection estimates from 2010 to 2020 by line of therapy varied by country. 

Among EU countries, the highest number of treated patients was in Germany, 

followed by United Kingdom (UK) and Italy. By 2020, the percentages of patients that 

are platinum sensitive and platinum refractory are expected to increase by about 17% 

in the US and 9% in the EU. Regional variation was observed across Europe with 

percentage increase in France being 12%, Germany 6%, Italy 10%, Spain 16% and UK 

7%. The table below refers to the number of ovarian cancer patients by line of therapy. 

Conclusions: Despite ongoing therapeutic efforts, only 44%of patients in US and 

65% in EU who receive 1L go on to 2L. This argues for continued efforts to be made 

for the development of more efficacious treatments for ovarian cancer. Real world 

data and disease based registries can help in validating emerging trends in therapy 

through providing up to date global projection estimates across line of therapy. 

Disclosure: J. Mehta: Employee of Sanofi R. Olivares: Employee of Sanofi O. 

Moulard: Employee of Sanofi P. Trask: Employee of Sanofi and owns stock A. 

Hamed: Employee of Sanofi. 

982P PLATINUM COMBINATION CHEMOTHERAPY VERSUS 

PLATINUM MONOTHERAPY IN PLATINUM-SENSITIVE 

RECURRENT OVARIAN CANCER: A META-ANALYSIS OF 

RANDOMISED TRIALS USING INDIVIDUAL PATIENT DATA 

(IPD) 

F.A. Raja 1 , N. Counsell 1 , N. Colombo 2 , M.K. Parmar 3 , J. Pfisterer 4 , I.B. Vergote 5 , 

A. Gonzalez Martin 6 , D. Alberts 7 , M. Plante 8 , J.A. Ledermann 1 

1 Cancer Research Uk & Ucl Cancer Trials Centre, UCL, London, UNITED 

KINGDOM, 2 Gynecologic Oncology Division, European Institute of Oncology, 

Milan, ITALY, 3 Cancer Group, Medical Research Council (MRC)MRC Clinical 

Trials Unit, London, UNITED KINGDOM, 4 Dept. of Gynecology, St, Solingen, 

GERMANY, 5 Obstetrics & Gynaecology, University Hospital Gasthuisberg, 

Leuven, BELGIUM, 6 Servicio de Oncologia Medica, MD Anderson Cancer 

CenterCenter Espana, Madrid, SPAIN, 7 Oncology, The University of Arizona 

Cancer Center, Arizona, UNITED STATES OF AMERICA, 8 Gynecologic Oncology 

Service, Centre Hospitalier Universitaire De Québec (chuq), L’hôtel-dieu De 

Québec, Laval University, Quebec, CANADA 

Objectives: The majority of women with ovarian cancer develop recurrent disease. 

For patients with a platinum free interval of > 6months, platinum based 

chemotherapy is the treatment of choice. The benefit of platinum-based combination 

chemotherapy in randomised trials varies and a meta-analysis was performed to gain 

more secure information on the size of the benefit of this treatment. 

Methods: we initiated a systematic review to determine whether combination 

chemotherapy is superior to single agent platinum chemotherapy in women with 

relapsed platinum-sensitive ovarian cancer. The systematic review and meta-analysis 

followed a pre-specified protocol. 

Results: A total of five potentially eligible trials that had used combination platinum 

chemotherapy versus single agent platinum chemotherapy in women with relapsed 

platinum-sensitive ovarian cancer were identified. For one trial adequate contact with 

the investigators could not be established. Therefore, four trials that randomly 

assigned 1,300 (87%) patients were included, with a median follow-up of 36.1 

months. OS analyses were based on 865 deaths and demonstrated a statistically 

significant benefit of combination platinum chemotherapy on survival (HR, 0.80; 

95% CI, 0.64 to 1.00; p = .050). PFS analyses were based on 1,167 events and 

demonstrated a highly statistically significant benefit of combination platinum 

chemotherapy on progression-free survival (HR, 0.68; 95% CI, 0.57 to 0.81; 

p < .00001). There was no evidence of a difference in the relative effect of 

combination platinum chemotherapy on either OS or PFS in patient subgroups 

defined by previous paclitaxel treatment, duration of treatment-free interval, or the 

number of previous lines of chemotherapy. 

Conclusions: In this IPD meta-analysis we have demonstrated that 

combination-platinum chemotherapy significantly improves overall survival and 

progression-free survival across all subgroups. This provides the strongest evidence to 

date of the benefit of combination-platinum over single agent platinum. 

Disclosure: J.A. Ledermann: Jonathan Ledermann has acted in an advisory role to 

Boehringer Ingelheim, Janssen and Roche. All other authors have declared no 


983P HOSPITAL FOLLOW UP IN OVARIAN CANCER: PHYSICAL 

EXAMINATION DOES NOT IMPROVE RELAPSE DETECTION 

OR SURVIVAL 

S. Chow, S. Ayers, A. Clamp, G.C. Jayson, J. Hasan 

Medical Oncology, The Christie NHS Foundation Trust, Manchester, UNITED 

KINGDOM 

Rationale: There are no trial data that define the optimum follow up strategy for 

patients with epithelial ovarian cancer (EOC). Relapse is suspected on the basis of 

symptoms, signs or elevated CA125. The relative merit of each of these is unclear 

because of a lack of data on cost-effectiveness and survival benefit. The aim of this 

study was to assess the utility of follow up procedures in relapse detection and survival. 

Study design: A cohort of 429 patients with FIGO stage I-III EOC in remission after 

first-line treatment was identified from the Christie Hospital ovarian cancer database. 

138 patients with recurrent disease were identified in this cohort. Patients were 

categorised as having symptomatic relapse, relapse with clinical signs, CA125 

elevation or combinations of the three. The clinical value of each of the three 

indicators of relapse and their effect on survival were analysed. 

Results: 41% of relapses were detected by single detection method. In 82% of 

patients, relapse was detected from a rising CA125 irrespective of symptoms or 

clinical signs. 18% of cases had disease that did not secrete CA125 at relapse. 66% 

of patients had symptoms at relapse, and 21% had at least one physical 

examination finding suspicious of relapse. A combination of rising CA125 and 

symptoms detected majority of relapses (98%) regardless of physical examination 

findings. Symptoms only were predictive of relapse in 13% of cases. Physical 

examination alone had the lowest detection rate of 2% (3/138). None of these 

patients were suitable for salvage surgery. CA125 and symptoms detected relapse in 

all 18 patients who had salvage surgery. 10/18 had single site relapse. There were 

no statistically significant differences in survival between detection methods at 1, 3 

and 5 year (p = 0.81). 

Conclusion: Physical examination is of limited benefit in the follow-up of EOC. It 

did not contribute to detection of disease suitable for salvage surgery. CA125 and 

symptom history can safely detect relapse in 98% of cases without compromising 

survival. This study questions the utility of routine hospital follow up in EOC 

patients.♦ Decimals rounded to nearest whole number. 


984P CONSERVATIVE SENSITIVITY ANALYSES OF 

PROGRESSION-FREE SURVIVAL (PFS) OF TRABECTEDIN 

PLUS PEGYLATED LIPOSOMAL DOXORUBICIN (PLD) VS. PLD 

ALONE IN PATIENTS WITH RELAPSED OVARIAN CANCER: 

OVA-301 STUDY 

I. Romero 1 , E. Pujade-Lauraine 2 , A. Tanovic 3 , J. Gómez García 4 , 

A.M. Poveda 1 

1 Area Clinica de Oncologia Ginecologica, Fundación Instituto Valenciano de 

Oncología, Valencia, SPAIN, 2 Medical Oncology, Hopital Hotel - Dieu, Paris, 

FRANCE, 3 Medical Affairs, PharmaMar, Barcelona, SPAIN, 4 Bio Statistics & Data 

Management, PharmaMar, Colmenar Viejo, SPAIN 

Background: Sensitivity analyses are critical to understanding the strength of 

conclusions made in the primary analysis. A randomised phase III trial OVA-301 

compared the efficacy of trabectedin 1.1 mg/m 2 in combination with PLD 30 mg/m 2 

given every 3 weeks vs. PLD 50 mg/m 2 every 4 weeks in patients with relapsed 

ovarian cancer. Primary endpoint was PFS based on independent radiology review 

(IRR) per RECIST. Secondary PFS analyses were based on independent oncologist 

(IO) and investigator’s assessments (IA). 

Methods: Patients were assessed symmetrically every 8 weeks in both arms. To avoid 

bias of the disease assessment time, two conservative sensitivity analyses of PFS were 

performed. Two different conservative analyses considered the scheduled date of PFS 

evaluation instead of the actual date of imaging moving the actual date to: #1) the 

last scheduled date of assessment immediately before the actual evaluation and to #2) 

the closest scheduled date before or after the actual evaluation. 

Results: The treatment effect based on the actual dates of assessment in favour of the 

combination arm is maintained across the performed sensitivity analyses. Summary 

of the two sensitivity PFS analyses compared with the pre-planned PFS analysis. 

Analysis n 

Trabectedin + 

PLD PLD HR CI 95% 


LR test 

(p value) 

PFS by IR* 645 328 317 0.789 0.646-0.963 0.0190 

PFS by IR (#1) 645 328 317 0.813 0.666-0.993 0.0245 

PFS by IR (#2) 645 328 317 0.822 0.674-1.004 0.0317 

PFS by IO* 671 336 335 0.724 0.599-0.876 0.0008 

PFS by IO (#1) 671 336 335 0.749 0.620-0.906 0.0010 

PFS by IO (#2) 671 336 335 0.757 0.626-0.916 0.0013 

PFS by IA* 672 337 335 0.723 0.608-0.859 0.0002 

PFS by IA (#1) 672 337 335 0.742 0.624-0.882 0.0001 

PFS by IA (#2) 672 337 335 0.747 0.629-0.888 0.0001 

*Main PFS analyses. 

#1: Conservative PFS sensitivity analysis; imputation to the previous schedule 

evaluation. 

#2: Sensitivity analysis with imputation to the closest scheduled evaluation. 

CI, confidence interval; HR, hazard ratio; IA, investigator assessment; IO, 

independent oncology review; 

IR, independent radiology review; LR, log-rank; PFS, progression-free survival; PLD, 

pegylated liposomal doxorubicin. 



Conclusions: The consistently observed significantly better PFS for the trabectedin 

combination based on adjusting progression times by moving assessments to 

scheduled times added methodological strengths and increased reliability and 

interpretability of the prior findings of this phase III trial. 

Disclosure: A. Tanovic: I am an employee at PharmaMar and stock owner. J. Gómez 

García: I am an employee at PharmaMar and stock owner. A.M. Poveda: I received 

funding for research from PharmaMar. All other authors have declared no conflicts 

of interest. 

985P THE EFFICACY OF TAXANS IN COMBINED TREATMENT OF 

OVARIAN CANCER 

O.M. Ahmedov, N.S. Yuldasheva, N. Umarova 

Gynaecology Department, National Cancer Centre, Tashkent, UZBEKISTAN 

Objective: The efficacy of paclitaxel plus carboplatin (TC) or gemcitabine plus 

carboplatin (GC) induction regimens with or without paclitaxel consolidation 

therapy were assessed in ovarian cancer (OC). 

Methods: Patients with stage T2NoMo- T3N1Mo were randomized to either GC 

(1 group) (gemcitabine 1,000 mg/m 2 ), days 1 and 8, plus carboplatin area under the 

curve [AUC] 5, day 1 and TC (2 group) (paclitaxel 175 mg/m 2 ) plus carboplatin 

AUC 6, day 1 every 21 days for up to six-eight cycles. Patients with complete 

response were allowed optional consolidation with paclitaxel 135 mg/m 2 every 28 

days for ≤ 12 months. Patients without complete response received single-agent 

crossover therapy at induction doses/schedules until complete response, disease 

progression, or unacceptable toxicity. Disease progression or death in 124 patients 

was required to compare induction arms with 80% statistical power for 

progression-free survival, the primary endpoint. 

Results: Randomized induction therapy was received by 230 of 256 patients enrolled; 

152 patients with complete response received paclitaxel consolidation whereas 56 

patients without complete response received single-agent crossover therapy. 

Progression-free survival was similar for GC and TC (median, 19.0 and 21.3 months, 

respectively; P = 0.199). Despite high censoring rates (>50%), overall survival was 

longer for TC (median, 48.3 versus 43.8 months for GC; P = 0.011). Controlling for 

patient characteristics including performance status, residual tumor size, and tumor 

stage, there was no statistical difference in a multivariate analysis. 

Conclusions: The regiment gemcitabine plus carboplatin does not improve 

progression-free survival over paclitaxel plus carboplatin as first-line induction 

chemotherapy in ovarian cancer. Although favouring paclitaxel plus carboplatin, 

overall survival analyses were limited by the study design and high censoring rates. 


986P BEVACIZUMAB PLUS METRONOMIC CYCLOPHOSPHAMIDE 

FOR HEAVILY PRETREATED OVARIAN CANCER: A SINGLE 

INSTITUTION EXPERIENCE 

I. Ghanem, C. Mendiola, A. Diaz, G. Velasco, L. Manso, E. Ciruelos, 

R.A. Manneh, S. Hoyos, T. Pascual, H. Cortes-Funes 

Medical Oncology, Hopital 12 de Octubre, Madrid, SPAIN 

Background: Bevacizumab in combination with chemotherapy has demonstrated 

activity for ovarian cancer in first and second lines. The purpose of this study is to 

evaluate the efficacy and safety of bevacizumab plus metronomic cyclophosphamide 

in heavily pretreated ovarian cancer patients 

Methods: We reviewed retrospectively 29 patients (p) with recurrent ovarian cancer 

treated with bevacizumab 10 mg/Kg IV every 14 days plus oral cyclophosphamide 

50 mg daily between January 2007 and January 2012 at a single institution. P 

characteristics, tumour features, survival data and adverse events (AE) were collected. 

Results: Twenty-nine p with a median age of 59 years old (31-79) and ECOG 1 (0-2) 

were analyzed. Fifteen (52%) and 14 (48%) p had stage IV and IIIC respectively 

before receiving bevacizumab-cyclophosphamide. The most frequent pathologic 

subtype was serous in 22 p (76%). The median of previous lines was 4 (2-9), 

including drugs as carboplatin 29p (100%), paclitaxel 29p (100%), pegylated 

liposomal doxorubicin 26p (90%), gemcitabine 20p (69%), altretamine 10p (34%), 

topotecan 9p (31%) or trabectedine 1p (3%). Twenty-three cases (79%) were 

platinum-resistant (progression free interval less than 6 months from last platinum 

treatment). The median of cycles administered was 9 (3-67). Twenty-six p were 

assessable for CA 125 marker evaluation: 4p (15%) had CA125 normalization, 7p 

(27%) partial response (PR), 8p (31%) stable disease (SD) and 7p (27%) progression 

disease (PD). The radiologic evaluation was performed in 23 patients: There were 6p 

(26%) with PR, 9p (39%) with SD and 8p (35%) with PD. Median progression free 

survival (PFS) and overall survival (OS) were 3.7 months and 12.1 months 

respectively. P with platinum-resistant disease had significantly worse PFS (3.2m vs 

36.0m) p = 0.001 and OS (12m vs not reached) p = 0.009. P with ECOG >1 also had 

worse PFS (2.8m vs 4.7m) p = 0.047 and OS (5.4m vs 34.5m) p = 0.011). Severe AE 

were G3 arterial hypertension (1p), G3 mucositis (1p), G3 anaemia and G4 digestive 

bleeding (1p). No alopecia and neurotoxicity deterioration were observed. 

Conclusions: This schedule consisting on bevacizumab plus metronomic 

cyclophosphamide shows activity in heavily pre-treated ovarian cancer with a well 

toxicity profile 


987P WHOLE ABDOMINOPELVIC RADIOTHERAPY (WAPRT) USING 

INTENSITY MODULATED ARC THERAPY (IMAT) AS 

PALLIATION FOR PLATINUM-RESISTANT OVARIAN CANCER 

A.P. Makar 1 , K. Vandecasteele 2 , P. Tummers 1 ,P.Ost 2 , L. Delrue 3 , S. Van Belle 4 , 

R. Van den Broecke 1 , V. Fonteyne 2 , W. De Never 2 , G. De Meerleer 2 

1 Department of Gynaecologic Oncology, University Hospital of Ghent, Ghent, 

BELGIUM, 2 Department of Radiation Oncology, University Hospital of Ghent, 

Ghent, BELGIUM, 3 Department of Radiology, University Hospital of Ghent, 

Ghent, BELGIUM, 4 Department of Medical Oncology, University Hospital of 

Ghent, Ghent, BELGIUM 

Background and aims: To asses the palliative effect of WAPRT using IMAT for 

patients with chemotherapy-resistant ovarian cancer. 

Methods: Forty-two patients were treated (33Gy; 22 daily fractions). At referral, 

median [range] age and Karnofsky performance score (KPS) was 59y [31 -76] and 80 

[40-90]. Disease-related symptoms were: intestinal (sub)-obstruction (n = 22), minor 

gastro-intestinal symptoms (n = 2), pain (n = 20), ascites (n = 11), and vaginal 

bleeding (n = 2). Median [range] CA125 serum level was 421 U/ml [6-13796]. All 

patients were heavily pre-treated. The actuarial overall survival (OS) and abdominal 

progression free survival (aPFS) were calculated from the start, response duration 

from the end of treatment. 

Results: Response rates (completed treatments; n = 30): The median [range] response 

duration (all symptoms) was 16 weeks [0-139]. For the whole population median 

[range] OS and aPFS was 4 months [0-32] and 11 weeks [0-142]. For those patients 

who completed treatment median [range] OS and aPFS was 8 months [2-32] and 17 

weeks [4-142]. Patients with a KPS ≥70 ended the treatment significantly more (p < 

0.001), had a better OS (8 vs. 1 month; P < 0.05), aPFS (18 vs 3 weeks; p < 0.001) and 

response duration (22 vs 5 weeks p < 0.001). 4) 

Conclusion: WAPRT offers important palliation for peritoneal metastasized 

/platinum resistant ovarian cancer patients. It can resolve intestinal obstruction for a 

substantial period. Carefull patient selection is mandatory (KPS ≥ 70). 


988P HXR9 AND PARP INHIBITION –A NOVEL THERAPEUTIC IN 

OVARIAN CANCER 

Z. Kelly, H. Pandha, R. Morgan, A. Michael 

Institute of Bioscience and Medicine, Department of Microbial and Cellular 

Science, University of Surrey, Guildford, UNITED KINGDOM 

Background: Ovarian cancer is the leading cause of cancer death among all 

gynaecological cancers. The majority of patients present with advanced stage disease 

having a median survival rate of only 3 years. A major obstacle in the treatment of 

ovarian cancers is the development of resistance to platinum-based therapies. It is 

therefore essential to introduce new therapeutic approaches. HOX genes are known 

to be deregulated in many solid tumours and in ovarian cancer. We have previously 

showed that HXR9, which inhibits the interaction between HOX and its 

down-stream cofactor-PBX induces apoptosis in the SKOV-3 epithelial ovarian cell 

line. HOXB7 is also known to have a role in DNA double strand break repair 

(DSBR). Another mechanism of cell death regulation through DNA DSBR is through 

inhibition of poly(ADP-ribose) polymerase (PARP). We have therefore tested the 

potential synergy between HXR9 and PARP-inhibitors. The objective of this study 

was to assess the cytotoxicity of HXR9 in cisplatin sensitive and resistant epithelial 

ovarian cancer cell lines, and to assess potential synergy with the PARP inhibitor, 

3-aminobenzamide. 

Methods: The MTS cell viability assay was used to show cytotoxicity in the ovarian 

cancer cell lines SKOV-3, COV-318, TOV-112D, PEO1, PEO4 and TOV-21G after 

treatment with HXR9, and in combination with presence PARP inhibitor 

3-aminobenzamide. Flow cytometric analysis and the caspase-3 assay was used to 

evaluate mode of cell death. 

Results: HXR9 induced apoptosis in all ovarian cancer cell lines treated compared to 

untreated cells with P values < 0.0001 for each of the cell lines tested, irrespective of 

cisplatin sensitivity status. The combination of HXR9 and 3-aminobenzamide 

induced enhanced cell death and showed clear synergy between the two drugs. The 

apoptosis rate in treated cells was confirmed by the capase-3 activity, which was 

increased for all cell lines (an average fold increases ranging from 1.3-3.4- compared 

to untreated controls). 

Conclusion: The combination of HXR9 with PARP inhibitor is synergistic and leads 

to enhancement of the apoptotic effect in the cisplatin-resistant ovarian cancer cell 

line SKOV-3. This strategy could potentially lead to a new therapeutic approach for 

patients with platinum-resistant ovarian cancer in the clinical setting. 



989P PHASE II STUDY OF COMBINATION CHEMOTHERAPY WITH 

ORAL S-1 AND OXALIPLATIN (SOX) IN PATIENTS WITH 

MUCINOUS ADENOCARCINOMA OF THE OVARY 

S. Nishio 1 , M. Shimada 2 , T. Kamura 1 , K. Ishitani 3 , K. Ochiai 4 , N. Takeshima 5 , 

Y. Yokoyama 6 , H. Furumoto 7 , T. Sugiyama 8 , J. Kigawa 2 

1 Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, 

JAPAN, 2 Obstetrics and Gynecology, Tottori University, Yonago, JAPAN, 

3 Obstetrics and Gynecology, Tokyo Women’s Medical University, Tokyo, JAPAN, 

4 Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, JAPAN, 

5 Gynecology, Cancer Institute Hospital, Tokyo, JAPAN, 6 Obstetrics and 

Gynecology, Hirosaki University Graduate School of Medicine, Hirosaki, JAPAN, 

7 Obstetrics and Gynecology, The University of Tokushima Graduate School, 

Tokushima, JAPAN, 8 Obstetrics and Gynecology, Iwate Medical University 

School of Medicine, Morioka, JAPAN 

We previously reported that patients with advanced or recurrent ovarian mucinous 

adenocarcinoma (MAC) had poor outcomes. Owing to similar biologic 

characteristics, chemotherapy for MAC has been based on standard 

chemotherapeutic regimens for colorectal cancer. Our basic studies also showed that 

a combination of oxaliplatin (L-OHP) and 5-fluorouracil was effective against MAC 

cells. This is the first phase II study of combination chemotherapy with oral S-1 and 

L-OHP (SOX) in patients with advanced or recurrent MAC. From July 2008 through 

December 2011, 40 patients, including 16 with recurrent disease, were enrolled. Two 

patients could not receive SOX chemotherapy because their performance status 

suddenly deteriorated after enrollment. L-OHP was administered at a dose of 100 

mg/m2 on day 1, and S-1 (80-120 mg/day) was given in 2 divided doses daily for 2 

weeks followed by a 1-week rest. This treatment schedule was repeated every 3 weeks 

until progressive disease. Tumor responses were evaluated according to the Response 

Evaluation Criteria in Solid Tumors, and toxicity was assessed with the Common 

Terminology Criteria for Adverse Events (version 3.0). Central pathological review 

(CPR) was also performed. On CPR, primary MAC was diagnosed in 13 patients, 

metastatic MAC in 15, endometrioid adenocarcinoma in 7, and other histological 

subtypes in 5. Of the 28 patients with a diagnosis of MAC, the objective response 

rate (RR) as assessed by an independent response review committee was 18% 

(complete response: 0, partial response: 5), and the disease control rate (CDR), 

including 14 patients with stable disease, was 68%. Among the 13 patients with 

primary MAC, the objective RR was 31%. Among the 38 patients who received SOX 

therapy, 2 discontinued the regimen because of toxicity. Grade 3 or 4 hematologic 

toxicities were neutropenia (28%), anemia (21%), and thrombocytopenia (10%). The 

most common grade 3 or 4 nonhematologic toxicities were anorexia (8%) and 

hyponatremia (8%). The present study showed a promising RR and good tolerance, 

suggesting that SOX therapy might contribute to prolonging survival. 


990P ERCC1 EXPRESSION AS PREDICTIVE BIOMARKER FOR 

PLATINUM CONTAINING CHEMOTHERAPY REGIMENS IN 

OVARIAN CARCINOMA 

M. Ulker 1 , B.B. Duman 2 , B. Sahin 3 , D. Gumurdulu 4 

1 Intenal Medicine, Cukurova University Medical Faculty, Adana, TURKEY, 

2 Medical Oncology, Adana Numune Education and Research Hospital, Adana, 

TURKEY, 3 Medical Oncology, Cukurova University Medical Faculty, Adana, 

TURKEY, 4 Pathology, Cukurova University Medical Faculty, Adana, TURKEY 

Background and aims: Platin based chemotherapy regimens are most important 

treatment choices for ovarian carcinoma. Significant numbers of patients develop 

resistance to platinum combination therapies. We aimed to show the role of ERCC1 

expression in the resistance to therapy in ovarian carcinoma. 

Patients and methods: Among all patients treated with platinum containing 

chemotherapy regimens, 27 eligible ovarian cancer patients were selected. Tissue 

samples were obtained from paraffin blocks and evaluated ERCC1 expression with 

immunohistochemical method in the pathology department. Expression level 0, 1(+), 

2(+) was assessed as low expression, 3(+) was assessed as high expression. The results 

were correlated with clinical findings and therapy response. Therapy response was 

assessed for RECIST criteria. 

Results: In this study 27 patients with pathologically proven ovarian cancer were 

enrolled to this study. Sixteen (59%) patients were stage III, and 11(41%) patients 

were stage IV. Complete response was determined in 18 (67%) patients, stable disease 

was determined in 3 (11%) patients and progressive disease was determined in 6 

(22%) patients. Median overall survival was 23 months. Treatment response rates 

were 50% in high ERCC1 expression group and 90% in low expression group. 

Statistically significant difference was found between two groups (p = 0.04). The 

median overall survival was 30 months(95% CI 23-37 months) in low ERCC1 

expression group and 15.8 months (95% CI 23-37 months) in high expression group 

(p = 0.183). 

Conclusion: Some primary tumors and most recurrent tumors develop drug 

resistance that lead to treatment failure. High ERCC1 expression levels are associated 

with the mechanism of cisplatin resistance in ovarian cancer. ERCC1 expression can 

be used as a predictive biomarker for the platin containing regimens in ovarian 

carcinoma. 



991P PATTERNS AND OUTCOMES OF TREATMENT IN ELDERLY 

PATIENTS WITH OVARIAN CANCER: A RETROSPECTIVE 

MONO-ISTITUTIONAL STUDY 

M.O. Nicoletto 1 , L. Furini 1 , M. Dalla Palma 1 , L. Borgato 1 , P. Fiduccia 1 , 

M. Rocchetto 2 , G.B. Nardelli 3 , M.T. Gervasi 4 , V. Zagonel 1 

1 Medical Oncology Unit 1, Istituto Oncologico Veneto, Padua, ITALY, 2 School of 

Medicine, University of Padua, School of Medicine, Padua, ITALY, 3 Deapartment 

of Gynecological Sciences and Human Reproduction, University of Padua, 

Padua, ITALY, 4 Ob/Gyn Unit Department for Health of Mothers and Children, 

Azienda Ospedaliera, Padua, ITALY 

Introduction: Ovarian cancer incidence is increasing in the elderly. We studied 

clinical and biological features of ovarian cancer in patients (OCP) aged >or = 70y. 

Methods: We conducted a retrospective analysis in 100 elderly OCP observed from 

1995 to 2011. We considered overall survival, comorbidities, surgery, hystotype and 

grading, chemotherapy (monochemotherapy vs polychemotherapy), response to 

treatment, and toxicities. 

Results: Median age was 75y (range 70-88y). Most of the pts (82%) had advanced 

stage at diagnosis (stage III, 70.2%), serous ovarian cancer histotype (67%), and grade 

3 (74 pts, 78.7%). Most pts had at least one comorbidity (84%) and more than half 

(53.2%) two or more. 29.8% of pts received an optimal debulking ( 5cm) tumour burden at multiple sites, radiological evidence 

of serosal disease and half developed bowel obstruction whilst receiving 

chemotherapy. Approximately 50% of patients presented with obstructive symptoms, 

but 25% presented with erratic bowel habit. Median survival following the first 

episode of bowel obstruction was 87 days (range 3-1754). Survival was similar 

between patients who underwent palliative surgery or chemotherapy (p = 0.89). 

Median survival for patients presenting in bowel obstruction with platinum-sensitive 

(PS) and platinum-resistant (PR) disease (but not chemonaïve patients) who 

proceeded to chemotherapy was prolonged compared with patients unsuitable for 

further treatment (PS 191 vs. 24 days, p < 0.0001; PR 149 vs. 50 days, p = 0.06). A 

feasibility trial investigating the efficacy of low residue diet and intravenous 



dexamethasone in the prevention and treatment of malignant bowel obstruction has 

been initiated. 

Conclusion: Overall survival in patients with malignant bowel obstruction is poor 

with no significant improvement over the last decade. Bowel obstruction in patients 

with chemonaïve disease represents an aggressive phenotype with poor prognosis. 

Judicious selection of patients for surgery and/or chemotherapy can significantly 

increase survival.1. ESMO Congress 2010, Milan. Poster 987P. 


993P FROM A WEBSITE TO A NATIONAL AND REGIONAL 

REFERENCE CENTRE NETWORK: THE FRENCH EXPERIENCE 

FOR RARE OVARIAN TUMORS 

I. Ray-Coquard 1 , P. Pautier 2 , J. Alexandre 3 , M. Vacher-Lavenu 4 , M. Fabbro 5 , 

A. Floquet 6 , F. Selle 7 , G. Ferron 8 , N. Chiannilkulchai 9 , E. Pujade-Lauraine 3 

1 Oncology, Centre Leon Berard, Lyon, FRANCE, 2 Medical Oncology, Institut de 

Cancerologie Gustave Roussy, Villejuif, FRANCE, 3 Oncologie Médicale, Hôpital 

Hôtel Dieu, Paris, FRANCE, 4 Service D’anatomie et Cytologie Pathologiques, 

Hôpital Cochin, Paris, FRANCE, 5 Médecine B2, CRLC Val d’Aurelle, Montpellier, 

FRANCE, 6 Oncologie, Institut Bergonié, Bordeaux, FRANCE, 7 Medical Oncology, 

Hôpital Tenon, Paris, FRANCE, 8 Médecine - Oncologie, Institut Claudius 

Regaud, Toulouse, FRANCE, 9 Hôpital Hôtel Dieu, Arcagy, Paris, FRANCE 

Background: Rare ovarian tumors (ROT) represent more than 20% of all ovarian 

cancers. Difficulties in histological diagnosis, absence of prognostic factors, evidence is 

not available for medical decision. In 2002, the GINECO group organized a dedicated 

website for sex cords (SCT) and germ cell (GCT) management. At the end of 2010, 

supported by the French NCI, a national network for all ROT was organized with 3 

national and 21 regional expert centers (REC). The objectives are to monitor the 

management of ROT and give equal access to expertise (systematic second opinion for 

histological diagnosis) and innovative treatments to all patients with ROT. 

Methods: The expected incidence of ROT in France is near 1000 new cases per year, 

including mostly SCT, GCT, mucinous (MC), clear cell (CCC), carcinosarcoma (CS), 

small cell carcinoma and borderline with invasive implants (BLT). A website collecting 

all files discussed in the REC was generated (www.ovaire-rare.org). The prospective 

collection of clinical data, dedicated multidisciplinary staff decision (MS), central 

pathological review and patient follow-up were implemented in the national database. 

Results: In 2011, 712 patients benefited of second opinion & were included by expert 

pathologists, representing 71% of expected incident cases. Major discordances 

concern 8% of patients. 294 patients gave informed consent & were included in the 

database before initial treatment in 229, (78 % of cases) or at the time of the first 

relapse in 65 (22%) : 85 (29 %) had SCT, 57 GCT, 61 BLT, 26 MC, 20 CCC, 45 

other. 280 (96%) patients cases were discussed in dedicated MS. 18 patients entered a 

clinical trial. Virtual tumor banking is on going to develop molecular diagnosis (as 

FOXL2 for SCT). 

Conclusion: This web-based tool supported by a national network including national 

and regional expert centers seems to be an efficient tool for the organisation of the 

management of rare ovarian cancer. The present project is under consideration for 

an EU project in 5 other countries interesting to duplicate such organisation. 


994P MALIGNANT OVARIAN GERM CELL TUMORS (MOGCT) AT A 

TERTIARY CARE SETTING IN PAKISTAN 

A. Hannan 1 , N. Siddiqui 2 , F. Badar 2 

1 Mediacal Oncology, Shaukat Khanum Memorial Cancer Hospital, Lahore, 

PAKISTAN, 2 Medical Oncology, Shaukat Khanum Memorial Cancer Hospital and 

Reserch Centre (SKM), Lahore, PAKISTAN 

Introduction: Malignant ovarian germ cell tumors (MOGCT) are rare neoplasms. 

Little is known about their behavior in the South East Asian populations. Aim of our 

study was to evaluate MOGCT patients treated at Shaukat Khanum Memorial Cancer 

Hospital and Research Centre, Lahore, Pakistan. 

Patients and methods: Of 638 females identified with ovarian cancer at our hospital 

from 1994 to 2007, 66 presenting with MOGCT were reviewed retrospectively. 

Histology was based on WHO classification. Tumors were staged according to FIGO 

system. Data was collected on presenting age, histopathology, stage, alpha-feto 

protein (AFP), B-human chorionic gonadotropins (B-hCG) levels, treatment, time to 

recurrence (TTR) and overall survival (OS). OS was the interval between the dates of 

diagnosis and last visit / death and TTR was between the dates of diagnosis and first 

recurrence. OS was determined by the Kaplan Meier method. Seven patients were 

not included in survival analysis as they were lost to follow up. 

Results: Mean presenting age: 18.1 years (6-45). Stage wise distribution (n): Stage 1 

(19), II (8), III (21), IV (18). Histology (n): Dysgerminoma (22), malignant teratoma 

(16), yolk sac tumor (15), Mixed germ cell (12) and embryonic carcinoma in 1 

patient only. AFP levels (n): elevated (29), normal (25) while unknown in 12 

patients. B-hCG levels (n): elevated n = 15, normal n = 42 and unknown in 9. Median 

follow up time was 48 months (0.2-183). All patients underwent initial surgery, with 

20 patients undergoing second look surgeries. Fertility sparing procedures were 

performed in 57 % of patients. Thirty four patients (57 %) achieved a complete 

remission at the end of treatment; while 18 (27.2%) patients did not show a response 

to any chemotherapy and had progressive disease. Seven patients relapsed, all within 

the first 3 years. The TTR was 11.2-32.5 months. Cumulative overall survival: 60 

months. 16 (88 %) of stage 1 patients while only 4 (26.6 %) of stage IV patients were 

alive at median follow up. 

Conclusions: The prognosis of MOGCT appears to be good and results are similar 

to what has been seen in the west. Fertility sparing surgery was possible in majority 

of cases and its feasibility should be explored in this young population of patients. 


995P DOES PACLITAXEL PLUS CARBOPLATIN (TC) SUBSTITUTE 

FOR PACLITAXEL PLUS CISPLATIN (TP) IN CERVICAL 

CANCER WITHOUT PRIOR PLATINUM TREATMENT? (SUBSET 

ANALYSIS OF JAPAN CLINICAL ONCOLOGY GROUP TRIAL 

(JCOG 0505)) 

H. Tanabe 1 , R. Kitagawa 2 , T. Shibata 3 , M. Saito 1 , S. Takakura 1 , A. Okamoto 1 , 

H. Sasaki 1 , K. Ochiai 1 , H. Yoshikawa 4 , T. Kamura 5 

1 Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, JAPAN, 

2 Obstetrics and Gynecology, NTT Medical Center Tokyo, Tokyo, JAPAN, 

3 Regulatory Science Section Multi-institutional Clinical Trial Support Center, 

National Cancer Center Hospital, Tokyo, JAPAN, 4 Obstetrics and Gynecology, 

Tsukuba University, Ibaraki, JAPAN, 5 Obstetrics and Gynecology, Kurume 

University School of Medicine, Kurume, JAPAN 

Objective: TP is the standard regimen for advanced or recurrent cervical cancer. 

However, JCOG0505 presented statistically significant non-inferiority of TC to TP in 

terms of overall survival (OS), for stage IVB or recurrent cervical cancer in ASCO ‘12 

annual meeting. By subset analyses of JCOG0505, we investigated whether the 

treatment effect of TP or TC is different among some specific subgroups including 

the one by prior platinum status. 

Methods: Patients (Pts) with stage IVB or recurrent cervical cancer; not amenable to 

curative therapy; 0-1 prior platinum; no prior taxanes; were randomized with 

minimization method to either TP (T 135 mg/m 2 24h d1 + P 50 mg/m 2 2h d2) or TC 

(T 175 mg/m 2 3h d1 + C AUC5 1h d1), both for maximum 6 cycles every 21 days. 

We estimated the hazard ratios and 95% confidence intervals in OS among 

subgroups (including prior platinum status) for the eligible patients, comparing TC 

and TP. Each hazard ratio (HR) was estimated by an unstratified Cox regression. 

Results: Total 253 pts were enrolled. Median follow-up of all randomized patients is 

17.4 months (mo). As was reported before, it was demonstrated that TC was not 

inferior to TP for OS (17.5 mo in TC and 18.3 mo in TP, HR 0.99 (non-inferiority 

p = 0.032 with a non-inferiority margin 1.29)). Both arms were comparable with 

respect to toxicity except for grade 4 neutropenia (45% in TC vs. 75% in TP). In a 

subset analysis (n = 244), TP was superior to TC for OS in non-prior platinum group 

(n = 117) (13.0 mo in TC and 23.2 mo in TP, HR 1.57 (95% CI:1.06-2.32)). Contrary, 

TC tended to show better survival than TP for OS in prior platinum group (n = 127) 

(19.0 mo in TC and 16.3 mo in TP, HR 0.69 (95% CI:0.47-1.02)). Furthermore, TP 

tended to be superior to TC for OS in stage IVB (n = 51) (14.8 mo in TC and 25.4 

mo in TP, HR 1.50 (95% CI:0.84-2.67)). 

Conclusion: Non-inferiority of TC to TP was demonstrated in the whole population 

of JCOG0505. By the subset analyses, however, TP may be still the first choice for 

patients without prior cisplatin-based treatment such as those with primary stage 

IVB cervical cancer. 


996P SHORTER SURVIVAL IN CERVICAL CANCER ASSOCIATION 

WITH HIGH EXPRESSION OF NOTCH-1 

N.G. Yousif 1 , J. Kamiran 2 , M.G. Yousif 3 , S. Anderson 2 , J. Albaghdadi 2 

1 Department of Medicine and Surgery, Box C-320, University of Colorado 

Cancer Center Anschutz Cancer Pavilion, Aurora, CO, UNITED STATES OF 

AMERICA, 2 Surgery, Colorado University, Aurora, CO, UNITED STATES OF 

AMERICA, 3 Biology, Al-Qadysia, IRAQ 

Background: Notch1 signaling has been shown to play a key role in carcinogenesis 

and progression of various human malignancies. Recent studies have implicated 

aberrant Notch signaling in cervical cancers. But, relatively little is known about the 

relation between expression of the Notch1 and survival rate in cervical cancer. In this 

study, we investigated the expression of Notch1 in cervical cancer to determine 

whether they could serve as prognostic predictors. 

Materials and methods: The expression of Notch1 was detected in 81 cases of 

cervical cancer; immunohistochemistry and Western blot were used to assay the 

expression level of Notch1. The predictive value of this expression for prognosis was 

investigated by Kaplan-Meier curves in a multivariate model. 

Results: Notch1 factor were intensively stained in cervical cancer 

immunohistochemically and expression was significantly increased with age and not 


elated with stage, nodal involvement and recurrence. Moreover, expression of 

Notch1 showed strong immunoreactive bands in Western blot analysis, survival time 

in patients with high Notch1 expression was significantly shorter than that in 

patients with low expression (Long rank p value = 0.0175). 

Conclusions: High expression of Notch1 is potentially a useful marker for survival in 

patients with cervical cancer. 


997P LONGTERM FOLLOW UP OF NEOADJUVANT CHEMOTHERAPY 

FOLLOWED BY SURGERY IN LOCALLY ADVANCED 

CARCINOMA OF THE CERVIX 

R. Majumder 1 , A. Mukhopadhyay 2 , S. Poddar 3 , A.N. Sen 1 , P. Gupta 2 

1 Surgical Oncology, Netaji Subhas Chandra BoseCancer Research Institute, 

Kolkata, INDIA, 2 Dept. Medical Oncology, Netaji Subhas Chandra BoseCancer 

Research Institute, Kolkata, INDIA, 3 Medical Oncology, Netaji Subhas Chandra 

BoseCancer Research Institute, Kolkata, INDIA 

Purpose: Neoadjuvant chemotherapy in cancer of the cervix has been tested for its 

efficacy over the last two decades. We evaluated the outcome of patients treated with 

neoadjuvant chemotherapy (NACT) followed by surgery for locally advanced bulky 

cancer of cervix. 

Methods: From July 2005 to August 2008 we treated 117 patients (median age 47 

years, range 38 years to 70 years) of locally advanced or bulky cancer of the cervix 

(stage IB2 to IIB) at Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata. 

The majority of the patients were of stage IIB (52%, N = 117). Squamous cell 

carcinoma was the most common histology (89%). All of them had undergone 2-3 

cycles of platin-based chemotherapy (Inj paclitaxel 175mg/m2 + Inj Carboplatin 

AUC 5) repeated every 21 days. Response assessment was done 2 weeks after the 2nd 

cycle. Good responders were taken for surgery and the rest were given 1 more cycle. 

After the 3rd cycle they were assessed and good responders were taken for surgery 

and the rest were treated with chemoradiation. 

Results: The overall response rate was 72.4%. The 5-year overall survival (OS), and 

disease-free survival (DFS), were 64.5% and 78%, respectively. DFS was better in 

NACT good responders (84% vs 68%, p = 0.04). No difference in survival (OS) was 

seen according to tumor size ( 8cm, p = 0.67) or disease stage ( FIGO IB2 

vs IIA1 vs IIA2 vs IIB, p = 0.1). Chemotherapy related morbidity was seen in 37% 

patients, surgery was delayed due to chemo toxicity in 15% of patients. Wound 

healing complication was seen in 26% of patients. 

Conclusion: Neoadjuvant chemotherapy followed by surgery is an alternative 

treatment option in locally advanced carcinoma of the cervix with acceptable 

morbidity and should be tested in proper clinical trials against chemoradiation. 


998P TO IMPROVE QUALITY OF LIFE OF REPRODUCTIVE AGE 

PATIENTS WITH CERVICAL CANCER 

V. Navruzova 

Oncogynaecology, National Cancer Center of Uzbekistan, Tashkent, 

UZBEKISTAN 

Background: Currently, there is a steady increase in the incidence of cervical cancer, 

especially among young women aged 40 – 44. Along with radical treatment, an 

important aspect is a quality of life of patients after therapy: 80% of women of 

reproductive age after ovarioectomy develop postovarioectomic syndrome, which 

includes the complex of pathological vegetovascular, neuro-psychiatric and 

metabolic-endocrine disturbances. In this connection there is need for a way to 

preserve ovarian hormonal activity, so as to ensure the quality of life in women of 

reproductive age. 

Materials and methods: One of the methods to preserve ovarian function is to shield 

them from radiation zone and it is called transposition. Our study included 189 

patients with cervical cancer (CC) T1b-2bN0-1M0 stage (I-III clinical stages) who were 

examined and treated at the department of Gynecology over 2007 to 2011. 1 st group 

comprised 90 (46.7%) patients, who received complex therapy including surgery with 

transposition of the ovaries. 2 nd group comprised 99 (53.3%) patients, who 

underwent surgery without ovarian transposition in the complex therapy. 

Results: In the main group patients complained of hot flushes - 2% (4 patients), 

sleep disturbance - 26% (26 patients), sexual dysfunction -19% (23 patients), 

sweating - 6% (5 patients), pain in bones - 19% (17 patients), weight gain - 29% (26 

patients). In the control group there were observed hot flushes - 86% (85 patients), 

sleep disturbance - 25% (36 patients), sexual dysfunction - 42% (42 patients ), 

sweating - 19% (19 patients), bone pains 29% (29 patients), weight gain 38% (38 

patients). This indicates the more mild post-operative state of patients with ovarian 

transposition, as well as better tolerance of further anticancer therapy compared with 

the control group. The study of history data showed that most of the patients 

symptoms had manifested within 1 to 3 months (in 48.1% of patients), which 

disappeared after appropriate correction. 


Conclusion: Transposition of the ovaries during treatment for cervical cancer in 

women of reproductive age can improve the quality of life of patients and reduce the 

terms of social and psychological rehabilitation. 


999P MODERN OUTCOMES OF CERVICAL CARCINOMA IN 

MOROCCAN WOMEN TREATED WITH CONCURRENT 

CHEMORADIOTHERAPY 

S. Elmajjaoui 1 , N. Ismaili 2 , K. Hassouni 1 , T. Kebdani 1 , N. Benjaafar 1 

1 Radiotherapy, National Institute of Oncology, Rabat, MOROCCO, 2 Medical 

Oncology, Hassan II Hospital Centre Régional d’Oncologie d’Agadir, Agadir, 

MOROCCO 

Purpose: To report contemporary outcomes for nonmetastatic cervical cancer in 

Morrocan women treated in the modern area of concurrent chemoradiotherapy 

(CCRT). 

Methods: we retrospectively reviewed the chart of 379 patients with nonmetastatic 

invasive cervical carcinoma treated with CCRT between January 2006 and December 

2006. Staging was performed on a clinical basis according to the FIGO classification. 

Chemotherapy was based on weekly cisplatin (40mg /m 2 ). Radiation treatment was 

based on external radiotherapy at a dose of 46 Gy followed by uterovaginal 

brachytherapy or additional radiotherapy at a dose of 24 Gy. Overall survival (OS), 

event-free survival (EFS) and locoregional recurrence free survival (LRRFS) were 

estimated by the Kaplan-Meier method. Treatment groups were compared by using 

log rank tests. Cox proportional hazard methods were used to determine prognostic 

factors for outcomes. 

Results: Median age was 49 years (23-79 years). Bleeding was the main symptom 

(93.4%). Median tumor size was 7cm. About 3.7%, 28.5%, 1.3%, and 42.5% of the 

patients were stages IB2, IIBd, IIIA, and IIIB, respectively. The most predominant 

histological type was squamous cell carcinoma (96.4%). Median follow-up was 35 

months(range2-78months).Therateofcompleteresponsewas93.9%.OS,EFS 

and LRRFS at 5 years were 76%, 56% and 82% respectively. On univariate 

analysis, we identified four prognostic factors: the stage, influencing OS, EFS and 

LRRFS (p < 0.001, p < 0.001 and p < 0.001, respectively); the tumor size, 

influencing OS and EFS (p = 0.034 and p = 0.019, respectively); the lymph node 

status (pelvic lymph node and/or para-aortic on imaging), influencing OS and 

EFS with trend to significance (p = 0.084 and p = 0.071, respectively). The 

anemia, influencing OS, EFS and LRRFS (p = 0.021, p = 0.027, and p = 0.087). On 

multivariate analysis, the stage was the only prognostic factor for OS ( p = 0.002), 

EFS and LRRFS. 

Conclusion: In Moroccan women with cervical carcinoma, CCRT is an efficient 

treatment which achieves a disease control in 93.9% of the cases. However, the 

prognosis remains relatively poor due to delayed diagnosis. On univariate analysis, 

prognostic factors were the stage, tumor size, lymph node involvement, and anemia. 

On multivariate analysis the stage was the only prognostic factor. 


1000P NEOADYUVANT CHEMOTHERAPY FOLLOWED BY 

CHEMORRADIATION IN LOCALLY-ADVANCED SQUAMOUS 

CERVICAL CANCER 

M. Vieito Villar 1 , N. Martinez Lago 1 , J.F. Cueva 1 , E. Gonzalez Patiño 2 ,M. 

T. Curiel 3 , P. Palacios Ozores 3 , S. Candamio Folgar 3 , N. Salvador Garrido 2 , 

B. Taboada 4 , R. Lopez 1 

1 Dept. of Medical Oncology, Complejo Hospitalario Universitario de Santiago de 

Compostela SERGAS, Santiago de Compostela, SPAIN, 2 Radiocherapy 

Oncology, Hospital Clínico de Santiago de Compostela, Santiago de 

Compostela, SPAIN, 3 Medical Oncology, Hospital Clínico de Santiago de 

Compostela, Santiago de Compostela, SPAIN, 4 Oncoloxia Radioterápica, 

Hospital Clinico Universitario de Santiago, Santiago de Compostela, SPAIN 

Introduction: Although there has not been a direct comparison between 

neoadjuvant chemotherapy followed by chemor-radiation with the standard 

treatment of concurrent chemor-radiation, neoadjuvant chemotherapy is active in 

squamous cervical cancer. 

Material and methods: In this open label 1 arm phase two trial we accrued 19 

patients from 2007 to 2011 diagnosed with squamous cervical cancer deemed to be 

unresectable and poor candidates to concurrent chemor-radiation. Patients had to 

be over 18 years of age, give informed consent, have a PS0-1 and adequate organ 

function.They received neoadjuvant chemotherapy with paclitaxel 80mg/m 2 and 

cisplatin33mg/m 2 days 1,7,15/28 for two cycles and then external radiation in 1.8 

Gy/ fraction with concurrent cisplatin 40mg/m 2 /weekly followed by brachytherapy 

in 5-6 applications. After completion of neoadjuvant treatment and after 

concurrent chemor-radiation patients were evaluated by RECIST 1,1 criteria for 

tumor response with a CT scan and pelvic MNR and data of dose intensity and 

toxicity was accrued. 



Results: Median age at diagnosis was 51 years (27 to 72 years); all the patients had 

PS1 due to local pain, asthenia or genital discharge. Neoadjuvant treatment was 

feasible in all patients with manageable toxicities; the dose intensity delivered was 

97% of the preplanned dose. Only 2 episodes of grade III anemia were observed. 

In the first radiologic evaluation 4 patients had a complete response, 12 had 

partial response and 3 disease stabilization. Patients received external 

radiotherapy in fractions of 1.8 Gy achieving a dose of 66 GY in patients that 

could not receive brachytherapy. Mean EQD2C for those who did (68%) was 72 

GY. Only 68% of the patients received the full preplanned concomitant dose due 

to toxicity, mainly grade III anemia and diarrhea. In the second radiological 

evaluation 9 patients had a complete response, 9 partial and only 1 stable disease. 

At a mean of 24 months of follow up only 5 patients (26%) thus far have 

developed recurrent disease, all of the recurrences were simultaneously local as 

well as systemic. 

Conclusion: Our weekly cisplatin-paclitaxel regimen has been demonstrated to be 

feasible and effective in terms of dose delivery, tolerance and radiological responses 

without compromising definitive treatment with chemor-radiation. 


1001P A PHASE II MULTICENTER RANDOMIZED OPEN-LABEL 

STUDY OF ORAL STEROID SULPHATASE (STS) INHIBITOR 

IROSUSTAT (BN83495) VERSUS MEGESTROL ACETATE (MA) 

IN WOMEN WITH ADVANCED/RECURRENT ENDOMETRIAL 

CANCER (EC) 

P. Pautier 1 , F. Joly Lobbedez 2 , B. Melichar 3 , E. Kutarska 4 , G. Hall 5 , N. Reed 6 

1 Medical Department, Institut Gustave-Roussy, Villejuif, FRANCE, 2 Service 

d’Oncologie Médicale, Centre François Baclesse, Caen, FRANCE, 3 Oncology, 

University Hospital Olomouc Palacky University, Faculty of Medicine, Olomouc, 

CZECH REPUBLIC, 4 Oddział Onkologii Ginekologicznej Radioterapii I 

Chemioterapii, Centrum Onkologii Ziemi Lubelskiej im. s´ w. Jana z Dukli, Lublin, 

POLAND, 5 St James’s Institute of Oncology, St James’s University Hospital, 

Leeds, UNITED KINGDOM, 6 Beatson Oncology Centre, Gartnavel General 

Hospital, Glasgow, UNITED KINGDOM 

Background: Despite the progress in the diagnosis and therapy of early EC, 

advanced (metastatic) or recurrent EC remains an incurable disease. Irosustat (also 

known as BN83495, STX64 and 667-coumate) is a selective irreversible STS inhibitor 

developed for the treatment of hormone-dependent tumors. Objective: A phase II, 

randomized, open-label study was designed to explore the safety and efficacy of 

irosustat as a single agent in advanced/recurrent EC. 

Methods: Post-menopausal women with histologically verified estrogen and/or 

progesterone receptor-positive EC (defined as ≥10% positive cells in primary tumor 

or metastasis), with recurrent/advanced disease, at least one measurable target lesion, 

life expectancy ≥6 months, not eligible for surgery or radiotherapy and no prior 

systemic treatment for EC (except adjuvant chemotherapy if completed ≥1 year 

before randomization) were randomized 1:1 to daily oral irosustat 40 mg or MA 160 

mg. The primary endpoint was the percentage of patients alive without progression 

after 6 months of treatment. Blinded central review of responses (evaluated using 

RECIST 1.0) was performed. Secondary endpoints included progression-free survival 

(PFS), time to progression, overall survival, quality of life and safety. 

Results: 73 patients were enrolled in 11 European countries, 36 were randomized to 

irosustat and 37 to MA. Median age was 68 years (range 37-85 years). 

Treatment-related severe toxicities (grade 3-4) were symptomatic hyponatremia, 

asthenia, dry skin and worsening of hypertension for irosustat (n = 1) and 

pulmonary embolism (n = 3, 1 led to death) and hyperglycemia with MA. 

Conclusion: This study demonstrates clinical benefit of hormonal treatment 

(irosustat and MA) in selected patients with advanced/recurrent EC with a different 

toxicity profile. 

Irosustat(n = 36) Megestrol acetate(n = 37) 

Alive without progression at 

6 months n (%) 

13 (36.1) 21 (56.8) 

Response (CR + PR) n (%) 4 (11.1) 12 (32.4) 

Stable disease n (%) 17 (47.2) 12 (32.4) 

Median PFS (weeks) 

[90% CI] 

16 [9-34] 32 [16-63] 

Disclosure: P. Pautier: Author is an advisory board member for Roche and Ipsen. F. 

Joly Lobbedez: Author is an advisory board member for Sanofi, Roche, Novartis, 

Janssen, Ferring, Pfizer. No conflit of interest with Ipsen or BN83495. N. Reed: 

Consultancy fees and lecturing for Novartis, Roche, AZ, Johnson and Johnson, 

Otsuka. All other authors have declared no conflicts of interest. 

1002P THE ROLE OF INTRAVAGINAL BRACHYTHERAPY IN 

SURGICALLY-STAGED 1988 FIGO STAGE IC GRADE 3 

ENDOMETRIAL CANCER 

B. Barney 1 , I.A. Petersen 1 , J.A. Call 1 , A. Grothey 2 , M.G. Haddock 1 

1 Radiation Oncology, Mayo Clinic, Rochester, MN, UNITED STATES OF 

AMERICA, 2 Medical Oncology, Mayo Clinic, Rochester, MN, UNITED STATES 

OF AMERICA 

Purpose/objectives: Patients with 1988 International Federation of Gynecology and 

Obstetrics (FIGO) Stage IC grade 3 (ICgr3) endometrial cancer (EC) were excluded 

or underrepresented on practice-defining intermediate-risk EC trials due to relatively 

high rates of occult nodal and/or distant metastasis. Adjuvant therapy 

recommendations in this population vary widely, but standard practice is to offer 

adjuvant pelvic external beam radiotherapy (EBRT) +/- chemotherapy. We report 

our single-institution’s experience using adjuvant high-dose rate (HDR) vaginal 

brachytherapy (VBT) alone +/- chemotherapy for patients with surgically-staged 

1988 FIGO ICgr3 EC. 

Methods: From 1998 to 2011, 47 women with FIGO ICgr3 EC underwent TAH/BSO 

with pelvic/paraaortic lymph node dissection (median nodes evaluated, 47; range, 

5-88) followed by VBT. All VBT was performed using a multi-channel cylinder, 

treating the entire vaginal mucosa from the cuff to within 1-2 cm of urethral meatus 

to 21 Gy in 3 fractions. No patient received pelvic EBRT. Twenty-one patients (45%) 

also received 3 to 6 cycles of adjuvant platinum-based chemotherapy. 

Results: At a median follow-up of 30 months (range, 1 to 127 months), 3 patients 

had experienced a vaginal relapse (VR), and the 3-year Kaplan-Meier (KM) estimate 

of VR was 8%. Rates of isolated pelvic (PR), locoregional (LRR, VR + PR), and 

distant relapse (DR) were similarly low, with 3-year estimates of 3, 10, and 14%, 

respectively. Estimates for 3-year disease-free (DFS) and overall survival (OS) were 87 

and 80%, respectively. On univariate analysis, administration of chemotherapy 

significantly correlated with improved DFS (p = 0.03). 

Conclusions: Rates of isolated vaginal and pelvic relapse after VBT +/chemotherapy 

in these women with surgically-staged 1988 FIGO ICgr3 EC were 

comparable to those seen with pelvic EBRT, implying additional radiotherapy is 

likely unnecessary. Adjuvant platinum-based chemotherapy was associated with 

improved disease-free survival. While VBT reduced the rate of pelvic relapse, the 

vagina remained the most common pelvic site of recurrence. 


1003P TREATMENT OUTCOMES AND PROGNOSTIC FACTORS IN 

MEXICAN PATIENTS WITH ENDOMETRIAL CARCINOMA: 

THE LATIN AMERICAN EXPERIENCE 

C. Flores-Balcázar 1 , A. Alvarado-Zermeño 2 , M. Blake-Cerda 2 , A. Mota-García 2 , 

A. Poitevin-Chacón 3 , S. Rosales-Pérez 4 , G. Trejo-Duran 2 

1 Radioterapia, Instituto Nacional de Cancerologia, Mexico City, MEXICO, 

2 Radioterapia, Instituto Nacional de Cancerelogía, Mexico City, MEXICO, 

3 Radioterapia, Hospital Medica Sur, Mexico City, MEXICO, 4 Depto. Radioterapia, 

Instituto Mexicano del Seguro Social, Mexico City, MEXICO 

Aim: To analyze the clinical characteristics and treatment outcomes in patients with 

endometrial carcinoma treated in a Latin American institute with emphasis on 

patients receiving radiotherapy and chemotherapy after surgery. 

Methods: A total of 412 patients with endometrial carcinoma admitted to our 

hospital between 1999 and 2008 were evaluated retrospectively. The mean age was 55 

years (28-87). Two hundred seventy patients received RT following surgery. Stage 

distribution was as follows: 221 patients (54%) stage I, 86 patients (21%) stage II, and 

103 patients (24.5%) stage III and 2 patients (0.5%) stage IVA. 

Results: Overall survival rate was 95% at 2 years, 84% at 5 years and 79% at 10 years. 

By the end of follow up, 338 patients (82%) were disease-free, and 13 (3%) were alive 

with disease. Univariate and multivariate analyses identified age, grade, serosal and 

adnexial involvement as significant predictors for overall survival. 

Conclusion: The results of our study suggests that early stage, low-grade endometrial 

cancer with no risk factors should not receive external beam radiotherapy, 

intermediate risk patients should receive only vaginal vault brachytherapy and the 

use of chemotherapy with radiotherapy for patients high risk and advanced stage 

carcinoma the addition of radiotherapy is associated with a better survival being an 

effective therapeutic option. To our knowledge this is the largest series exploring the 

characteristics of Mexican patients treated for endometrial carcinoma in literature. 

We conclude that adjuvant radiotherapy should be considered an integral component 

of definitive treatment for women with unfavorable disease as a mean to decrease 

mortality and improve patient outcome. 



1004P CASE CONTROL STUDY ON TWO DIFFERENT 

CHEMOTHERAPY REGIMENS IN ADVANCED MIXED 

MULLERIAN TUMOURS 

M. Mancini 1 , S. Ramondino 1 , R. Di Rocco 1 , M. Ratti 1 , D. Lorusso 1 , 

F. Raspagliesi 2 

1 Gynecology Oncology, Fondazione IRCCS National Cancer Institute of Milan, 

Milan, ITALY, 2 Department of Gynaecologic Oncology, National Cancer Institute 

of Milan, Milan, ITALY 

Background: Malignant mixed Mullerian tumours (MMMTs) of the uterus and 

adnexa represent aggressive gynaecologic malignancies with a high rate of 

loco-regional and distant failure. There is no consensus in the community about the 

preferred chemotherapy regimen in this population. We evaluated two different 

chemotherapy combinations in terms of toxicity and oncologic outcome in patients 

with advanced MMMTs. 

Methods: Female patients with advanced MMMTs, residual tumor < 1 cm at 

cytoreductive surgery, no prior chemotherapy, normal haemopoietic and organ 

function were eligible. Chemotherapy was administered according to two different 

regimens: Cisplatin 20 mg/mq- Ifosfamide 1500 mg/mq d 1-4 q 21+ Pegfilgrastim 

(Group A) and Carboplatin AUC 5-Paclitaxel at 175 mg/m2 day 1 q21 (Group B). 

Results: Twenty-four patients (pts) of a median age 64 (49-75) years, performance 

status


no postoperative mortality and no excess in morbidity. One patient needed a 

re-intervention due to large lymphocoeles. At 3 years OS and DFS were 81% and 

91% respectively in the wertheim group. Non of patients in the brachytherapy group 

survived 3 years. 

Conclusion: Wertheim surgery following IMAT ± cisplatin is associated with no 

mortality and acceptable morbidity IMAT has low toxicity and is excellent in 

rendering irresectable cervical cancer resectable. 


1008 THE ROLE OF FUNCTION- SPARING SURGERIES IN PATIENTS 

WITH INVASIVE LOCALLY ADVANCED CERVICAL CANCER 

V. Navruzova 1 , S. Navruzov 2 

1 Oncogynaecology, National Cancer Center of Uzbekistan, Tashkent, 

UZBEKISTAN, 2 Administration, National Cancer Center of Uzbekistan, Tashkent, 

UZBEKISTAN 

Background: The incidence rate among young women leads to the necessity of the 

development of new methods and improvement of used surgical, combined and 

complex treatment for patients with locally spread cervical cancer (LACC).As a result 

of large radical operations, different complications which quite often result in 

“qualitative characteristic of life” (physical, functional, psychological and social) with 

feasible disability of women are possible. Surgical deprivation of ovarian function 

leads to a sharp fall-off of the level of sex hormones (first of all, estradiol) in blood. 

Patients with bilateral salpingo-oophorectomy, particularly at young age, have 

long-term effects of estrogen deficit of more severe character than women with 

natural menopause. For patients with invasive and LACC ovarian transposition the 

function- sparing surgery is the option in order to exteriorize them from supposed 

fields of radiation in patients with invasive and locally advanced cervical cancer. 

Material and methods: 156 patients with LACC received complex treatment that 

included surgery expansion of extended uterectomy with ovarian transposition at 

National Oncological Research Centre of MH of RUz over 2008-2012 yy. Patients aged 

from 23 to 45 yrs. Follow–up period were from 1 month till 3 years. Reproductive age 

patients with ovarian transposition had the level of sex hormones in blood according 

to normal in 94,7% cases after conducted surgery. Estradiol level in patients’ blood was 

up to143,6 ng/ml (normal -phase 77-277 ng/ml) in preoperative period.This rate being 

up to 140 ng/ml after surgery. After radiotherapy these patients’ rate of estradiol level 

in blood made up to139 ng/ml. This showed that ovarian function (gonads) is retained 

for 80 % of patients after performing of radiotherapy. 

Conclusions: Our study results showed that the conduction of organ-preserving 

exposure allows not only to cure the malignant process at early stages of its advance 

without lowering of therapy effect but also to preserve the important functions of 

woman body that promote full-fledged medical and social rehabilitation of patients. 


1009 PROGNOSTIC FACTORS AND TREATMENT OF CERVICAL 

CANCER (CC) IN ELDERLY 

I.Q.S. Caires 1 , R.C.A.D. Lima 1 , R. Barroso-Sousa 1 , E.M.P.D. Andrade 2 , 

J.R.D. Silva 3 , F.B. Sanchez 3 , P.M. Hoff 1 , M. Diz 1 

1 Clinical Oncology, Instituto do Câncer do Estado de São Paulo, São Paulo, 

BRAZIL, 2 Clinical Medicine, Hospital Agamenon Magalhães, Recife, BRAZIL, 

3 Faculdade De Medicina, Universidade de São Paulo, São Paulo, BRAZIL 

Background: Cancer diagnostics in the elderly is increasing over the years. Although 

elderly represent less than 10% of CC patients (pts), they usually present more 

advanced disease and do’t receive aggressive treatment. 

Methods: Retrospective analysis of pts ≥ 70 years old with CC consecutively admitted 

at single institution from Aug/2002 up to Feb/2012. Primary endpoint was overall 

survival (OS). Secondary endpoint was assessment of prognostic factors for OS and 

treatment received. Survival was estimated using the Kaplan-Meier methods, the 

curves were compared by the log-rank test and frequencies with chi-square test. 

Results: 70 pts were analyzed (7.5% of all CC pts). Median age was 76 years old 

(range, 70-91y). Squamous carcinoma was the most common histological type (61 

pts, 87.1%), 57 (81.4%) were performance status (PS) 0 or 1 and 37 (52.5%) were 

eutrophic (Body Mass Index 18.5- 25 Kg/m 2 ). In terms of initial staging, 14 pts 

(20%) were stage I, 30 pts (42.8%) II, 10 pts (14.2%) III, 14 pts (20%) IVa and 2 pts 

(2.8%) IVb. Regarding the treatment, 32 pts (45.7%) underwent chemoradiotherapy 

(CRT), 19 pts (27.1%) isolated radiotherapy (RT), 12 pts (17.1%) surgery and 7 pts 

(10%) best supportive care (BSC). Among CRT pts, 19 (59.3%) completed the full 

treatment (platinum-based chemotherapy administered for 6 weeks concomitantly 

with external radiotherapy in the pelvis, total dose of 45 Gy, and 4 inserts from 7 to 

7.5 Gy of brachytherapy); 16 (50%) received cisplatin and 16 (50%) carboplatin. In a 

median follow up of 15.3 mo (range, 0.1- 79.8 mo), mean OS was 79.8 mo for all pts 

in this analysis. Hemoglobin level ≥ 10 mg/dL pretreatment correlated with better 

mOS (HR 0.10; IC95% 0.02 to 0.42; p = 0.002), while creatinine ≥ 1 mg/dL before the 

treatment (HR 8.1; IC95% 1.87 to 34.88; p = 0.005) was considered risk factor to 

mortality. Pts who received QRT, RT had better mOS (HR 0,18; IC 95% 0,06 to 0.54; 

p= 0.002). Age, PS, BMI and comorbidities (pneumopathy, cardiopathy, dementia) 

did’t correlate with mOS. 

Conclusions: CRT is feasible in the elderly. Pts submitted to QRT, RT had better 

survival than those who did not undergo treatment and age alone can not be used to 

decide the conduct. Pts at baseline with Hb < 10 mg/dL and kidney disfunction had a 

poor prognosis. 


1010 A RETROSPECTIVE ANALYSIS OF CERVICAL CANCER 

PATIENTS TREATED WITH CARBOPLATIN AND PACLITAXEL 

IN FIRST PALLIATIVE LINE AT BRAZILIAN NATIONAL CANCER 

INSTITUTE (INCA) 

A.H. Ingles Garces 1 , P. Mora 2 , F. Alves 2 , A. Mangia 2 , C. Calazan 2 , 

A. Rodrigues 2 , A. Melo 2 

1 Oncologia Clínica, Instituto Nacional do Cancer - INCA 2, Rio de Janeiro, 

BRAZIL, 2 Oncologia Clínica, Insituto Nacional do Cancer - INCA 2, Rio de 

Janeiro, BRAZIL 

Cervical cancer represents a public health problem. Currently, it is the second most 

common neoplasia worldwide, with approximately 85% of the cases in developing 

countries. Most of the patients presents with advanced disease. The treatment based 

on cisplatin and radiotherapy is considered standard to patients with locally 

advanced cervical cancer, stages IIB to IVA. However, the results are not good 

enough, especially in stages III e IVA, which shows five-year survival rates of 40 and 

15%, respectively. The combination of cisplatin and paclitaxel (CDDP + P) is the 

standard treatment in first palliative line in several oncology institutions. The 

replacement of CDDP by carboplatin (C) is regularly done and probably presents less 

non-hematologic toxicity; however, there is no data in the literature related to the 

specific efficacy and toxicity to the combination of C + P in this context. At INCA, 

the combination of C + P has been the standard treatment in first palliative line since 

August 2008. 

Objectives: To evaluate response rate (RR), progression-free survival (PFS), overall 

survival (OS) and toxicity of patients with recurrent or metastatic cervical cancer 

treated with C + P. 

Material and methods: A retrospective analysis of cervical cancer patients treated 

with C + P in first palliative line at INCA, between August 2008 and January 2010. 

Results: A total of 154 patients were enrolled in the study. The most frequent 

histology was squamous carcinoma and 51.3 % of the patients were diagnosed as 

stages III and IV. 50% of the patients received 6 or more cycles of C + P as first 

palliative line. Objective responses were documented in 35.1% (5.2% complete 

responses plus 29.9 % partial responses). The median PFS and OS was 4.07 (IC95% 

2.8 – 5.3) and 8.4 (IC95% 6.2 – 10.7) months respectively. Hematologic toxicity was 

the most common: Grade 3 and 4 anemia, neutropenia and thrombocytopenia were 

42.2%, 18.1% and - 9.1%, respectively. 

Conclusion: Indirect comparison with published data of the prospective trial using 

CDDP + P our results were only slightly different, probably related to differences in 

patients clinical and demographics data. 


1011 BORDERLINE TUMORS OF THE OVARY: 19 YEARS 

EXPERIENCE FROM A TERTIARY CENTER IN SOUTH INDIA 

K. Kannan, N. Sridharan, R. Pourrli Neelakantan 

Introduction: Borderline tumours of the ovary are neoplasms of low malignant 

potential (LMP) and constitute 10-15% of all epithelial ovarian cancers. This 

retrospective analysis was done to determine the outcome of patients with LMP 

tumours treated at our institution. 

Methods and results: Data was collected from the department master records which 

were updated at every patient visit. Between 1993 and 2008, 68 patients were 

diagnosed with LMP tumours of ovary. The median age at presentation was 39.8 

years. Sixty percent of patients were post menopausal. Eight patients presented with 

infertility (11.7%). Ascites was present in 50% of patients. Forty nine patients 

underwent radical surgery (72%) and 19 patients had fertility sparing surgery (FSS) 

(28%). Mucinous tumours were seen in 39 patients (57.3%), serous in 25 patients 

(36.7%), Brenner tumour in three (4.4%) and endometroid tumour in one patient 

(1.4%). Fifty five patients presented in FIGO stage I (80%) and 13 patients in stage 

III (20%). Micropapillary serous tumours were seen in eight patients (11.7%), 

invasive peritoneal implants in five patients (7.3%) and microinvasion in four 

patients (5.8%). Seven patients underwent chemotherapy post operatively. The 

median overall survival (OS) was 178 months and the median progression free 

survival (PFS) was 175 months. Micropapillary serous tumours, invasive peritoneal 

implants, microinvasion, suboptimal surgery and advanced stage were found to be 

poor prognostic factors for PFS and OS on univariate analysis. Recurrence was seen 

in seven patients of whom five patients died of progressive disease. Eighteen patients 

are on follow up and are free from disease. There was no difference in outcome 

between patients who underwent radical surgery and FSS (p = 0.11). Seven out of 


eight patients who had infertility at diagnosis were able to conceive and deliver 

normally after treatment. 

Conclusion: Borderline ovarian tumours have an excellent prognosis. Fertility 

sparing surgery is a feasible option in these patients and is compatible with a 

favourable long term outcome. 


1012 THE PROGNOSTIC FACTOR ANALYSIS OF MALIGNANT 

MIXED MüLLERIAN TUMOR; BASED ON 

CLINICOPATHOLOGIC FACTORS 

B. Kang 1 , S. Noh 2 , S. Lee 3 

1 Internal Medicine, Yonsei Univ. Severance Hospital, Seoul, KOREA, 2 Pathology, 

Yonsei Univ. Severance Hospital, Seoul, KOREA, 3 Department of Internal 

Medicine, Yonsei University College of Medicine, Seoul, KOREA 

Background: Malignant mixed müllerian tumor (MMMT) is a rare and highly 

aggressive malignancy with biphasic pathologic characteristics; epithelial and 

mesenchymal components. Until now, its prognosis is still poor and there is no 

individualized therapy according to the biological characteristics. The aim of this 

study was to analyze the clincopathological features and identify the prognostic 

factors which impact the survival outcome. 

Methods: A retrospective review of patients with MMMT who treated between 1994 

and 2011 in our institution was undertaken. The clinical variables such ad age, BMI, 

CA-125 at diagnosis, stage, extent of surgery, pathologic findings, adjuvant 

chemotherapy and radiation therapy were analyzed. Univariate and multivariate 

analysis were done. 

Results: The study included 62 patients. The median age was 58 years 

(range37.8-79.6). FIGO stages I, II, III, and IV were identified in 38.7%, 4.8%, 32.3%, 

and 24.2% respectively. Epithelial dominant, similar, and mesenchymal dominant 

pathologic type were 56.3%, 16.7%, and 27.1%. Fifty nine of 62 patients had 

undergone hysterectomy and salpingo-oophrectomy and 43 of 62 patients had 

lymphadenectomy. Chemotherapy was given to 50 patients (ifosfamide + cisplatin 17, 

taxol/taxotere + cisplatin 17, ifosfamide mono 4, other regimens 14). The pattern of 

recurrence was mainly local. Median progression-free- survival after diagnosis is only 

13.3months and median overall survival is 18.3months. Adjuvant chemotheray and 

radiation therapy had no significant survival benefit. Univariate analysis showed 

CA-125 at diagnosis (HR 2.39; p = 0.02), FIGO stage I, II vs III, IV (HR 4.07; p = 0.00), 

myometrial invasion depth (HR 0.87; p = 0.05), lymphovascular invasion(HR 2.35; p 

= 0.03), and lymphadenectomy (HR 0.37; p = 0.01) had an independent influence on 

progression free survival. In multivariate analysis, FIGO stage I, II vs III, IV (p = 0.05) 

and lymphadenectomy (p = 0.05) were significant. However, pathologic type and 

chemotherapy regimen were not associated with risk of recurrence or death. 

Conclusions: According to this study, the comprehensive surgical staging is more 

important to predict the prognosis than its pathologic characteristics. Further molecular 

studies are needed to find out for breakthrough the poor prognosis of MMMT. 


1013 PREDICTING FACTORS OF SECONDARY RESECTION AFTER 

NEOADJUVANT CHEMOTHERAPY IN LOCALLY ADVANCED 

EPITHELIAL OVARIAN CANCERS. A RETROSPECTIVE STUDY 

OF 82 CASES 

L. Ben Fatma 1 , S. Said 1 , M. Boudagga 1 , M. Hochlef 1 , F. Zairi 1 , H. Khairi 2 , 

O. Gharbi 1 , H. Boussen 3 , S Ben Ahmed 1 

1 Medical Oncology, Hopital Farhat Hached, Sousse, 2 Gynecologic Dept, Hopital 

Farhat Hached Sousse and, 3 Medical Oncology, Hopital A Mami, Tunis, TUNISIA 

Objective: The aims of our study were to assess the rate of optimal interval 

debulking surgery (IDS) and the potential predictors of chemotherapy responsiveness 

in patients treated with neoadjuvant chemotherapy(NACT). 

Methods: We present a retrospective study including 82 EOC cases (stage IIIC or IV) 

collected in the medical oncology department of Farhat Hached Hospital-Sousse 

(Tunisia) during a period of 9 years (from 2002 to 2010). All patients received 

NACT followed by a clinical, radiological and biological assessment. 

Results: The mean age of our patients was 54.5 years (27-80 years). Stage IIIC 

represented 69.5% of all cases and stage IV 30.5% (8 cases with pleural metastases, 

14 cases with liver metastases, and 3 with pleural and liver metastases). CA-125 

serum level was normal in only 7 cases. All patients received a mean number of 5 

cycles of platinum-based NACT associated with paclitaxel in 78% of cases. Twenty 

seven patients achieved complete clinical response (CCR), 28 a partial clinical 

response (PCR) and 17 cases have disease progression. In 46/82 pts(56%), serum 

CA-125 was normalized after NACT. Ten patients achieved a radiological CR. 

Radiological PR was noted in 44 cases, while 19 patients had radiological disease 

progression. The rate of secondary resection was 51% (61.4% for stage IIIC and 28% 

for stage IV). Thirty one patients (74%) had an optimal IDS. We observed 9 

pathological complete responses (pCR). Secondary optimal resection was 

significantly correlated to CA-125 serum level at the end of NACT (p = 0.001) and 


the quality of radiological response (CR or PR) (p = 0.001). Overall survival was 28.4 

months, significantly better in cases of clinical or radiological complete response 

(p = 0.001) and in patients with optimal IDS (p = 0.01). pCR was associated with 

higher survival but without significant value (p = 0.08). In multivariate analysis, the 

parameters predicting a prolonged survival were: radiological complete or partial 

response (p = 0.05), optimal surgery (p = 0.001) and pCR (p = 0.03). 

Conclusion: In initially unresectable EOC, NACT platinum-based chemotherapy 

followed by IDS is a therapeutic alternative leading to a higher rate of optimal 

surgery with an improvement of survival. Pre-operative CA-125 serum level as well 

as the radiological response appeared to be good predictors of secondary R0 surgery 

and tumor chemosensitivity. 


1014 IMPACT OF CHEMOTHERAPY BEYOND THE THIRD LINE IN 

PATIENTS WITH RECURRENT EPITHELIAL OVARIAN CANCER 

L. Mansi 1 , E. Kalbacher 1 , M. Demarchi 2 , F. Bazan 3 , M. Schneider 4 , A. Vuillemin 5 , 

S. Bernhard 6 , V. Nerich 7 , C. Borg 8 , X. Pivot 9 

1 Doubs, Oncology, Besancon, FRANCE, 2 Valencia, Oncology, Valencia, SPAIN, 

3 Besancon, Oncology, Besancon, FRANCE, 4 Nice, Oncology, Nice, FRANCE, 

5 Medical Oncology, Hôpital Jean Minjoz, Besançon, FRANCE, 6 Department of 

Medical Oncology, University Hospital J. Minjoz, Besancon, FRANCE, 

7 Pharmacy, Hopital Minjoz, Besançon, FRANCE, 8 Medical Oncology, University 

Hospital Besançon, Besançon, FRANCE, 9 Medical Oncology, Hopital Minjoz, 

Besançon, FRANCE 

Objectives: The goal of this study was to determine the benefit in terms of time to 

disease control (TDC) achieved by the succession of chemotherapy lines beyond the 

third line in patients treated for recurrent epithelial ovarian cancer (EOC). Secondary 

objective were to identify patients who benefit from treatments beyond line three, 

and overall survival beyond the fourth line. 

Methods: The cohort of patients was identified from a pharmacy database of 

cytotoxic chemotherapy administered between 1992 and 2010 at our regional center. 

Among 591 cases of EOC, a total of 122 patients were treated by more than 3 lines 

of chemotherapy. The evaluation of benefit obtained by each chemotherapy lines was 

based on TDC. Cox proportional hazards model was used to identify factors that 

could influence the TDC in each line of chemotherapy. Survival data was computed 

according to Kaplan-Meier method. 

Results: Median OS was 53 months (95% CI, 47 to 67 months), and median OS 

after the third line was 15,3 months (95% CI, 12 to 20 months). Factors associated 

with longer OS after third line were performance status lower than 2 (p = 0.0058), no 

hepatic (p = 0.0098) and no pulmonary disease progression (p = 0.0003). Median 

durations of TDC was 4.15 (0 – 54.7), 4 (0 – 21.7), 3.34 (0 – 29.6), 4.97 (0 – 29.2), 

and 3.13 months (0 – 15), in fourth, fifth, sixth, seventh, eighth line, respectively. 

TDC was longer than 6 months in 34% to 40% of patients treated by line 4 to 

8. The most important factor influencing TDC length in multivariate analysis 

beyond the third lines was the TDC duration obtained by the 2 previous lines of 

therapy (p = 0.03). 

Conclusion: One can consider that those results might justify the administration of 

chemotherapy beyond the third line, in particular when the 2 previous lines are 

effective and let a disease control for more than six months. 


1015 PROGNOSTIC FACTORS AND TREATMENT OUTCOMES OF 

PATIENTS WITH UTERINE LEIOMYOSARCOMA: A 

RETROSPECTIVE STUDY OF ANATOLIAN SOCIETY OF 

MEDICAL ONCOLOGY 

A. Durnali 1 , S. Tokluog˘ lu 2 , N. Ozdemir 3 ,M.I˙nanc 4 , N. Alkis 1 , N. Zengin 3 , 

O.U. Sonmez 1 , M. Kucukoner 5 , M. Ozkan 6 , B. Oksuzoglu 1 

1 Department of Medical Oncology, Ankara Dr.A.Y.Oncology Research and 

Education Hospital, Ankara, TURKEY, 2 Medical Oncology, Güven Hospital, 

Ankara, TURKEY, 3 Medical Oncology, Numune Education and Research 

Hospital, Ankara, TURKEY, 4 Department of Medical Oncology, Erciyes University, 

Kayseri, TURKEY, 5 Medical Oncology, Dicle University, Diyarbakir, TURKEY, 

6 Medical Oncology, Erciyes University Medical FacultyM.Kemal Dedeman, 

Oncology Hospital, Kayseri, TURKEY 

Background: Uterine leiomyosarcomas are infrequent and aggressive malignancies of 

female genital tract. 

Methods: Data of 54 uterine leiomyosarcoma patients who were diagnosed and 

treated at 4 different centers from November 2000 to October 2010 were analysed 

retrospectively. 

Results: Mean age was 50.8 years (range 34-72), and 54.9% of patients were 

premenapousal. According to last International Federation of Gynecology and 

Obstetrics (FIGO) staging system, 26 (48.1%) patients had stage I disease, 14 (25.9%) 

stage II, 5 (9.3%) stage III, and 9 (16.7%) stage IV. Of the 52 patients who 

underwent surgery, 38.4% (20 patients) were given adjuvant chemotherapy, 17.3% (9 



patients) adjuvant radiotherapy, 23% (12 patients) adjuvant sequential chemotherapy 

and radiotherapy. Median relapse free survival (RFS) was 19 months. One, 2 and 5 

year RFS were 65.2%, 42.6%, 17.2% respectively. Median overall survival (OS) was 56 

months, OS after 1, 2, 5 years were 87.7%, 78.7%, 41.9% respectively. 

Clinicopathologic parameters that were statistically evaluated included age (

abstracts 

head and neck cancer 

1016O PHASE 2, RANDOMIZED TRIAL (CONCERT-2) OF 

PANITUMUMAB (PMAB) PLUS RADIOTHERAPY (PRT) 

COMPARED WITH CHEMORADIOTHERAPY (CRT) IN 

PATIENTS (PTS) WITH UNRESECTED, LOCALLY ADVANCED 

SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK 

(LASCCHN) 

J. Giralt 1 , J.M. Trigo 2 , S. Nuyts 3 , E.M. Ozsahin 4 , K. Skladowski 5 , G. Hatoum 6 , 

J. Daisne 7 , A. Zhang 8 , K. Oliner 9 , A. Vanderwalde 10 

1 Radiation Oncology, Vall d`Hebron University Hospital, Barcelona, SPAIN, 

2 Medical Oncology, Hospital Universitario Virgen de la Victoria, Malaga, SPAIN, 

3 Radiation Oncology, University Hospitals Leuven, Leuven, BELGIUM, 4 Radiation 

Oncology, Lausanne University Medical Center (Centre Hospitalier Universitaire 

Vaudois), Lausanne, SWITZERLAND, 5 Radiation Oncology, Centrum Onkologii 

Instytut M. Sklodowskiej-Curie, Gliwice, POLAND, 6 Clinical Biomedical Sciences, 

Florida Atlantic University, Lake Worth, FL, UNITED STATES OF AMERICA, 

7 Radiation Oncology, Clinique & Maternité Ste-Elisabeth, Namur, BELGIUM, 

8 Global Biostatistics, Amgen, Thousand Oaks, CA, UNITED STATES OF 

AMERICA, 9 Medical Sciences - Ivd, Amgen, Thousand Oaks, CA, UNITED 

STATES OF AMERICA, 10 Oncology Therapeutics, Amgen, Thousand Oaks, CA, 


Background: We evaluated the safety and efficacy of pmab, a fully human 

monoclonal antibody against the epidermal growth factor receptor, by comparing 

PRT with CRT in pts with LASCCHN. 

Methods: Pts with stage III, IVA, or IVB previously untreated LASCCHN of all sites 

excluding the nasopharynx were randomized 2:3 to open-label CRT or PRT. CRT 

included 2 cycles of cisplatin 100 mg/m2 during accelerated fractionation 

radiotherapy (XRT; 70-72 Gy over 6-6.5 weeks). Pmab included 3 cycles at a dose of 

9.0 mg/kg with each cycle administered with XRT. This was an estimation study with 

no formal hypothesis testing. The primary endpoint was locoregional control (LRC) 

rate at 2 years; key secondary endpoints were progression free survival (PFS), overall 

survival (OS), and safety. Preplanned HPV subset analysis (determined by p16 

immunohistochemistry) was performed on available samples. 

Results: Of 151 treated pts (90 PRT, 61 CRT), 84% were men; median age was 58 

years; ECOG PS 0: 64%. Overall, the 2-year LRC rate (95% CI) was 51% (40%-62%) 

for PRT and 61% (47%-72%) for CRT. For both PFS (hazard ratio [HR] = 1.73 [95% 

CI: 1.07-2.81]; p = 0.03) and OS (HR = 1.59 [95% Cl: 0.91-2.79]; p = 0.10), outcomes 

favored the CRT arm. Of 99 pts with tumors evaluable for HPV, 24% were HPV+. In 

75 HPV- tumors, a difference was observed in PFS (HR = 2.04 [95% Cl: 1.05-3.96]; p 

= 0.04), with trends also favoring CRT in LRC and OS. Overall, dose intensity was 

high for all components of therapy in both arms (median relative dose intensity: 

100% for pmab and 99% for cisplatin, median XRT dose: 100% in both arms). Grade 

3+ adverse events (AEs) occurred in 85% PRT vs 81% CRT pts. Key differences in 

grade 3+ toxicity between arms (PRT, CRT) included skin disorders (which is a 

composite of skin-related AEs) (35%, 3%), neutropenia (0%, 13%), and febrile 

neutropenia (0%, 8%). 

Conclusions: Trends favored the CRT arm for the primary endpoint (LRC at 2 

years), as well as other measures of efficacy, in this predominantly HPV- LASCCHN 

population. Small numbers limit conclusions in the HPV+ group. Both PRT and 

CRT appeared well tolerated. 

Disclosure: G. Hatoum: Advisory Board Member for AmgenK. Oliner: Amgen 

stockA. Vanderwalde: Corporate-sponsored research (Amgen), full-time employee of 

AmgenAll other authors have declared no conflicts of interest. 



1017O PRECLINICAL RATIONAL, SAFETY, AND PRELIMINARY 

EFFICACY RESULTS OF WEEKLY EVEROLIMUS, 

CARBOPLATIN AND PACLITAXEL AS AN INDUCTION 

THERAPY FOR PATIENTS WITH UNRESECTABLE LOCALLY 

ADVANCED HEAD & NECK SQUAMOUS CELL CARCINOMA 

(CAPRA): A GERCOR-IRC PHASE I/II STUDY 

S. Faivre 1 ,C.Dreyer 1 , E. Raymond 1 , J. Fayette 2 , J.P. Delord 3 , M. Gatineau 4 , 

B. Chibaudel 5 , N. Aissat 5 , K. Slimane 6 , C. Le Tourneau 7 

1 Oncology Department, Beaujon University Hospital, Clichy, FRANCE, 2 Medical 

Oncology, Centre Léon Bérard, LYON, FRANCE, 3 Clinical Resarch Unit, Centre 

Claudius-Regaud, Toulouse, FRANCE, 4 Medical Oncology, Hôpital 

Saint-Joseph, Paris, FRANCE, 5 Medical Oncology, GERCOR-IRC, Paris, 

FRANCE, 6 Oncology, Novartis Pharmaceuticals, Rueil-Malmaison, FRANCE, 

7 Department of Medical Oncology, Clinical Trial Unit, Institut Curie, Paris, FRANCE 

Background: PI3K/mTOR is a survival pathway that was shown activated in 57-81% 

of patients (pts) with head & neck squamous cell carcinoma (HNSCC) and might 

drive resistance to cytotoxics. 

Methods: We have previously shown synergistic cell-cycle dependent effects between 

rapamycin/everolimus and carboplatin, or paclitaxel in HNSCC cells (Aissat 2008). 

Based on this preclinical translational rationale, a two-step phase I/II trial was 

designed using 9 consecutive weekly (w) cycles of oral everolimus combined with 

carboplatin (AUC2) and paclitaxel (60mg/m2) followed by chemoradiotherapy in pts 

with untreated locally advanced HNSCC. 

Results: A total of 27 pts with stage IV HNSCC (median age 58, range 46-84; ECOG 

0-2) have been enrolled in this phase I/II study (42 pts scheduled for the phase II). 

Among the 7 pts enrolled in the everolimus dose escalation phase I step, 6 pts were 

evaluable for safety (3pts at 30 mg/w and 3pts at 50 mg/w). No dose-limiting toxicity 

(defined during the first 4 weeks of treatment) was reported. Transient asymptomatic 

grade 3 neutropenia (3 pts), anemia (3 pts), and thrombocytopenia (1 pt) were observed. 

The most frequently reported adverse events were mild to moderate asthenia, skin 

toxicity, and alopecia. The recommended dose of everolimus for the phase II step was 50 

mg/w. So far, among pts treated in the phase I/II, 11/13 objective responses (1CR, 10 PR, 

2SD) were observed in evaluable pts. Interestingly, several major responses (ranging -60 

to -80% by RECIST) were observed in large necrotic primary tumors and lymph nodes of 

>6cm diameters. Preliminary genetic analysis of tumors showed neither KRAS, BRAF, 

PI3KCA, nor EGFR mutations in tumors responding to this combination. 

Conclusions: Weekly 50 mg everolimus combined with carboplatin and paclitaxel 

was well tolerated with no DLT, allowing repeated cycles. Major clinical responses in 

pts with bulky, locally advanced and necrotic diseases deserve further evaluation of 

this combination in pts with HNSCC. Updated results will be presented at meeting. 

Disclosure: S. Faivre: Novartis, honorarium, compensatedE. Raymond: Novartis, 

honorarium, compensatedK. Slimane: Novartis, employment, compensatedAll other 


1018O SAFETY AND EFFICACY OF CISPLATIN PLUS 5-FU AND 

CETUXIMAB IN HPV-POSITIVE AND HPV-NEGATIVE 

RECURRENT AND/OR METASTATIC SQUAMOUS CELL 

CARCINOMA OF THE HEAD AND NECK (R/M SCCHN): 

ANALYSIS OF THE PHASE III EXTREME TRIAL 

A. Psyrri 1 , L. Licitra 2 , B. De Blas 3 , I. Celik 4 , J.B. Vermorken 5 

1 Internal Medicine Propaedeutic, University of Athens Medical School, Attikon 

University Hospital, Athens, GREECE, 2 Head & Neck Medical Oncology Unit, 

Istituto Nazionale Tumori, Milan, ITALY, 3 Global Clinical Development Unit 

Oncology, Merck KGaA, Darmstadt, GERMANY, 4 Global Research & Early 

Development, Merck KGaA, Darmstadt, GERMANY, 5 Department of Medical 

Oncology, University Hospital Antwerp, Edegem, BELGIUM 

Background: Tumor human papillomavirus (HPV) status is a strong predictor of 

survival and response to treatment in patients (pts) with early and locally advanced 

oropharyngeal cancer, but its effects in R/M SCCHN remain to be clarified. This 

retrospective analysis of data from the EXTREME trial assessed the role of tumor 

HPV status in pts with R/M SCCHN receiving cisplatin + 5-FU chemotherapy (CT) 

alone or in combination with cetuximab. Material and methods: 

Immunohistochemical detection of p16 INK4A was used to determine HPV status: 

p16-positive and p16-negative disease is referred to as HPV-positive (HPV+) and 

HPV-negative (HPV-) disease, respectively. 

Results: 196/222 (88%) pts in the CT + cetuximab and 185/220 (84%) pts in the CT 

arm had tissue evaluable for p16. Of these, 91% and 88%, respectively, had HPVtumors. 

Among HPV- pts, CT + cetuximab (n = 178) improved overall survival (OS), 

progression-free survival (PFS) and overall response rate (ORR), compared with 




Table: 1018O: Tumor HPV status: effects on prognosis and efficacy of CT + cetuximab and CT in R/M SCCHN. 

Population 

CT + cetuximab vs CT 

Comparison OS PFS ORR 

HPV- (n = 340) Median (months)/rate (%) 9.7 7.3 5.7 3.1 37 17 

HR/odds ratio 95% CI p 0.822 

0.486 

2.753 (1.655–4.579) 

(0.647–1.043) 

(0.376–0.628) 

same CT/RT; Arm B2: 3 cycles of induction TPF followed by CET/RT. A total of 204 

deaths (420 ptsincluding the 101 randomized in the phase II part of the study 

comparing CT/RT with or w/o induction TPF) were required to detect a HR of death 

of 0.675 (A1 + A2 vs. B1 + B2; 2-sided a = 0.05; b = 0.20) and a 10% difference in 

G3-4 in-field mucosal toxicity (A1 + B1 vs. A2 + B2). 

Results: Accrual was completed (421 pts) in April 2012. By May 2012, 348 patients 

were evaluable for toxicity during the planned concomitant treatments. 82% of pts 

were male; median age was 60y; PS of 0 (77.8%) or 1 (22.2%). Stage was III (31%) or 

IV (69%). Sites of disease were: oral cavity: 21.7%, oropharynx: 54.8%, hypopharynx: 

23.5%. Data on G3-4 in-field toxicity (primary endpoint) and compliance to CT/RT 

vs CET/RT are shown in table 1. 

CT/RT N 

215 

CET/RT N 

133 p 

In-field mucositis Grade 3 Grade 4 37% 4% 35% 2% 0.79 0.45 

In-field skin reaction Grade 3 Grade 4 13% 1% 20% 1% 0.07 0.58 

RT median dose, Gy (range) 70 (8-70) 70 (14-70) 0.32 

RT median duration, weeks (range) 7 (1-13) 8 (1-14) 3days 32% 38% 0.22 

RT modification due to acute toxicity 37% 40% 0.58 

Conclusions: No advantage for CET/RT over CT/RT were observed regarding G3-4 

in-field toxicities and feasibility. Pts are still being followed-up to assess OS. Table 1: 


1021PD MODULATION OF THE PERITUMORAL 

MICROENVIRONMENT BY CETUXIMAB: A WINDOW 

PRE-OPERATIVE STUDY IN PATIENTS WITH SQUAMOUS 

CELL CARCINOMA OF THE HEAD AND NECK (SCCHN) 

S. Schmitz 1 , M. Hamoir 2 , H. Reychler 3 , M. Magremanne 3 , B. Weynand 4 , 

R. Lhommel 5 , F. Hanin 5 , D. Rommel 6 , N. Michoux 6 , J.P. Machiels 7 

1 Head and Neck Surgery and Medical Oncology, Cliniques Universitaires 

Saint-Luc, Brussels, BELGIUM, 2 Head and Neck Surgery, Cliniques 

Universitaires St-Luc, Brussels, BELGIUM, 3 Maxillofacial Surgery, Cliniques 

Universitaires Saint-Luc, Brussels, BELGIUM, 4 Anatomopathology, Cliniques 

Universitaires Saint-Luc, Brussels, BELGIUM, 5 Nuclear Medicine, Cliniques 

Universitaires St-Luc, Brussels, BELGIUM, 6 Radiology, Cliniques Universitaires 

Saint-Luc, Brussels, BELGIUM, 7 Medical Oncology, Cliniques Universitaires 

St. Luc, Brussels, BELGIUM 

Background: Only a subset of SCCHN pts benefits from anti-EGFR mAbs. Trials 

with pre- and post-therapy tumor biopsies (windows studies) in treatment-naïve 

patients are crucial to better characterize the molecular pathways involved in 

treatment response or resistance. 

Methods: Cetuximab (C) (400mg/m2 first wk followed by 250mg/m2/wk) was given 

pre-operatively during 2 wks (day -15 until day -1, 3 infusions) before surgery (day 

0) to 20 treatment-naïve SCCHN pts selected for primary curative surgery. As 

controls, 5 additional pts were included without C treatment but with the same 

requirements regarding biopsies and imaging. Tumour biopsies, FDG/PET, and CT 

were performed at diagnosis and surgery. The aims of the study were (i) safety, 

(ii) C activity by FDG-PET (Po = 0.10, P1 = 0.35, a = 0.05 and b= 0.10) and (iii) 

translational research. We compared pathologic changes in surgical specimens of the 

C group with control specimens and correlated these results with microarray analysis 

performed on paired biopsies in the C group. 

Results: C infusion given 24 hrs before surgery was safe. 90 % had a FDG-PET 

partial response (PR) (EORTC guideline) in the C group vs 0% in the controls. 52% 

had a ΔSUVmax decrease of >50%. In surgical specimens we detected modifications 

of the peritumoral environment. By immunochemistry, we found more fibrosis 

arranged in a compact manner in the C group than in the non-treated samples 

(histological score) (p = 0.04). Genome-wide expression analysis (Affymetrix HG 

U133 Plus 2.0) of the paired biopsies taken in the tumor center before and after C 

supports this histological observation. Results show a significant increase in 

expression (Student’s T test p = 0.02; n = 20) of a previously published stroma 

signature (Finak et al., Breast Cancer Res 2006) after C. A trend was also observed 

between this stroma signature score and the fibrosis histological score. 

Conclusions: Pre-operative study with C is safe. Our findings suggest that C induces 

quantitative modifications in the microenvironment of the tumor. We are currently 

investigating other components of the peri-tumoral environment (inflammation and 

vascularization). 

Disclosure: J.P. Machiels: consultant/advisory role: Boehringer IngelheimAll other 



1022PD PHASE II STUDY OF PEMETREXED PLUS CISPLATIN AND 

CETUXIMAB IN ADVANCED SQUAMOUS CELL CARCONIMA 

OF THE HEAD AND NECK 

J.B. Vermorken 1 , T.C. Gauler 2 , J. Stoehlmacher-Williams 3 , A. Dietz 4 , J.M. Lopez- 

Picazo 5 , O. Hamid 6 , A.M. Hossain 6 , T. Burkholder 6 , S. Chang 6 , L. Licitra 7 

1 Department of Oncology, U.Z.A. University Hospital Antwerp, Edegem, BELGIUM, 

2 Oncology, University Hospital, Essen, GERMANY, 3 Oncology, University 

Hospital Dresden, Dresden, GERMANY, 4 Oncology, Universitatsklinikum Leipzig, 

Leipzig, GERMANY, 5 Oncology, Clinica Universidad de Navarra, Pamplona, 

SPAIN, 6 Oncology, Eli Lilly and Company, Indianapolis, IN, UNITED STATES OF 

AMERICA, 7 Oncology, Instituto Nazionale Tumori, Milan, ITALY 

Background: Patients (pts) with recurrent or metastatic SCCHN have a very poor 

prognosis. Platinum-based chemotherapy has long been standard treatment. Adding 

cetuximab to cisplatin-based combinations has improved overall survival (OS) and is 

currently standard treatment in SCCHN. In a phase III study, pemetrexed has shown 

benefit in SCCHN, particularly in performance status (PS) 0-1 pts. 

Patients and methods: Pts who had no more than 1 prior systemic therapy for 

locally-advanced disease received cetuximab 250 mg/m 2 (loading dose:400 mg/m 2 ), 

pemetrexed 500 mg/m 2 , with vitamin supplementation, and cisplatin 75 mg/m 2 day 

1, up to 6 cycles. Pts completing at least 4 cycles had the option to receive 

maintenance with pemetrexed and cetuximab, or monotherapy, if toxicity occurred. 

Primary objective was progression-free survival (PFS); secondary objectives were OS, 

overall response rate (ORR) and safety. Sixty-five patients were needed to meet an 

objective median PFS of 5.5 months (mos.), with 90% power; 2-sided α of 0.05. 

Results: Sixty-six Caucasians (53 male), median age of 62 years (42-87) received at least 

1 dose of therapy. Nineteen pts had a PS of 0; 47 pts had a PS of 1. Median cycles 

received = 5.0 (1-27). Median PFS was 4.4 mos. (95% CI: 3.6, 5.4); median OS was 9.7 

mos. (95% CI: 6.5, 13.1). Fifty-eight pts were evaluable for ORR analysis. ORR was 29.3% 

(95% CI: 18.1, 42.7); 1 complete response (1.7%); 16 partial responses (27.6%); 20 pts had 

stable disease (34.5%). An exploratory subgroup analysis showed larynx tumor pts had 

greater improvement in survival than non-larynx pts; median OS = 20.8 mos.(HR = 0.44; 

95% CI= 0.20, 0.95); p = 0.032. Drug-related grade 3/4 toxicities included leukopenia 

(34.8%), neutropenia (33.4%), fatigue (24.2%), anorexia (12.1%) and hypomagnesemia 

(10.6%). There were 5 drug-related deaths (7.6%) on treatment (respiratory failure = 2; 

implant site hemorrhage = 1, sepsis = 1; death, not otherwise specified = 1). 

Conclusions: Efficacy results were consistent with current standard treatment for 

SCCHN, but the pre-specified goal of median PFS of 5.5 mos. was not met. 

Although toxicities were consistent with the safety profiles of this combination, there 

were 5 deaths on treatment. 

Disclosure: J.B. Vermorken: Dr. Jan B. Vermorken is a member of an advisory board 

for Merck-Serono, Amgen, Boehringer-Ingelheim, Genentech and Sanofi-Aventis and 

has lectured (compensated) for Merck-Serono, Amgen, Bristol-Byers Squibb and 

Sanofi-Aventis.T.C. Gauler: Dr. Gauler is an Advisory board member and received 

honoraria from Eli Lilly and Company.J. Stoehlmacher-Williams: 

Dr. J. Stoehlmacher-Williams received honoraria for an advisory board and 

presentations, travel support and various translational research grants from Eli Lilly 

and Company.J.M. Lopez-Picazo: Dr. Lopez-Picazo is an advisory board member for 

Eli Lilly and Company.O. Hamid: Dr. Hamid is an employee of Eli Lilly and 

Company and has stock ownership.A.M. Hossain: Anwar Hossain is an employee of 

Eli Lilly and Company and has stock ownership.T. Burkholder: Tiana Burkholder is 

an employee of Eli Lilly and Company and has stock ownership.S. Chang: Dr. Chang 

is an employee of Eli Lilly and Company and has stock ownership.L. Licitra: Dr. 

Licitra served as an advisory board member and received research sponsorship from 

Eli Lilly and Company.All other authors have declared no conflicts of interest. 

1023PD TEMSIROLIMUS IS ACTIVE IN REFRACTORY SQUAMOUS 

CELL CARCINOMA OF THE HEAD AND NECK (SCCHN) 

FAILING PLATINUM-BASED CHEMOTHERAPY AND 

CETUXIMAB: EFFICACY AND TOXICITY DATA FROM THE 

PHASE II TEMHEAD STUDY 

V. Grünwald 1 , U. Keilholz 2 , A. Boehm 3 , O. Guntinas-Lichius 4 , B. Hennemann 5 , 

H.J. Schmoll 6 , P. Ivanyi 1 , A. Zörner 7 , A. Zapf 8 , T.C. Gauler 9 

1 Clinic for Hematology, Hemostaseology, Oncology, Hannover Medical School, 

Hannover, GERMANY, 2 Hematology & Oncology, Charite, Berlin, GERMANY, 

3 Clinic and Policlinic for Ear, Nose and Thorat, Universitätsklinikum Leipzig, 

Leipzig, GERMANY, 4 Clinic for Ear, Nose and Throat, Universitätsklinikum Jena, 

Jena, GERMANY, 5 Clinic for Heamatology and Medical Oncology, Ev. Bethesda- 

Johanniter Klinikum GmbH, Duisburg, GERMANY, 6 Dept. Hematology/ 

Oncology, University of HalleMartin Luther University Hospital, Halle, GERMANY, 

7 Clinical Pharmacology, Medical School Hannover, Hannover, GERMANY, 

8 Biostatistics, Medical School Hannover, Hannover, GERMANY, 9 Dept. Int. 

Medicine (Cancer Research), University Hospital EssenWestdeutsches 

Tumorzentrum, Essen, GERMANY 

Background: Prognosis of patients with failure of cisplatin-based 1st line 

chemotherapy for recurrent or metastatic SCCHN remains poor. We therefore 

evaluated temsirolimus after failure of cisplatin and cetuximab in SCCHN. 



Methods: Patients with progressive SCCHN and failure of platinum-based 

chemotherapy and cetuximab were eligible. Patients with loco-regional recurrence as the 

sole lesion had to have a progression free survival (PFS) of at least 6 months from last 

therapy. 18 years of age, ECOG 0-2, life expectancy of at least 3 months, and adequate 

organ function are key inclusion criteria. Brain metastases were allowed, provided local 

therapy has been completed successfully. Tumor assessment was performed every 6 

weeks and assessed according to RECIST 1.0. Primary endpoint was the progression 

free survival rate (PFR) at 12 weeks >20%. Secondary endpoints were time to 

progression (TTP), objective response rate (ORR), overall survival and toxicity 

(according CTCAE 3.0). 25 mg temsirolimus was given i.v. weekly until progression or 

toxicity prevail. PFS, PFR, and OS estimates were calculated by Kaplan-Meier-Curves. 

Results: A total of 42 patients entered the trial, of whom 40 were eligible. ECOG 

performance status of 0/1/2 was found in 7/29/5 pts and missing in 1 patient. Mean 

age was 61.6y (range: 42-79y) with male predominance (31 pts; 74%). Progression 

free survival rate at 12 weeks was 40% (CI95% 25-55%), TTP was 56 d (CI95% 

36-113d), and OS 152d (CI95% 76-256d). Stable disease (SD) was obtained in 19 pts. 

(56%), progressive disease (PD) in 10 pts. (29%), 1 pts. was not evaluable for 

response, and 10 pts. had missing scans. Treatment with temsirolimus was well 

tolerated. Safety data will be presented at the meeting. 

Conclusions: Temsirolimus reaches its prespecified endpoint with a PFR at 12weeks of 

40%. Efficacy data is encouraging and compare to single agent cetuximab activity in 

platinum-refractory SCCHN. Further studies with this drug in SCCHN are warranted. 

Disclosure: V. Grünwald: research funding: Pfizer Advisory Board: Merck KGU. 

Keilholz: Research support and honorarium Whyeth / Pfizer.T.C. Gauler: 

ADVISORY BOARD: MERCK KG, Pfizer HONORARIA: PfizerAll other authors 


1025P PLASMATIC EPSTEIN-BARR VIRUS MICRO-RNA -BART-17 

IN NASOPHARYNGEAL CARCINOMAS PATIENTS: HIGH 

POTENTIAL AS A TUMOR BIOMARKER ASSOCIATED TO EBV 

DNA CONCENTRATION 

F.R. Ferrand 1 , C. Gourzones 2 , B. Verillaud 2 , E. Saada 3 , P. Lang 4 , V. Schneider 5 , 

C. Amiel 5 , J. Guigay 3 , P. Busson 2 

1 Oncologie, Hopital du Val de Grace, Paris Cedex, FRANCE, 2 UMR8126, Institut 

Gustave Roussy, Villejuif, FRANCE, 3 Head and Neck Departement, Institut 

Gustave Roussy, Villejuif, FRANCE, 4 Medical Oncology, CHU Pitié-Salpetrière, 

Paris, FRANCE, 5 Maladies Infectieuses, CHU Tenon, Paris, FRANCE 

Background: Because latent Epstein Barr (EBV)-infection is a specific characteristic of 

malignant Nasopharyngeal carcinoma (NPC) cells, various molecules of viral origin are 

obvious candidate biomarkers. EBV microRNAs are of particular interest because at 

least some of these (such as miR-BARTs) deregulate the expression of key cellular and 

viral genes. 

Patients and methods: We performed RT- real-time quantitative PCR targeted on two 

cellular miRNAs (has miR16 and 146) and two viral miRNA (ebv-miR BART7 and 

17-5p) after RNA extraction on plasma samples from 27 advanced NPC patients,10 

patients with advanced head and neck Squamous cell carcinoma and 3 EBV healthy 

carriers. 

Results: We showed presence of cellular miRNAs in all the samples, whereas viral 

miRNAs were mostly found in NPC patients plasma samples, with significant 

differences for ebv-miR-BART-17 (p = 9,69910 −6 Wilcoxon test) but not for 

miR-BART7 and cellular miRNAs. A detection threshold of 0,3 ebv-miR-BART17 

copy/plasma µL was specific for NPC diagnosis (ROC curve analysis (AUC= 0,919) 

with a sensitivity of 0.9259 and specificity of 0,973) There was no significant 

relationship between plasma concentrations of either ebv-DNA copy number or viral 

and cellular miRNAs and studied clinicopahtological factors. 

Conclusion: miR-BART-17 concentrations seem specific of nasopharyngeal 

carcinomas and could bring additional information to viral DNA concentrations 

especially when DNA is undetectable. Further investigations are needed especially in 

the context of new generation immunoadpative treatment. 


1026P EXPRESSION PROFILING OF 21 BIOMOLECULES IN 

LOCALLY ADVANCED NASOPHARYNGEAL CARCINOMAS 

(LA-NPC) OF CAUCASIAN PATIENTS TREATED WITH 

CHEMOTHERAPY OR CHEMO-RADIOTHERAPY (CRT) IN THE 

CONTEXT OF A HELLENIC COOPERATIVE ONCOLOGY 

GROUP RANDOMIZED TRIAL 

M. Bobos 1 , D. Krikelis 1 , G. Karayannopoulou 1 , L. Resiga 2 , S. Chrysafi 1 , 

E. Samantas 1 , D. Andreopoulos 1 , V. Vasiliou 1 , E. Ciuleanu 3 , G. Fountzilas 1 

1 Data Office, Hellenic Cooperative Oncology Group (HECOG), Athens, GREECE, 

2 Pathology Department, Cancer Institute Ion Chiricuta, Cluj, ROMANIA, 3 Medical 

Oncology - Radiation Oncology, Cancer Institute Ion Chiricuta, Cluj, ROMANIA 

Introduction: Since scarce data exist on the pathogenesis of NPC in Caucasian patients, 

we attempted to elucidate the responsible molecular pathways in this patient population. 

Patients and methods: Formalin-Fixed Paraffin-Embedded tumor tissue samples 

from 107 patients, diagnosed with LA-NPC and treated with chemotherapy or CRT, 

were analyzed by immunohistochemistry (IHC) for the expression of the following 

proteins: E-cadherin, P-cadherin, Fascin-1, Cyclin D1, COX-2, EGFR, VEGFA, 

VEGFC, VEGFR-2, VEGFR-3, ERCC1, p53, p63, Ki67, MAPT, phospho-p44/ 

42MAPK, PTEN, phospho-Akt, phospho-mTOR, and phospho-GSK3b. EBER status 

was assessed by in situ hybridization. The majority of cases were included in tissue 

microarray. All stains were performed and assessed centrally by two pathologists. The 

median follow-up time was 76.8 (42.3 – 99.2) months. 

Results: Biomolecules expressed in >90% of cases were: p53, COX-2, P-cadherin, 

EBER, phospho-GSK3b, and Fascin-1. WHO II + III tumors were more frequently 

EBER & PTEN positive and VEGFA negative. Advanced age was significantly 

associated with positive phospho-GSK3b and ERCC1 expression, male gender with 

positive phospho-Akt and phospho-p44/42MAPK, and worse performance status 

(PS), 1 or 2, with negative Ki67, ERCC1, PTEN, and phospho-mTOR expression. 

Earlier TNM stage was closely associated with p63, MAPT, PTEN, and Cyclin D1 

positivity. Univariate Cox regression analysis highlighted Cyclin D1 as a negative 

prognostic factor for Disease-Free Survival (DFS) (p = 0.034) and EBER as a positive 

one for Overall Survival (OS) (p = 0.048). In multivariate analysis, advanced age and 

stage, poor PS, and positive ERCC1 emerged as predictors of worse DFS and OS, as 

opposed to positive phospho-mTOR. Clustering analysis defined two 

protein-expression groups being predictive of better OS (p = 0.043). 

Conclusion: Our study is the first to examine the activation and interaction of 

established biomolecules and signaling pathways in Caucasian NPC patients in an 

effort to reveal new therapeutic targets. 


1027P PRECLINICAL ANTI-TUMOR ACTIVITY OF XL880 IN 

NASOPHARYNGEAL CARCINOMA 

M. Xie 1 ,Z.Li 2 

1 Medical Oncology, The First Affiliated Hospital of Guangzhou Medical University, 

Guangzhou, CHINA, 2 Department of Medical Oncology, Cancer Center of Sun 

Yat-Sen University, Guangzhou, CHINA 

Background: Outcomes for locoregionally advanced nasopharyngeal carcinoma 

(NPC) patients have certainly improved with chemoradiation but eventually local 

and distant failure remains a very important clinical problem. An earlier study 

showed increased c-Met and VEGFR2 expression in NPC sample compared to 

normal nasopharyngeal tissue. XL880 (Foretinib, GSK1363089) is an oral, 

ATP-competitive small molecular inhibitor against multiple kinases, in particular 

c-Met and VEGFR2 that are involved in tumor cell growth, migration, and 

angiogenesis. The objective of this study was to investigate the therapeutic potential 

of XL880 in NPC. 

Methods: Expressions of total and phosphorylated c-Met, VEGFR2, PDGFR, AXL 

and Tie-2 were evaluated by western blot in a panel of six NPC cell lines. The effect 

of XL880 on NPC cell proliferation was evaluated by Tilter-Glo luminescent Cell 

Viability Assay. We further studied the effect of XL880 on NPC cell cycle and 

apoptosis. In vivo activities of XL880 as single agent and in combination with 

Cetuximab were investigated in NPC xenografts. 

Results: In vitro study showed that XL880 inhibited phosphorylation of both c-Met 

and VEGFR2. XL880 repressed the growth of both c-Met amplified tumor cells and 

endothelial cells stimulated with either HGF or VEGF. For the most XL880-sensitive 

NPC cell line (HK1-LMP1), which harbored the highest levels of both c-Met and 

VEGFR2, inhibition of cell growth was associated G0/G1 cell cycle arrest as well as 

significant downregulation of FAK, Mcl-1 and cyclin D1. XL880 eliminated ∼70% of 

tumor vasculature in xenograft models, inhibited tumor growth, and slowed regrowth 

of the tumor vasculature after drug withdrawal. Importantly, XL880 decreased 

invasiveness of primary tumors and reduced metastasis. XL880 in combination with 

Cetuximab achieved greater antitumor responses than treatment with either agent 

alone in NPC xenograft models. Additionally, mRNA levels of EGFR ligands TGF 

alpha and Epiregulin were significantly downregulated by XL880 in vivo. 

Conclusions: This is the first report of preclinical activity of c-Met/VEGFR2 inhibitor 

XL880 in NPC. LMP1 (latent membrane protein 1)-positive NPC shows a higher 

sensitivity to XL880. Further clinical investigation of XL880 is warranted in NPC patients. 


1028P PLASMA EBV DNA CONCENTRATION CORRELATES WITH 

FDG PET IN NASOPHARYNGEAL CARCINOMA TREATED 

WITH INDUCTION CHEMOTHERAPY 

M. Rahal, H. Abdullah, H. Halawani, H. Zagloul, A. Al Buali, A.A. Alfaraj, 

H. Abdulkhalek, E.A. Hassan, A. Ahluwalia, F. Medhat 

Oncology, King Fahad Specialist Hospital, Dammam, SAUDI ARABIA 

Background: While local control rate in locally advanced NPC (LA-NPC) 

has improved with concurrent Cisplatin and IMRT, development of distant 

metastases remains common in these patients and limits survival. The role of 


induction chemotherapy in the treatment of LA- NPC is still a matter of debate. 

The aim of this retrospective review is to evaluate the effect of induction 

chemotherapy and to correlate between EBV-DNA concentration and tumor 

response by PET-CT. 

Methods: Patients with stage III-IVB, WHO II/III received induction chemotherapy 

with 2 cycles of TPF : Docetaxel: 75 mg/m2, Cisplatin: 75 mg /m2, 5Fluorouracil: 

750 mg / m2 CI for 96 hours followed 3-4 weeks later by concurrent weekly Cisplatin 

( 40 mg /m2) and IMRT (GTV:70 Gy over 35 fractions). EBV-DNA quantification 

was performed at baseline and repeated before each cycle of TPF. PET scans were 

performed at baseline and repeated before IMRT. The max standard uptake values 

(SUV) were recorded in the primary tumors. Metabolic response was defined as a 

decrease in maximum SUV of 35% or more. 

Results: 20 patients with LA-NPC (75%Stage IVA/IVB) were reviewed. All but one 

completed therapy. Objective response, according to RECIST criteria: CR: 4; PR: 14 

NE: 2. Median concentration of EBV-DNA was 11,300 copies /ml (range: 1,184 - 

43,000). Post TPF, reduction of EBV-DNA copies by >50% was observed in 83% pts 

and 66% achieved complete biochemical response. In the FDG-avid tumor pts, the 

median SUV at baseline was 12 (range 10.5 - 17.4); post TPF metabolic response was 

observed in 100% and was complete in 33%.All patients with complete biochemical 

response had also a complete metabolic response by PET. At 2-year loco-regional 

progression free rate is 95% and 2 year overall survival rate is 85%. No recurrence 

was seen in complete (biochemical / metabolic) responders. 

Conclusion: A negative post induction FDG-PET and complete biochemical 

response after TPF are of significant value in LA-NPC and are useful determinant to 

predict outcome. 


1029P CIRCULATING TUMOR CELLS (CTCS) IN PATIENTS WITH 

RECURRENT/METASTATIC HEAD AND NECK SQUAMOUS 

CELL CARCINOMA (HNSCC): FREQUENCY, CLINICAL 

SIGNIFICANCE AND EGFR EXPRESSION 

S. Grisanti 1 , C. Almici 2 , F. Consoli 3 , R. Verardi 2 , M. Buglione 4 , V.D. Ferrari 1 , 

A. Bolzoni-Villaret 5 , P. Nicolai 5 , S.M. Magrini 4 , E. Simoncini 3 

1 Medical Oncology, Azienda Spedali Civili, Brescia, ITALY, 2 Lab Manipulation of 

Stem Cells, Azienda Spedali Civili, Brescia, ITALY, 3 U.O. Oncologia Medica, 

Azienda Spedali Civili, Brescia, ITALY, 4 Radiation Oncology, Università di Brescia, 

Brescia, ITALY, 5 Otorhinolaryngology, University of Brescia, Brescia, ITALY 

Introduction: Recurrent/metastatic (R/M) HNSCC have a poor prognosis. Palliative 

chemotherapy is often used without adequate prognostic and predictive 

stratification due to the lack of validated predictors in this setting. Furthermore, 

anti-EGFR therapy is used under the assumption that more than 80% of the 

primary tumors overexpresses EGFR. CTCs have been identified as prognostic and 

predictive indicators in several metastatic cancers. We prospectively studied the 

frequency, clinical significance and EGFR expression of CTCs in pts with R/M 

HNSCC. 

Patients and methods: Pts with local and/or distant relapse of HNSCC at first 

or second relapse were included between January 2009 and December 2011. 

CTCs were measured at baseline and at end of treatment or progression. CTCs 

analysis was performed with the CellSearch® system. The diagnostic performance 

of the system with squamous cancer cells was tested with cell lines spiking 

experiments. The CellSearch® fourth channel was used to analyze EGFR 

expression on CTCs. 

Results: Fifty-three pts were evaluable for CTCs analysis and clinical response. CTCs 

were detected in 14 (26%) pts at baseline and in 22 (41%) pts at any time point. 

Median CTCs number was 1 CTC/7.5 mL. CTCs were not associated to any of the 

clinico-pathological variables considered. EGFR was expressed in 45% of 

CTC-positive pts. After treatment, CTC numbers decreased, remained stable and 

increased in 8%, 54% and 38% of pts, respectively. Baseline CTCs or their increase 

were predictive of stable or progressive disease (p .007). In 42 evaluable pts, baseline 

CTCs were prognostic indicators of worse progression-free (PFS) (3 vs 8 months, p 

.003) and overall (OS) (5 vs 10 months, p .013) survivals, respectively. 

Conclusion: This study demonstrates that: a) low numbers of CTCs are detectable by 

CellSearch® in more than 40% of R/M HNSCC pts; b) CTCs at baseline or at any 

time point are independent predictors of poor PFS and OS; c) presence of CTCs 

during treatment is predictive of chemo-resistant disease; d) EGFR is expressed on 

CTCs with a high intra-sample and inter-patient variability. These results encourage 

further development of CTCs in this setting. 


1030P INSULIN GROWTH FACTOR RECEPTOR AS A PROGNOSTIC 

MARKER IN OPERABLE SQUAMOUS-CELL LARYNGEAL 

CANCER 

G. Mountzios 1 , I. Kostopoulos 2 , V. Kotoula 3 , S. Levva 4 , E. Fountzilas 4 , 

K. Markou 5 , I. Karasmanis 6 , N. Angouridakis 5 , A. Nikolaou 6 , G. Fountzilas 4 

1 Medical Oncology, 251 Airforce General Hospital, Athens, GREECE, 2 Pathology, 

Aristotle University of Thessalonikii School of Medicine, Thessaloniki, GREECE, 

3 Molecular Biology, Hellenic Foundation for Cancer Research, Thessaloniki, 

GREECE, 4 Medical Oncology Clinic Aristotle University of Thessaloniki, 

Papageorgiou General Hospital Aristotle University of Thessaloniki, Thessaloniki, 

GREECE, 5 Department of Otorhinolaryngology, AHEPA Hospital, Aristotle 

University of Thessaloniki School of Medicine, Thessaloniki, GREECE, 6 Ent 

Department, “G. Papanikolaou” General Hospital, Thessaloniki, GREECE 

Introduction: Prognosis of patients with operable squamous-cell laryngeal cancer is 

highly variable and therefore potent prognostic biomarkers are warranted. The 

Insulin-Growth Factor Receptor (IGFR)-mediated signaling pathway plays a critical 

role in laryngeal carcinogenesis. 

Patients and methods: We identified all patients with localised TNM stage I-III 

laryngeal cancer managed with potentially curative laryngectomy between May 1985 

and June 2008. Immunohistochemical (ICH) expression of IGFR1-alpha, IGFR1-beta 

and IGFR2 was evaluated using the Histo-score (H-score) climax and mRNA levels 

of important effectors of the IGFR-mediated pathway were assessed, including 

IGFR1, IGF-binding protein 3 (IGFBP3), suppressor of cytokine signaling 2 (SOCS2) 

and members of the MAP-kinase (MA2K1, MAPK9) and phosphatidyl-inositol-3 

kinase (PI3KCA, PI3KR1) families. Cox-regression models were applied to assess the 

predictive value of the components of the IGFR-mediated pathway on disease-free 

survival (DFS) and overall survival (OS). 

Results: Among 289 eligible patients, 95.8% were male, 95.2% were current or ex 

smokers, 75.4% were alcohol abusers, 15.6% had node-positive diease and 32.2% had 

received post-operative irradiation. After a median follow-up of 74.5 months, median 

DFS was 94.5 months and median OS was 106.3 months. Using the median H-score as 

the pre-defined cut-off value, IGFR1-alpha overexpression was associated with decreased 

DFS (p = 0.0538) and OS (p = 0.0157). Increased mRNA levels of MAPK9 were 

associated with prolonged DFS (p = 0.0209) and OS (p = 0.0108), as were increased 

mRNA levels of PI3KCA, albeit not significantly (p = 0.0723 and 0.0726 for DFS and 

OS respectively). In multivariate analysis, IGFR1-alpha overexpression was associated 

with a 46.6% increase in the probability for relapse (p = 0.0374). Independent predictors 

for poor OS included node-positive disease (HR = 2.569, 95%CI: 1.610-4.100, p < 

0.0001), subglotic or transglotic location (HR = 1.756, 95%CI: 1.016-3.036, p = 0.0438) 

and IGFR1-alpha IHC overexpression (HR = 1.475, 95%CI: 1.000-2.178, p = 0.05). 

Conclusion: IGFR1-alpha IHC overexpression may serve as an independent 

predictor of relapse and survival in operable laryngeal cancer. Prospective evaluation 

of IGFR1-alpha prognostic utility is warranted. 


1031P CYCLIN D1, EGFR AND AKT/MTOR SIGNALLING 

IN LOCALIZED LARYNGEAL SQUAMOUS CELL 

CARCINOMA 


D. Dionysopoulos 1 , K. Pavlakis 2 , V. Kotoula 3 , E. Fountzilas 1 , K. Markou 4 , 

I. Karasmanis 5 , N. Angouridakis 6 , A. Nikolaou 7 , K.T. Kalogeras 8 , G. Fountzilas 1 

1 Medical Oncology Clinic Aristotle University of Thessaloniki, Papageorgiou 

General Hospital Aristotle University of Thessaloniki, Thessaloniki, GREECE, 

2 Pathology, National & Kapodistrian University of Athens, Athens, GREECE, 

3 Department of Pathology, Aristotle University of Thessaloniki School of 

Medicine, Thessaloniki, GREECE, 4 1st Ent Clinic Aristotle University of 

Thessaloniki, AHEPA General Hospital, Thessaloniki, GREECE, 5 Ent Department, 

Ippokration General Hospital, Thessaloniki, GREECE, 6 Ent Department 

Aristotle University of Thessaloniki, Papageorgiou General Hospital, 

Thessaloniki, GREECE, 7 Ent Department, Papanikolaou General Hospital, 

Thessaloniki, GREECE, 8 Data Office, Hellenic Cooperative Oncology Group, 

Athens, GREECE 

Introduction: EGFR pathway, Akt/mTOR and Cyclin D1 are activated and interact 

in squamous cell head and neck cancer. 

Patients and methods: We assessed relative mRNA expression of EGFR, Akt1, 2, 3, 

mTOR and cyclin D1, copy number variants of EGFR and CCND1 genes and 

immunohistochemical (IHC) expression of EGFR, pAKT308, pAKT473, pmTOR, 

PTEN, p53 and cyclin D1 in paraffin-embedded tissue of localized laryngeal 

carcinomas. 

Results: In 289 patients with T3-4 (77.8%), node-negative (84.1%) tumours of the 

larynx, high EGFR and CCND1 mRNA correlated with never or ex smoking, (p = 

0.003) and (p = 0.029) respectively, while low AKT3 correlated with alcohol abuse. 

At a median follow-up of 74.5 months, high mTOR RNA was marginally associated 

with shorter DFS, HR = 1.54, p = 0.093 and high Akt3 mRNA with shorter OS, HR = 

1.49, p = 0.0786 whereas high EGFR IHC expression was associated with shorter DFS 

HR = 1.60, p = 0.0311 and OS HR = 1.57, p = 0.056, pAKT308 with shorter OS, HR = 

1.003, p = 0.0586 and pAKT473 with shorter DFS HR = 1.004, p = 0.021 and OS HR 



= 1.004, p = 0.033, all in univariate analysis. An interaction between mRNA levels of 

mTOR and cyclin D1 was found to be associated with shorter DFS, namely at high 

mTOR mRNA expression, one unit increase of CCND1 mRNA expression had a 

HR = 2.16 and this remained statistically significant in multivariate analysis 

(p-value for interaction = 0.0010). In multivariate analysis, node-positive status, 

subglottic-transglottic localization, surgery other than total laryngectomy and mTOR/ 

cyclin D1 mRNA interaction, were independent predictors of relapse, while 

node-positive status, and subglottic-transglottic localization were associated with 

higher risk of death. 

Conclusions: In laryngeal cancer, an interaction of high mTOR and cyclin D1 

mRNA expression is associated with poor patient outcome. 


1032P GENOME-WIDE ASSOCIATION STUDY OF BASE OF TONGUE 

SQUAMOUS CELL CARCINOMA RISK 

G.J. Lourenco1 , B. Carvalho2 , R. Pellegrino3 , L. Khater1 , C.T. Chone1 ,F. 

F. Costa 1 , C.S. Passos Lima1 1 

Department of Internal Medicine, State University of Campinas, Faculty of 

Medical Sciences, Campinas, BRAZIL, 2 Department of Oncology, University of 

Cambridge, Computational Biology Group, Cambridge, UNITED KINGDOM, 

3 

Department of Psychobiology, Federal University of São Paulo, São Paulo, 

BRAZIL 

Background: Inherited genetic alterations, such as single nucleotide polymorphisms 

(SNPs), were described in association with oropharyngeal cancer risk. However, 

existing studies have analyzed a limited number of genetic variants. Base of tongue 

(BT) squamous cell carcinoma (SCC) is a common tumor of oropharynx; however, 

the association of SNPs and BTSCC risk is still not clarified and, therefore, this was 

the aim of the present study. 

Methods: Genomic DNA of 49 BTSCC patients and 49 controls was extracted from 

peripheral blood samples using the QIamp kit (Qiagen®). Each sample was 

genotyped individually using DNA high-resolution microarrays containing 500.568 

SNPs (SNP array 5.0, Affymetrix®). Further sample processing, including digestion, 

adaptor ligation, amplification, fragmentation, labeling, hybridization, washing and 

scanning was assayed according to the standard protocol. Genotype data were 

acquired by genotyping calling of samples using the crlmm algorithm provided by 

Bioconductor software. The differences between groups were analyzed by the logistic 

regression model. The SNPs localized in genes of interest were selected by data base 

analysis in DAVID and NCBI websites. The validation of selected SNPs was 

performed by RT-PCR, using TaqMan® SNP Genotyping Assays (Applied 

Biosystems®) in all samples studied. 

Results: We observed 6.609 SNPs with distinct frequencies between BTSCC patients 

and controls. Fifty-two SNPs (0.8%) were located in coding sequence (CDS), 51 

(0.8%) in 3’ and 5’-untranslated regions (UTR), 3.461 (52.4%) in up or downstream 

regions (DWS) and 3.045 (46.0%) in introns. Ten SNPs were selected for validation 

and eight of them were validated, evidencing those localized in genes related to cell 

cycle (3’-UTR: ERP29, rs7114; MCC, rs7033; DWS: LEF1, rs2107028 and rs4245926; 

PTCH1, rs16909856 and rs16909859) and transcription process (CDS: IKBKAP, 

rs3204145; 3’-UTR: ZNF415, rs3814). 

Conclusions: Our preliminary results suggest that SNPs in genes involved in tumor 

origin and development may predispose individuals to BTSCC in southeastern Brazil. 

However, the roles of these SNPs in BTSCC susceptibility should be confirmed by 

functional protein studies and validated in larger epidemiological studies from 

distinct parts of the world. Financial support: FAPESP and FINEP. 


1033P HYPOXIA AND METABOLISM GENE EXPRESSION PROFILE 

PREDICTS POOR SURVIVAL IN HEAD AND NECK 

CARCINOMA 

S. Gouerant 1 , S. Mareschal 2 , J.M. Picquenot 3 , A. Berghian 3 , M. Cornic 3 , 

O. Choussy 4 , M. Benard 5 , F. Di Fiore 1 , F. Jardin 2 , F. Clatot 2 

1 Medical Oncology, Centre Henri Becquerel, Rouen, FRANCE, 2 Unité INSERM 

918, Université de Rouen, Rouen, FRANCE, 3 Pathology, Centre Henri Becquerel, 

Rouen, FRANCE, 4 Head and Neck Surgery, CHU Charles Nicolle, Rouen, 

FRANCE, 5 Plateforme Primacen, Université de Rouen, Rouen, FRANCE 

Background: Despite multimodal treatments combining surgery, radiotherapy, 

chemotherapy and now targeted therapies, head and neck squamous cell 

carcinomas (HNSCC) remain of poor prognosis. Hypoxia being an important 

biological characteristics of many HNSCC, we aimed to assess the prognostic value of 

the expression of 42 genes related to hypoxia and metabolism in non metastatic 

HNSCC. 

Patients and methods: Expression of 42 genes was retrospectively analyzed by high 

throughput real-time PCR in 80 patients treated for a non metastatic HNSCC. Fresh 

tissue samples were collected at diagnosis. After extraction, RNA quality was 

evaluated by an Agilent 2100® Bioanalyzer. After reverse transcription of total RNA, 

cDNA were analysed using a 1536 LightCycler®. An unsupervised hierarchical 

clustering analysis was performed. Usual prognostic factors and clustering analysis 

results were related to overall survival (OS). 

Results: Only 61 patients presented suitable quality RNA for gene expression 

analysis. With a median follow-up of 39.4 months, 41 patients were alive and 20 

were dead of cancer evolution. Among usual prognostic factors, capsular rupture of 

involved nodes and lymphovascular invasion were related to poor OS (p = 0.008, p = 

0.03, respectively). Gene expression profile distinguished 2 groups. The group 1 

composed of 34 patients (7 dead, 27 alive) had a better OS than the group 2 

composed of 27 patients (13 dead, 14 alive) (2 years OS = 85.3% and 2 years OS = 

63.0%, respectively, p = 0.02). The group 1 had frequent overexpression of genes 

related to inflammation (SDF1, CXCR4, EP4). The group 2 had frequent 

overexpression of genes related to lactate metabolism (LDHA, GLUT1, HK2), 

hypoxia (HIF1, BNIP3) or pH regulation (CA9, MCT1). Multivariate analysis based 

on the usual prognostic factors and the clustering analysis confirmed that capsular 

rupture, lymphovascular invasion and gene expression profile were related to poor 

OS (p = 0.005, p = 0.02, p = 0.003, respectively). 

Conclusion: In this cohort, clustering analysis underlined the prognostic value of 

hypoxia and lactate metabolism gene expression. If confirmed by further studies, 

tumor metabolism in HNSCC may become a promising target for anticancer drugs. 


1034P STUDY ON ASSOCIATION OF POLYMORPHISM OF CYP P 

450 2D6 WITH HEAD AND NECK CANCER AND TREATMENT 

RESPONSE IN PATIENTS RECEIVING NEOADJUVANT 

CHEMOTHERAPY (TPF) FOLLOWED BY CHEMORADIATION 

D. Kumar, M.C. Pant, N. Jamal, D. Parmar, S. Kumar, S. Singh, M. Bhatt 

Dept. of Radiotherapy, VMMC, Safdurjung Hospital, New Delhi, INDIA 

Aim of study: 1.To study the association of genetic polymorphism in Cyp 2D6 in 

patients of locally advanced head and neck cancer. 2. Try to assess a correlation 

between this polymorphism & response to treatment. Need of the study- To find out 

a possible genetic level explanation for the different response achieved in patients 

with similar histopathology, stage, exposure to carcinogen & ethinicity undergoing 

similar treatment. 

Material & method: A study comprising of 150 patients & 150 controls was done to 

analyse the association between polymorphs of Cyp 450 2d6 with Head & neck cancer 

and treatment response (TPF- > CTRT). Two cycles of TPF(paclitaxel-175 mg/m2 D1, 

cisplatin 35 mg/m2 D2-D3 and 5Fu 1gm/m2 D1-D3 ) were given followed by 

radiotherapy with concurrent cisplatin (40 mg/m2).The response to the treatment was 

assessed clinically, radiologically & by laryngoscopy- post treatment .Genotyping of the 

blood samples was done. Analysis of the association between genetic polymorphisms 

and risk of HNSCC was estimated by calculating crude odds ratio (OR). A p-value of 

CT + 

RT) is polymorph graded. Our study, thus provides an insight in to the concept of 

“Right therapy to the right patient” & may also explain to the fact that why, only 

some people are more prone to develop head and neck cancer despite the usage of 

tobacco,alcohol by so many people. 


1035P THE RANDOMIZED STUDY COMPARING THE EFFICACY AND 

SAFETY OF RADIO-CHEMOTHERAPY PLUS ADJUVANT 

CHEMOTHERAPY (CCRT) VS. NEO-ADJUVANT 

CHEMOTHERAPY PLUS RADIO-CHEMOTHERAPY (NAC-RT) 

FOR LOCALLY ADVANCED NASOPHARYNGEAL CANCER 

S. Chakrabandhu 1 , I. Chitapanarux 1 , R. Jiratrachu 2 , K. Pruegsanusak 2 , 

A. Pinitpatcharalerd 3 , J. Sukhaboon 4 , C. Tovanabutra 5 , A. Srisuthep 6 , 

N. Prasongsook 7 , V. Lorvidhaya 1 

1 Division of Therapeutic Radiology and Oncology, Chiangmai University, 

Chiangmai, THAILAND, 2 Division of Radiotherapy, Songklanagarind Hospital, 

Songkla, THAILAND, 3 Therapeutic Radiology, Rajavithi Hospital, Bangkok, 

THAILAND, 4 Medical Oncology Unit, Lopburi Cancer Center, Lopburi, 

THAILAND, 5 Division of Radiation Oncology, Chonburi Cancer Center, Chonburi, 

THAILAND, 6 Radiology, Bhumibol Adulyadej RTAF Hospital, Bangkok, 

THAILAND, 7 Medical Oncology Unit, Department of Internal Medicine, 

Phramongkutklao Hospital, Bangkok, THAILAND 

Purpose: Nasopharyngeal carcinoma is radio-chemosensitive. Local control and 

survival of patients with advanced disease treated by radiotherapy alone remains 

unsatisfactory. Chemotherapy has been combined with radiotherapy to increase 

local-regional control, decrease distant metastasis, and improve survival of the 


patients. We have developed a randomized trial comparing the efficacy and toxicities 

of CCRT versus NAC-RT for locally advanced nasopharyngeal cancer. 

Patients and methods: A total of 175 patients were included in the study. The 87 

patients received concurrent radio-chemotherapy daily 70 Gy/7 weeks with cisplatin 

100 mg/m 2 q 3 weeks then followed by adjuvant chemotherapy for 3 cycles (q 3 

weeks), consisting of cisplatin 80 mg/m 2 on day 1 and 5-FU 1,000 mg/m 2 on day 1-4. 

The 88 patients received neoadjuvant chemotherapy for 3 cycles (q 3 weeks) 

consisting of docetaxel 75 mg/m 2 on day 1, cisplatin 75 mg/m 2 on day 1, and 5-FU 

750 mg/m 2 on days 1- 4 followed by concurrent radiotherapy daily 70 Gy/7 weeks 

with carboplatin AUC 1.5 weekly for 6 weeks. 

Results: The number of patients who completed treatment for the CCRT group was 

34 (39.1%) and for the NAC-RT group was 54 (61.4%). The most common reasons 

for study discontinuation were adverse events and patient’s willingness. The grade 3 

and 4 treatment-related adverse events were two times higher in the CCRT group 

(p < 0.06), mostly mucositis / stomatitis and nausea / vomiting. There was no 

difference in hematologic adverse events between groups. The 1-year progression-free 

survival rate was 91.8% and 89.3% in the CCRT and NAC-RT group, respectively. 

No evidence of disease at the time of this interim analysis was found in 76.5% in the 

CCRT group and 85.2% in the NAC-RT group. 

Conclusion: Induction chemotherapy with docetaxel / cisplatin and 5-fluoro-uracil 

followed by concurrent radio-chemotherapy was tolerable and provided well control 

of disease. These interim early results revealed no difference in PFS but less side 

effects and increase number of the patients with no evidence of disease in the 

NAC-RT arm. 


1036P INDUCTION THERAPY WITH CETUXIMAB, DOCETAXEL, 

CISPLATIN, AND FLUOROURACIL IN PATIENTS WITH 

RESECTABLE NON METASTATIC STAGE III OR IV 

SQUAMOUS CELL CARCINOMA OF THE OROPHARYNX. A 

GERCOR PHASE II STUDY 

B. Chibaudel 1 ,R.Lacave 2 , J. Belloc 3 , A. Banal 4 , S. Albert 5 , F. Chabolle 6 , 

M. Lefevre 7 , P. Soussan 8 , R. Moukoko 9 , J. Lacau Saint Guily 10 

1 Department of Medical Oncology, Hôpital Saint Antoine, Paris, FRANCE, 

2 Laboratoire d’Histologie et Biologie Tumorale, Hôpital Tenon, PARIS, FRANCE, 

3 Oto-Rhino-Laryngologie, Hôpital Simone Veil, Eaubonne, FRANCE, 4 Chirurgie 

de la Face et du Cou, Centre René Huguenin, Saint-Cloud, FRANCE, 

5 Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Bichat Claude 

Bernard, Paris, FRANCE, 6 Oto- Rhino-Laryngologie et Chirurgie Cervico-Faciale, 

Hôpital Foch, Suresnes, FRANCE, 7 Anatomie et Cyto Pathologie, Hôpital Tenon, 

Paris, FRANCE, 8 Virologie, Hôpital Tenon, Paris, FRANCE, 9 Groupe Coopérateur 

Multidisciplinaire en Oncologie, GERCOR, Paris, FRANCE, 10 Oto- 

Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Tenon, Paris, FRANCE 

Background: Docetaxel/cisplatin/5-FU (TPF) has been reported to be more active 

than cisplatin/5-FU in Squamous Cell Carcinoma (SCC) of the head and neck (HN). 

A clinical Complete Response (CR) rate of 8.5% was achieved after TPF induction 

therapy (IT) in patients (pts) with unresectable pharyngolaryngeal SCC (Vermorken 

et al, NEJM 2007). EGFR is overexpressed in up to 90% of HN cancers. Cetuximab 

(Cet) was active in combination with radiotherapy and with cisplatin. The aim of this 

multicenter single-arm phase II study was to evaluate Cet with TPF as IT in 

oropharyngeal SCC. 

Methods: Main inclusion criteria were: previously untreated histologically proven 

oropharyngeal SCC, non-metastatic stage III or IV disease (UICC 2002), surgically 

resectable, age 18-75 years, ECOG Performance Status (PS) 0-1. Pts received Cet iv 

/1-2h (400 mg/m 2 loading dose, then weekly 250 mg/m 2 ) followed by docetaxel iv 

75mg/m 2 /1h and cisplatin iv 75mg/m 2 /1h (day 1); and 5-FU iv 750mg/m 2 /day 

continuously (days 1-5), every 3 weeks for 3 courses. After completion of IT, the 

treatment of the primitive tumor was at the investigator’s discretion. The primary 

endpoint was the clinical and radiological CR of primitive tumor at 3 months. 

Correlative studies investigated several EGFR-related biomarkers and HPV analyses 

in tumor and blood samples. 

Results: Among 42 pts enrolled from 07/2008 to 11/2011 in 9 centers, 41 pts were 

treated. The main pts characteristics were: male 81%, mean age 56y, PS0 79%, tonsil 

area 88%, stage III/IV 76%/24%. The planned 9 infusions were given in 31 (76%) 

pts. A clinical and radiological CR of the primitive tumor at 3 months was achieved 

in 9 (22%) pts, and a clinical CR in 17 (41%) pts. The most frequent G3-4 toxicities 

were: neutropenia (39%), febrile neutropenia (20%), diarrhea (10%), and mucositis 

(12%). Any grade acnea-like syndrome was observed in 18 (44%) pts. One toxic 

death occurred secondary to chemo-induced colitis with colonic perforation. 

Conclusions: The combination of cetuximab with TPF is highly active. A systematic 

therapy with granulocyte colony-stimulating factor is necessary to prevent febrile 

neutropenia. 



1037P DOCETAXEL, CARBOPLATIN AND FLUORO-URACIL (TCF) 

INDUCTION THERAPY IN LOCALLY ADVANCED HEAD AND 

NECK SQUAMOUS CELL CARCINOMA (HNSCC) PATIENTS 

WITH CONTRAINDICATION FOR CISPLATIN BASED 

COMBINATION (TPF) 

E. Saada 1 , F.R. Ferrand 1 , M. Fekih 2 , D. Hamdan 1 , F. Janot 1 , S. Temam 2 , 

M. Julieron 1 , A.M. Leridant 1 , A. Schilf 1 , J. Guigay 1 

1 Head and Neck Departement, Institut Gustave Roussy, Villejuif, FRANCE, 2 Head 

and Neck, Institut Gustave Roussy, Villejuif, FRANCE 

Background: TPF regimen is a standard induction combination for fit locally 

advanced HNSCC patients (pts). TCF with carboplatin may be an option in frail pts 

with contraindication for cisplatin, but data are missing about safety and efficacy of 

such an approach. 

Method: Retrospective study of monocentric cohort of HNSCC patients treated from 

2007 to 2011 with TCF induction regimen at Gustave Roussy Institute. TCF regimen 

combined Docetaxel 75mg/m 2 , Carboplatin AUC4, and 5FU: 750 mg/m 2 /day for 

5days. 

Results: Population included 34 pts, median age 59 years (44-78), all with Charlson 

Comorbidity Index score ≥ 2, with oropharynx, hypopharynx, oral cavity, larynx 

and paranasal sinuses HNSCC localization (32.3, 23.5, 17.6, 14.7 and 11.8% 

respectively). TNM stage were: T1-2 : 4 pts (11.7%), T3-4: 27 pts (79.4%), rTx: 3 

pts (8.8%); N0: 8 pts (23.5%), N1: 4 pts (11.8%), N2a-N2b: 6 pts (17.6%), N2c-N3: 

13 pts (38.2%); M1: 1 pt (2.9%). TPF contraindications were respiratory disease 

(di.) (11 pts: 32.3%), heart di. (6 pts: 17.6%), liver di. (3 pts: 8.8%), alcohol related 

neuropathy (3 pts: 8.8%), hearing di. (5 pts: 14.7%), renal di. (5 pts: 14.7%), other 

co-morbidities (3 pts: 8.8%).Patients received 2 to 4 cycles of TCF. GCSF was 

delivered in 31 pts (91.2%). Cumulated incidence of Grade 3-4 toxicity was 37.2%, 

and one toxic death occurred at C2. Five pts (14.7%) stopped treatment because of 

toxicity. RECIST evaluation found complete response in 1 patient (2.9%), partial 

response in 23 pts (67.6%), stable disease in 6 pts (17.7%), and progression disease 

in 1 pt (2.9%). Subsequent treatment was surgery followed by radiotherapy (9 pts, 

26.5%), radiotherapy or chemoradiotherapy (22 pts, 64.7%), chemotherapy (3 pts, 

8.8%). Response after RT was: CR: 16 pts (64%), PR: 4 pts (16 %), SD: 3 pts (12 

%), PD: 2 pts (8 %). Median recurrence-free survival was 8.7 months, median 

overall survival (OS): 22.9 months. Personal history of cancer (HR = 4.6, p = 0.02), 

tobacco (HR = 37.5, p = 0.04), alcohol intake (HR = 0.12, p = 0.01), hypertension ( 

HR = 4.4, p = 0.01), T4 stage ( HR = 0.1, p = 0.02), N2c-N3 stage (HR = 18.5, p = 

0.003), BMI < 20 (HR = 9.6, p = 0.02) and lymphopenia (HR = 4.3, p = 0.01) were 

associated with OS in multivariate analysis. 

Conclusion: TCF induction regimen was manageable and provided objective 

responses in 70% of frail HNSCC patients. 


1038P INDUCTION CHEMOTHERAPY WITH DOCETAXEL, 

CISPLATIN AND 5-FLUOROURACIL FOLLOWED BY 

RADIOTHERAPY WITH CETUXIMAB FOR LOCALLY 

ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD 

AND NECK 

F. Keil 1 , E. Selzer 2 , A. Berghold 3 , K. Kapp 4 , A. De Vries 5 , R. Greil 6 , S. Reinisch 7 , 

W. Anderhuber 8 , M. Burian 9 , G.V. Kornek 10 

1 Internal Medicine, Hanusch Krankenhaus, Vienna, AUSTRIA, 2 University Clinic of 

Radiation Therapy and Radiation Biology, Medical University Vienna, Vienna, 

AUSTRIA, 3 Institute for Med. Informatics, Statistics and Documentation, Institute 

for Med. Informatics, Statistics and Documentation, Graz, AUSTRIA, 4 Radiation 

Therapy - Radiooncology, University Clinic, Graz, AUSTRIA, 5 Radiation Therapy, 

LKH Feldkirch, Feldkirch, AUSTRIA, 6 Internal Medicine III, University Hospital 

Salzburg, Salzburg, AUSTRIA, 7 Clinical Departement of General Hnc, Medical 

University Graz, Graz, AUSTRIA, 8 Departement of HNC, LKH Leoben, Leoben, 

AUSTRIA, 9 HNC Departement, Hospital of Barmherzigen Schwestern, Linz, 

AUSTRIA, 10 Oncology, Medical University of Vienna, Vienna, AUSTRIA 

Purpose: To determine the efficacy and feasibility of induction chemotherapy with 

docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy and cetuximab in 

patients with locally advanced head and neck cancer. 

Patients and methods: Forty-nine previously untreated patients (median age: 53 

years) with local advanced stage III and IV squamous cell carcinoma of the head and 

neck received three courses of induction chemotherapy consisting of docetaxel 75 

mg/m 2 day 1, cisplatin 75 mg/m 2 day 1, and infusional 5-Fluorouracil 750 mg/m 2 / 

day on days 1-5 followed by radiotherapy plus cetuximab at 250mg/m 2 /week (after 

an initial loading dose of 400mg/m 2 ). Patients with an ECOG performance score of 0 

or 1 without severe co-morbidities adequate hematopoietic, hepatic, and renal 

functions were eligible. 

Results: After completion of induction chemotherapy 44 of 49 patients received 

radiotherapy plus cetuximab. In 45 patients ICT was delivered without delay or dose 



reduction and 38 patients received RT at the full dose. Three months after therapy 

completion tumor response was observed in 33 patients and after 2 years, 25 patients 

were in complete remission. Although treatment was accompanied with a rate of 

grate 3 and 4 toxicity of 30% during induction chemotherapy and up to 68% during 

radiotherapy with cetuximab, our treatment seems feasible. Toxicities resolved within 

3 months after end of treatment and only two patients became dependent on gastric 

feeding tubes after two years, compared to 21 patients during treatment. We lost one 

patient because of treatment related toxicity and 73% of the 49 included patients 

finished treatment without dose reduction or delay of treatment. 2-year 

progression-free survival rate was 59% and 2-year overall survival rate was 63%, 

respectively. 

Conclusion: Concurrent radiotherapy plus cetuximab after three courses of 

induction chemotherapy was feasible and associated with promising complete 

remission, progression-free and overall survival rates. Further optimization of dose 

and sequence is warranted. 


1039P INDUCTION CHEMOTHERAPY USING DOCETAXEL, 

CISPLATIN AND FLUOROURACIL (TPF) FOLLOWED BY 

CONCOMITANT CHEMORADIOTHERAPY VS THE SAME 

CONCOMITANT CHEMORADIOTHERAPY IN PATIENTS WITH 

LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF 

THE HEAD AND NECK (LASCCHN) 

W. El-Sadda, I. Abdel Halim, K. Abul Khair, R. Abdel Latif 

Clinical Oncology and Nuclear Medicine, Mansoura University Hospital School of 

Medicine, Mansoura, EGYPT 

Background: Concomitant chemoradiotherapy (CCRT) with cisplatin is considered a 

standard treatment of LASCCHN. The role of induction chemotherapy (IC) followed 

by CCRT remains controversial. Our aim was to compare neoadjuvant chemotherapy 

with 3 cycles of TPF followed by CCRT to CCRT alone. The 1ry objective of the 

study was ORR and the 2ry objectives were toxicity, PFS and OS. 

Patients and methods: Between 2006 & 2008, 100 patients with histologically proven 

SCC of the Head & Neck (stage IIB-IVA) were enrolled. WHO PS 0-1, with adequate 

bone marrow, liver and kidney functions. Fifty patients received 3 cycles of IC 

including docetaxel 75 mg/m 2 IV over 1h D1, cisplatin 75mg/m 2 IV over 3h D1 and 

5-FU 750 mg/m 2 IV continuous infusion over 24h D1-5 (repeated every 3 wks). 

Premedications before and after docetaxel and cisplatin with prophylactic antibiotic 

on D5 and G-CSF on D6. This was followed by CCRT in the form of radiotherapy 

using conventional fractionation (2Gy/day, 5 fr/week, total dose of 70Gy) with 

concurrent weekly cisplatin 20 mg/m 2 IV (Gp A). In gp B, patients received CCRT 

alone. Response was assessed by physical examination, CT scan and endoscopy after 

2 cycles, after completion of IC, and 6-8 wks after completion of CCRT. 

Results: All patients in both gps had completed the treatment schedule and were 

evaluable for response, toxicity and survival. The median age was 44.5 years in both 

gps (range 27-62). Seventy percent of patients had PS 0, 65 patients had cervical LN 

involvement (N 2-3). The ORR after the completion of CCRT were 88% & 68% in the 

two groups respectively. Toxicity was manageable in both groups. The main severe 

toxicities during IC were G3 alopecia and neutropenia. During CCRT, the most 

severe side effects in both groups were mucositis and weight loss. The 2-year PFS and 

OS rates were 70%, 86% and 75%, 80% respectively. 

Conclusion: Induction chemotherapy using TPF followed by CCRT is safe, tolerable 

and effective treatment and can significantly improve survival in patients with 

LASSCHN. 


1040P THE IMPACT OF INDUCTION CHEMOTHERAPY ON 

CISPLATION DOSE INTENSITY DURING 

CHEMO-RADIOTHERAPY (CTRT) IN OROPHARYNGEAL 

SQUAMOUS CELL CANCER (OPC) 

R. Granata 1 , P. Bossi 1 , E. Orlandi 2 , L. Locati 1 , C. Bergamini 1 , C. Resteghini 1 , 

T. Ibba 3 , G. Scaramellini 3 , C. Fallai 2 , L. Licitra 1 

1 Head & Neck Unit, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, 

ITALY, 2 Radiation Oncology, Fondazione IRCCS Istituto Nazionale Tumori Milano, 

Milan, ITALY, 3 Otorhinolaryngology Unit, Fondazione IRCCS Istituto Nazionale 

Tumori Milano, Milan, ITALY 

Background: Induction (IC) with TPF (Taxotere, Cisplatin, 5-FU) has been 

associated with improved outcome in advanced head and neck squamous cell cancer 

patients (pts). Full dose of cisplatin (300 mg/m 2 ) during CTRT has been 

demonstrated to impact on patients’ outcome. The aim of the current study is to 

investigate whether the IC could impact on cisplatin dose intensity during CTRT in a 

homogeneous population of OPC. 

Materials and methods: The study population consisted of 101 pts with stage III-IV 

OPC treated from 07/2004 to 12/2011 with IC (n = 53) plus CTRT or CTRT alone 

(n= 48). IC consisted of TPF, while weekly 50 mg/m 2 or 3-weekly 100 mg/m 2 

cisplatin was administered concurrently with RT (planned chemotherapy dose = 300 

mg/m 2 ; planned RT dose = 66-70 Gy, 3DRT or IMRT with a conventional or 

accelerated fractionation). Carboplatin substituted cisplatin in case of creatinine 

clearance less than 60 mL/min. HPV status, concurrent cisplatin dose intensity and 

RT overall treatment time (OTT) were analyzed. 

Results: Stage IV pts were 100% in the IC group and 83% in CTRT, while HPV 

positive OPCs were detected in 58% and 63% of the cases respectively. TPF median 

number of cycles was 3, with induction cisplatin median dose administered of 200 

mg/ m 2 . RT median total dose administered was 70 Gy in both group. Accelerated 

fractionated RT was adopted in 65% of CTRT alone group and in 21% of IC group. 

Two pts (1 in each group) did not complete CTRT because of cardiovascular events. 

Mean and median dose intensity of cisplatin concurrent to RT in the IC group was 

77.7% and 75% (35%-100%) while in CTRT group was 86% and 91.7% (33%-100%), 

with a p value = 0.014. In 11 pts (21%) treated with IC and only in 1 pts (2%) 

treated with CTRT alone cisplatin was substituted with carboplatin. No different 

cisplatin dose intensity was identified in HPV positive versus HPV negative cases. 

Prolonged OTT (longer than 5 days) was observed in two patients in IC group due 

to sepsis and severe mucositis as well as in one patient in CTRT group due to 

machine failure. 

Conclusions: Concurrent cisplatin dose intensity was significantly reduced in pts 

receiving IC compared to CTRT alone, irrespective of HPV status. Whether this has 

an impact on the results of IC followed by full dose CT/RT has to be clarified. 


1041P THE TOLERANCE OF TPF CHEMOTHERAPY REGIME 

STANDARD OR MODIFIED IN HEAD NECK CANCER 

PATIENTS OVER 65 YEARS OLD 

S.M. Ilie 1 , I. Ruginescu 2 , E. Saada 2 , F.R. Ferrand 2 , A. Schilf 2 , F. Janot 2 , 

J. Guigay 2 


Alexandru Treistoreanu, Bucharest, ROMANIA, 2 Head and Neck Cancer 

Treatment, Institute Gustave Roussy, Villejuif, FRANCE 

Background: Docetaxel, Cisplatin, 5FU regimen (TPF) has became a standard for 

induction chemotherapy in locally advanced squamous cell cancer of head and neck 

(SCCHN). However, little is known about tolerance and efficacy of TPF in older 

patients Objective of the study was to evaluate the tolerance of induction 

chemotherapy with TPF regimen in SCCHN patients over 65 years, looking for side 

effects especially degree 3 and 4. 

Materials and methods: retrospective study of the database of Head and Neck 

Cancer Department of Gustave Roussy Institute between 2006 and 2009: all patients 

over 65 years who received a TPF induction chemotherapy were included. 

Results: Among 300 patients treated with TPF induction chemotherapy, we found 57 

pts over 65 years : 41 (70%)between 65 - 70, 9 (15%)between 70 - 75 and 7 (12%) 

over 75. Most of patients received an organ preservation treatment for T3N0-1M0 

hypopharynx and larynx cancer (52%) . 30 pts had an impaired nutritional status 

and 37(64%) an ACE 27 index superior of 2. 40 pts (70%) accomplished their planed 

cycles but only 37( 65%) received the planed doses. 23 pts (41%) presented a grade 3 

or 4 hematological or gastrointestinal adverse events and 5 toxic deaths were 

observed. 

Conclusion: This retrospective study confirms the high risk of toxicity of induction 

chemotherapy with TPF combination in elderly SCCHN patients that may 

compromise the postsurgical outcome in patients over 65 years presenting at least 

one comorbidity and denutrition. Geriatric assessment is probably useful in this 

population to better select candidates to induction chemotherapy. 


1042P SERIAL COMPREHENSIVE GERIATRIC EVALUATION IN 

ELDERLY HEAD AND NECK CANCER PATIENTS 

UNDERGOING RADIOTHERAPY 

P.R. Debruyne 1 , M. Lycke 1 , T. Boterberg 2 , H. Pottel 3 , L. Goethals 1 , N. van den 

Noortgate 4 , F. Duprez 2 , S. Rottey 5 , K. Kargar-Samani 6 , L. Pottel 1 

1 Campus Loofstraat - Cancer Center, General Hospital Groeninge, Kortrijk, 

BELGIUM, 2 Department of Radiation Oncology, Ghent University Hospital, 

Ghent, BELGIUM, 3 Department of Biostatistics, Catholic University Leuven 

KULAK, Kortrijk, BELGIUM, 4 Department of Geriatrics, Ghent University Hospital, 

Ghent, BELGIUM, 5 Department of Medical Oncology, Ghent University Hospital, 

Ghent, BELGIUM, 6 Department of Medical Oncology, Centre Hospitalier de 

Wallonie Picarde, Tournai, BELGIUM 

Background: Elderly head and neck (H&N) cancer patients can present with 

significant co-morbidities whilst treatment induces additional morbidity. 

Comprehensive geriatric assessment (CGA) has been proposed as a key treatment 

approach in elderly cancer patients. We studied the feasibility of serial CGA during 

radiotherapy in this population. 

Material and methods: Patients aged ≥ 65 years with primary H&N cancer 

undergoing curative radiotherapy (with or without systemic treatment), were 


evaluated by the screening instruments Vulnerable Elders Survey-13 (VES-13) and 

G8, and CGA, at baseline and in the 4 th week of their treatment at General Hospital 

Groeninge or Ghent University Hospital. 

Results: Ninety eligible patients with a median age of 72 (range 65-87) consented. 

Patients mostly presented with an advanced stage tumour (67.8%, stage III-IV) of the 

larynx (46.7%) and pharynx (32.2%). Thirteen patients declined assessment in the 4 th 

week of therapy. Of those patients, one withdrew from further study participation, 

one died and in two patients, a change of therapeutic intent was indicated. Nine 

patients declined because they felt too ill. At baseline, 40.3%, 64.9% and 71.4% of 

patients were defined vulnerable, based on respectively VES-13 (cut-off ≥3), G8 

(cut-off ≤14) and CGA (defined as impairments in two or more domains). 

Significantly more patients were considered vulnerable at week 4 by VES-13 (55.8%, 

P < 0.0001), G8 (90.9%, P < 0.0001) and CGA (81.8%, P < 0.05). Patients presented 

with deficits in the following domains: co-morbidity (CIRS-G), nutrition (MNA), 

community functioning (IADL), physical status (Tinetti), self-care (ADL), emotional 

wellbeing (GDS) and cognition (MMSE) at both points in time. In addition, the 

incidence of vulnerability in all health domains increased during treatment, with 

especially deterioration of nutritional (P < 0.0001), functional (P < 0.0001), mental 

(P < 0.01) and emotional (P < 0.01) status. 

Conclusion: Serial CGA identifies multidimensional health problems and their 

evolution during radiotherapy. It indicates the need for re-evaluation of a patient’s 

health status and could guide intensive supportive care in elderly patients treated for 

H&N cancer. Acknowledgement: Our work is supported by a grant from the Belgian 

Government, National Cancer Plan (NKP_024_018). 


1043P PHASE II STUDY OF BIWEEKLY DOSE-INTENSE PACLITAXEL 

PLUS GEMCITABINE (GEM/TAX) IN PATIENTS WITH 

RECURRENT LOCOREGIONAL OR METASTATIC HEAD AND 

NECK SQUAMOUS CELL CARCINOMA 

A. Sukari1 , M. Salem1 , M. Al-Hajeili1 , J. Jacobs2 , S. Taylo1 ,G.Yoo2 , H. Lin2 , 

L. Heilbrun1 , A. Alousi3 , O. Kucuk4 1 

Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI, 

UNITED STATES OF AMERICA, 2 Department of Otolaryngology and Head and 

Neck Surgery, Karmanos Cancer Center, Wayne State University, Detroit, MI, 

UNITED STATES OF AMERICA, 3 Division of Hematology and Oncolog, MD 

Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA, 

4 

Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, UNITED 


Background: Patients with metastatic head and neck squamous cell carcinoma 

(HNSCC) have a poor prognosis, limited treatment options, and median survival of 

6 to 9 months. Paclitaxel (TAX) and gemcitabine (GEM) have both shown activity in 

HNSCC. The optimal combination, dosing, and scheduling of both drugs is, 

however, unknown. Thus, we investigated the efficacy and safety of biweekly 

dose-intense GEM/TAX in patients with recurrent locoregional or metastatic 

HNSCC. 

Methods: An open-label, single-institution, single-arm, phase II study was conducted 

for patients (pts) who were previously treated with no more than two cytotoxic 

regimens. The pts received paclitaxel (150 mg/m 2 IV) and gemcitabine (3000 mg/m 2 

IV) on day 1 and 15. The treatments were repeated every 28 days (one cycle), until 

disease progression or unacceptable toxicity. The primary end point was response 

rate. RECIST-defined response was evaluated every 2 cycles (8 wks) and toxicities 

were evaluated after each cycle (4 wks). 

Results: Fifty-five pts were enrolled into the trial (M: F 42:13, median age (range): 56 

years (23-84), performance status 0-2, 48 pts had previous radiation therapy and 39 

had previous surgery), 41 of whom were response evaluable. Of these 41 patients, 

two pts (4.8%) achieved complete response (CR) and 17 (41.4%) demonstrated a 

partial response (PR). Thus, the overall response rate was 46%. Thirteen pts (31.7%) 

had stable disease (SD), resulting in tumor control in 32 of 41 pts (78% with CR, PR 

or SD), whereas 9 pts (21.1%) had disease progression (PD). Among those pts who 

achieved objective response or stable disease, the median response duration was 5 

months and median time to progression was 4 months. Median overall survival (OS) 

was 15 months. Myelosuppression was the most common adverse event. Grade 3-4 

neutropenia and anemia were observed in 5 (12%) and 11 (26%) pts, respectively. 

Eight (19%) pts developed grade 3 infection. None of these pts, however, had febrile 

neutropenia and there were no treatment-related deaths. 

Conclusions: The combination of biweekly dose intense GEM/TAX was tolerable 

and active regimen in patients with recurrent locoregional or metastatic HNSCC. 

Our findings warrant further investigation in a larger patient population. 



1044P PHASE IB TRIAL OF IMO-2055 IN COMBINATION WITH 5-FU, 

CISPLATIN AND CETUXIMAB IN 1ST-LINE PTS WITH 

RECURRENT/METASTATIC SQUAMOUS CELL CARCINOMA 

OF THE HEAD AND NECK (R/M SCCHN) 

J.P. Machiels 1 , M.C. Kaminsky 2 , U. Keller 3 , T.H. Brümmendorf 4 , T. Goddemeier 5 , 

U. Forssman 6 , J.P. Delord 7 

1 Medical Oncology, Cliniques Universitaires St. Luc, Brussels, BELGIUM, 

2 Département d’Oncologie Médicale, Centre Alexis Vautrin, Nancy, FRANCE, 3 III. 

Medizinische Klinik, TU München, Munich, GERMANY, 4 Hämatologie und 

Onkologie, Universitätsklinikum Aachen, Aachen, GERMANY, 5 Global Clinical 

Operations / Global Biostatistics, Merck KGaA, Darmstadt, GERMANY, 6 Global 

Clinical Development Unit Oncology, Merck Serono S.A, Geneva, 

SWITZERLAND, 7 Clinical Resarch Unit, Centre Claudius-Regaud, Toulouse, 

FRANCE 

Purpose: IMO-2055 is a toll-like receptor 9 agonist with potential to enhance the 

efficacy of antitumor agents through immune stimulation. 

Methods: IMO-2055 was administered to 1st-line pts with R/M SCCHN on days 1, 8 

and 15 of each 3-wk cycle in combination with 5-FU, cisplatin and cetuximab. 

IMO-2055 doses were to be escalated (3 + 3 design) from dose level (DL) 1 (0.16 mg/ 

kg) to DL2 (0.32 mg/kg) and DL3 (0.48 mg/kg) if


Results: Globally, 171 pts were considered, 56 in surgical and 115 in CTRT series. In 

CTRT series, 40% of the pts received induction TPF chemotherapy; in surgical series 

57% of the pts had extracapsular extension and/or microscopically involved surgical 

margins. 

Surgical series CTRT series 

p16 expression 39% 59% 

Stage III 13% 7% 

Stage IV 87% 93% 

Low risk 20% 20% 

Intermediate risk 23% 41% 

High risk 57% 39% 

Five-year (yr) OS for p16 positive pts was 50% in surgical and 88% in CTRT series, 

while for p16 negative was 38% and 49% respectively (p < 0.0001).When stratifying 

for risk profile, 5-yr OS of low risk CTRT pts was 100% vs 54% of surgical pts (p = 

0.0042) and 5-yr DFS was 93% vs 53% (p = 0.0079); 5-yr OS of intermediate risk 

CTRT pts was 76% vs 46% of surgical pts (p = 0.0141) and 5-yr DFS was 79% vs 

38% (p = 0.0359). High risk CTRT pts had a 5-yr OS of 51% vs 36% of surgical pts 

(p = 0.1902) and a 5-yr DFS of 24% vs 36% (p = 0.6411). 

Discussion: In this retrospective analysis, low and intermediate risk OPC pts had a 

greater survival benefit when treated with CTRT compared with surgery followed by 

RT. Although with the limits of different RT techniques and lack of CT in adjunct to 

postoperative RT, these data should be considered as hypothesis generating for new 

trials design. 


1046P ELECTROCHEMOTHERAPY (ECT) WITH BLEOMYCIN AS A 

PALLIATIVE TREATMENT OF REGIONAL RELAPSE IN HEAD 

AND NECK CANCER (H&NC) PATIENTS (PTS). A PILOT 

STUDY 

J.J. Grau 1 , M. Caballero 2 , A. Vilalta 3 , I. Victoria 1 , O. Reig 1 , P. Gascon 1 , 

C. Carrera 3 , J. Malvehy 3 


2 Head and Neck Department, Hospital Clinic Barcelona, Barcelona, SPAIN, 

3 Dermatology, Hospital Clinic Barcelona, Barcelona, SPAIN 

Background: ECT is the administration of electrical pulses in the tumour during 

perfusion of chemotherapy allowing the introduction of the drug in neoplastic cell. 

H&N regional relapse no suitable for local or systemic treatment has a median 

survival of 3 months causing local pain and anxiety to the pts. We prospecively 

analysed antitumoral activity of ECT in regional relapse of H&NC not suitable for 

other therapies. 

Methods: Pts with local-regional relapse of H&NC from mucosa (squamous 

carcinoma), thyroid gland, salivary gland, cutaneous squamous or cutaneous 

melanoma were included. Other inclusion criteria were good general condition, no 

history of reaction to Bleomycin, life spectancy of 3 or more months and no 

possibility of salvage local surgery. All pts were previously treated with local radiation 

and systemic chemotherapy. 

Results: Between 2009-2011, 26 ECT courses were performed in 18 consecutive pts 

with local relapse of squamous H&NC n = 7(39%); malignant melanoma n = 6(33%); 

thyroid carcinoma n = 4(22%); or parotid carcinoma n = 1(6%). Objective responses 

were: complete n = 3(17%); partial n = 11(61%); complete plus partial n = 14(78%); or 

no response n = 4(22%). The median follow-up was 12 moths, time to progression 

was 6 months and overall survival was 9 months for all the pts. All responding pts 

had a reduction of local pain and anxiety. Mild local pain for few days and skin 

necrosis were the only side effects. 

Conclusions: ECT has a high antitumoral activity in regional relapse of H&NC of 

different histologies. This local therapy may have a place in the future as palliative 

treatment of H&NC. 


1047P PSYCHOLOGICAL DISTRESS AND QUALITY OF LIFE 

EVALUATION IN HEAD AND NECK CANCER: THE ROLE OF 

FAMILY CAREGIVER 

O. Ostellino 1 , M. Airoldi 1 , M. Garzaro 2 , L. Raimondo 2 , G. Riva 2 , C. Bartoli 2 , 

S. Carnio 1 , G. Fora 1 , C. Giordano 2 , G. Pecorari 2 

1 Medical Oncology Division - Medical Oncology Department, San Giovanni 

Battista Hospital, Turin, ITALY, 2 1st Ent Division - Physiopathology Department, 

University of Turin, Turin, ITALY 

Background: Recently the figure of family caregiver (FCG) has become a hot 

topic and is still largely un-investigated among head and neck cancer patients; 

aim of our study was to describe in a more detailed way the role of FCG, to 

evaluate quality of life (QoL) and psychological distress of FCGs and patients, 

and to investigate relationships between FCG’s wellbeing and patient’s QoLand 

emotional pattern. 

Methods: Sixty couples of patients and their caregivers were enrolled in this 

observational cross-sectional study between April 2007 and May 2011 at 1st ENT 

Division, 2th Medical Oncology Division and 2th Radiotherapy Division of San 

Giovanni Battista Hospital of Turin. Inclusion criteria were: histological diagnosis 

of SCC, advanced stage (III-IV), completion of curative treatment and no 

evidence of disease at the enrolment. Psycho-oncological assessment was 

performed using Distress Thermometer (DT), Stay-Trait Anxiety Inventory 

Manual in Y1 and Y2 form (STAI Y1-Y2), Beck Depression Inventory (BDI), 

Montgomery-Asberg Depression Rating Scale (MDRS), EORTC-QLQ-C30 and 

Head and Neck-35 module and Caregiver Quality of Life Index-Cancer 

(CQOLC). 

Results: Patients state and trait anxiety are 46,7% (STAI Y1 mean value 40,2 ± 10,2; 

cut-off 40) and 36,7% (STAI Y2 mean value 36,7 ± 8,2; cut off 40) respectively; self 

reported and clinician rated depression are 31,6% (BDI mean value 8,2 ± 5,3; cut-off 

9) and 48,3% (MDRS mean value 7,9 ± 5,9; cut-off 6) respectively. FCGs: state and 

trait anxiety are 50% (STAI Y1 mean value 42,5 ± 9,9; cut-off 40) and 41,7% (STAI 

Y2 mean value 39,1 ± 8,7; cut off 40) respectively; self reported and clinician rated 

depression are 28.3% (BDI mean value 7,3 ± 4,7; cut-off 9) and 41.7% (MDRS mean 

value 7,6 ± 5,8; cut-off 6) respectively. Data analysis underlined a positive association 

among emotional scales of patients and caregivers. Patients’ psychological aspects are 

negatively associated with caregivers’ QoL and viceversa. 

Conclusions: Anxiety and depression are often present in FCGs and cured HNC 

patients. Long term patient’s QoL is the result of a frail balance between FCG and 

patient emotional and psychological distress. A psychological support for FCG could 

improve patient wellbeing. 


1048P RADIATION-INDUCED MALIGNANCY FOLLOWING 

DEFINITIVE RADIOTHERAPY FOR NASOPHARYNGEAL 

CARCINOMA 

M. Xi, L. Zhang, M. Liu, Q. Li 

Department of Radiation Oncology, Cancer Center, Sun Yat-Sen University, 


Purpose: To analyze the clinicopathological characteristics, treatment modalities, and 

potential prognostic factors of radiation-induced malignancy (RIM) in patients with 

nasopharyngeal carcinoma (NPC). 

Methods: We reviewed institutional electronic medical records of 39,118 patients 

with NPC treated by definitive radiotherapy between February 1964 and 2003. A 

total of 228 patients with confirmed RIM were included in this study. 

Results: The median latency between radiotherapy for NPC and the diagnosis of 

RIM was 9.5 years (range, 3.1 to 30.2 years). Squamous cell carcinoma was the most 

common histologic type, followed by fibrosarcoma, osteosarcoma, and 

adenocarcinoma. Median progression-free survival and overall survival (OS) of the 

216 patients who underwent treatment were 18.7 months (95% CI, 12.8 to 24.5) and 

32.0 months (95% CI, 23.8 to 40.1), respectively. Five-year OS rates were 36.9% and 

20.2% for carcinoma and sarcoma, respectively (P = 0.004). The 5-year OS rates were 

45.4%, 21.8%, and 0% for the surgery (140 patients), radiotherapy (44 patients), and 

chemotherapy (32 patients) groups, respectively (P = 0.000). The independent 

prognostic factors associated with improved OS were histologic diagnosis of 

carcinoma and complete surgical resection. 

Conclusion: Histologic type and treatment modality were the significant prognostic 

factors for patients with RIM. Complete resection apparently offers the best chance 

for long-term survival. In select patients with locally advanced and unresectable RIM, 

reirradiation should be strongly considered as a curative option. 


1049P THE CHANGING ORAL MICROBIAL ECOSYSTEM IN OSCC 

FROM DIAGNOSIS TO RADIOTHERAPY 

S.W. Ghate 1 , A.T. Sivakumar 2 ,K.Bhat 3 , B.R. Patil 4 , M.V. Muddapur 5 

1 Oral Pathology, Hitkarini Dental College and Hospital, Jabalpur, INDIA, 2 Oral 

Pathology, S.D.M. College of Dental Sciences & Hospital, Dharwad, INDIA, 

3 Microbiology, Maratha Mandal’s Nathajirao G. Halgekar Institute of Dental 

Sciences & Research Centre, Belgaum, INDIA, 4 Surgical Oncology, Karnataka 

Cancer Treatment and Research Institute, Hubli, INDIA, 5 Statistics, Karnataka 

University, Dharwad, INDIA 

Purpose: Multiple factors influence the oral microflora (OMF) in oral squamous cell 

carcinoma (OSCC). These could range from tobacco habits to radiotherapy 

administered. A preliminary study performed in our hospital revealed the differential 

support offered by each of these factors on various microbial groups - aerobes, 

anaerobes, gram negative anaerobes (GNAB) and Candida. 

Method: The study attempts to analyse the microbial alteration so as to improve 

understanding of the possible impact that OMF could create on mucositis and other 


morbidities that radiation would leave behind. Microbial analysis of saliva samples 

was done from healthy volunteers (n = 35), tobacco chewers (n = 37) (Age & Sex 

matched), OSCC (n = 32) and during radiotherapy (n = 31) of these patients (∼ 50% 

study samples form a series). Frequency of isolation and mean colony forming units 

obtained were subjected to Kruscal - Wallis, Mann - Whitney (unpaired values) and 

Wilcoxson - signed rank test (paired values) for comparison. 

Results: No isolation of Citrobacter, Enterobacter, Proteus in normal samples and 

Corynebacteria, Staphylococcus epidermidis in study samples. Tobacco – induced 

change: Among aerobes, E. coli, Citrobacter, Proteus, Klebsiella pneumonia and 

Enterobacter increased (p < 0.05), whereas, Streptococcus pneumoniae, 

Corynebacteria, Staphylococcus epidermidis, aerobic Streptococci decrease (p < 0.05) 

significantly. Amongst the anaerobes, anaerobic Streptococci, Prevotella decreased 

while Fusobacteria, P. gingivalis increased, but, all non - significantly (p > 0.05). 

Tumor - induced change: E. coli, Enterobacter and anaerobic Streptococci, 

Fusobacteria, Prevotella (anaerobes & GNAB) significantly increased (p < 0.05). 

Radiation – induced change: Among aerobes, Streptococcus pneumoniae, 

Staphylococcus epidermidis decreased. Proteus, Klebsiella pneumoniae, Enterobacter, 

and amongst anaerobes, Streptococci increased (p < 0.05) significantly. A 

non-significant increase was noted in Fusobacteria and P. gingivalis. 

Conclusions: The study impresses on the rapidly modifying nature of OMF that 

accommodates non – residents and increasing proportions of more pathogenic 

microorganisms that may contribute to the enhanced morbidity. 


1050P WHOLE-BODY DIFFUSION MRI AND SKELETAL LESIONS IN 

THYROID CANCER: DIAGNOSTIC AND THERAPEUTIC 

IMPLICATIONS 

L. Locati 1 , R. Granata 1 , P. Potepan 2 , G. Aliberti 3 , E. Civelli 4 , P. Bossi 1 , 

E. Montin 2 , L. Licitra 1 

1 Head & Neck Unit, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, 

ITALY, 2 Department of Radiodiagnostic, Fondazione IRCCS - Istituto Nazionale 

dei Tumori, Milan, ITALY, 3 Department of Nuclear Medicine, Fondazione IRCCS - 

Istituto Nazionale dei Tumori, Milan, ITALY, 4 Department of Diagnostic Imaging 

and Radiotherapy, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, 

ITALY 

Background: Forty-fifty percent of the patients with metastatic TC suffer from bone 

metastases. 99m Tc scintigraphy is employed to assess bone lesions although it lacks of 

accuracy, mostly in lytic lesions of differentiated thyroid cancer (DTC). CT scan has 

a sensitivity of 71-100% while data on the accuracy of 18 F-FDG-PET/CT are scanty. 

MRI captures both bone and bone marrow involvement, more common in medullary 

thyroid cancer (MTC). Whole body MRI (WB) and whole-body diffusion 

(WB-DWI) are emerging as accurate tools for detection and therapy monitoring of 

bone metastases. We investigated the role of WB and WB-DWI in bone lesions from 

TC i) sensitivity and specificity; ii) evaluation of response during TKIs. 

Material and methods: Radiological records of patients with metastatic TC 

submitted to WB-DWI at the baseline staging were reviewed. For our first purpose, 

patients with at least one another bone imaging were included. A false-positive was a 

positive bone imaging not confirmed by histopathology or/and another imaging 

technique or by two imaging exams. A false-negative was a negative finding on bone 

imaging and a positive one on another imaging method plus histopathology or by 

two imaging methods. For each imaging modality, sensitivity, specificity and accuracy 

were calculated. For the secondary aim were considered only patients scanned by 

WB-DWI at baseline and during TKIs treatment. 

Results: Since 2010, nine MTC (5M/4F) and five DTC (3M/2F) patients were 

selected. Results of the first aim are listed in the table. 

WB-DWI Bone scan Bone CT 

Number of 

exams 

14 12 12 

True-positive 10 8 8 

True-negative 4 4 4 

False-positive 0 1 (MTC) 0 

False-negative 0 1 (DTC) 1 (MTC) 

Sensitivity % 100 88 88 

Specificity % 100 80 100 

Accuracy % 100 86 92 

In five (4 MTC/1 DTC) out eight (62%) true-positive bone scan, WB-DWI 

demonstrated a higher number of bone lesions. In three patients (2 MTC/1 DTC), 

WB-DWI showed a cystic evolution in the responding lesions during TKI (apart 

from the histotype). 

Conclusions: In our hands WB-DWI is the best imaging method to identify bone 

lesions from TC. It could potentially address unmet clinical and therapeutic needs 

for a reliable measure of bone lesion response in this rare tumors. 


1706P ANTI-ANDROGEN THERAPY FOR THE PATIENTS WITH 

RECURRENT AND/OR METASTATIC SALIVARY DUCT 

CARCINOMA EXPRESSING ANDROGEN RECEPTORS: A 


Y. Yajima 1 , S. Fujii 2 , T. Kobayashi 1 , H. Ishiki 1 , R. Hayashi 3 , M. Tahara 4 

1 Head And Neck Medical Oncology, National Cancer Center Hospital East, 

Kashiwa, Chiba, JAPAN, 2 Pathology, National Cancer Center Hospital East, 

Kashiwa, Chiba, JAPAN, 3 Head And Neck Surgery, National Cancer Center 

Hospital East, Kashiwa, Chiba, JAPAN, 4 Endoscopy & Gi Oncology, National 

Cancer Center Hospital East, Kashiwa, Chiba, JAPAN 

Background: Salivary duct carcinoma (SDC) is one of the WHO classified 

histological types of salivary gland tumors (SGT) and consists of less than 10% 

among all the SGT. SDC is known as highly malignant with its aggressive clinical 

course, high rate of recurrence and metastasis and 2-3 years of median survival time. 

Up-front therapy is surgery, but treatment option is quite limited when it recurs and/ 

or metastasis not being suitable for surgical resection. Androgen receptor (AR) is 

expressed in about 90% of SDC. Several reports suggest that AR would be a good 

candidate for treatment target for this entity. 

Patients and methods: We conducted a retrospective analysis in patients with AR 

positive, recurrent and/or metastatic SDC treated anti-androgen therapy in our 

institution from January 1997 and April 2012. AR positivity was defined by 

immunohistochemistry (AR441, DAKO). Anti-androgen therapy was given as a 

single agent LH-RH analogue every four weeks until disease progression or 

intolerable adverse events. Responses to anti-androgen therapy were assessed 

according to RECIST. 

Results: Eight patients were included. All were male. Median age was 57 years (range 

40-76). Primary site was parotid gland in 7 and submandibular gland in 1. Initial 

clinical stage was II in 2, IVA in 5 and IVC in 1. All patients had received surgery for 

SDC prior to anti-androgen therapy. The patterns of relapse were locoregional 

recurrence in 4 and distant metastasis in all. Median number of cycles of 

anti-androgen therapy was 4 (range 2-10). No serious adverse event was seen. The 

best responses were PR in 2 and SD in 3, and median time of response duration was 

4.6 months. After progression of anti-androgen therapy, all but one received 

chemotherapy included platinum compounds, taxanes and fluorouracil. Median 

overall survival time from receiving anti-androgen therapy was 22 months. 

Discussion and conclusion: Anti-androgen therapy was well tolerated and 

demonstrated promising clinical activity for patients with recurrent and/or metastatic 

SDC. This might delay the start of chemotherapy and provide survival benefits, and 

this approach warrants further investigation. 


1051 INDUCTION CHEMOTHERAPY (CT) WITH DOCETAXEL, 

CISPLATIN, AND FLUOROURACIL (TPF) FOLLOWED BY 

CONCOMITANT CISPLATIN PLUS RADIOTHERAPY IN 

LOCALLY ADVANCED NASOPHARYNGEAL CANCER (NPC) 

RESULTS AFTER 03 YEARS 

E. Kerboua, N. Lagha, A. Arab, S. Chami, F. Mekki, K. Bouzid 

Medical Oncology, Centre Pierre et Marie Curie, Algiers, ALGERIA 


Backround: in squamous cell carcinoma of head and neck cancer,TPF induction CT 

improved survival over cisplatin and fluorouracil (MR POSNER NEJM, vol 357 oct 

2007 ). The main objectif of this study is to evaluate the activity and safety of TPF in 

patients (pts) with locally advanced NPC followed by concomitant cisplatin plus 

radiotherapy (cCTRT). 

Methods: pts with undifferenciated NPC were enrolled from December 2006 to 

December 2010, and received 3 cycles of TPF (docetaxel 75mg/m2 day, and cisplatin 

75mg/m2 day 1, plus fluorouracil 750 mg/M2 days 1-5, every 4 wks) with G-CSF days 

1-5 post CT. Induction CT was follwed by cCTRT with cisplatin 40 mg/m2/wk and 

radiotherapy (65-70 gy) starting 4-6 wks after the third cycle of induction CT. The 

primary endpoint was overall response rate (ORR) after induction CT and after cCTRT. 

Secondary end points were toxicity, disease free survival (DFS), and overall survival (OS). 

Results: Fourty-two (42) pts with locally advanced NPC have been enrolled (26M/16F). 

UICC 1997 classification: n = 9 stage II, n = 10 stage III, n= 23 stage IV (n = 10 IVA; n = 

11 IVB). Median age is 37 yrs (range 18-64). Evocative clinical signs are cervical nodes n 

= 20, rhinologic n = 13, otologic n = 5, and neurologic n = 4. All pts were evaluated for 

safety and 38 for response. TPF was well tolerated with main toxicities grade 3-4 (WHO) 

consisting of neutropenia 36%, thrombocytopenia 23%, anemia 18%, diarrhea 6%,and 

mucositis 18%. Four pts died from sepsis that was probably treatment-related. ORR was 

90% with 71,4% (n = 27) complete response (CR) rate, 23,6% (n = 9) partial response 

(PR), and 5,2% (n = 2) stable disease. No pts progressed after induction CT. Main toxicity 

during cCTRT was neutropenia grade 3-4 in 9%, mucositis grade 3 in 45% and grade 4 

in 4%. Late toxicities were xerostomia grade 3 in 50%. At treatment completion, CR and 

PR rates were 79% and 20%; 2 pts had stable disease. At a median follow up of 36 

months (7-48), 5% of pts have shown recurrence or progressive disease. DFS and OS 

rates at 36 months were 70% and 75%, respectively. 



Conclusion: TPF followed by cCTRT appears to be an active and feasible regimen 

with an acceptable tolerability profile and may be a promising therapeutic option for 

pts with high stage NPC. 


1052 DNA-REPAIR GENE POLYMORPHISMS ASSOCIATED WITH 

FAVORABLE CLINICAL OUTCOME FOLLOWING 

CETUXIMAB-BASED THERAPY FOR ELDERLY AND 

MULTI-MORBID PATIENTS WITH PRIMARY AND RECURRENT 

SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK 

Y. Chang 1 ,N.Su 1 ,Y.Leu 2 , J. Lee 2 , C. Liu 3 , Y. Chen 4 , H. Chen 4 , I. Fang 5 , 

A. Lo 5 , R. Hsieh 1 

1 Hematology and Oncology, Mackay Memorial Hospital, Taipei, TAIWAN, 

2 Otolaryngology- Head &neck Surgery, Mackay Memorial Hospital, Taipei, 

TAIWAN, 3 Oral and Maxillofacial Surgery, Mackay Memorial Hospital, Taipei, 

TAIWAN, 4 Radiology Oncology, Mackay Memorial Hospital, Taipei, TAIWAN, 

5 Good Clinical Research Center, Mackay Memorial Hospital, Taipei, TAIWAN 

Background: Recent evidences suggest adding cetuximab to standard treatment is an 

effective option for recurrent and metastatic head and neck cancers. While 

platinum-based chemotherapy is challenging for elderly and multi-morbid patients, 

DNA-repair gene polymorphisms may help identifying patients who are more likely 

to benefit from the regimen. 

Methods: Fifty-two patients were retrospectively identified from patients with 

treatment-naïve, primary, recurrent, or metastatic squamous cell carcinoma of the 

head and neck, who had received cetuximab-based therapy during 2006 and 2011. 

Treatment response, survival, and the presence of the single nucleotide 

polymorphisms, XPD-Asp312Asn, XPD-Lys751Gln, ERCC1-C8092A, and 

XRCC1-Arg399Gln, were currently obtained for twelve patients. 

Results: Complete or partial remission was observed in all six patients (100%) who 

had one or more polymorphic variants, compared to that in three of the six patients 

(50%) who had only common alleles (one tailed Fisher’s exact test P = 0.091). Annual 

overall survival (OS) was 75.0% (median not reached), one-year progression-free 

survival (PFS) was 60.0% (median not reached) in the patients with any polymorphic 

variant, while one-year OS and PFS was 33.3% (median 11.5 months) and 16.7% 

(median 3.7 months) in the patients with only common alleles (Log-rank P = 0.321 

for OS and 0.078 for PFS). 

Conclusion: Our preliminary results suggest cetuximab might be an effective and 

safe option for elderly and patients with multiple comorbidities, especially for 

patients with DNA-repair gene polymorphic variant. Further investigation is needed 

to validate our findings and adjust for other prognostic factors. 


1053 THE USEFULNESS OF G8 EVALUATION IN THERAPEUTIC 

DECISION AND PREDICTION OF TOLERANCE IN LOCALLY 

ADVANCED OR METASTATIC SQUAMOUS CELL HEAD AND 

NECK CANCER (SCCHN) PATIENTS OLDER THAN 65 YEARS 

S.M. Ilie 1 , I. Ruginescu 2 , E. Saada 2 , F.R. Ferrand 2 , A. Schilf 2 , F. Janot 2 , 

J. Guigay 2 


Alexandru Treistoreanu, Bucharest, ROMANIA, 2 Head and Neck Cancer 

Treatment, Institute Gustave Roussy, Villejuif, FRANCE 

Background: 2/3 of H&N cancer patients are locally advanced or metastatic and 20% 

are older than 65. Those not amenable to radiation or surgery, must be treated 

evaluating their biological age. The current standard is Erbitux based chemotherapy 

and there are not enough dates about the tolerance for aged pts. G8 was validated 

like tool in geriatric oncology but the presence of swallowing difficulties and weight 

loss in most of HNC patients may alter its usefulness in this population. 

Objective: evaluate prospectively the G8 score and to report to the incidence and 

degree of chemotherapy toxicities. 

Methods: Prospective study of SCCHN patients over 65 years old, addressed from 

January to April 2012 to the Department of Head & Neck Cancer of Gustave Roussy 

Institute. Parameters studied: G8 score; age, TNM, histology, nutritional status, ACE 

-27 index, toxicity of treatment. 

Results: We studied 21 patients: 9 pts (42%) less than 70, 4 pts (19%) between 

70 -75 and 7 pts (33%) over 75, mostly locally advanced, squamous histological 

type; denutrition in 9 pts (42%) 2 over 75 years; 33% had swallowing problems 

and 25% loss weight superior of 10% in the last 3 months before treatment. 

ACE 27 index was over 2 for 18 (85%) patients.We found a G8 score < 14 for 9 

(42%), of whom 8 aged over 70 years, 7 with denutrition, 5 with ACE 27 at 

3. 16 patients (47%) were treated with Cetuximab based chemotherapy. The 

mostly observed toxicities were cutaneous with 3 grade 3 and 1 grade 4, 41% 

hematological and g-I from whome only 4 pts (19%) degree 3 or 4. One toxic 

death was observed. 12 pts were evaluated and 4 (33%) were in PR, 5 (41%) 

were SD and only 3 (25%) were in progression. 

Conclusions: this preliminary prospective study demonstrates that G8 score identify 

frailty in 42% of elderly SCCHN patients older than 65 years. An adapted tool for 

geriatric asessement in SCCHN patients seems necessary. 


1055 EFFICACY OF MYOFIBROBLASTS AS AN INDICATOR FOR 

INVASION AND NODAL METASTASIS IN OSCC 

A.T. Sivakumar 1 ,P.Sowmya 2 , B.M. Jyothi 2 , M.V. Muddapur 3 

1 Oral Pathology, SDM College of Dental Sciences & Hospital, Dharwad, INDIA, 

2 Oral Pathology, SDM College of Dental Sciences, Dharwad, INDIA, 3 Statistics, 

Karnataka University, Dharwad, INDIA 

Purpose: Tumour cells work in close coordination with stromal elements from its 

stage of initiation to metastasis. Oral squamous cell carcinoma (OSCC) is one of the 

top ten cancers in the world with only survival rate of 56%. Myofibroblasts (MF), a 

cell that is identified transiently in the wounds have also been shown in tumor 

stromogenesis in a variety of malignancies. MFs been highlighted for their 

proinvasive role in tumors. These cells remain less explored in OSCC in terms of 

invasion and nodal metastasis – Prognosticators. 

Method: The study was aimed towards understanding the possibility of MF being an 

indicator of invasion and nodal metastasis. This was achieved through assessing the 

presence and distribution pattern of MF in OSCC using α-SMA. To improve further 

our understanding a semiquantative analysis (0= No staining, 1= Focal Positivity, 2 = 

Multifocal Positivity) was performed and compared with that from normal mucosa 

(NM, number of cases (n) =10), chronic inflammatory lesions (CIL, n= 22), surgical 

margins of OSCC patients (SM, n = 24) and pN0, pN+ OSCC samples (n = 56, 28 

each). Mann-Whitney test was applied. 

Results: No MFs were present in NM and SM. 84% and 32% of OSCC and CIL 

showed MFs respectively. Heterogenous pattern (Presence/absence in a location, 

Loose/Syncitial arrangements, and Focal/Multifocal distribution) of MFs was seen in 

OSCC while they were seen closer to the center of the lesion away from the 

epithelium in CIL. Lesions reported for longer duration showed MF in CIL. The MFs 

were not seen in all the invasive fronts. Significant difference in the number of MFs 

was observed between NM and OSCC (p = 0.00), CIL and SM (p = 0.003), CIL and 

SCC (p = 0.00), SM and OSCC (p = 0.00). 

Conclusion: MF formation and its retention seems to be influenced by duration 

(reactive lesions), and basement membrane invasion with stressed extracellular 

matrix (OSCC). Stress-dictated distribution patterns may prove valuable in 

distinguishing pN0 and pN+ groups. Smaller incisional biopsies may not be useful in 

predicting both invasion and nodal metastasis either by quantitation or by 

distribution pattern analysis owing to the heterogeneity that is displayed. 


1056 TREATMENT FAILURE IN HIGH-RISK HEAD AND NECK 

CANCER TREATED WITH ADJUVANT CHEMORADIATION 

S. Torres, M.T. Marques, M. Ferreira, I. Sargento, E. Netto, J. Oliveira, 

M. Roldão, A. Moreira 

Medical Oncology, Instituto Portuguès de Oncologia de Lisboa Francisco Gentil, 

E.P.E. (IPOLFG EPE), Lisboa, PORTUGAL 

Background: Adjuvant chemoradiation (adCRT) is the standard of care in 

resectable high-risk head and neck squamous cell carcinoma (HNSCC). We 

select patients (pts) for adCRT if they are physically fit and have at least 1 

major (extra-capsular nodal spread or positive resection margins) and/or 2 

minor (pT4, pN2, perineural or vascular invasion) high risk pathological factors. 

Loco-regional control and disease-free survival (DFS) are good and the toxicities 

manageable. The aim of our study was to evaluate the patterns of treatment (tt) 

failure with this therapy. 

Methods: We reviewed the charts of all pts with resected high-risk HNSCC treated 

with adCRT, from 2007 to 2011. Pts and disease characteristics, compliance to tt, 

date and first site of tt failure and disease status at last follow-up (FU) were reviewed. 

Overall survival (OS) and DFS were estimated using Kaplan-Meier method. 

Results: 221 consecutive pts were included, 93.6% male, median age 52 years. The 

incidence of stage IV A−B disease (72.8%) and major high risk pathological features 

such as involved surgical margins (50.6%) and extranodal spread of the disease 

(52.0%) was high. Compliance to tt was good with 94.5% of pts completing at least 2 

cycles of chemotherapy. There were no toxic deaths. With a median FU of 18.8 

months, 57 pts (25.8%) experienced disease recurrence. Local or regional recurrence 

as the first site of tt failure occurred in 25 pts (11.3%) and distant metastasis (mets) 

occurred in 32 pts (14.5%). The most common site of metastatic disease was the lung 

(26 pts; 11.7%). Lung recurrence occurred at a median FU of 8 months. Nine pts 

(4%) recurred with lung mets less than 6 months after the end of adCRT. Five pts 

were diagnosed of primary lung cancer during FU. At last FU 175 pts (79.2%) were 

alive; 154 (69.9%) in complete remission. The Kaplan-Meier estimates of 3-year OS 

and DFS were 68% and 59%, respectively. 


Conclusions: Through adequate selection of pts and supportive measures, high tt 

compliance and manageable toxicity of adCRT are achieved. The observed early 

recurrence in a small number of pts, mainly in the lung, might suggest that more detailed 

pretreatment staging and FU evaluation for early lung disease detection are warranted. 


1057 PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF 

5-FLUOROURACIL IN CHINESE HEAD AND NECK CANCER 

(HNC) PATIENTS 

L. Zhao 1 ,W.Liu 2 , X. Guo 2 , C. Zhao 2 , Y. Huang 2 ,F.Xu 2 , L. Zhang 2 

1 Department of Medical Oncology, Cancer Center of Sun Yat-Sen University, 

Guangzhou, CHINA, 2 Medical Oncology, Sun Yat-Sen University Cancer Center, 


Background: Pharmacokinetic (PK) variability of 5-fluorouracil (5-FU) has been 

demonstrated for +30 years and a significant link between exposure and therapeutic 

response has been identified. A maximum tolerated exposure (MTE) from the area 

under curve (AUC) has been characterized for various regimens and therapeutic dose 

management (TDM) has been used to optimize dosing. 

Objective: The objective of this study was to characterize the PK variability of 5-FU 

in the Chinese HNC population and examine the relationship between AUC, toxicity 

and efficacy. The 5-FU MTE in this population was compared with MTE identified 

for European HNC patients. 

Methods: 89 treatment naïve patients with HNC were administered cisplatin (80mg/ 

m 2 , d1) and 5-FU (4g/m 2 , 120h IV). Blood samples were collected at steady state 

after the first 18h of 5-FU infusion. Plasma was analyzed by a 5-FU immunoassay 

and AUC was calculated. Relationship between 5-FU AUC and 5-FU related 

toxicities was examined. Preliminary efficacy results were evaluated for 5-FU related 

toxicity. 

Results: The patient 5-FU AUC values varied widely: from 15 to 103 mg · h/L. 33% 

of patients were within the target range of 25-35 mg· h/L; 18% were below and 49% 

were above . Toxicity was recorded for 89 patients. Among the 44 patients with AUC 

above the target range, severe mucositis or mylesupression was experienced by 32 

patients. By comparison, among the 45 patients within or below target range, only 3 

experienced severe toxicities. ROC analysis for 5-FU AUC and severe mucositis 

identified a cut-point of 36 mg· h/L (p < 0.0001). These results are listed in the table 

below. 

Incidence of severe mucositis and myelosuppression with 5-FU AUC 

AUC ≤35 mghr/L >35 mghr/L 

Grade 3 3% 36% 

Grade 0 - 2 47% 13% 

Conclusion: Results of this study demonstrate wide PK-variability of 5-FU exposure 

and a significant relationship between severe toxicity and AUC in HNC cancer 

patients. The study confirms that the MTE in this population is similar to a 

European HNC population treated with cisplatin/5-FU. TDM using the target range 

of 25-35 mg· h/L may have benefit in lowering toxicity in HNC patients. 


1058 CISPLATIN + VINORELBINE (DDP + VNB) ADMINISTERED IN 60 

CASES OF RECURRENT/METASTATIC SALIVARY GLAND 

MALIGNANCIES (RMSGM): FINAL REPORT 

O. Ostellino 1 , M. Airoldi 1 , M. Garzaro 2 , F. Pedani 1 , L. Raimondo 2 , G. Riva 2 , 

S. Carnio 1 , G. Pecorari 2 , G. Fora 1 , C. Giordano 2 

1 Medical Oncology Division - Medical Oncology Department, San Giovanni 

Battista Hospital, Turin, ITALY, 2 1st Ent Division - Physiopathology Department, 

University of Turin, Turin, ITALY 

Background: RMSGM are not amenable to the usual treatment with surgery and 

post-operative radiotherapy. The role of chemotherapy (CT) for RMSGM is palliative 

only. VNB showed moderate activity in our experience (Bull Cancer 85:892; 1998) 

and in a randomized phase II trial we had demonstrated that the DDP + VNB 

combination had a better outcome than VNB alone (Cancer 91:541; 2001). In this 

abstract we report the final results of this combination in 60 cases. 

Methods: From April 2001 to February 2009, 60 cases with RMSGM were enrolled. 

All patients received the following regimen: DDP 80 mg/sm d.1 + VNB 25 mg/sm d. 

1,8 every 3 weeks. The study foresees a maximum of 6 cycles. 

Results: Patients characteristics were as follows: 35 males (58%) and 25 females 

(42%); median age: 56 yrs (range 20-68); median ECOG PS: 1 (0-2); histology: 

adenocarcinoma 15 (25%), adenoid cystic ca. 34 (57%), others 11 (18%); site of 

disease: local 30 (50%), mts +/- local 30 (50%). Forty-two pts received DDP + VNB 

as first line CT (70%) while 18 pts (30%) had the combination as second-line CT 

(30%). After a median of 5 cycles of first line DDP + VNB responses were: 3 CR 

(7%), 10 PR (24%), 14 NC (33%) and 15 PD (36%). After a median of 4 cycles of 


second line CT responses were: 0 CR; 1 PR (5%), 6 NC (33%) 11 PD (62%). Median 

survival: 10 months (3-29) for first line CT; 4 months (1-12) for second line CT. 

G3-4 toxicity: neutropenia (20%), anemia (12%), nausea/vomiting (12%), peripheral 

toxicity (3%). 

Conclusions: DDP + VNB is an effective first line CT in RMSGM; second line CT 

has a low palliative activity. Toxicity seems acceptable. This regimen could be 

suitable for an integration with new biologic target agents. 


1059 ANTI OXIDANT CAPACITY OF CALENDULA OFFICINALIS 

FLOWERS EXTRACT AND PREVENTION OF RADIATION 

INDUCED OROPHARYNGEAL MUCOSITIS IN PATIENTS WITH 

HEAD AND NECK CANCERS: A RANDOMIZED CONTROLLED 

CLINICAL STUDY 

D. Moslemi 1 , N. Babaee 2 , A. Moghaddamnia 3 , G. Mazdai 4 

1 Biochemical, Babol University of Medical Sciences, Babol, IRAN, 2 Department 

of Oral Diseases, Babol University of Medical Sciences, Babol, IRAN, 

3 Department of Pharmacology, Babol University of Medical Sciences, Babol, 

IRAN, 4 Radiation Oncology, Laleh hospital, Tehran, IRAN 

To determine the effect of Calendula officinalis flower extract mouthwash as gel 

formulation on radiation-induced oropharyngeal mucositis (OM) in patients with 

head-and-neck cancer. Forty patients with neck and head cancers who were treated 

with radiotherapy or chemoradiotherapy were randomly assigned to receive either 2% 

calendula extract mouthwash or placebo (20 patients in each group). The subjects 

were treated with telecobalt radiotherapy at conventional fractionation (2 Gy/fraction, 

five fractions weekly, 20–35 fractions within 4–7 weeks). Oropharyngeal mucositis 

was evaluated by two doctors (a radiation oncologist and a dentist), using the oral 

mucositis assessment scale (OMAS). The patients also received concurrent 

chemotherapy. Calendula mouthwash significantly decreased the intensity of OM 

compared to placebo at week 2 (score: 5.5 vs. 6.8, p = 0.019), week 3 (score: 8.25 vs. 

10.95, p < 0.0001) and week 6 (score: 11.4 vs. 13.35, p = 0.031). Total antioxidant, 

polyphenol and flavonoid contents and quercetin concentration of the 1% extract 

were 2353.4 ± 56.5 µM, 76.66 ± 23.24, 313.40 ± 6.52 mg/g and 19.41 ± 4.34 mg/l, 

respectively. Calendula extract gel could be effective on decreasing the intensity of 

radiotherapy- induced OM during the treatment and antioxidant capacitiy may be 

partly responsibe for the effect. 


1060 HORIZONTAL LATERAL THYROIDECTOMY-“THOMAS 

TECHNIQUE”A NOVEL SURGICAL APPROACH TO THYROID 

NEOPLASMS 

T. Varughese 

Surgical Oncology and Reconstructive Surgery, Lakeshore Hospital and Reserch 

Center, Cochin, INDIA 

Background: Kochers’ anterior approach is the universal standard for thyroidectomy 

but with several complications. Feasibility of horizontal lateral thyroidectomy 

(Thomas’ Technique,) based on 3 D volumetric anatomy is a novel concept to 

minimize complications to the superior, Recurrent Laryngeal nerves, Para thyroids 

and vessels which are posterior and lateral. Unique anatomy of platysma, 

safeguarding of sub platysmal venous plexus and investing layer of deep fascia in 

relation to Cosmetic outcome is highlighted. 

Objectives: This feasibility study was designed to avoid all the known complications 

of thyroidectomy and an unaesthetic anterior scar. 

Methods: Superior results from the pilot study, prompted to extend the study for the 

next 2 years.Of 283 subjects thus enrolled, 231 were females and 52 males. 118 had 

benign disease out of which 75 were MNGs, 31 adenomas and 9 cysts. Out of 165 

Cancers, 160 were differentiated (96papillary, 44 follicular, 20 mixed and 5 

medullary).18 had intra thoracic extensions. Using single ipsilateral incision 40 hemi 

thyroidectomies, 70 total thyroidectomies of benign and 55 total thyroidectomies of 

early cancers were done. Bilateral approach used in 110 cases of carcinomas 

requiring bilateral node dissection and for 8 benign cases of bilateral intrathorasic 

extensions. Para thyroids were dissected pulverized and injected into 

Sternocleidomastoid muscle before dissection if required. 

Results: Blood loss was 10-15 ml and hospital stay 24 hrs. There were no nerve 

injuries. Parathyroid deficiency was reported in 10/283. 165 thyroidectomies (115 

totals) were performed with single lateral incision. Within 6 months scar 

disappeared, touch sensations returned to normal. Cosmesis and quality of life were 

excellent. 

Conclusions: “Horizontal lateral thyroidectomy”–”Thomas technique”, is a novel 

method applicable for all thyroid neoplasms. Avoidance of “handling” of the gland 

upfront, direct vision of nerves, and ligation of vascular pedicles upfront leading to 

an avascular gland makes this approach unique and “bloodless”. It facilitates better 

lymph adenectomy and is safest for hemi as well as Total thyroidectomy and for 



intrathorasic extensions. Complications described in the literature are minimised. 

Superior cosmetic results compared to Kocher’s technique. 


1061TiP FIRST-IN-MAN PHASE I STUDY OF TPCS2A-BASED 

PHOTOCHEMICAL INTERNALISATION (PCI) OF 

BLEOMYCIN IN LOCALLY RECURRENT OR ADVANCED/ 

METASTATIC, CUTANEOUS OR SUBCUTANEOUS 

MALIGNANCIES 

M. Forster, A. Sultan, W. Jerjes, C. Simeon, S. Morley, D. Carnell, C. Hopper 

Head and Neck, University College London Hospital, London, 


Objective: PCI is a novel technique in which chemotherapeutic cytotoxicity is 

enhanced with a photosensitiser and light exposure. This dose-escalation study 

assessed the safety and tolerance of TPCS 2a (tetraphenyl chlorin disulphonic acid, 

Amphinex®) in bleomycin PCI, pharmacokinetic profiles, and determined the 

maximum tolerated dose (MTD). 

Method: Cohorts of 3 to 6 patients were enrolled and the TPCS2a dose escalated by a 

pre-specified amount until dose-limiting toxicity (DLT) occurred in at least two 

patients (≥33%). Patients received TPCS2a at a starting dose of 0.25mg/kg. Four days 

later they received bleomycin (15,000IU/m 2 IV) and after 3 hours red light laser 

(652nm) was applied to target lesions for 600 seconds to initiate a therapeutic 

response. Patients were followed for 3 months. 

Results: Nineteen patients were enrolled: 4 with cutaneous breast cancer, 13 

squamous cell carcinoma (SCC) of head and neck and other regions, 2 other cancers. 

17/19 patients experienced 94 AEs, most commonly pain, photosensitivity and 

nausea. Most (83%) were mild or moderate. Fourteen episodes of pain (3 severe) 

were treatment-related. Mean patient-reported pain using a VAS scale declined from 

4.9 to 1.3 24 hours after treatment. Four patients experienced skin photosensitivity 

reactions; 3 were in the highest dose cohort. 10/19 patients experienced 15 serious 

adverse events: 3 (swelling, and blistering of hands, tongue oedema) were probably 

related to treatment. The MTD of TPCS 2a was found to be 1.5mg/kg. At day 28, 11/ 

16 patients had a complete response (CR) in target lesions, 2 had a partial response 

(PR), 2 had stable disease (SD) and 1 had progressive disease (PD). At last visit there 

were 8 CRs, 2 PRs, 2 SDs and 2 PDs. During the course of the study four patients 

died (no relation to treatment) and six were withdrawn prematurely. 

Conclusion: With appropriate analgesia and anaesthesia TPCS 2a-based PCI of 

bleomycin was well tolerated in these patients with locally advanced cancer. 

Treatment-related AEs were as expected and can be managed. Preliminary 

efficacy data are very encouraging and a phase II study in HNSCC has just 

begun. 



abstracts 

hematological malignancies 

1062O A NATIONWIDE SURVEY OF ADULT T-CELL LEUKEMIA/ 

LYMPHOMA (ATL) NEWLY DIAGNOSED OVER THE LAST 

DECADE IN JAPAN 

H. Katsuya 1 , K. Ishitsuka 1 , A. Utsunomiya 2 , S. Hanada 3 , T. Eto 4 , Y. Moriuchi 5 , 

Y. Saburi 6 , T. Yamanaka 7 , J. Suzumiya 8 , K. Tamura 1 

1 Department of Medicine, Division of Medical Oncology, Hematology and 

Infectious Diseases, Fukuoka University, Fukuoka, JAPAN, 2 Hematology, 

Imamura Bun-in Hospital, Kagoshima, JAPAN, 3 Hematology, National Hospital 

Organization Kagoshima Medical Center, Kagoshima, JAPAN, 4 Hematology, 

Hamanomachi Hospital, Fukuoka, JAPAN, 5 Hematology, Sasebo City General 

Hospital, Sasebo, JAPAN, 6 Hematology, Oita Prefectural Hospital, Oita, JAPAN, 

7 Research Center for Innovative Oncology, National Cancer Center Hospital East, 

Kashiwa, JAPAN, 8 Cancer Center, Shimane University, Izumo, JAPAN 

Introduction: ATL is a malignancy of mature T-lymphocytes caused by human 

T-lymphotropic virus type I (HTLV-1), and it is classified into 4 clinical subtypes, 

i.e. acute, lymphoma, chronic, and smoldering type according to the analysis of the 

former nationwide survey performed in late 80’s. During the 2 decades after this 

analsysis, treatment for ATL has improved, e.g. intensive sequential combination 

chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). We 

therefore performed a nationwide survey to know the outcome of ATL patients newly 

diagnosed during the last decade. 

Patients and methods: The clinical data was collected retrospectively from the 

medical record of patients who were diagnosed as ATL between 2000 and 2009 in 

participating institutions. Approval of this study was obtained from the Ethics 

Committee and Institutional Review Board of Fukuoka University where the central 

office is located and at each participating center based on their institutional policies. 

Results: A total of 1552 patients’ survey form was submitted from 81 institutions 

across Japan. Fifty-four patients were excluded due to missing data, and the 

remaining 1498 were analyzed. The median survival time (MST) of 897 for acute 

type and that of 355 for lymphoma type were 8.3 and 10.6 months, and overall 

survival (OS) rates at 5 years were 9% and 13%, respectively. Fifty % of patients had 

received CHOP/CHOP-like regimen, 31 % had VCAP-AMP-VECP regimen, and 

single agent was used in 6% of the patients. The number of patients with allogeneic 

HSCT was 227 (46% from a sibling donor and 51% from an unrelated donor), a half 

of them were transplanted at first remission. The MST and OS at 5 years from 

transplantation were 5 months and 25%, respectively. The MST of 172 for chronic 

and that of 74 for smoldering type were 30.3 and 36.7 months, respectively. 

Conclusion: The prognosis of acute and lymphoma type was still poor despite the 

recent progress in treatment modalities, and it is of disappointment that their 

therapeutic outcome was not remarkably improved as compared to former survey. It 

is also a surprise that the prognosis of smoldering type is not good as expected from 

the previous survey. To note, 25% of patients who underwent transplantation 

experienced a long survival, but it should be validated by the prospective study. 


1063O SEQUENTIAL THERAPY WITH BRENTUXIMAB VEDOTIN IN 

NEWLY DIAGNOSED PATIENTS WITH SYSTEMIC 

ANAPLASTIC LARGE CELL LYMPHOMA 

M. Fanale 1 , R. Advani 2 , N.L. Bartlett 3 , A. Davies 4 , T. Illidge 5 , D.A. Kennedy 6 

,A.R. Shustov 7 

1 Lymphoma/myeloma, University of Texas, MD Anderson Cancer Center, 

Houston, TX, UNITED STATES OF AMERICA, 2 Medicine, Stanford University 

Medical Center, Palo Alto, CA, UNITED STATES OF AMERICA, 3 Medicine, 

Washington University School of Medicine, St. Louis, MO, UNITED STATES OF 

AMERICA, 4 Medical Oncology, University Hospitals Southampton, Southampton, 

UNITED KINGDOM, 5 Medical & Human Sciences, University of Manchester 

Christie Hospital NHS, Manchester, UNITED KINGDOM, 6 Clinical Affairs, Seattle 

Genetics, Inc., Bothell, WA, UNITED STATES OF AMERICA, 7 Division of 

Hematology, University of Washington Medical Center, Seattle, WA, UNITED 


Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by 

a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin 

E (MMAE). In a pivotal phase 2 study in patients (pts) with relapsed/refractory 

systemic anaplastic large cell lymphoma (sALCL), objective response rate was 86% 



and median duration of response was 12.6 months. A phase 1, open-label, 

multicenter study was implemented to determine the safety and activity of sequential 

and combination treatment approaches of brentuximab vedotin with CHOP or CH-P 

chemotherapy in newly diagnosed pts with CD30-positive mature T- and NK-cell 

lymphomas (ClinicalTrials.gov NCT01309789). This abstract presents data from Arm 

1 of the study, which employs sequential treatment in sALCL pts. Single-agent 

brentuximab vedotin (1.8 mg/kg) was administered q3 wks as a 30-minute outpatient 

IV infusion for 2 cycles prior to up to 6 cycles of CHOP. Pts in complete or partial 

remission (CR, PR) following CHOP were eligible to continue single-agent 

brentuximab vedotin up to 16 total cycles. Investigator-evaluated response 

assessments utilize the Revised Response Criteria for Malignant Lymphoma (Cheson 

2007). All 13 pts in Arm 1 had sALCL; 10 had ALK- and 3 had ALK+ disease. 9 

were male. Median age was 62 years (range, 23-81). The most common (≥6 pts) 

AEs, regardless of severity, were nausea, peripheral sensory neuropathy, and 

vomiting. The most common (>1 pt) Grade 3/4 AEs were anemia, fatigue, and 

peripheral sensory neuropathy; all have improved or resolved. Thus far, no pts had a 

Grade 5 AE or discontinued due to an AE. All 13 pts were evaluable at Cycle 2 and 

achieved remission after single-agent brentuximab vedotin (5 CR, 8 PR). Following 

CHOP, 10/12 evaluable pts maintained remission (7 CR, 3 PR). 2 pts with PR after 

single-agent brentuximab vedotin experienced PD on CHOP treatment. 3 pts have 

completed 16 cycles of therapy, all in CR. Sequential therapy with brentuximab 

vedotin was generally well tolerated and all pts achieved remission after 2 cycles of 

single-agent therapy. The level of activity observed in newly diagnosed pts with this 

aggressive lymphoma is promising; a phase 3 randomized study is in development. 

Disclosure: M. Fanale: I have acted as a consultant for and served on Advisory Board 

for Seattle Genetics, Inc. I have received honoraria and travel expenses from 

SeattleGenetics, Inc. Seattle Genetics, Inc. has provided research funding to my 

institution.R. Advani: I have served on scientific advisory boards for Seattle Genetics, 

Inc., Celgene, and Allos Therapeutics. My institution has received research funding from 

Seattle Genetics, Inc., Abbott, Genentech, Pharmacyclic, and Allos Therapeutics.N.L. 

Bartlett: I have acted as a consultant to Seattle Genetics, Inc., and have been reimbursed 

for travel expenses by Seattle Genetics, Inc. My institution has also received research 

funding from Seattle Genetics, Inc.A. Davies: I have served on a scientific advisory 

board for Seattle Genetics, Inc. My institution has also received research funding from 

Seattle Genetics, Inc.T. Illidge: I have acted as a consultant to Seattle Genetics, Inc. and 

Millennium/Takeda. I have received honoraria from Millennium/Takeda. My institution 

has received research funding from Seattle Genetics, Inc.D.A. Kennedy: I am an 

employee of and have equity ownership in Seattle Genetics, Inc. A.R. Shustov: I have 

acted as a consultant to Seattle Genetics, Inc. I have received honoraria from 

Millennium. My institution has received research funding from Seattle Genetics, Inc. 

1064O IMPACT OF NUMBER OF PREVIOUS TREATMENT LINES 

AND PRE-TREATMENT WITH BORTEZOMIB OR 

LENALIDOMIDE ON EFFICACY OF 

BORTEZOMIB-BENDAMUSTINE-DEXAMETHASONE (BBD) IN 

PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE 

MYELOMA (MM) 

H. Ludwig 1 , H. Kasparu 2 , C. Leitgeb 1 , R. Greil 3 , E. Rauch 1 , W. Linkesch 4 , 

N. Zojer 1 , L. Pour 5 , M. Fillitz 6 , Z. Adam 5 

1 1st Department of Medicine, Wilhelminenspital, Wien, AUSTRIA, 2 Department of 

Internal Medicine, Hospital Elisabethinen, Linz, AUSTRIA, 3 IIIrd Medical 

Department With Hematology and Oncology, Paracelsus Medical University, 

Salzburg, AUSTRIA, 4 Hematology, Medical University Graz, Graz, AUSTRIA, 

5 Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, 

CZECH REPUBLIC, 6 Internal Medicine III, Hanusch Hospital, Wien, AUSTRIA 

Introduction: The number of previous treatment lines and pre-treatment with 

Bortezomib (B) or lenalidomide (L) likely impacts the efficacy and tolerance of BBD 

in r/rMM. 

Patients and methods: 71 pts with r/rMM have been enrolled. Median age: 65 yrs 

(range 40-86), male/female: 32/39, ISS stage I/II/III: 22, 29, and 20 pts, respectively. 

ECOG status 0/I/II: 37, 31, and 3 pts, respectively. Previous treatment lines: 1-2: 44, 

3-6: 27 pts, 43 pts had previously been exposed to B and 37 to L. Full data 

documentation for response evaluation (≥2 cycles) is available for 65 pts. 

Treatment: Benda 70 mg/m2 day 1 + 4, B 1.3 mg/m2 and Dex 20 mg on days 1, 4, 8 

and 11, q 4 wks. Planned number of treatment cycles was 8, with discontinuation after 4 

cycles in case of no response. K-M survival curves were compared using the log-rank test. 

Results: After a median follow up of 7.1 mos, myeloma response (ORR: CR-PR) was 

noted in 38 (58.5%), CR/nCR in 11 (16.9%), VGPR in 10 (15.4%), PR in 17 (26.2%), 

MR in 11 (16.9%), and SD in 16 (24.6%) pts. Median time to response was 77 days. 

Tab 1 shows response rates and PFS in pts in regards to number of previous 




treatment lines and pre-exposure to B, L, and to both B and L. Median OS was not 

reached in any of the cohorts. 

All Pts 

1-2 

Treatment 

lines 

3-6 

Treatment 

lines 

Pre-exposure 

B L B and L 

ORR (%) 58.5% 61% 54% 76% 60% 44% 

PFS (mos) 12.2 13.0 7.8 12.2 5.9 6.0 

G4 anemia, leucopenia and thrombopenia were reported in < 5%. Incidence of G3-4 

infections and GI toxicities was low. G1-2 PNP was documented in 18% of pts at 

baseline and remained constant in almost all pts with only 3 developing G3 PNP and 1 

G4 PNP. Univariate analysis employing age, FISH ISS, ß2M, LDH, Hb, and 

pre-treatment with either B or L or both revealed a significant negative correlation 

between combined L and B pre-treatment and ORR (p < 0.02), which in multivariate 

analysis also proved to be independently associated with ORR (p < 0.02). Conclusio: 

The BBD regimen resulted in remarkable response rate and PFS in the entire cohort of 

pts and in those pre-exposed to B. Pre-treatment with both B and L was associated with 

lower response rates and significantly shorter PFS. Median OS was not reached in the 

total cohort or in any of the subgroups. The regimen was well tolerated. 

Disclosure: H. Ludwig: Received honoraria for speakers bureau from Mundipharma, 

Celgene and Janssen-Cilag. Scientific research grants from Mundipharma and 

Janssen-Cilag. All other authors have declared no conflicts of interest. 

1065O COMORBIDITY INDEX IN ELDERLY MYELOMA PATIENTS: 

DOES IT AFFECT CLINICAL OUTCOMES? 

S. Kim 

Medicine, Samsung Medical Center, Seoul, KOREA 

Background: Multiple myeloma occurs mainly in elderly patients older than 60-70 years. 

Considering high prevalence of comorbid conditions in these age groups, comorbidity 

may be an important issue in the management of myeloma. However, the effect of 

comorbidity index on clinical outcome of elderly myeloma patients is not clear, and there 

is few data analyzing the association between comorbidity and prognosis of myeloma. 

Methods: We retrospectively analyzed patient aged ≥ 65 years with symptomatic 

myeloma. All patients were newly diagnosed and not eligible for undergoing 

autologous stem transplantation. Comorbidity was assessed at the time of diagnosis 

according to the Charlson Comorbidity Index (CCI). 

Results: 132 patients were analyzed in this study, and their median age was 71 years 

(range: 65-92 years) and median follow-up duration was 20 months. Approximately a 

half of patients (48.5%) had disorders other than myeloma at diagnosis. Diabetes 

mellitus was the most frequent comorbid disorder (n = 22, 16.7%). The range of CCI 

score was from 0 to 6. Thus, we classified three groups according to the value of CCI 

score (0, 1-2, 3-6). When overall survival was compared, the CCI-based classification 

failed to show a significant survival difference (p = 0.456) although the median 

survival of each group was as follows: 42.6, 34.1, and 25.3month, respectively). Its 

relationship with age and performance state was not significant, either (p = 0.151, 

0.537). In accordance with this, the frequency of treatment-related complication was 

also similar among them (p = 0.737). 

Conclusions: These results suggest that comorbidity does not affect survival and 

complications in elderly myeloma patients. Therefore, comorbid disorders may not 

become a huddle for deciding active treatment in elderly myeloma patients. 


1066PD OVEREXPRESSION OF ENHANCER OF ZESTE HOMOLOG 2 

IS ASSOCIATED WITH CLINICAL OUTCOME IN ACUTE 

MYELOID LEUKEMIA PATIENTS 

P. Lin 1 ,S.Yeh 2 , L. Bai 2 , C. Lin 2 , C. Chiu 2 

1 Medical Genetics and Internal Medicine, Division of Hematology/Oncology, China 

Medical University Hospital, Taichung City, TAIWAN, 2 Internal Medicine, Division 

of Hematology/Oncology, China Medical University Hospital, Taichung, TAIWAN 

Background: Enhancer of zeste homolog 2 (EZH2), a subunit of polycomb repressive 

complex 2 functioned as methyltransferase causing trimethylation at lysine-27 of 

histone 3, is involved in stem cell regulation and various cancers. It was reported two 

faces that both increased expression and mutation/deletion were implicated in cancer 

development and progression of different malignancies. For acute myeloid leukemia 

(AML), the clinical significance of EZH2 was not explored. In this study, we 

examined EZH2 expression and mutation and evaluated the association between 

EZH2 and patient survival. 

Methods: A total of 105 patients, who were newly diagnosed as de novo AML and 

received intensive chemotherapy between 2004 January and 2010 December, were 

retrospectively analyzed. All patients received French-American-British (FAB) 

classification, karyotype analyses, immunophenotyping, detection of NPM mutation 

and FLT3 internal tandem duplication (FLT3/ITD). The mutation of EZH2 was 

identified by direct sequencing. An immunohistochemical analysis of EZH2 was 

performed on bone marrow biopsy samples, and overexpression was defined as more 

than 50% positive staining among the leukemic marrow. 

Results: EZH2 overexpression was identified in 57 patients (54.3%), and no 

associated with age, gender, FAB classification, karyotype, FLT3/ITD and NPM 

mutation. Only two mutations were detected in this cohort. Patients with EZH2 

overexpression had a significant shorter median overall survival (OS; 18.5 vs 40.7 

months, p = 0.047) as well as a higher trend of relapsed/refractory disease (47.9% vs 

66.7%, p = 0.052). Karyotype and FLT3/ITD were also the significant prognostic 

factors for the entire cohort and NPM mutation was a trend of favorable prognostic 

factor in intermediate-karyotype patients by univariate analysis. We defined a 

prognostic classification based on these four factors that was able to classify patients 

into four risk groups showing significant different survivals (median OS: not reached, 

not reached, 22.0 and 10.6 months, respectively; p < .0001) and probabilities of 

disease relapsed/refractory (p = 0.048). 

Conclusion: EZH2 overexpression is a novel poor prognostic biomarker in AML 

patients. The current result indicated that EZH2 expression status may be 

incorporated into prognostic classification. 


1067PD HIGH CO-EXPRESSION OF CD135 AND CD117 PREDICTS 

POOR OUTCOME IN ACUTE MYELOID LEUKEMIA: A 

PROSPECTIVE STUDY 

S.K. Sharawat 1 , R. Gupta 2 , V. Sreenivas 3 , V. Raina 4 , L. Kumar 1 , A. Sharma 1 , 

R. Bakhshi 5 , S. Iqbal 1 , S. Bakhshi 4 

1 Medical Oncology, All India Institute of Medical Sciences, New Delhi, INDIA, 

2 Lab Oncology, All India Institute of Medical Sciences, New Delhi, INDIA, 

3 Biostatistics, All India Institute of Medical Sciences, New Delhi, INDIA, 4 Medical 

Oncology, Bhim Rao Ambedkar IRCH, New Delhi, INDIA, 5 University of Delhi, 

Rajguru College of Applied Sciences, New Delhi, INDIA 

Background: The significance of the mutations in FLT3 and c-kit genes in AML has 

been well established but the role of their expression is not studied together. The aim 

of this study was to evaluate clinical significance of FLT3 (CD135) and c-kit 

(CD117) co-expression on myeloblasts in AML. 

Methods: Five ml peripheral blood/bone marrow from consecutive AML patients at 

diagnosis from April 2008 to May 2010 was evaluated by flow-cytometry. CD135 and 

CD117 expression was evaluated on dim CD45 positive myeloblasts. Positive 

expression was considered as >20% surface antigen expression. 

Results: During the study period, there were 115 AML patients with median age 16 

years and male:female ratio 2.02:1. M2 was the most common subtype 57% (66/115) 

followed by M4 14% (16/115). Cytogenetically (n = 85) these patients were classified 

as good risk in 20 (23%), intermediate risk in 50 (59%) and poor risk in 15 (18%) 

patients. Flt3 internal tandem duplication was present in 20 (17%) patients. CD135 

was positive in 95 (82%) patients; CD117 was positive in 104 (90%) patients; 

co-expression of CD135 and CD117 was observed in 74 (64%) patients. In those 

patients who co-expressed CD135 and CD117, the median expression was 34.1% of 

the gated myeloblasts and patients were classified as high co-expression (>/= 34.1% 

expression) and low (

anthracyclines in vitro. A favorable impact on the dismal clinical course of acute 

myeloid leukemia (AML) was suggested (Schlenk et al. ASH 2008). Recently, a phase 

I/II trial assessing the efficacy and safety of two schedules of Bel in patients unfit for 

intensive induction therapy has shown anti-leukemic effect both of Bel alone and in 

combination with idarubicin (ClinicalTrials.gov ID: NCT00878722). 

We evaluated the role of cytogenetic aberrations on response to Bel therapy in 41 

patients (pts), of whom cases with intermediate risk cytogenetics in trend responded 

better to Bel than patients with high risk cytogenetics (p = 0.14). Five complete 

remissions (CR) and 2 partial remissions (PR) were observed in 25 pts (28%) AML 

cases with low/intermediate risk cytogenetic aberrations, whereas no CR and 2 PR 

were seen in 16 pts (13%) high risk AML cases. 

Gene expression profiling based on 13 pts (4 CR + PR and 9 PD) revealed a strong 

gene expression pattern associated with the response to Bel. MLL, a gene well known 

to be involved in epigenetic deregulation, was among the top 20 strongest 

correlations. Furthermore, differential expression of TP53 was also of special interest 

as histone deacetylases have been shown to modulate p53 transcriptional activity. In 

accordance, gene ontology class comparison analysis showed a significant enrichment 

of categories associated with epigenetic regulation such as “histone methyltransferase 

activity” and “histone deacetylase activity”. In addition, the respective gene 

expression pattern harbored predictive information as based on an in vitro cell line 

derived predictor and a blinded Bel response prediction was feasible. 

A trend indicating the potential association of Bel response and intermediate risk 

cytogenetics AML has been found. High risk AML cases might also benefit from an 

epigenetic treatment approach with a HDACi. Further randomized studies are 

warranted to explore the benefit of Bel in pts with AML. 

Disclosure: S. Knudsen: MPI EmployeeJ. Tjørnelund: Employment Topotarget. All 


1069PD PREDICTING RESPONSE RATES OF HIGH GRADE NON 

HODGKIN’S LYMPHOMA: A COMPARATIVE STUDY OF 

INTERNATIONAL PROGNOSTIC INDEX (IPI) WITH 

SUBJECTIVE GLOBAL ASSESSMENT (SGA) 

V.S. Ostwal 1 , P. Bagayatkar 2 , P. Pawaskar 1 , R. Thippeswamy 1 , M. Sengar 1 , 

H. Menon 1 , N. Khattry 1 , B. Bagal 1 , R. Nair 1 , M.K. Mallath 3 

1 Medical Oncology, Tata Memorial Hospital Centre, Mumbai, INDIA, 2 Medical 

Oncology, Tata Memorial Hospital, Mumbai, INDIA, 3 Digestive Diseases, Tata 

Memorial Hospital Centre, Mumbai, INDIA 

Introduction: Malnutrition is common in patients with cancer and no study has corelated 

the effect of malnutrition on outcomes of non Hodgkins Lymphoma (NHL) 

from India. Besides, there are no studies validating the international prognostic index 

(IPI) from India. This study was done to compare the prognostic abilities of IPI and 

subjective global assessment (SGA) for early outcomes in NHL. 

Methods: This is a prospective observational study set in the lymphoma clinic of 

Tata Memorial Hospital, Mumbai between January to December 2010. All patients 

were screened for malnutrition at entry using a modified SGA tool. Baseline clinical 

factors of prognostic importance including IPI scores were recorded. Univariate and 

multivariate comparison were made using SPSS or EpiInfo 2000 software. 

Results: There were 401 patients with high grade NHL. The analysis of 389 patients 

with all information available showed that the IPI scores were low risk, low 

intermediate risk, intermediate high risk, high risk in 133 (34.3%), 95 (24.4 %), 91 

(23.4%) and 70 (17.9 %) patients respectively. The SGA scores were A, B, and C in 

188 (48.6%), 129 (33.2%) and 72 (18.2 %) patients respectively. Early outcomes 

included CR in 241 (62.6 %), EFS in 73% and overall survival in 81% patients at 

1-year. Univariate analysis revealed that the SGA scores were significantly associated 

with the IPI variables - age, serum LDH, performance status (ECOG), stage (Ann 

Arbor), extranodal sites as well as hemoglobin, response rates, one year survival and 

disease progression. Multivariate analysis revealed that SGA was a highly significant 

independent predictor of all early outcome parameters. Some IPI scores lost 

significance in the multivariate model. 

Conclusions: The SGA is a highly significant and independent predictive biomarker 

(for CR) and a prognostic biomarker (for 1-year OS and PFS) with good 

discriminative function in patients with NHL. 


1070PD RELATIONSHIP BETWEEN PROGRESSION-FREE SURVIVAL 

AND OVERALL SURVIVAL IN CHRONIC LYMPHOCYTIC 

LEUKEMIA 

C. Beauchemin 1 , J.B. Johnston 2 , M. Lapierre 1 , F. Aissa 3 , J. Lachaine 1 

1 Faculty of Pharmacy, University of Montreal, Montreal, QC, CANADA, 2 Cancer 

Research, Manitoba Institute of Cell Biology, Winnipeg, MB, CANADA, 3 Market 

Access and Health Outcome Department, Lundbeck Canada Inc., Montreal, QC, 

CANADA 

Objectives: Overall survival (OS) represents a universally recognized measure to 

evaluate clinical benefits for a new anti-cancer drug. Due to the limitations of this 

measure of survival, surrogate endpoints are frequently used, such as progression-free 


survival (PFS) and time-to-progression (TTP). However, the surrogacy of these 

endpoints for OS is not validated in all cancer settings. The main objective was to 

evaluate the relationship between median PFS/TTP and median OS in the context of 

chronic lymphocytic leukemia (CLL) using a trial-based approach. 

Methods: A systematic review of the literature was conducted using the PICO method: 

Population consisted of patients with CLL; Interventions and Comparators (when 

applicable) were standard therapies for CLL and Outcomes were median PFS/TTP and 

median OS. Two independent reviewers screened titles, abstracts, and full papers for 

eligibility, and then extracted data from selected studies. Correlation coefficient was 

calculated to assess the relationship between median PFS/TTP and median OS. 

Subgroup correlation analyses were also conducted according to characteristics of 

selected studies such as line of treatment and type of treatment under investigation. 

Results: Among the 1,263 potentially relevant studies identified by the literature 

search, 23 articles were included. The mean number of patients included in these 

studies was 118 patients (min: 30, max: 724). The median age was 63.0 years and the 

median follow-up period was 33.7 months. On average, median PFS/TTP was 14.0 

months (sd =12.4) and median OS was 35.0 months (sd = 31.2). The results of the 

correlation analysis demonstrated that median PFS/TTP is highly correlated with 

median OS, with a Spearman’s correlation coefficient of 0.813 (p ≤ 0.001). A 

significant correlation between median PFS/TTP and median OS was observed in the 

second-line and subsequent-line therapy, but not in the first-line setting. 

Conclusion: The present results demonstrate a very strong correlation between 

median PFS/TTP and median OS in the context of CLL, which reinforce the 

hypothesis that PFS/TTP would be adequate surrogate endpoints for OS in this 

cancer setting. These findings would strongly support the use of PFS/TTP in the 

appreciation of the clinical efficacy of new drugs in CLL. 


1071P 3D TELOMERE SIGNATURES OF HODGKIN-CELLS AT 

DIAGNOSIS IDENTIFY PATIENTS WITH POOR RESPONSE 

TO CONVENTIONAL CHEMOTHERAPY 

H. Knecht 1 , N. Kongruttanachok 2 ,B.Sawan 3 , J. Brossard 4 , S. Prévost 5 , 

É. Turcotte 5 , Z. Lichtensztejn 2 , D. Lichtensztejn 2 , S. Mai 2 

1 Haematology, CHUS, Sherbrooke, QC, CANADA, 2 MICB, Unversity of 

Manitoba, Winnipeg, MB, CANADA, 3 Pathology, CHUS, Sherbrooke, QC, 

CANADA, 4 Pediatrics, CHUS, Sherbrooke, QC, CANADA, 5 Medical Imaging, 

CHUS, Sherbrooke, QC, CANADA 

In classical Hodgkin’s lymphoma (HL) the malignant mononuclear Hodgkin (H) and 

multinuclear Reed-Sternberg (RS) cells are characterized by a distinct 3D nuclear 

telomere organization with shortening of the telomere length and the formation of 

telomeric aggregates. We asked if the severity of these telomere changes correlates 

with clinical behaviour of the disease. We evaluated (mainly prospectively) the 3D 

telomere organization by quantitative fluorescent in situ hybridization (Q-FISH) on 

diagnostic biopsies from 20 patients who were good responders and compared them 

with 20 diagnostic biopsies of 11 patients with refractory or relapsing HL (11 initial 

biopsies, five confirming progressions and four confirming relapses). The H-cells from 

patients with refractory/relapsing disease contained a significantly higher percentage 

of very small telomeres (p < 0.05) and telomere aggregates (p < 0.05) compared with 

H-cells of patients entering rapid remission. In order to eliminate therapy related 

changes of the 3D nuclear telomere organization we compared (prior to any 

treatment) 10 initial diagnostic biopsies of refractory/relapsing HL with diagnostic 

biopsies of 10 patients with ongoing long lasting remission (mean 51 months). 

Importantly, the differences between both groups were highly significant (p < 0.005) 

for very small telomeres and for aggregates (p < 0.02). Since both groups were treated 

with standard ABVD chemotherapy, long lasting remission or progression/relapse are 

independent of the choice of chemotherapy and have to rely on intrinsic factors of the 

tumour cells. Thus, H-cells of refractory/relapsing HL are characterized by a specific 

3D telomere signature, i.e. abundant very small telomeres. 3D telomere Q-FISH 

identifies these highly aggressive mononuclear H-cells at the first diagnostic biopsy 

and thus may offer a novel molecular tool to optimize initial treatment. 


1072P RECRUIT-TANDAB AFM13 - OVERCOMING LIMITATIONS OF 

MONOCLONAL ANTIBODIES IN HODGKIN LYMPHOMA 

E. Zhukovsky 1 , M. Ravic 2 , A. Rothe 3 , M. Topp 4 , A. Younes 5 , S. Knackmuss 6 , 

U. Reusch 6 , E. Rajkovic 6 ,C.Hucke 2 , M. Little 6 

1 Affimed Therapeutics AG, Heidelberg, GERMANY, 2 Clinical Department, Affimed 

Therapeutics AG, Heidelberg, GERMANY, 3 Klinikum D.Universität zu Köln Klinik 

f. Innere Medizin I, University of Cologne, Cologne, GERMANY, 4 GSLS, 

University of Wuerzburg, Med. Klinik und Poliklinik II Immun- und Gentherapie, 

Wuerzburg, GERMANY, 5 Department of Lymphoma/Myeloma, University of 

Texas M.D. Anderson Cancer Centre, Houston, TX, UNITED STATES OF 

AMERICA, 6 Research, Affimed Therapeutics AG, Heidelberg, GERMANY 

AFM13 is a RECRUIT-TandAb (CD30xCD16A) for treating Hodgkin Lymphoma by 

recruiting NK-cells and macrophages to the specific CD30 surface antigen on 



Reed-Sternberg cells. This redirected immune response leads to potent tumor cell 

killing. RECRUIT TandAbs are tetravalent and bispecific, and address key 

deficiencies of monoclonal antibodies such as (i) differential binding to V/F allotypes 

of CD16A receptor and (ii) non-selective binding to activating CD16A and 

non-signalling CD16B receptors. Furthermore, RECRUIT-TandAbs have significant 

advantages over other antibody fragment technologies such as (i) bivalent binding to 

the targets and, (ii) longer half-life. 

AFM13 binds with high affinity to both CD30 and CD16A and is able to rapidly 

induce lysis of CD30+ cells at picomolar concentrations in the presence of PBMCs. 

Intensive in vitro characterization demonstrated that AFM13 is specific for the 

CD16A receptor, which becomes activated only in the presence of tumor cells: there 

is no systemic activation of NK-cells in the absence of target cells. A robust GMP 

production process in mammalian cells and a lyophilized formulation with excellent 

stability have been established. Toxicology testing in Cynomolgus monkeys did not 

reveal any toxicity. Currently, AFM13 is being investigated in a single arm phase I 

dose escalation trial for patients with relapsed and/or refractory Hodgkin Lymphoma 

(HL). Patients receive a single cycle of 4 weekly doses, which are escalated in cohorts 

of 3 patients at the dose levels of 0.01, 0.04, 0.15, 0.5, 1.5, 4.5 and 7.0 mg/kg. Study 

objectives are the assessment of safety and tolerability, PK, immunogenicity, 

antitumor activity, as well as the determination of the maximum tolerated dose 

(MTD) or the optimal biological dose (OBD). The safety of the MTD or OBD will 

be confirmed in further patients receiving 2 cycles of AFM13. 

AM13 was shown to be safe and well tolerated by highly pre-treated Hodgkin 

Lymphoma patients in weekly doses of up to 7.0 mg/kg. Adverse events were 

generally mild, with the most frequent drug-related event being fever. An objective 

response was achieved on the dose level 1.5mg/kg. Nine cases of stable disease/minor 

response were also observed. In ex vivo assays AFM13 restored impaired cytotoxic 

activity of NK cells from HL patients. Preclinical and interim clinical data will be 

presented, showing that AFM13 may become a safe and effective targeted therapy for 

CD30 positive malignancies. 

Disclosures: E. Zhukovsky: The author is the employee of Affimed Therapeutics and 

the member of the Management Board, M. Ravic: A consultant to Affimed 

Therapeutics and a Chief Medical Officer, M. Topp: Consultant to Affimed, S. 

Knackmuss: The coauthor is an employee of the company. U. Reusch: The coauthor 

is an employee of the company. E. Rajkovic: The coauthor is an employee of the 

company. C. Hucke: The co-author is a former employee of Affimed Therapeutics 

and currently is a clinical development consultantM. Little: The co-author is a 

consultant to Affimed Therapeutics and owns the warrants of the company. 

1073P CONSOLIDATION TREATMENT WITH Y90-IBRITUMOMAB 

TIUXETAN AFTER R-CHOP INDUCTION IN HIGH-RISK 

PATIENTS WITH FOLLICULAR LYMPHOMA (FL) 

(GOTEL-FL1LC): A MULTICENTRIC, PROSPECTIVE STUDY 

M. Provencio Pulla 1 , M.A. Cruz Mora 2 , J. Gomez Codina 3 , C. Quero 4 , 

M. Llanos 5 , F.R. Garcia Arroyo 6 , L. De La Cruz 7 , J. Guma 8 , J.R. Delgado 9 , 

A. Rueda 10 

1 Medical Oncology, Hospital Universitario Puerta de Hierro Majadahond, 

Majadahonda, SPAIN, 2 Medical Oncology, Hospital Virgen de la Salud, Toledo, 

SPAIN, 3 Medical Oncology, Hospital Universitari i Polit, Valencia, SPAIN, 

4 Radiotherapy, Hospital Universitario Virgen de la Victoria, Malaga, SPAIN, 

5 Medical Oncology, Hospital Universitario de Canarias, Tenerife, SPAIN, 6 Medical 

Oncology, Complejo Hospitalario de Pontevedra, Pontevedra, SPAIN, 7 Medical 

Oncology, Hospital Universitario Virgen Macarena, Sevilla, SPAIN, 8 Medical 

Oncology, Hospital Universitario San Juan de Reus, Reus, SPAIN, 9 Medical 

Oncology, Hospital Universitario Virgen de las Nieves, Granada, SPAIN, 

10 Medical Oncology, Hospital Costa del Sol, Marbella, SPAIN 

Relapse is the main cause of therapeutic failure in FL, which makes it necessary to 

investigate strategies that aim to eradicate minimal residual disease. This is why we 

set out to evaluate the role of consolidation with Y90-Ibritumomab Tiuxetan (RIT) 

in high-risk FL patients. As we possessed data making us suspect that prior 

treatment with Rituximab could reduce the efficacy of RIT, we designed a study with 

RIT after 4 cycles of CHOP-R and 2 CHOP, but without R. 

Material and Patients: Between April 2008 and April 2010, 30 patients were 

included in this trial: 17 male (56.7%) and 13 female (43.3%). Their median age was 

54.8 (range, 34-76). 20 (69%) patients had ECOG 0. There were no delays or 

reductions in RIT doses. 

Results: The objective rate of clinical response was 92.1% (CR + CRi + PR), [CI 95%: 

83-100%]. Of the 18 patients who presented with partial remission to the induction 

treatment, 11 (61.1%) had complete CR or remission after the consolidation 

treatment. There was only one exitus, due to H1N1 viral pneumonia. The most 

important G 3/4 toxicity was hematological, with 46% thrombopenia and 56% 

neutropenia. None of the patients in the trial died because of Lymphoma. With 

median follow-up of 26 months (12-37), the means for disease-free survival or 

overall survival were not reached. 

Conclusion: The induction procedure with 4 CHOP-R + 2 CHOP prior to consolidation 

with RIT gives good response rates and RIT improves CR. This combination is safe and 

shows a high activity in both, induction and consolidation procedures. 


1074P A RETROSPECTIVE SINGLE CENTRE ANALYSIS OF SAFETY, 

TOXICITY AND EFFICACY OF RITUXIMAB (ORIGINAL) AND 

ITS BIOSIMILAR IN DIFFUSE LARGE B-CELL LYMPHOMA 

PATIENTS TREATED WITH CHEMO-IMMUNOTHERAPY 

P.S. Roy 1 , M. Sengar 1 , H. Menon 1 , B. Bagal 1 , N. Khattry 1 , E. Shridhar 2 , 

S. Gujral 2 , S. Laskar 3 , V. Rangarajan, 4 , R. Nair 5 

1 Medical Oncology, Tata Memorial Hospital, Mumbai, INDIA, 2 Pathology, Tata 

Memorial Hospital, Mumbai, INDIA, 3 Radiation Oncology, Tata Memorial 

Hospital, Mumbai, INDIA, 4 Radiology, Tata Memorial Hospital, Mumbai, INDIA, 

5 Medical Oncology, Tata Memorial Hospital Centre, Mumbai, INDIA 

Background: Rituximab with chemotherapy (CHOP regimen) has been the standard 

of care for diffuse large B-cell lymphoma (DLBCL). Mabthera® is being used in India 

since early 2000. Reditux®, a biosimilar molecule of Rituximab, was developed in 

India & approved for use since March 2007. This retrospective audit aims to 

compare the safety, toxicity and efficacy of Mabthera® with Reditux®. 

Methods: Two hundred twenty-three patients aged ≥ 18 years who underwent 

treatment from January 2004 to June 2010 were included. All patients received 4-8 

cycles of R-CHOP. CT scan of chest & abdomen was done at baseline and within 4 

weeks of completion of treatment. Grade 3-4 hematological and non-hematological 

toxicities according to CTC version 3.0 were recorded. Response rates [complete 

response (CR), partial response (PR)] in both groups were evaluated as per Cheson’s 

criteria & compared by Chi-Square test. Overall survival (OS) and progression-free 

survival (PFS) were estimated by Kaplan-Meier method & compared by two-sided 

log rank test. 

Results: One hundred one patients received Mabthera®, 72 received Reditux®. In 17 

patients, the brand used was unknown and 33 patients received both. Baseline 

characteristics such as, age, gender, performance status, stage of disease & revised IPI 

score at presentation were similar in both groups. Median number of treatment cycle 

received was 6 in each group. Overall response rate (CR + PR) was 88% (Mabthera®) 

and 90% (Reditux®). OS at 5 years was 85% (Mabthera®) and 93% (Reditux®); P = 0.13. 

PFS at 5 years was 76% (Mabthera®) and 84% (Reditux®); P = 0.44. At a median 

follow-up of 35 months (18 to 58 months) treatment related death was seen in 3 in 

Mabthera® and 2 in Reditux® group. Grade 3-4 febrile neutropenia was observed in 23% 

(Mabthera®) & 20% (Reditux®); grade 3-4 oral mucositis and diarrhea was seen in 25% 

(Mabthera®) & 10% (Reditux®). No difference in infusional reactions were observed. 

Conclusion: Reditux® is as efficacious as Mabthera® in terms of response rates, OS & 

PFS with comparable toxicity. However, randomized prospective trial is needed to 

validate these results. 


1075P DETECTION OF CAGA EXPRESSION IN GASTRIC 

MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA— 

BIOLOGIC SIGNIFICANCE AND CLINICAL IMPLICATION 

S. Kuo 1 , L. Chen 2 , C. Lin 3 ,M.Wu 4 , P. Hsu 4 , Y. Tzeng 1 , H. Tsai 2 , H. Wang 4 , 

K. Yeh 1 , A. Cheng 1 

1 Departments of Oncology, National Taiwan University Hospital, Taipei, TAIWAN, 


Tainan, TAIWAN, 3 Departments of Pathology, National Taiwan University 

Hospital, Taipei, TAIWAN, 4 Departments of Internal Medicine, National Taiwan 

University Hospital, Taipei, TAIWAN 

Background: We recently reported that a direct contact of Helicobacter pylori (HP) 

with B cells resulted in CagA translocation into the cells (Cancer Res 

2010;70:5740-8). The translocated CagA further activates extracellular 

signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), 

and up-regulates the expressions of Bcl-2 and Bcl-xL. In this study, we sought to 

verify if CagA exists in the malignant B cells of gastric mucosa-associated lymphoid 

tissue (MALT) lymphoma. 

Methods: Expression of CagA protein, phospho-SHP-2, phospho-ERK, 

phospho-p38MAPK, Bcl-2 and Bcl-xL in a series of 26 gastric MALT lymphoma was 

determined by immunohistochemistry. Western blot analysis was done to confirm 

immunohistochemical detection of CagA and biopsies from non-gastric MALT 

lymphoma served as negative controls. The association of CagA expression and the 

tumor response to HP-eradication (HPE) therapy was evaluated in 77 stage IE/IIE1 

low-grade gastric MALT lymphoma patients. 

Results: The expression of CagA was detected in 35 (45.5%) of 77 patients. CagA 

expression was closely associated with the expression phospho-SHP-2 (P = .016), 

phospho-ERK (P < .001), phospho-p38MAPK (P = 0.014), Bcl-2 (P = 0.009), and 

Bcl-xL (P = 0.008). CagA expression was detected in 30 (69.8%) of 43 HP-dependent 

cases, and in 5 (14.7%) of 34 HP-independent cases (P < 0.001). Furthermore, 

patients with CagA expression responded to HPE more rapidly than those without 

(median time to complete remission, 3.0 months versus 7.0 months, P = 0.032). 

Conclusion: CagA protein can be translocated into malignant B cells of MALT 

lymphoma. The expression of CagA in lymphoma cells appears to be biologically and 

clinically significant. 



1076P RITUXIMAB PLUS SUBCUTANEOUS CLADRIBINE IN 

PATIENTS WITH EXTRANODAL MARGINAL ZONE B-CELL 

LYMPHOMA OF THE MUCOSA ASSOCIATED TISSUE 

(MALT-LYMPHOMA): A PHASE II STUDY BY THE AGMT 

(ARBEITSGEMEINSCHAFT MEDIKAMENTöSE 

TUMORTHERAPIE) 

M. Troch 1 , B. Kiesewetter 2 , W. Willenbacher 3 , E. Willenbacher 3 , A. Zebisch 4 , 

W. Linkesch 4 , M.A. Fridrik 5 , L. Müllauer 6 , R. Greil 1 , M. Raderer 2 

1 Hematology, Medical Onoclogy, Hemostaseology, Infectious Disease, 

Rheumatology, Oncologic Center, Paracelsus Medical University of Salzburg, 

Salzburg, AUSTRIA, 2 Clinical Oncology and Comprehensive Cancer Center, 

Medical University of Vienna, Vienna, AUSTRIA, 3 Hematology and Oncology, 

Medical University of Innsbruck, Innsbruck, AUSTRIA, 4 Hemato/Oncology, 

Medizinische Universit, Graz, AUSTRIA, 5 Internal Medicine 3, Allgemeines 

Krankenhaus Linz, Linz, AUSTRIA, 6 Institute of Pathology, Medical University 

of Vienna, Vienna, AUSTRIA 

Background: Currently, there is no standard systemic treatment for extranodal 

marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue 

(MALT-lymphoma). Both rituximab (R) and 2-chlorodeoxyadenosine (2CdA) have 

shown activity to some extent in this disease, but the combination has not been 

tested so far. In view of this, we have initiated a phase II study to assess the activity 

and safety of R/2CdA in patients with MALT-lymphoma. 

Patients and methods: Patients with histologically verified MALT-lymphoma were 

included in this study. Treatment consisted of R 375 mg/m 2 i.v. day 1 and 2CdA 0.1 

mg/kg s.c. days 1 – 4 every 21 days. In case of complete remission (CR) after two 

courses, another two cycles of therapy were administered, while patients achieving 

partial response (PR) or stable disease (SD) were scheduled to receive 6 cycles of 

treatment. 

Results: Out of 40 evaluable patients (14 female, 26 male), 39 received treatment as 

scheduled while one patient died before initiation of therapy and was rated as PD in 

the intent to treat analysis. Twenty-one patients had gastric lymphoma, while 19 

suffered from extragastric MALT-lymphoma (6 lung, 2 salivary gland, 5 ocular 

adnexae, 4 intestinal, one breast and one cutaneous lymphoma, respectively). Side 

effects were manageable and consisted mainly of hematotoxicity including 

leukopenia, lymphopenia, anemia and thrombocytopenia. Twenty-three patients had 

a CR (58 %), 9 PR (23%) for an overall reponse rate of 81%, while 5 had SD (13%) 

and two progressed during therapy. After a median follow-up of 16.7 months (Inter 

Quartile Range; 15.9 – 18.7months), 35 patients are alive (88 %) while four patients 

have died (one patient of post-stenotic pneumonia during the follow-up period, one 

of urosepsis before initiation of therapy, one due to myocardial infarction and one 

patient due to lymphoma progression) and one patient withdrew consent and did 

not allow further follow up. 

Conclusion: Our data demonstrate that R plus 2CdA is active and safe in patients 

with MALT-lymphoma. 


1077P EFFICACY OF THE ANTHRACYCLINE-BASED 

CHEMOTHERAPY IN ANGIOIMMUNOBLASTIC T CELL 

LYMPHOMA PATIENTS 

S. Lee 1 , H. Kim 2 , I. Kim 3 , S.R. Lee 4 , D.S. Kim 5 , C.W. Choi 5 , B.S. Kim 1 ,Y.Park 1 

1 Department of Hemato-Oncology, Korea University Medical Center, Anam 

Hospital, Seoul, KOREA, 2 Hematooncology, KUMC Anam Hospital, Seoul, 

KOREA, 3 Department of Pathology, Korea University Medical Center, Anam 

Hospital, Seoul, KOREA, 4 Department of Hemato-Oncology, Korea University 

Medical Center, Ansan Hospital, Ansan, Kyong Gi-do, KOREA, 5 Department of 

Hemato-Oncology, Korea university Medical Center, Kuro Hospital, Seoul, 

KOREA 

Background: Peripheral T cell lymphoma (PTCL) is a heterogeneous disease, 

composed of five distinctive subtypes. Angioimmunoblastic T-cell lymphoma (AITL) 

represents a distinct clinicopathological entity in PTCLs, but there have been limited 

data concerning the efficacy of treatment for the rarity of this disease. Here, we 

report the efficacy of treatment with anthracycline-based chemotherapy in 49 AITL 

patients. 

Material and method: A total of 49 patients diagnosed with AITL between April 

1994 and October 2011 after the histopathological and immunohistochemical review 

were analyzed. All patients analyzed were treated with anthracycline-based 

chemotherapy. Overall survival (OS) was defined as the date of diagnosis to death. 

Progression free survival (PFS) was defined as the date of diagnosis to the first date 

of disease progression, relapse, death as a result of any cause, or the last date of 

follow-up. OS and PFS were analyzed according to the Kaplan-Meier methods. 

Results: 14 of 49 patients (28.6%) were treated with adriamycin-based chemotherapy 

(CHOP), and 35 patients (71.4%) received epirubicin-based chemotherapy (CEOP). 4 

patients (8.16%) received high-dose chemotherapy with autologous stem cell 

transplantation when the disease relapsed. Overall response rate was 69.4%, and 

complete remission was shown in 21 patients. (42.9%). 6 cases (12.2%) of the AITLs 

had progressive disease, and the response was not evaluated in 9 cases due to 


follow-up loss or early death. Only 2 patients of 49 (4.1%) were related to treatment 

related death, defined as death within 28 days after the initial day of therapy. 

21-month OS rates were 77%, reaching a plateau level around 2 years. 2-year and 

5-year PFS rates were 34% and 23%, respectively. 

Conclusion: Anthracycline-based chemotherapy could be a choice of chemotherapy 

regimen, given the acceptable outcome of long term survival. The initial 2-year 

survival after initiation of the treatment is poor, and further analysis is required for 

factors associated with the initial poor treatment outcome in AITL patients. 


1078P POLYMORPHISMS OF GSTT1 AND GSTM1 GENES IN 

DIFFUSE LARGE B CELL LYMPHOMA EGYPTIAN PATIENTS 

H.A. Alagizy 1 , E. Essa 2 

1 Clinical Oncology Dept., Menofia University, Shebin Elkom, EGYPT, 2 Clinical 

Pathology, Menofia University, Shebin Elkom, EGYPT 

Background: Evidence, although not so extensive, did show that genetic variations in 

glutathione S-transferase (GST) might be associated with risk of developing 

lymphoma; overall and/or subtype. Genetic data on the contribution of GST genes in 

the prognosis of lymphomas is scarce even in occupationally exposed populations. 

Aim: The study aimed to investigate the influence of polymorphisms in GSTM1 and 

GSTT1 genes on both the risk and prognosis of diffuse large B-cell lymphoma 

(DLBCL). 

Subjects and methods: The study included 83 newly diagnosed DLBCL patients that 

were compared to 89 age and gender matched control subjects.Patient’s stage, LDH, 

performance status, extranodal disease and age were assessed and international 

prognostic index (IPI) was plotted . Treatment outcome and follow up relapse/ 

progression and death was done. .GSTM1 and GSTT1 genotyping was performed by 

a multiplex PCR protocol. 

Results: We found 2.35 fold increase in the risk of DLBCL associated with 

GSTT1-null genotype (OR = 2.35, 95% CI: 1.02 – 5.40, P = 0.04). Three times 

increased risk in individuals with the GSTM1/T1-double null genotype (OR3.06, 95% 

CI: 1.04 – 8.95, P = 0.03) compared with both GSTM1 and GSTT1 genes undeleted 

(wild genotype) was observed. Patients; overall and those with favorable IPI (


developed HCV reactivation by PCR, 2 cases after cycle 6 and 2 within 6 months of 


Outcome: Complete Remission for uncertain CR was 29/43 (67%). With the 

median follow up of 32 months, The 2 year overall survival was 70% (95%CI 

59-81%) and disease free survival was 59% (95% CI 48-70%) with no recorded 

treatment related mortality. Dose reduction was required for toxicity in 25% of 

all patients. 

Conclusion: Rituximab plus CHOP is an effective and marginally tolerable regimen 

in therapy of HCV +ve lymphoma patients. Role of prophylactic antiviral therapy has 

to be evaluated for those patients. 


1080P ADVERSE PROGNOSTIC IMPACT OF VASCULAR 

ENDOTHELIAL GROWTH FACTOR GENE POLYMORPHISM IN 

PATIENTS WITH NON-HODGKIN LYMPHOMA 

M.H. Han 1 , H. Eom 1 , H. Lee 1 , H. Kim 1 , W.S. Park 1 , S. Kong 2 

1 Hematology-Oncology Clinic, National Cancer Center, Goyang-si, Gyeonggi-do, 

KOREA, 2 Laboratory Medicine, National Cancer Center, Goyang, KOREA 

Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis 

and progression of many types of cancer and VEGF expression has been known to 

be associated with polymorphism of gene. However, the impact of polymorphisms of 

the VEGF gene on non-Hodgkin lymphoma (NHL) prognosis has not been fully 

elucidated. Here we investigated the association between VEGF polymorphisms and 

prognosis of NHL. The study involved 96 NHL patients treated at the National 

Cancer Center, Korea. The median patient age was 57 years, and 60 patients (62.5%) 

were men. A total of 5 polymorphisms with heterozygous allele were analyzed. 

Clinical characteristics (e.g., cell lineage) and international prognostic index (IPI), 

including age, performance, LDH, stage and extra-nodal involvement, were evaluated 

and related to VEGF polymorphism. Hazard ratios (HRs) were determined in terms 

of risk for overall survival using Cox proportional hazard regression analysis. Diffuse 

large B cell lymphoma (n = 73) was most common histologic type, and others were 

as follows: T-cell lymphoma (n = 14), mantle cell lymphoma (n = 6), and Burkitt 

lymphoma (n = 3). IPI and stage were predictors for prognosis (p 5 cm) 

was presented in 61.4%. Patients received only 2 regimens were 63.7% and 31.8% 

had > 2 involved sites. No treatment related toxicity was observed. The overall 

response rate was 88.7%; complete response was reached in 59.1% and stable disease 

in 6.8%, progressive disease in 4.5% .Median time to local progression was 33 

months (95% CI 23.70-42.29), 2 –year local progression free survival was 78%. 

Response rate was found to be dependent on age, number of involved sites and 

lymph node size but independent on sex, pathological type, number of prior 

regimens, LDH level and time since diagnosis. 

Conclusion: Short-course-low dose palliative radiotherapy (2 x 2 Gy) affords an 

attractive option for treatment of relapsed low-grade non-Hodgkin’s lymphoma due 

to high response rates. However, these results had to be confirmed in a larger 

number of patients. 


1082P VERY HIGH EFFICACY OF CYTARABINE + G-CSF COMPARED 

TO CYCLOPHOSPHAMIDE + G-CSF AS HEMATOPOIETIC 

STEM CELL MOBILIZATION IN PATIENTS WITH LYMPHOID 

MALIGNANCIES REFERRED FOR AUTOLOGOUS 

TRANSPLANTATION 

T. Kruzel, T. Czerw, M. Sadus-Wojciechowska, J. Najda, M. Glowala-Kosinska, 

A. Chwieduk, J. Holowiecki, S. Giebel 

Department of Bone Marrow Transplantation, Maria Sklodowska-Curie Memorial 

Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, POLAND 

High-dose therapy followed by autologous peripheral blood stem cell 

transplantation (autoPBSCT) is widely applied in the treatment of lymphoid 

malignancies. However, a significant proportion of patients fail to mobilize 

sufficient number of stem cells. So far, no standards for mobilization have been 

elaborated with G-CSF alone or G-CSF in combination with cyclophosphamide 

(CTX) being most commonly used regimens. 

In this study we evaluated efficacy of mobilization based on cytosine 

arabinoside (AraC) 1600 mg/m2 + G-CSF (filgrastim) 5-10 ug/kg. Results of 67 

subsequent patients were compared with 45 individuals mobilized with 

cyclophosphamide (CTX) (4 g/m2) + G-CSF, according to our preceding standard 

protocol. The median age of patients in the AraC group was 57 years; the 

indications were: multiple myeloma (MM, n = 37), Hodgkin’s lymphoma (HL, n = 

9) and non-Hodgkin lymphoma (n = 21). Patients had previously been treated 

with 8 (3-36) cycles of chemotherapy, 2 (1-6) lines of chemotherapy; 33% had 

received radiotherapy. The characteristics of the CTX group were comparable. 

All but two patients (97%) treated with AraC reached > 15 CD34 + cells/uL in 

peripheral blood, which was required to start leukapheresis, compared to 67% in 

the CTX + G-CSF cohort (p < 0.0001). Median peak level was 127 (3-780) CD34 

+ cells/uL vs. 33 (1-240), respectively (p < 0.0001). After AraC treatment, 65 

(97%) patients collected > = 2x10e6 CD34 + cells/kg, required for single 

autoPBSCT, while 54 (81%) collected > = 5x10e6 CD34 + cells/kg, needed for 

double transplantation. Respective proportions in the CTX cohort were 56% 

(p < 0.0001) and 42% (p < 0.0001). The total number of harvested CD34 + cells 

was 14.9 (2.2-57.2) x10e6/kg for AraC and 5.1 (2-14.3) for CTX (p < 0.0001). The 

toxicity related to both regimens was comparable. 

We conclude that mobilization based on intermediate doses of AraC + G-CSF is 

highly effective allowing adequate CD34+ harvest in almost all patients with 

lymphoid malignancies, including heavily pre-treated and elderly individuals. The 

level of mobilized CD34+ cells is four times higher compared to commonly used 

protocol based on CTX. Hence, AraC + G-CSF may be a preferable option for 

predicted poor mobilizers, especially when high number of CD34+ cells is 

required for transplantation. 


1083P PERIPHERAL BLOOD STEM CELL (PBSC) MOBILIZATION 

AND ENGRAFTMENT AFTER BRENTUXIMAB VEDOTIN 

TREATMENT IN ANAPLASTIC LARGE CELL LYMPHOMA 

(ALCL) PATIENTS 

A.R. Shustov 1 , J.D. Rosenblatt 2 , D.A. Kennedy 3 , M. Fanale 4 

1 Division of Hematology, University of Washington School of Medicine, Seattle, 

WA, UNITED STATES OF AMERICA, 2 Hematology-Oncology, University of 

Miami, Miami, FL, UNITED STATES OF AMERICA, 3 Clinical Affairs, Seattle 

Genetics, Inc., Bothell, WA, UNITED STATES OF AMERICA, 4 Lymphoma/ 

Myeloma, University of Texas, MD Anderson Cancer Center, Houston, TX, 


Background: Brentuximab vedotin is a CD30-targeted antibody conjugated to the 

microtubule-disrupting agent, monomethyl auristatin E (MMAE), by a 

protease-cleavable linker. In a pivotal phase 2 study (ClinicalTrials. 

gov NCT00866047), an objective response was achieved in 50 of 58 (86%) 

relapsed/refractory ALCL patients (pts) treated with brentuximab vedotin. More 

than half of the pts achieved a complete remission (CR) (59%), enabling some pts to 

subsequently receive a stem cell transplant (SCT) as consolidation. A 

retrospective evaluation was performed to characterize PBSC mobilization and 

engraftment following brentuximab vedotin treatment (tx). 

Methods: Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute 

outpatient IV infusion for up to 16 cycles. Antitumor efficacy was based on response 

assessments by independent review according to Cheson 2007. 

Results: Eight pts received autologous SCT as the first therapy after discontinuing tx 

with brentuximab vedotin in remission. PBSC collection was completed prior to 

initiation of brentuximab vedotin tx in 2 pts, and following brentuximab vedotin tx 

in 6 pts. These 6 pts achieved a best clinical response of CR with brentuximab 

vedotin tx. After brentuximab vedotin tx, PBSCs were mobilized using 

chemomobilization (n = 3 pts), plerixafor (n = 1), and granulocyte colony-stimulating 

factor alone (G-CSF) (n = 2). The number of CD34+ cells/kg obtained and the days 

of collection are shown in the table. The CD34 + /kg yield for each pt was greater 


than the standard target of ≥2.5 x 10 6 , with a median of 7.0 x 10 6 . All pts engrafted, 

and the median time to engraftment was 10.5 days (range 9–14) for neutrophils and 

11.5 days (range 9–13) for platelets. The 100-day mortality rate post SCT was 0%. 

Conclusions: Brentuximab vedotin does not appear to have a negative impact on the 

outcome of PBSC mobilization or engraftment in pts receiving high-dose therapy 

and auto SCT. 

Age Sex 

Cycles of 

B-V 

Mobilization 

Regimen 

Days 

Collected 

46 M 4 IE/GCSF 1 46.9 

57 F 8 IE/GCSF 2 7.1 

61 M 7 plerixafor 4 4.1 

41 F 8 GCSF 2 6.9 

50 F 8 CED/GCSF 1 28.1 

45 F 4 GCSF 2 4.0 

IE = ifosfamide, etoposide 

CED = cyclophosphamide, etoposide, dexamethasone 

CD34+ Cells/kg 

(x 10 6 ) 

Disclosure: A.R. Shustov: I have a consultancy relationship with and have received 

research funding from Seattle Genetics, Inc. I have also received honoraria from 

Millennium.J.D. Rosenblatt: Seattle Genetics, Inc. has provided research support to 

my institution.D.A. Kennedy: I am an employee of and have equity ownership in 

Seattle Genetics, Inc.M. Fanale: I have acted as a consultant and served on Advisory 

Board for Seattle Genetics, Inc. I have received honoraria and travel expenses from 

Seattle Genetics, Inc. Seattle Genetics, Inc. has also provided research funding to my 

institution. 

1084P AUTOLOGOUS STEM CELL TRANSPLANTATION (HCT) WITH 

OR WITHOUT TOTAL BODY IRRADIATION (TBI) IN NEWLY 

DIAGNOSED MANTLE CELL LYMPHOMA (MCL) PATIENTS 

M. Szymczyk 1 , J. Romejko-Jarosinska 1 , B. Brzeska 1 , W. Osiadacz 1 , 

K. Domanska-Czyz 1 , M. Smorczewska 2 , O. Hermine 3 , M.H. Dreyling 4 ,J. 

A. Walewski 1 

1 Department of Lymphoid Malignancies, Maria Sklodowska-Curie Institute and 

Oncology Centre, Warsaw, POLAND, 2 Radiology Department, Maria 

Sklodowska-Curie Institute and Oncology Centre, Warsaw, POLAND, 

3 Department of Hematology, Hopital Necker, Paris, FRANCE, 4 Klinikum der 

Universität Münchenmedizinische Klinik und Poliklinik III, 

Ludwig-Maximilians-Universität München, München, GERMANY 

Introduction: MCL is considered incurable due to relapsing course and eventual 

resistance despite initial responses to treatment. The 1st line treatment in advanced 

disease is immunochemotherapy induction followed by high-dose chemotherapy +/- 

TBI and HCT in the first complete (CR) or partial remission (PR). The best 

conditioning regimen is unknown and the TBI role is one of the main issues. Very 

few retrospective analyses are available. 

Methods: We retrospectively evaluated all MCL patients treated 1st line +/- TBI as a 

part of myeloablative procedure at the Oncology Institute in Warsaw between 

1999-2011 with some patients treated in the European MCL Network trial for 

younger. We analyzed data for 7 women and 26 men, median age 56 years (39-63). 

Most (82%) had disease stage III-IV with bone marrow involvement in 64%. 

Majority received chemotherapy with rituximab for induction (79%). All received 

doxorubicin and 45% cytarabine. 22 had TBI conditioning (TBI group). Most of the 

remaining 11 patients received BEAM (non-TBI group). Before conditioning 18 had 

CR (12 before TBI, 6 before conditioning without TBI) and 15 PR (10 before TBI, 5 

before conditioning without TBI). There were no statistically significant differences 

between groups, including age, sex, disease stage and MIPI. After HCT 27 patients 

had CR (18 in TBI, 9 in non-TBI), 6 remained in PR (4 in TBI, 2 in non-TBI). 

Median observation time from the start of therapy was 50.9 months (6.9-144.8) and 

from HCT 49.5 months (0.85-139.7). 

Results: After HCT the 1, 3 and 5-year overall survival (OS) rates were 96.9%, 89.8%, 

75% and the progression free survival (PFS) 93.7%, 73.1% and 67.9% respectively. In 

bivariate analysis the 1, 3 and 5-year OS rates were similar in TBI vs. non-TBI 

groups: 95.4% vs. 100%; 90.4% vs. 88.8%; 82.2% vs. 66.7% (p= 0.41). Comparison of 

1, 3 and 5-year PFS rates between TBI vs. non-TBI groups: 95.2% vs. 90.9% and 

86.6% vs. 47.1% and 78 % vs. 47.1% (p= 0.046) indicated superiority of TBI. In a 

multivariate analysis TBI was an independent PFS prognostic factor with relative risk 

0.24 (95% CI 0.06–1.02) (p = 0.04). 

Conclusion: The results showed PFS advantage of TBI conditioning prior to HCT in 

newly diagnosed MCL patients and no OS advantage. 


1085P FIRST 100 DAYS OUTCOME OF AUTOLOGOUS 

NON-CRYOPRESERVED PERIPHERAL BLOOD STEM CELL 

TRANSPLANTS IN MULTIPLE MYELOMA 

S. Kayal 1 , V. Raina 1 , A. Sharma 1 , R. Kumar 2 , S. Iqbal 1 

1 Dept. of Medical Oncology, All India Institute of Medical Sciences (AIIMS) 

Institute Rotary Cancer Hospital, New Delhi, INDIA, 2 Lab Oncology, All India 

Institute of Medical Sciences, New Delhi, INDIA 

Background: We report the outcome of autologous stem cell transplant (ASCT) in 

multiple myeloma (MM) after high dose melphalan with peripheral blood stem cell 

(PBSC) rescue without cryopreservation in terms of feasibility, safety and 100 day 

morbidity and mortality. 

Methods: Between Sept 1994 and Feb 2012 a total of 81 patients (56 males, 25 

females) were treated with non cryopreserved ASCT, with conditioning regimen of 

high dose melphalan 140-200 mg/m 2 given on day-1. PBSC was collected after 

G-CSF mobilization with a mean number of leukapheresis of 1.5 (range 1-3) and was 

stored at 4 0 C for 1-3 days (median = 2) before reinfusion on day 0. The median 

MNC was 3.0 x 10 8 /kg (range 0.99 – 8.07) and CD34 dose was 2.34 x 10 6 /kg (range 

0.18 – 7.67). 

Results: Median age was 50 years (range 22-65). The median time from diagnosis 

to transplant was 12.1 months (range 4.3 - 99.9). Prior to transplant, 67 patients 

(83%) had chemosensitive disease (CR, VGPR, PR) and 13(16%) had 

chemoresistant (stable, refractory or progressive) disease. Forty five (55%) patients 

had an ECOG PS of 0-1. The median score for hematopoietic cell transplant 

comorbidity index (HCT-CI) was 0 (range 0-6). The median time to neutrophil 

engraftment was 10 days (range 8-27) and platelet engraftment was 14 days 

(range 9-38). Febrile neutropenia occurred in 98.7% patients with a clinically 

defined focus observed in 14.8%, microbiologically documented infection in 27.1% 

and fever of unknown origin in 56.7% cases. Antibiotics were used for a median 

of 10 days (range 5-42). Total toxicity score (sum of toxicity grades for all organs 

as per Seattle criteria) ranged from 0-13 (median =2) and the median length of 

hospital stay (LOS) was 18 days (range 12-62). Day 100 mortality was 2.4% (n = 

2). Disease status post transplant was CR in 14.8%, VGPR in 60.4% and PR in 

11.1% with stable or refractory disease in 8.6%. LOS significantly correlated with 

age ≥ 50 yrs and HCT-CI of > 0 (p = 0.028 and 0.007 respectively) but not with 

ECOG PS (p = 0.28). Cumulative toxicity score had no significant correlation with 

either age, HCT-CI or PS. 

Conclusion: ASCT in MM using non cryopreserved PBSC graft is safe and effective. 

It may be a prudent alternative with potential for wider applicability. 


1086P AGGREGATED ANALYSIS OF REPORTED EFFICACY FOR 

SALVAGE AUTOLOGOUS STEM-CELL TRANSPLANTATION 

FOR MYELOMA 

D.P. Smethurst 

Medical, Immunoncore Ltd, Oxfordshire, UNITED KINGDOM 


The rate of complete response (CR) achieved soon after autologous stem cell 

transplantation (ASCT) is often used as a measure of relative success when 

comparing interventions in similar or randomized identical settings. New therapies 

are often tried in salvage and rescue settings early on in development and some of 

these therapies may electively or necessarily be combined with ASCT also in the 

rescue/salvage setting. Response rates in such settings are anecdotally low however 

few studies exist and many variables confound their understanding not least of which 

is the small numbers of patients involved. 

Methods: A pubmed/medline/googlescholar search strategy along with 

hand-searching key haematology and oncology journal archives and key paper 

bibliographies was adopted. 13 published cohorts were identified that reported CR as 

an outcome from second/salvage ASCT across a total of 1064 patients (table 1). 

Reported data that included patients who did not have measurable disease (i.e. 

already in CR) going into the second transplant were excluded as the intent was to 

observe salvage ASCT effects in measurable disease. Complete response rate (CR), 

Event free survival/Progression free survival (EFS ∼ PFS were considered heuristically 

similar) and overall survival (OS) were aggregated. Weighted mean estimates (WME) 

of efficacy were derived for each setting adjusted according to the number of patients 

associated with each CR rate. 

Results: The WME CR rate after a second ASCT was calculated to be ∼24%. 

Aggregated WME of EFS was 11.2 months and OS 20.8 months. 

Conclusions: Complete responses can be expected in approximately 1 in 4 patients 

who are selected for clinical trials and given a second transplant for relapsed or 

non-responding disease. Variability in reported rates is considerable.CR rate Percent 

Number of Patients PFS/EFS months OS months 



Table: 1086P 

CR rate % 

Number of 

patients 

PFS/EFS 

Months OS Months 

Krishnan 2011 35 295 

Olin 2007 5 41 8.5 20.7 

N Shah 2011 11 44 12.3 31.7 

Simpson 2007 33 45 12.5 30.6 

Jiminez 2011 7 81 

Mehta 1998 33 42 12.5 32 

Qazilbash 2006 21.4 14 6.8 29 

Elice 2006 3.8 26 14.8 38.1 

Giaccone 2011 17.4 46 

Cavo 2007 19.4 103 

Sirohi 2002 31.3 94 10.5 15 

Rosinol 2012 11 85 

Cook 2011 26 148 

Sum 1064 

Weighted Average 23.8 11.3 20.8 

Disclosure: D.P. Smethurst: Full time employee of Immunocore Ltd. and 

Consultant to Adaptimmmune Ltd. Share options in Immunocore Ltd. and 

Adaptimmune Ltd. 

1087P LEUKOCYTOSIS IN POLYCYTHEMIA VERA AND 

SPLENOMEGALY IN ESSENTIAL THROMBOCYTHEMIA ARE 

INDEPENDENT RISK FACTORS OF HEMORRHAGE 

Y. Chou 1 , J. Gau 1 , J. Liu 1 ,Y.Yu 1 ,J.Pai 2 , L. Hsiao 1 , Y. Hong 1 , C. Liu 1 , P. Chen 1 , 

C. Tzeng 1 

1 Department of Medicine, Division of Hematology and Oncology, Taipei Veterans 

General Hospital, Taipei, TAIWAN, 2 Department of Medicine, National Yang-Ming 

University Hospital, Yilan, TAIWAN 

Background: Long term outcomes are generally favorable for patients with 

polycythemia vera (PV) or essential thrombocythemia (ET), however, complications 

of thrombosis and hemorrhage do cause significant morbidity and mortality. 

Methods: Patients diagnosed with PV (n = 101) and ET (n = 146) in a single medical 

center from 2001 to 2010 were retrospectively recruited for analysis. 

Results: The median overall survival (OS) was 111 months for patients with PV and not 

reached for ET (p = 0.872) after a median follow-up period of 36 months. Patients with 

PV and ET shared similar hemorrhage-free survival (HFS) (p =0.410). 17.8% of patients 

with PV and 18.5% of ET has experienced complications of hemorrhage (p =1.000) 

while 9.9% of patients with PV and 14.4% of ET had major bleeding which necessitated 

blood transfusion, hospitalizations or caused mortality. Upper gastrointestinal bleeding 

was most frequently encountered followed by intracranial hemorrhage (ICH) and 

subdural hemorrhage (SDH). Univariate analysis revealed age ≥ 60 years (OR: 4.77, 95% 

CI: 1.03-22.15, p = 0.046) and WBC ≥ 16 x10^9/L (OR: 4.15, 95% CI: 1.41-12.24, p = 

0.010) as risk factors predicting hemorrhage in PV patients, while for ET patients, the 

risk factors of hemorrhage includes age ≥ 60 years (OR: 3.25, 95% CI: 1.06-10.03, p = 

0.040), WBC ≥ 16 x10^9/L (OR: 2.89, 95% CI: 1.15-7.25, p = 0.024), albumin< 4.0 g/dl 

(OR: 4.10, 95% CI: 1.67-10.09, p = 0.002), and splenomegaly (OR: 5.19, 95% CI: 

1.80-14.95, p = 0.002). Medications for treating or preventing thrombosis and 

cytoreductive agents such as aspirin, persantin, antiplatelet, hydroxyurea or anagrelide 

demonstrated no elevated risk of hemorrhage of statistical significance. Multivariate 

analysis showed that WBC ≥ 16 x 10^9/ L was the only significant risk factor of 

hemorrhage in PV patients (OR: 3.51, 95% CI: 1.16-10.58, p = 0.026) and splenomegaly 

the only risk factor in ET patients (OR: 3.54, 95% CI: 1.25-10.00, p = 0.017). The risk 

factors of WBC ≥ 16 x10^9/L and splenomegaly also predicted worse HFS for PV and 

ET patients, respectively (p = 0.041 for PV and 0.009 for ET, respectively). 

Conclusion: Although the pathogenic mechanism(s) of hemorrhage behind 

leukocytosis in PV and splenomegaly in ET remains elusive, the clinical implication 

warrants further investigation. 


1088P EFFECT OF 13Q DELETION ON IL-6 PRODUCTION IN 

PATIENTS WITH MULTIPLE MYELOMA 

T. Yakout 1 , H.A. Azim 2 , N.M. Kassem 2 , R.H. Khalifa 3 

1 Medical Oncology, Cairo Oncology Center -CairoCure, Cairo, EGYPT, 2 Clinical 

Oncology Department (Nemrock), Faculty of Medicine, Cairo University, Cairo, 

EGYPT, 3 Clinical Pathology, Kasr Al-Aini Hospital, Cairo, EGYPT 

Background: Numerous studies have shown a correlation between 13q deletion and 

poor prognosis in multiple myeloma (MM), but the mechanisms are not fully 

understood. Earlier studies suggest that this lesion involves large segments or the 

entire long arm involving the retinoblastoma (Rb) gene. In myeloma, Rb gene is 

believed to downregulate interleukin -6 (IL-6) which plays a central role in the 

pathogenesis of MM. Therefore, it has been hypothesized that loss of Rb gene might 

be associated with very high expression of IL-6 and subsequent bad prognosis. 

Materials and methods: Forty MM patients and 20 matched controls were included 

in this study. Interphase fluorescence in situ hybridization (FISH) analysis was 

performed using LSI 13q14-specific probe. Serum levels of IL-6 were determined by 

ELISA. All patients received conventional chemotherapy. Refractory patients received 

other therapeutic regimen of Thalidomide or Bortezomib. 

Results: Significant increase (p < 0.001) of IL-6 production was recorded in patients 

with 13q deletion compared to patients with normal chromosome 13q status .These 

patients were also refractory to conventional chemotherapy but showed striking 

response to Thalidomide or Bortezomib. 

Conclusion: This study suggests that 13q deletions are associated with increased 

production of IL-6 in MM and this could be a possible cause of the associated bad 

prognosis. In addition, the results also show the potential to improve responses in 

patients with refractory MM with the introduction of novel therapies. 


1089P MALNUTRITION AT DIAGNOSIS INDEPENDENTLY PREDICTS 

MORTALITY IN PATIENTS WITH SYSTEMIC 

IMMUNOGLOBULIN LIGHT-CHAIN AMYLOIDOSIS (AL) 

R. Caccialanza 1 , G. Palladini 2 , C. Klersy 3 , E. Cereda 1 , C. Bonardi 1 , L. Quarleri 1 , 

G. Merlini 2 

1 Nutrition and Dietetics Service, Fondazione IRCCS Policlinico San Matteo, 

Pavia, ITALY, 2 Amyloidosis Research and Treatment Center, Biotechnology 

Research Laboratories, Department of Molecular Medicine, Fondazione IRCCS 

Policlinico San Matteo and University of Pavia, Pavia, ITALY, 3 Biometry and 

Clinical Epidemiology Service, Fondazione IRCCS Policlinico San Matteo, Pavia, 

ITALY 

Rationale: We have previously shown that malnutrition is associated with reduced 

survival in outpatients with immunoglobulin light-chain amyloidosis (AL). However, 

these findings were obtained in a mixed population of treated and untreated patients 

with different disease duration and in whom the Mayo Clinic cardiac staging system 

was not considered. The aim of this study was to investigate the prognostic role of 

nutritional status of AL patients at diagnosis. 

Methods: One hundred and twenty eight consecutive newly diagnosed and 

previously untreated patients with AL were enrolled. Anthropometric, biochemical 

and clinical variables were measured. 

Results: Prevalence of relevant unintentional weight loss (WL; ≥10% in 6 months), 

reduced body mass index (BMI;

Patients: From November 2002 to May 2010, 634 patients with CML in any stage of 

the disease were treated with imatinib at our tertiary cancer research institute. 

Among them 274 were female and 221 were of 17 to 50 years age group. We report 

information of 8 accidental pregnancies and 10 planned pregnancies involving 18 

patients (10 females and 8 males) who conceived while receiving imatinib for the 

treatment of CML. 

Observations: Among 10 pregnancies reported in female sufferers there were two 

spontaneous and one elective abortion all in unplanned group and seven live births 

including one twin. There was one case of hypospadius which could be surgically 

corrected. Among the eight male patients whose wives conceived four pregnancies 

were planned, there was one spontaneous abortion, two elective abortions. The 

conceptions resulted in the birth of five healthy babies (two females). There was no 

other identifiable congenital anomaly. 

Discussion: In the patients, who do become pregnant while on treatment, balancing 

the risk to the fetus of continuing imatinib versus the risk to the mother of 

interrupting treatment remains difficult. From the fetal perspective, imatinib should 

be discontinued due to the potential risk of serious developmental abnormalities; 

from the maternal perspective also there is chance of drug interruption induced 

cytogenetic relapse. In conclusion, exposure to imatinib during pregnancy might 

result in an increased risk of serious fetal abnormalities or spontaneous abortion. 

Women and men (pregnant wife of male patient) with childbearing potential should 

use adequate contraception while taking imatinib. 


1091P IMPACT OF NUTRITION ON TREATMENT OUTCOME IN 

ACUTE LYMPHOBLASTIC LEUKAEMIA OF CHILDHOOD IN 

DEVELOPING COUNTRY 

S. Poddar 1 , A. Mukhopadhyay 1 , P. Hor 1 , A. Nandi 1 , P. Gupta 1 , 

S. Mukhopadhyay 2 

1 Medical Oncology, Netaji Subhas Chandra Bose Cancer Research Institute, 

Kolkata, INDIA, 2 Medical Oncology, Calcutta Hospital Calcutta, West Bengal, 

Kolkata, INDIA 

Background: All conventional modalities of anti-cancer therapy interfere with 

normal nutrition. Therefore, malnutrition is a major problem in children with 

cancer. In this study we retrospectively analyzed 500 children suffering from Acute 

Lymphoblastic Leukemia (ALL), who were being intensively treated by National 

Cancer Institute protocol (MCP 841) during period beginning from August, 1999 to 

December, 2011, in a tertiary cancer institute. Our aim was to determine the 

nutritional status at preliminary diagnosis of ALL children and to study the influence 

of nutrition on complete remission, disease free survival (DFS) and 

chemotherapeutic toxicity. 

Procedure: The variables studied were height for age (HFA), weight for age (WFA), 

mid-arm circumference (MAC), biceps skinfold thickness (BSFT) and serum 

albumin levels. The HFA, WFA, MAC and BSFT were taken as normal if they were 

between 3rd and 97th percentile curve of the growth chart as recommended by the 

Indian Council of Medical Research (ICMR). The albumin level was considered 

normal if the value was equal to or more than 3g%. 

Results: It was observed that 16.8% children were low weight for age and 10.4% were 

low height for age during diagnosis. Low WFA (p value 0.001), low HFA (p value 

0.0001) and low albumin (p-value 0.0001) were significant in DFS. 

Conclusion: We conclude that malnutrition has high impact on ALL prognoses in 

developing countries. Major nutritional indicators are HFA, WFA, MAC, BSFT and 

serum albumin. Patients with malnutrition have less DFS duration, more chances for 

relapse and more therapeutic toxicity when compared to well-nourished children. 


1092P COST OF TREATMENT OF ACUTE MYELOID LEUKEMIA – 

EXPERIENCES FROM A DEVELOPING COUNTRY 

D. Arya 1 , B. Parikh 2 , P.M. Shah 2 , K.M. Patel 2 , S.N. Shukla 2 , A.S. Anand 2 , 

S.S. Talati 2 , S.A. Shah 2 , A.A. Patel 2 , B.B. Parekh 2 

1 Medical Oncology, Action Cancer Hospital, Delhi, INDIA, 2 Dept. of Medical and 

Pediatric Hemato Oncology, Gujarat Cancer and Research Institute Civil Hospital 

Campus, M.P. Shah Cancer Hospital, Ahmedabad, INDIA 

Background: Acute Myeloid leukemia (AML) is a difficult disease to treat requiring 

specialised induction facilities, doctors, supportive staff and laboratory services. We 

try to analyse how the cost of diagnosis and treatment combined with socio-cultural 

and logistical issues affect treatment delivery and outcomes in AML in developing 

countries like India. 

Materials and methods: We conducted a retrospective analysis of case records of 

adult patients diagnosed with AML between 2009 and 2010 at the Gujarat Cancer 

and Research Institute, Ahmedabad, India. Patients diagnosed with AML-M3 were 

excluded. Data reviewed included epidemiological and demographic details, AML 

subtype, cytogenetic anomalies, co morbidities, treatment offered, complications, and 


duration of hospital stay. Billing information and other relevant data were retrieved 

from the hospital electronic records and analysed. 

Results: A total of 76 case records of patients with AML were identified (excluding 

AML- M3). Females comprised 51% of all patients. Majority of diagnosed patients 

(65%) worked as daily wage labourers. AML-M1 was the predominant subtype 

(35%). Three % patients expired during initial workup and 27% were offered 

supportive care only in view of significant co morbidities, advanced age or poor 

performance status. Thirty four % patients refused treatment because of financial, 

social or logistical constraints. Only 37 % of all patients received standard 7 + 3 

(cytosine arabinoside with daunorubicin) induction treatment. Complication rate 

during induction therapy was 71% with induction mortality rate being 8%. Average 

stay in hospital was 34 days and cost of remission induction was equivalent of 1000 

dollars with nearly 85% of that amount spent for supportive care. Remission rate was 

71%, however only 29% patients were disease free at one year. Survival rate at one 

year was 61%. 

Conclusions: Nearly one third of patients were not candidates for standard treatment 

in view of significant co morbidities, advanced age or poor performance status. Only 

50% of patients candidate for standard treatment received it with the rest refusing the 

same due to financial constraints, expected prolonged hospital stay, lack of social 

support and logistical issues. 


1093P BCR ABL FUSION PROTEIN DETECTION BY A MODERN 

APPROACH: FLUROSCENT IMMUNO BEAD ASSAY 

S. Dasgupta 1 , U.K. Ray 1 , A. Mukhopadhyay 2 , J. Basak 1 , S. Mukhopadhyay 1 

1 Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, 

Kolkata, INDIA, 2 Dept. Medical Oncology, Netaji Subhas Chandra Bose Cancer 

Research Institute, Kolkata, INDIA 

Introduction: Chronic Myeloid Leukemia (CML) is probably the most extensively 

studied human malignancy. CML patients (90-95%) harbor the Philadelphia (Ph) 

chromosome, a shortened chromosome 22, resulting from a reciprocal 

translocation t (9; 22) (q34; q11) between the long arms of chromosome 9 and 

22, fusion ABL proto-oncogene on chromosome 9 with the BCR gene on 

chromosome 22. BCR-ABL fusion gene plays a key role in pathogenesis of the 

disease. Approximately 15-30% of adult and 2-5% of childhood ALL and


cardiovascular disease (CVD), by monitoring specific markers of the coagulation 

profile. 

Material and methods: The study comprises 40 patients divided in 2 groups: 20 

patients with ET (ET) and 20 patients with ET with CVD associated (ET + CVD). 

The patients were tested by determining three factors of coagulation profile: von 

Willebrand factor, Protein S and PAI-1, before and after administration of 

anticoagulant therapy. Warfarin® was administrated as anticoagulant treatment, in 

doses that were adjusted according to the INR (International Normalized Ratio) 

values. 

Results: The level of the studied parameters were found significantly modified in 

both groups of patients (ET, ET + CVD) (p < 0,001). After the administration of 

anticoagulant treatment, in the first group (ET), it was observed a direct correlation 

between the treatment and the values of investigated parameters; in this group, the 

levels of studied parameters returned close to normal values. This correlation was less 

evident in the second group of patients (ET + CVD), as the monitored values, 

although lower than the levels at the begining of the treatement, remained within 

pathologic levels. 

Conclusions: In ET the risk for thrombosis is due to endothelial dysfunction and 

changes in prothrombotic circulating factors. The anticoagulant treatment prevents 

only partially the occurrence of thrombotic events, but does not completely stop it. 

In spite of the anticoagulant therapy, the patients with ET present a high risk for 

developing thrombotic complications. 


1095 APLASTIC ANEMIA: A SINGLE INSTITUTION EXPERIENCE 

M. Almeida 1 , L. Queiroz 1 , N. Domingues 2 , A. Espírito-Santo 2 , I. Oliveira 2 , 

Â. Oliveira 2 , I. Moreira 2 , L. Viterbo 2 , J. Mariz 2 

1 Medical Oncology, Hospital de Braga, Braga, PORTUGAL, 2 Onco-Hematologia, 

Portuguese Insittute of Oncology - Porto, Porto, PORTUGAL 

Background: Aplastic anemia (AA) is an extremely rare disease characterized by 

pancytopenia and hypocellular bone marrow (BM). Diagnosis is difficult and requires 

high degree of suspicion. Bone marrow transplantation (BMT) and 

Immunosuppressive Therapy (IST) are the only therapeutic options with a curative 

aim. 

Objectives: Analysis of clinical and pathological features, therapeutic approach and 

overall survival of patients diagnosed with idiopathic AA in IPO-Porto. 

Methods: Retrospective analysis of idiopathic AA patients from September/1995 to 

October/2011. The overall survival (OS) analysis was performed by Kaplan Meier 

method. 

Results: During this period, 12 patients were identified with a median age of 31 

years (16-49), 75% were younger than 40 years. 50% were female. The main 

symptom at diagnosis was asthenia (58.3%), followed by ecchymosis (16.7%) and 

fever (16.7%). At diagnosis, 33.3% had neutrophil counts less than 1.5x10 9 /L and 

41.7% had platelet counts less than 20.0x10 9 /L. All patients had BM cellularity less 

than 25%. Only one patient had BMT as 1 st line treatment; this patient is in 

complete remission with a follow-up of 15 years. The remaining patients 

underwent IST with anti-thymocyte immunoglobulin, cyclosporine and 

methylprednisolone; three patients had complete remission but relapsed, with a 

disease-free interval of 55 months. As a 2 nd line treatment, three patients received 

unrelated BMT and two had complete remission. Of the seven patients who 

underwent 2 nd line IST, three had complete remission, two underwent BMT on 

the 3 rd line, and two patients were treated, respectively, with alemtuzumab and 

cyclosporine. Patients receiving IST had a median follow-up of 56 months. Three 

deaths occurred and OS at 15 years is 70%. Patients with neutrophil counts less 

than 1.5x10 9 /L had a lower OS (P = 0.01). There was no secondary myelodysplastic 

syndromes or acute leukemias. 

Conclusion: BMT is considered to be the most appropriate treatment in young 

patients with a compatible donor. However, IST is also a valid treatment for those 

without a donor, with a good survival. 


1096 TREATMENT OF PRIMARY AND THERAPY-RELATED 

MYELODYSPLASTIC SYNDROME WITH 5-AZACYTIDINE – 

COMPARATIVE RESULTS FROM A SINGLE CENTRE 

J.S. Augusto 1 , F. Pierdomenico 2 , S. Barroso 1 , A. Almeida 2 

1 Oncology, Hospital Espirito Santo Evora, Evora, PORTUGAL, 2 Haematology, 

Instituto Portugues Oncologia Lisboa, Lisbon, PORTUGAL 

Introduction: Therapy-related Myelodysplastic Syndrome (tMDS) is a late and rare 

complication of chemotherapy, especially that with alkylating agents or 

topoisomerase II inhibitors., They are often associated with unfavourable karyotypes, 

lower remission rates and shorter survival. PURPOSE: Retrospective analysis of 

clinical, analytical and cytogenetic features of patients diagnosed with primary 

(pMDS) and tMDS treated with 5-Azacytidine (AZA) between 2005 and 2011 in our 

Institute. 

Methods: Data was obtained from patient notes and analysed with SPSS. 

Results: 48 MDS patients treated with AZA were identified. 43 patients had pMDS, 

57% male, median age of 67 years. The IPSS was Intermediate 2 in 42.9% and high 

in 40.5%; cytogenetics were normal in 33%, complex in 16.7%. A median of 7 

courses (range 1-23) of AZA were administered, 52.4% as 2 nd line therapy. Response 

assessment revealed 14.3% complete responses, 31% partial responses and 16.7% 

stable disease; best responses were reached after a median of 4 courses (range 2-6). 

Progression to secondary AML occurred in 38%; the mean survival was 25 months. 

Five patients had tMDS: 60% male, median age of 62 years. Previous chemotherapy 

included alkylating agents in 100% and topoisomerase II inhibitors in 80%. The 

median time to MDS development was 12 years. The IPPS risk was high in 80%; all 

with complex cytogenetics. A median of 6 courses of AZA were administered, 60% as 

1 st line therapy, with partial response in 40% (4 courses until response) and failure in 

60%; 40% developed sAML and the mean survival was 12 months. DISCUSSION: 

Despite the small cohort size, our results were similar to those described in literature. 

Even with AZA treatment, tMDS patients had a worse clinical outcome, with shorter 

mean survival, compared to pMDS. 

Conclusion: tMDS is a rare complication of chemotherapy with a very poor 

outcome. Careful review and individualization of chemotherapeutic regimens may 

help reduce its incidence. 


1097 EXTRANODAL NON-HODGKIN LYMPHOMAS IN A NORTHERN 

PORTUGAL INSTITUTION - 2006/2010 

L. Queiroz 1 , A.D. Marques 1 , M. Almeida 1 , E. Couto 1 , I. Trindade 2 , C. Portela 1 , 

J. Amorim 1 , T. Macedo 2 , R. Nabiço 1 , H. Marques 1 

1 Medical Oncology, Hospital de Braga, Braga, PORTUGAL, 2 Internal Medicine, 

Hospital de Braga, Braga, PORTUGAL 

Introduction: Non Hodgkin lymphomas (NHL) can arise in nodal or extranodal 

lymphoid tissue. In about 20% of cases the initial presentation affects the extranodal 

sites, which characterize the primary extranodal NHL (PENL). 

Objectives: Analyze the clinical and pathological characteristics of patients with 

PENL and evaluate prognostic factors. 

Material and methods: Retrospective study of 66 patients diagnosed with PENL in 

an institution, between January 2006 and December 2010, and clinical-pathological 

data collection. 

Results: The median age was 63 years (17-87), 52.3% were women and 17% had 

ECOG performance status greater than two. The most frequent location was the 

stomach (32.3%) followed by skin and subcutaneous tissue (23.1%). Seventy two 

percent were high grade lymphomas and 17% had T phenotype. The most common 

histologic type was diffuse large B cells NHL (DLCBL) (55.4%). In 3 (4.6%) cases 

there was extranodal secondary attainment. 76.9% of patients had stage I or II at 

diagnosis, 29.2% had B symptoms and 23% had increased lactate dehydrogenase 

(LDH). The albumin was decreased in 7,7% of the cases and the β2 microglobulin 

levels were increased in 12,3% of patients. Sixty-three percent were in the category of 

low-risk IPI. Seventy seven percent of patients underwent chemotherapy, 4.6% 

primary radiotherapy (RT) and 28% adjuvant radiotherapy. Seventy two percent of 

patients had complete remission and 23,1% were submitted to a second line 

treatment. In a median follow-up of 31 months, 13.8% relapsed. The estimated 

survival at 50 months was 79%. The high levels of LDH and β2 microglobulin, low 

albumin, high IPI and ECOG and extraganglionar secondary involvement constituted 

factors of poor prognosis. 

Conclusion: This study showed a high prevalence of PENL of gastric and cutaneous 

location and of histologic subtype DLCBL. Most patients presented in early stages 

and with low IPI prognosis index. The response to primary treatment and the overall 

survival were high. We identify clinical and biological factors with prognostic value 

in univariable analysis. 


1098 CRIZOTINIB IN ALK-POSITIVE DIFFUSE LARGE B-CELL 

LYMPHOMA: A CASE REPORT 

M. Wass, T. Behlendorf, U. Gläser, J. Rüssel, F. Güntsch, K. Jordan, H. Schmoll 

Klinik für Innere Medizin IV, Universitätsklinikum Halle (Saale), Halle, GERMANY 

Background: Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell 

lymphoma (DLBCL) is a distinct variant of DLBCL characterized by very aggressive 

clinical course with an estimated median survival of only 11.0 months. Crizotinib, an 

ALK inhibitor, has demonstrated impressive clinical efficacy in patients with 

alk-rearranged tumors. The potential role of Crizotinib in ALK-positive DLBCL has 

not been established yet. 

Case report: A 27-year-old female patient with ALK-positive DLBCL was primary 

refractory to 6 cycles of standard chemotherapy with CHOP. She was subsequently 

treated with salvage combination chemotherapy regimens including high-dose 

chemotherapy with autologous stem-cell transplantation. However, disease followed a 

very aggressive course. 6 weeks after transplantation patient presented with right cervical 


lymphadenopathy and multiple cutaneous lesions. CT scan revealed additional bilateral 

cervical, axillary, mediastinal and abdominal lymphadenopathy and involvement of lung 

and liver. LDH levels were exorbitant elevated (233 mmol/l). On an individual base, our 

patient received the ALK inhibitor Crizotinib 250 mg per os twice daily. No 

glucocorticoids or other drugs with antineoplastic activity were co-administered. Within 

72 hours LDH levels were halved (89 mmol/l). On day 8 cervical palpable 

lymphadenopathy disappeared. Initial erythematous papular cutaneous lesion decreased 

from 4.0 x 2.5 cm to a residual hyperpigmented macule of 1.5 x 2.5 cm. On day 16 LDH 

levels were almost within normal limits (6 mmol/l). However, remission was not 

sustained and patient developed resistance to Crizotinib. By day 21 after beginning the 

treatment with Crizotinib LDH levels increased again and patient presented with a 

swollen left arm due to lymphatic obstruction, detected by CT scan, which showed a 

general progressive disease, causing death one month later. 

Conclusion: To our knowledge, this is the first case which reports sensitivity in 

ALK-positive DLBCL to ALK inhibition with Crizotinib. Despite remission duration 

was short our results indicate a potential role of ALK in the pathogenesis of 

ALK-positive DLBCL and suggest ALK inhibition as a potential treatment modality 

in the therapy of this fatal disease. 


1100 LIVER INVOLVEMENT BY LYMPHOMA – INDICATOR OF POOR 

RESPONSE AND MORTALITY 

S. Kumar, I.A. Muazzam, N. Siddiqui, N. Muzaffar, K. Das, U.E.K. Awan 

Medical Oncology, Shaukat Khanum Memorial Cancer Hospital and Reserch 

Centre (SKM), Lahore, PAKISTAN 

Total = 46 Hodgkin’ Lymphoma (n = 24) 

Heptic 

(n = 12) Non-hepatic = 12 

NonHodgkin’s Lymphoma 

(n = 22) 

hepatic 

(n = 5) 

Non-hepatic 

(n= 17) 

B-symptoms 9 (75%) 9 (75%) 3 (60%) 17 (77%) 

Bulky 1 (8%) 1 (8%) 1 (20%) 7 (41%) 

CR 8 (67%) 12 (100%) 4 (80%) 11 (64%) 

PR 2 (16.5%) 0 (0) 1 (20%) 6 (36%) 

PD 2 (16.5%) 0 (0) 0 (0) 0 (0) 

ORR = CR + PR 83.5% 100% 100% 100% 

Died 4 (33%) 0 (0) 1 (20% ) 6 (36%) 

Introduction: Hepatic involvement is more common in Non-Hodgkin’s as compared 

to Hodgkin’s Lymphoma (HL) at presentation. It is a poor prognostic feature. We 

determined prognosis of our stage IV lymphoma patients who had liver involvement 

at baseline. 

Material and method: In last 1 year, 70 patients presented in our lymphoma clinic 

with stage IV disease. Out of these, 46 had completed their treatment at the time of 

analysis. Diagnosis of lymphoma was confirmed on excision or core biopsy of a nodal 

site at presentation. PET/CT was done for staging before starting chemotherapy and 

response assessment was done after 2-4 cycles of planned chemotherapy. Histologic 

evaluation of any residual FDG-avid disease was made in patients who responded to 

chemotherapy at all the other sites. Response rate (RR) was calculated by adding 

percentage of patients in complete (CR) and partial (PR) remission. 

Results: Out of these 46 patients, 24 had HL and intermediate-to-high grade NHL was 

diagnosed in 22 patients. Median age at diagnosis was 29.5 years (range 16 to 60). 

Secondary liver involvement was found in 17 patients (HL = 12/24; NHL = 5/22). More 

NHL patients presented with B-symptoms and bulky disease than HL. Presence of 

liver involvement predicted a lower response to initial therapy in patients with HL (RR 

83.5%) as compared to NHL (RR 100%). Despite this initial response to treatment, 

one-third of advanced stage HL patients died before the completion of therapy. Such 

relationship was not observed in advanced stage NHL patients (see table). 

Conclusion: Despite initial response to treatment, secondary liver involvement at 

presentation predicted higher mortality in stage IV HL patients. This effect should be 

further validated in larger studies. 


1101 AN OVERVIEW OF YOUNG CHRONIC LYMPHOCYTIC 

LEUKEMIA PATIENTS: A SINGLE CENTRE EXPERIENCE OF 

117 CASES FROM NORTHERN INDIA 

A. Gogia 1 , A. Sharma 1 , V. Raina 2 , L. Kumar 1 , R. Gupta 3 , R. Kumar 3 

1 Medical Oncology, All India Institute of Medical Sciences, New Delhi, INDIA, 


Institute Rotary Cancer Hospital, New Delhi, INDIA, 3 Lab Oncology, All India 

Institute of Medical Sciences, New Delhi, INDIA 

Background: In this study, the clinical characteristics, survival, and prognostic factors 

of 117 cases of young ( = < 55 years) chronic lymphocytic leukemia (CLL) patients 

were analysed at IRCH, AIIMS, a large tertiary care centre of Northern India. 


Methods: Patients records collected from computer database using ICD code 

(C-91.1) between period of 2000-2010 were retrospectively evaluated. 

Results: Over a period of 11 years, 285 CLL patients (117 [41.05%] = < 55 years of 

age and 168 [58.95%] > 55 years of age) were evaluated. There were similar 

distribution of sex, lymphadenopathy, organomegaly, and absolute lymphocyte 

count in both groups At diagnosis, younger patients were less incidentally detected 

(p < .0001), more B- symptoms (p = 0.001) and advanced Rai stage ( p = 0.021), 

than older patients. Response rate and toxicity profile were same in both groups 

with chlorambucil and fludarabine based chemotherapy. Overall response rate 

(ORR) seen with chlorambucil and fludarabine was 69% and 88% with complete 

remission (CR) rate was 3% and 44 % respectively. Richter’s transformation was 

significantly higher in younger patients (3.41% v 0.5%; p = 0.001). Median follow 

up period was 36 months. Younger and older patients showed a similar overall 

median survival but were characterized by a different distribution of causes of 

deaths. CLL unrelated deaths predominated in the older age group, as one third 

of patients have different co-morbities like diabetes, hypertension, coronary artery 

disease e.t.c, whereas the disease related death were prevalent in the younger age 

group. Multivariate analysis showed that for young CLL patients, advanced clinical 

stage (Rai III and IV) was associated with poor overall survival [HR 2.08 (95% CI 

1.19-4.11) p = 0.001]. 

Conclusion: Forty one percent our CLL population was young. Young CLL patients 

presented with more B symptoms and advanced stage (Rai III and IV) than elderly 

CLL patients. 


1102 CHRONIC MYELOID LEUKEMIA IN CHILDREN- EXPERIENCE 

WITH IMATINIB MESYLATE AT A REGIONAL CANCER 

INSTITUTE, BANGALORE, INDIA 

K.V. Belathur, L. Appaji, K.C. Lakshmaiah, A.K. B S,, S. Purohith, D. 

S. Madhumathi 

Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, INDIA 

Background: Childhood Philadelphia chromosome-positive (Ph+) CML constitutes 

about 3- 5% of the total leukemias. Allogeneic stem cell transplantation (SCT) offers 

best survival but in view of unaffordability and non availability of suitable donor, 

Imatinib Mesylate becomes the next best treatment option. The present study was 

thus undertaken to evaluate the clinical profile, response, survival and adverse effects 

of the drug. 

Methods: This is a retrospective study of Ph + CML in the age group of 4-18 yrs, at 

Medical & Paediatric Oncology department of our institute.50 patients of CML, 

enrolled under the Glivec International Patient Assistance Program (GIPAP) between 

Jan 2004 to Dec 2011 and started on Imatinib at 340 mg /m2/day were analyzed. 

Complete hemogram, liver function tests, bone marrow aspiration studies and 

BCR-ABL by RT-PCR were done at intervals as per institution protocol. 

Results: Mean age of patients enrolled in the study was 12.8 yrs. Mass and pain 

abdomen were the predominant presentations in 21(42%) and 18(36%) respectively. 

One patient each was in accelerated phase and blast crisis. Complete Hematological 

Response (CHR) was achieved in 100% with 43 (86%) within 3 months. Complete 

cytogenetic response was achieved in 20(40%) with median duration of 14 months 

(8-18).13(26%) patients showed Major molecular response with a median of 16 

months (6-29) & complete molecular response in 4 (8%) with a median of 21 

months(16-22). One out of 4 patients with progressive disease is in blast crisis 

waiting for transplantation, 3 are on escalated dose of Imatinib and either Cytarabine 

or Interferons to maintain CHR. All 4 were negative for Imatinib Mutations. Most 

common adverse events were grade 1/2 skin toxicities and weight gain in about 40% 

of patients. About 8 (16%) patients had grade2/3 myelosupression which was 

manageable. Event free survival and overall survival were 94.4% and 64% at a median 

follow up of three years.Sokal score was evaluated with respect to the survival 

outcome but was not found to be statistically significant. 

Conclusions: In view of good response and tolerance, our results reaffirm previously 

reported favorable results from various other centers. Imatinib can be considered as 

an alternative to SCT in Pediatric CML population to improve the survival and 

merits further evaluation. 


1103 COMPLICATIONS OF “VERY HIGH” LEUKOCYTOSIS IN 

PEDIATRIC ACUTE LEUKEMIA PATIENTS MANAGED 

WITHOUT RASBURICASE AND LEUCOPHERESIS 

R.B. Singh, K. Munot, S. Pathania, S. Bakhshi 

Dept. of Medical Oncology, All India Institute of Medical Sciences (AIIMS) 

Institute Rotary Cancer Hospital, New Delhi, INDIA 

Background: Hyperleukocytosis in pediatric leukemias is associated with acute 

complications of tumor lysis syndrome (TLS) and leucostasis. In developing 

countries, rasburicase is not available and even if available, it may not be affordable 

by all patients. Rasburicase became freely available in India in 2010. We evaluated 



acute complications pertaining to hyperleukocytosis in pediatric acute leukemia 

patients prior to free availability of rasburicase, and without leucopheresis. 

Method: Records of pediatric acute leukemia patients and “very high” leucocytosis 

(VHL) (WBC > 100,000/mm 3 in AML and > 200,000/mm 3 in ALL) were analyzed. 

None of these patients received rasburicase and /or leucopheresis. Patients were 

managed with allopurinol and aggressive hydration. Data was analyzed for baseline 

presentation, TLS and other complications pertaining to leucostasis. 

Results: Out of 457 pediatric acute leukemia patients from Jun 2003-Dec 2009, there 

were 45 (10%) patients with VHL. Median age was 10 years (SD-4.4; range 3-18) and 

male: female ratio was 6.5:1. B-ALL, T-ALL and AML constituted 11 (24.4%), 16 

(35.5%) and 18 (39.9%) patients respectively. Mean baseline WBC for ALL and AML 

patients was 296,500/mm 3 (SD- 104,793; range 200,000-615,220) and 206,300/mm 3 

(SD- 110,000; range 106,100-541,900) respectively. Laboratory TLS was seen in 17 

(37.7%) patients [ 2 (4.4%) at baseline while 15 (33.3%) patients developed it after 

chemotherapy initiation]. Clinical TLS was observed in 6 (13.3%) and renal 

dysfunction in 7 (15.5%) patients; none required dialysis. CR was achieved in 32 

(71.1%) pts and there were 3 (6.6%) deaths. No relation was seen between laboratory 

TLS and baseline features or mortality. Thrombocytopenia below median (

prospective non-interventional study with TEMS in rel/refr MCL-pts was started. 

Here we report on interim results of the study. 

Methods: A registry for rel/refr MCL pts treated with TEMS was started in Germany 

in Oct 2009 (NCT00700258). Primary objective: evaluation of the safety profile of 

TEMS, secondary objectives: tolerability and anti-tumor activity of TEMS, patient’s 

profile and the sequence of systemic therapies. 

Results: 29 pts have been recruited in 12 active centers until Apr 2012. Baseline 

characteristics are available for 23 pts: 69.6% male; median age 72.1 yrs; ECOG PS 0 

or 1 in 74%, ECOG PS 2 in 26% of the pts; MIPI score: 13.0%, 30.4%, and 56.5% of 

the pts are classified as low, intermediate and high risk at the time of enrollment; Bone 

marrow involvement: 47.8% of the pts. Median time between diagnosis and start oft 

treatment with TEMS is 36 months. The median number of prior therapies is 5 with 

65.2% treated in ≥5 th line. Most frequent adverse events are leucopenia, anaemia and 

thrombocytopenia. Severe adverse events (drug related) are general, metabolism, 

psychiatric disorders and infections (in 2 pts each), thrombocytopenia, leukocytosis, 

skin and renal disorder (in 1 pt each). Preliminary efficacy analyses (n = 18) shows a 

clinical benefit in 7 pts, PD in 5 pts and 6 pts are not assessable. Median PFS 

(assessable pts) is 157 days. 

Conclusions: This registry was started to evaluate the safety and efficacy of TEMS in 

pts with rez/refr MCL in the clinical routine. Though the here included pts are more 

heavily pretreated TEMS shows a predictable, acceptable toxicity and efficacy remains 

comparable with phase III-data. 

Disclosure: G. Krekeler: Employee of Pfizer Pharma GmbH GermanyC. Herzberg: 

Employee of Pfizer Pharma GmbHM.H. Dreyling: Pfizer: Scientific advisory Board, 

speaker’s honoraria, support of IITsG. Hess: Research funding and speaker honoraria 

from PfizerD. Kalanovic: Employee of Pfizer Pharma GmbH, Germany. 

1108TiP DENOSUMAB COMPARED WITH ZOLEDRONIC ACID FOR 

PREVENTING SKELETAL COMPLICATIONS IN PATIENTS 

WITH MULTIPLE MYELOMA: A RANDOMIZED, PHASE 3, 

DOUBLE-BLIND, DOUBLE-DUMMY TRIAL 

A. Palumbo 1 , B.G. Durie 2 , N. Raje 3 , R. García Sanz 4 , O. Sezer 5 , K. Shimizu 6 , 

E. Terpos 7 , W. Willenbacher 8 , Y. Qian 9 , A. Balakumaran 10 

1 Division of Hematology, University of Torino, A.O.U., Torino, ITALY, 

2 Hematology, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, UNITED 

STATES OF AMERICA, 3 Hematology/Oncology, Massachusetts General Hospital 

Cancer Center, Boston, MA, UNITED STATES OF AMERICA, 4 Hematology, 

University Hospital of Salamanca, Salamanca, SPAIN, 5 Hematology and 

Oncology, University Medical Center Hamburg, Hamburg, GERMANY, 

6 Multimodal Therapy For Multiple Myeloma, Aichigakuin University School of 

Dentistry, Nagoya, JAPAN, 7 Department of Clinical Therapeutics, University of 

Athens School of Medicine, Athens, GREECE, 8 Hematology and Oncology, 

Medical University of Innsbruck, Innsbruck, AUSTRIA, 9 Biostatistics, Amgen Inc., 

Thousand Oaks, CA, UNITED STATES OF AMERICA, 10 Global Development, 

Amgen Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA 

Patients with multiple myeloma (MM) experience osteolytic bone destruction 

resulting in skeletal-related events (SREs: pathologic fracture, spinal cord 

compression, surgery or radiation to bone). Severity of bone destruction 

correlates with significant morbidity and is associated with decreased survival. 

Osteoclast activity is enhanced in MM and is primarily regulated by RANK 


Ligand (RANKL) and osteoprotegerin. Denosumab is a fully human monoclonal 

antibody which binds RANKL, preventing activation of RANK and inhibiting 

osteoclast differentiation, activation and survival. Bone resorption and 

cancer-induced bone destruction are thereby reduced. Denosumab was superior 

to zoledronic acid (ZA) in 3 large randomized trials in patients with breast, 

prostate, or solid tumors-only analysis. Denosumab is approved for the 

prevention of SREs in patients with bone metastases from solid tumors in many 

regions worldwide. The current trial will evaluate the efficacy and safety of 

denosumab compared with ZA in preventing skeletal complications in patients 

with MM. The primary endpoint will determine if denosumab is non-inferior to 

ZA in prevention of the first on-study SRE. If denosumab is found to be 

non-inferior to ZA, superiority in time to first on-study SRE and time to 

first-and-subsequent SRE will be assessed as secondary endpoints. Patients will be 

randomly assigned 1:1 to receive subcutaneous (SC) denosumab 120 mg and 

intravenous (IV) placebo or IV ZA 4 mg and SC placebo every 4 weeks (Q4W). 

Randomization will be stratified by planned autologous transplantation (yes/no), 

anti-myeloma therapy (novel therapy-based vs non-novel therapy-based), disease 

stage (International Staging System 1, 2, or 3), previous SRE (yes/no), and region 

(Japan vs other). Daily supplements of calcium ≥500 mg and vitamin D ≥400 

IU will be strongly recommended. Patient screening and enrollment is underway. 

In this event-driven study, data cutoff for the primary efficacy analysis is planned 

for when approximately 800 patients are anticipated to experience an on-study 

SRE. The trial is sponsored by Amgen Inc. and registered with ClinicalTrials.gov 

(NCT01345019). 

Disclosure: A. Palumbo: Advisory Board Member: Celgene and Janssen-Cilag 

Honoraria: Celgene, Janssen-Cilag, Bristol-Myers Squibb, Millenium, Merck, Onyx 

and Amgen Consultancy: Celgene and Janssen-CilagB.G. Durie: Advisory Board 

Member: Celgene Corporation, Millenium Pharmaceuticals, and Onyx 

PharmaceuticalsN. Raje: Advisory Board Member: Celgene, Millenium, 

Amgen Corporate-sponsored Research: Eli-Lilly, AcetylonR. García Sanz: 

Honoraria: Amgen, Jansen Cilag, Celgene, NovartisO. Sezer: Advisory Board 

Member: Amgen, JanssenE. Terpos: Advisory Board Member: Amgen, 

NovartisW. Willenbacher: Advisory Board Member: AmgenY. Qian: Employee 

and Stock Ownership: AmgenA. Balakumaran: Employee and Stock 

Ownership: AmgenAll other authors have declared no conflicts of interest. 


melanoma and other skin tumors 

1109O CLINICAL ACTIVITY AND SAFETY OF ANTI-PROGRAMMED 


PATIENTS (PTS) WITH ADVANCED MELANOMA (MEL) 

J. Sosman1 , M. Sznol2 , D.F. McDermott3 , R. Carvajal4 , D.P. Lawrence5 , 

S.L. Topalian6 , J.M. Wigginton7 , G. Kollia8 , A. Gupta9 , F.S. Hodi10 1 

Melanoma and Tumor Immunotherapy Program, Vanderbilt University Medical 

Center, Nashville, TN, UNITED STATES OF AMERICA, 2 Section of Medicine 

Oncology, Yale Cancer Center, New Haven, CT, UNITED STATES OF AMERICA, 

3 

Biology Therapy Program, Beth Israel Deaconess Medical Center, Boston, MA, 

UNITED STATES OF AMERICA, 4 Melanoma-sarcoma Division, Memorial 

Sloan-Kettering Cancer Center, New York, NY, UNITED STATES OF AMERICA, 

5 

Department of Hematology/Oncology, Massachusetts General Hospital Cancer 

Center, Boston, MA, UNITED STATES OF AMERICA, 6 Melanoma Program, 

Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD, 

UNITED STATES OF AMERICA, 7 Discovery Medicine-clinical Oncology, 

Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA, 

8 

Biostatistics and Data Management, Bristol-Myers Squibb, Princeton, NJ, 

UNITED STATES OF AMERICA, 9 Discovery Medicine, Immuno-oncology, 


10 

Melanoma Center, Dana-Farber Cancer Institute, Boston, MA, UNITED 


Purpose: BMS-936558 is a monoclonal antibody that blocks the PD-1 co-inhibitory 

receptor expressed by activated T cells. This study describes its activity and safety in 

pts with previously treated advanced MEL. 

Methods: BMS-936558 was administered IV q2wk to pts with various tumors at 

0.1 − 10 mg/kg during dose-escalation and/or cohort expansion. Pts received up to 

12 cycles (4 doses/cycle) of treatment or until unacceptable toxicity, confirmed 

progressive disease, or complete response. Clinical activity was assessed by RECIST 

v1.0. 

Results: As of Feb 24, 2012, 104 MEL pts had received BMS-936558 at 0.1 (n = 17), 

0.3 (n = 19), 1 (n = 31), 3 (n = 17), or 10 mg/kg (n = 20). ECOG performance status 

was 0/1/2 in 63/38/3 pts, respectively. Most pts (67/104) had received prior 

immunotherapy (IT); prior anti-CTLA-4, -PD-1, or -PD-L1 was not permitted. The 

number of prior therapies was 1 (39%), 2 (35%), or ≥3 (26%). Median therapy 

duration was 20 wks (range 2.0 − 121.7 wks). The incidence of grade 3 − 4 related 

AEs was 20% and included gastrointestinal (4%), endocrine (2%), and hepatobiliary 

disorders (1%). There were no drug-related deaths in MEL pts. Clinical activity 

(responses or prolonged stable disease) was observed at all doses (Table). Of the 26/ 

94 (28%) evaluable responders, 19 (73%) are ongoing ranging from 1.9+ to 24.9+ 

months. For the 23 responders followed ≥6 months from first dose on study, 16 

(70%) are progression free. ORs occurred in pts with visceral or bone metastases. Six 

pts (6%; 95% CI 2 − 13%) had prolonged SD (≥24 wk); 3 pts had a persistent 

decrease in target lesion tumor burden in the presence of new lesions and were not 

categorized as responders. 

Conclusions: BMS-936558 had durable clinical benefit in pts with advanced MEL, 

including those who had received prior IT. Additional long-term follow-up data will 

be reported. 

Dose, (mg/kg) No. pts a 

ORR, 

No. pts (%) 

[95% CI] 

PFSR at 

24 wk (%) 

[95% CI] 

0.1 14 4 (29) [8 − 58] 40 [13 − 66] 

0.3 16 3 (19) [4 − 46] 31 [9 − 54] 

1 27 8 (30) [14 − 50] 45 [26 − 65] 

3 17 7 (41) [18 − 67]* 55 [30 − 80] 

10 20 4 (20) [6 − 44] 30 [9 − 51] 

*1 CR a Response-evaluable pts dosed by 7/01/2011 ORR = objective response rate 

([{CR + PR} ÷ n] × 100); PFSR = progression-free survival rate. 

Disclosure: J. Sosman: Research Funding: Bristol-Myers Squibb (myself). M. Sznol: 

Consultant or Advisory Role: Bristol-Myers Squibb (myself, compensated). Research 

Funding: Bristol-Myers Squibb (myself, clinical trials funding). D.F. McDermott: 

Advisory Board Role: Bristol-Myers Squibb (myself). R. Carvajal: Research Funding: 



Bristol-Myers Squibb (myself). S.L. Topalian: Consultant or Advisory Role: 

Bristol-Myers Squibb (myself, immediate family member, uncompensated). Research 

Funding: Bristol-Myers Squibb (myself). J.M. Wigginton: Employment or Leadership 

Position: Bristol-Myers Squibb (myself, employment, compensated). Stock 

Ownership: Bristol-Myers Squibb (myself). G. Kollia: Employment or Leadership 

Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: 

Bristol-Myers Squibb/BMY stocks (myself). A. Gupta: Employment or Leadership 

Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: 

Bristol-Myers Squibb (myself). F.S. Hodi: Consultant or Advisory Role: Bristol-Myers 

Squibb (myself, uncompensated). Research Funding: Bristol-Myers Squibb (myself). 


1110O IMMUNOGENICITY AND SAFETY OF THE PRAME CANCER 

IMMUNOTHERAPEUTIC IN METASTATIC MELANOMA: 

PHASE I/II DOSE ESCALATION STUDY 

R. Gutzmer 1 , L. Rivoltini 2 , E. Levchenko 3 , A. Testori 4 , J. Utikal 5 , P.A. Ascierto 6 , 

B. Salaun 7 , N. Vanhoutte 8 , M. Gillet 9 , V. Brichard 10 

1 Dermatology and Allergy, Hannover Medical School, Hannover, GERMANY, 

2 Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale 

dei Tumori, Milan, ITALY, 3 Thoracic Oncology, Petrov Research Institution of 

Oncology, St. Petersburg, RUSSIAN FEDERATION, 4 Melanoma Division, 

European Institute Of Oncology, Milan, ITALY, 5 Skin Cancer Unit, German 

Cancer Research Center, Heidelberg, Germany and Department of Dermatology, 

Venereology and Allergology, University Medical Center Mannheim, 

Ruprecht-Karl University of Heidelberg, Mannheim, Germany, German Cancer 

Research Center, Mannheim, GERMANY, 6 Melanoma, Cancer Immunotherapy 

and Innovative Therapies, Istituto Nazionale Tumori Fondazione “G. Pascale”, 

Napoli, ITALY, 7 R&D DAP Cancer, GlaxoSmithKline Biologicals, Rixensart, 

BELGIUM, 8 Immunotherapeutics, GlaxoSmithKline Biologicals, Rixensart, 

BELGIUM, 9 Global Vaccine Development, GlaxoSmithKline Biologicals, 

Rixensart, BELGIUM, 10 Immunotherapeutics Bu, GlaxoSmithKline Biologicals, 

Rixensart, BELGIUM 

Introduction: Patients (pts) with metastatic melanoma have a poor prognosis. The 

PRAME tumor antigen, expressed at high frequency in different cancers and at lower 

levels in a limited number of normal cells, offers an attractive target for active 

immunization. This open-label, dose-escalation phase I/II study aimed at 

determining the optimal dose of PRAME immunotherapeutic (PRAME recombinant 

protein (recPRAME) with AS15 immunostimulant) by evaluating its safety and 

immunogenicity in pts with advanced melanoma. 

Methods: Pts with stage IV PRAME-positive melanoma were enrolled to 3 

consecutive cohorts to receive up to 24 injections of recPRAME (20 µg, 100 µg, and 

500 µg) with AS15 (fixed dose) over approximately 4 years. Adverse events (AEs), 

including pre-defined dose-limiting toxicity (DLT), were recorded throughout the 

study. The anti-PRAME humoral and cellular responses were evaluated post-dose 4 

by ELISA and flow cytometry (PRAME-specific T-cells producing both IFNγ and 

TNFα), respectively. 

Results: 66 pts were treated in the study (20 pts received 20 µg recPRAME, 24 pts 

received 100 µg recPRAME and 22 pts received 500 µg recPRAME). AEs considered 

by the investigator to be causally related were mostly grade 1/2, 2 pts reported grade 

3 AEs, and 1 serious AE causally related to PRAME administration was reported. 2 

DLTs were recorded in 2 pts (cohorts 2 and 3; post-dose 6 and 8) but no maximum 

tolerated dose was reached. Humoral and cellular immunological results are shown in 

table 1. No cellular response for CD8+ T-cells was detected. 

Conclusions: PRAME cancer immunotherapeutic was well-tolerated and induced 

similar humoral and cellular responses in all 3 cohorts. Based on these results, a 

phase II was initiated to further evaluate the clinical activity, safety and 

immunogenicity of the PRAME immunotherapeutic containing 500 µg recPRAME. 

Immunogenicity post-dose 4 (ATP population). 

Cohort (recPRAME dose) 1 (20 µg) 2 (100 µg) 3 (500 µg) 

Humoral responders, n/N* 13/13 13/13 17/17 

CD4+ T-cell responders, n/N* (%) 7/9 (78%) 7/11 (64%) 11/15 (73%) 


number of patients enrolled into each group; * number of patients with pre and 

post-vaccination results; n, number of responders; ATP, according-to-protocol 



abstracts

Funding: GSK Biologicals 

Disclosure: R. Gutzmer: Roche Pharma, BMS, GSK, Novartis, MSD/Essex, Celgene, 

Lilly, EISAI, Astra-Zeneca, Vical, Cytavis, Centocor, Genta, SwedishOrphan, 

Philogen, Amgen, Almirall-Hermal, Merck Serono (Clin. studies, Research, Lectures, 

Advisory honoraria, Meetings). L. Rivoltini: Participation to one single GSK Advisory 

Board on MEK/BRAF inhibitors in Melanoma. A. Testori: I declare to have a 

consultant or advisory relationship with Bristol Meyers Squibb, AMGEN, 

GlaxoSmithKline advisory boards and I received honoraria from them. I have other 

remuneration to disclose: travel expenses refunded by Oncovision and IGEA. J. 

Utikal: I dońt have any financial interest in products or processes involved in this 

research abstract. I dońt own GSK stocks. I served as a member on an advisory of 

GSK and Roche in the past time. P.A. Ascierto: Consultant for MSD; Advisory role 

for BMS, MSD, Roche-Genetech, GSK, Amgen, Celgene, Medimmune, Novartis; 

received honoraria from BMS, MSD, and Roche-Genentech. B. Salaun: Currently 

employed by GSK Biologicals as a scientist. N. Vanhoutte: Employee of GSK 

Biologicals. M. Gillet: Employee of GSK Biologicals. V. Brichard: GSK employee. 


1111PD EXPANDED ACCESS STUDY OF ADVANCED BCC PATIENTS 

TREATED WITH THE HEDGEHOG-PATHWAY INHIBITOR 

VISMODEGIB 

G.J. Weiss1 ,A.Oro2 , A.L.S. Chang3 , J.A. Solomon4 , P.M. LoRusso5 , O. Hamid6 , 

D.M. Chen7 , E. McKenna7 , S. Feng7 , J.D. Hainsworth8 1 

Virginia G. Piper Cancer Center Clinical Trials, Scottsdale Healthcare, 

Scottsdale, AZ, UNITED STATES OF AMERICA, 2 Department of Dermatology, 

Stanford University School of Medicine, Stanford, CA, UNITED STATES OF 

AMERICA, 3 Department of Dermatology, Stanford University School of Medicine, 

Redwood City, CA, UNITED STATES OF AMERICA, 4 Clinical Research, 

Ameriderm Research, Ormond Beach, FL, UNITED STATES OF AMERICA, 

5 

Research Administration, Karmanos Cancer Institute, Detroit, MI, UNITED 

STATES OF AMERICA, 6 Melanoma Center, The Angeles Clinic and Research 

Institute, Los Angeles, CA, UNITED STATES OF AMERICA, 7 Medical Affairs, 

Genentech, South San Francisco, CA, UNITED STATES OF AMERICA, 

8 

Oncology Research, Sarah Cannon Research Institute, Nashville, TN, UNITED 


Background: Patients (pts) with advanced basal cell carcinoma (aBCC; disease that 

is locally advanced [laBCC] or metastatic [mBCC]) have limited therapeutic 

alternatives. The Hedgehog signaling pathway is a key driver in the pathogenesis of 

BCC. In a pivotal Phase II study, vismodegib (Erivedge)—a first-in-class 

small-molecule inhibitor of Hedgehog pathway signaling—demonstrated significant 

clinical activity in aBCC with an acceptable safety profile. This US-only expanded 

access study initiated prior to FDA approval, provided vismodegib for aBCC pts and 

further characterized its safety profile and clinical activity. 

Methods: Pts with histologically confirmed mBCC or laBCC inappropriate for, or 

recurring after surgery or radiotherapy, received daily oral vismodegib 150 mg until 

disease progression or intolerable toxicity. Interim data for the first 96 pts, enrolled 

Jul 2010–Nov 2011, are summarized; final results will be presented at the meeting. 

Results: Of 96 pts (52 laBCC, 44 mBCC), 74% were male; median age was 63 (28– 

100) years. Median disease duration from diagnosis was 3.6 (0.02–53.2) years. Prior 

treatments included surgery (92%) and radiotherapy (51%). Pts received vismodegib 

for a median of 4.3 (0.6–16.1) months (median follow-up [f-u] 4.7 [0.6–16.1] 

months). Treatment-emergent adverse events (AEs) of any grade in ≥15% pts were: 

muscle spasms (60.4%), dysgeusia (55.2%), alopecia (45.8%), diarrhea (17.7%), 

nausea (17.7%), and fatigue (17.7%), with median times to first event of 30, 36, 84, 

27, 25, and 22 days, respectively. No serious AEs related to vismodegib were 

reported. Discontinuations (n = 26) were due to disease progression (n = 14), AEs 

(n = 3), death (n = 1), lost to f-u (n = 1), physician (n = 1) or subject decision (n = 5), 

or other (n = 1). Of 69 evaluable patients with RECIST-measurable disease, the 

investigator-assessed response rate was 20/40 (50%; 95% CI 34–66%) for laBCC and 

10/29 (34%; 95% CI 18–54%) for mBCC. 16 pts (40%) with laBCC and 14 (48%) 

with mBCC had stable disease. 

Conclusions: Incidence and severity of AEs and clinical activity reported in this 

analysis are similar to those reported in the pivotal study in pts with aBCC. 

Vismodegib is an effective treatment option for aBCC pts. 

Disclosure: G.J. Weiss: Speaker’s bureau: Genentech, Pfizer Funding to my 

institution: Genentech, Novartis, Eli Lilly, Infinity. A. Oro: Trial funding: Genentech, 

Novartis, Infinity. A.L.S. Chang: Studies sponsored: Genentech, Novartis, Infinity, 

NuSkin, Galderma. J.A. Solomon: Advisory Committee/Group: GenentechP.M. 

LoRusso: Research funding: Genentech Advisory Board: Genentech Speakers’ Bureau: 

Genentech. O. Hamid: Consulting fee: Genentech Speaker bureau: BMS, Lilly, 

Genentech, Dendreon Research fee: GSK, Roche, merck, ArQule, Morphotek, EISAI, 

Lilly, BMS, Millenium. D.M. Chen: Employee: Genentech Shareholder: Genentech. E. 

McKenna: Employee: Genentech Shareholder: Genentech. S. Feng: Employee: 

Genentech Shareholder: Genentech. All other authors have declared no conflicts of 

interest. 

1112PD EFFICACY AND SAFETY OF THE HEDGEHOG PATHWAY 

INHIBITOR VISMODEGIB IN PATIENTS WITH ADVANCED 

BASAL CELL CARCINOMA (BCC): 12-MONTH ERIVANCE 

BCC STUDY UPDATE 

A. Sekulic 1 , M.R. Migden 2 , A. Oro 3 , K. Lewis 4 , J.D. Hainsworth 5 ,S.Yoo 6 , 

L. Dirix 7 , J. Hou 8 , H. Yue 8 , A. Hauschild 9 

1 Dermatology Department, Mayo Clinic, Scottsdale, AZ, UNITED STATES OF 

AMERICA, 2 University of Texas, MD Anderson Cancer Center, Houston, 

Houston, TX, UNITED STATES OF AMERICA, 3 Department of Dermatology, 

Stanford University School of Medicine, Stanford, CA, UNITED STATES OF 

AMERICA, 4 Cutaneous Oncology, University of Colorado Cancer Center, Denver, 

CO, UNITED STATES OF AMERICA, 5 Oncology Research, Sarah Cannon 

Research Institute, Nashville, TN, UNITED STATES OF AMERICA, 6 Department 

of Dermatology, Northwestern University, Evanston, IL, UNITED STATES OF 

AMERICA, 7 Clinical Trials Oncology, Sint Augustinus Hospital, Antwerp, 

BELGIUM, 8 Product Development Clinical Oncology, Genentech Inc., South 

San Francisco, CA, UNITED STATES OF AMERICA, 9 Klinik für Dermatologie, 

Venerologie und Allergologie, Universitätsklinikum Schleswig-Holstein, Kiel, 

GERMANY 

Background: Vismodegib (Erivedge, GDC-0449) is a first-in-class small-molecule 

inhibitor of the Hedgehog signaling pathway, which is implicated in the pathogenesis 

of BCC. ERIVANCE BCC is the pivotal trial of vismodegib for treatment of locally 

advanced (laBCC) and metastatic BCC (mBCC) patients (pts) for whom there are no 

other effective therapies. The study met its primary endpoint of overall response rate 

by independent review (Dirix, ESMO 2011 LBA#1). On behalf of the ERIVANCE 

BCC investigators, we present the previously unreported updated 

investigator-assessed (I-A) efficacy and safety endpoints as of Nov 28, 2011 

(additional 12 months of follow-up). 

Methods: In this multicenter, nonrandomized 2-cohort study, pts with histologically 

confirmed laBCC (deemed inoperable or for whom surgery would be significantly 

disfiguring) or mBCC with RECIST-measurable disease, received 150 mg oral 

vismodegib daily. 

Results: 104 pts (71 laBCC/33 mBCC) enrolled at 31 global sites. I-A efficacy 

endpoints were: 

Parameter 

Overall Response Rate 

(ORR), n (%) 

[95% CI] 

Median Duration of 

Response (DOR), 

months [95% CI] 

Median Progression-free 

Survival (PFS), 

months [95% CI] 

Median Overall Survival 

(OS), months [95% 

CI] 

Nov 26, 2010 Data Cut Nov 28, 2011 Data Cut 

mBCC 

(n = 33) 

15 (45.5) 

[28.1–62.2] 

(n = 15) 

12.9 

[5.6–12.9] 

9.2 

[7.4–NE] 

laBCC 

(n = 63) 

38 (60.3) 

[47.2–71.7] 

(n = 38) 

7.6 

[7.4–NE] 

11.3 

[9.5–16.8] 

mBCC 

(n = 33) 

16 (48.5) 

[30.8–66.2] 

(n = 16) 

14.7 

[5.6–NE] 

9.3 

[7.4–16.6] 

NA NA 24.1 

[14.3–NE] 


laBCC 

(n = 63) 

38 (60.3) 

[47.2–71.7] 

(n = 38) 

NE 

[9.0–NE] 

12.9 

[10.2–NE] 

NE 

[NE–NE] 

With a median follow-up of 22.3 months, 1- and 2-year survival rates were 78% 

(95% CI 63.6–92.4%) and 60% (95% CI 42.6–78.1%), for mBCC and 93.1% (95% CI 

86.6–99.6%) and 85% (95% CI 75.6–94.7%), for laBCC. Adverse events (AEs) in 

>30% of pts were muscle spasms, alopecia, dysgeusia, weight decrease, fatigue, 

nausea, and amenorrhea (in 2/6 female nonmenopausal pts). Serious AEs were 

reported in 33 pts (32%), compared with 26 (25%) in Nov 2010. 

Conclusions: This 12-month update of I-A efficacy and safety data from the 

ERIVANCE BCC study confirms the significant clinical benefit of vismodegib in 

laBCC and mBCC reported at primary analysis. Median DOR and PFS increased 

numerically with further follow-up. The AE profile was consistent with the prior data 

cut. Following approval of vismodegib by the FDA, these data further support 

vismodegib as an effective treatment option for pts with advanced BCC. 

Disclosure: A. Sekulic: Speaker bureau: Genentech/Roche. M.R. Migden: Advisory 

board: Genentech. A. Oro: Grant: Genentech, Novartis, Infinity. K. Lewis: Grant: 

Genentech Consulting fee/honoria: Genentech. J. Hou: Employee: Genentech 

Shareholder: Genentech. H. Yue: Employee: Genentech Shareholder: Genentech. A. 

Hauschild: Consult/honoraria:Roche, AZ, Biovex, BMS, Boehringer-Ingelheim, 

Celgene, Eisai, GSK, IGEA, Merck/MSD, Novartis,SOBI Reviews:Roche Spker bureau: 

Roche, AZ, Biovex, BMS, Boehringer-Ingelheim, Celgene, Eisai, GSK, IGEA, Merck/ 

MSD, Novartis,SOBI. All other authors have declared no conflicts of interest. 



1113PD THE MELANOMA RISK LOCI AS DETERMINANTS 

OF MELANOMA PROGNOSIS 

J. Rendleman 1 , S. Shang 2 , C. Brocia 3 ,M.Ma 4 , R. Shapiro 4 , R. Berman 4 , 

A. Pavlick 4 , Y. Shao 2 , I. Osman 4 , T. Kirchhoff 3 

1 Cancer Institute, NYU Medical Center, New York, NY, UNITED STATES OF 

AMERICA, 2 Division of Biostatistics, NYU Medical Center, New York, NY, 

UNITED STATES OF AMERICA, 3 Division of Epidemiology, Nyu Cancer Institute, 

NYU Medical Center, New York, NY, UNITED STATES OF AMERICA, 

4 Dermatology, NYU Medical Center, New York, NY, UNITED STATES OF AMERICA 

Background: Genetic risk factors of human cancer emerge as promising markers of 

clinical outcome. Recent melanoma genome-wide scans (GWAS) have identified loci 

associated with disease risk, nevi or UV/pigmentation, but prognostic potential of these 

variants is yet to be determined. In this study, we performed the first-to-date systematic 

evaluation of the association between established melanoma risk loci and progression. 

Methods: 891 melanoma patients prospectively accrued and followed up at NYU 

Medical Center were studied. We examined the association of 108 melanoma 

susceptibility single nucleotide polymorphisms (SNPs), selected or imputed from recent 

GWAS on melanoma, nevi or pigmentation, with recurrence-free survival (RFS) and 

overall survival (OS). The genotyping was performed using Sequenom I-plex. Univariate 

and multivariate Cox PH model were used to test association between each SNP and 

RFS and OS. Multivariate adjustments included age at diagnosis, gender, tumor stage, 

histological subtype, thickness, ulceration status, and mitotic index. ROC curves were 

used to measure utility of SNPs in predicting 3-year recurrence. 

Results: Strong associations were observed from the multivariate analysis for 

rs7538876 (RCC2) with RFS (HR = 1.48, 95% CI 1.20 – 1.83, p = 0.0002) and 

rs9960018 (DLGAP1) with both RFS and OS (HR = 1.43, 95% CI = 1.07-1.91, p = 

0.0159, HR = 1.52, 95% CI = 1.09-2.22, p = 0.0138, respectively). Subgroup analyses 

for ulceration and tumor thickness have identified several SNPs which show 

associations for RFS and OS among these different groups. In addition, we identified 

the classifiers rs7538876 and rs9960018, that when combined with stage and 

histological type, achieve a higher area under the ROC curve (AUC = 84%), 

compared to the baseline (AUC = 78%), in predicting 3-year recurrence. 

Conclusions: Our data revealed associations between specific melanoma 

susceptibility variants and worse disease outcome. The strength of associations 

observed for rs7538876 and rs9960018 suggest biological implication of these loci in 

melanoma recurrence. The observed predictive patterns of associated variants with 

clinical outcome provide the evidence for the potential utilization of genetic markers 

in melanoma prognostication. 


1114PD SKIN-TEST INFILTRATING LYMPHOCYTES PREDICT 

CLINICAL OUTCOME OF DENDRITIC CELL BASED 

VACCINATION IN METASTATIC MELANOMA 

K. Bol1 , E. Aarntzen1 , W.R. Gerritsen1 , G. Schreibelt2 , J. Jacobs1 , 

W.J. Lesterhuis1 , M. van Rossum3 , C.J.A. Punt4 , C. Figdor2 , J. De Vries2 1 

Medical Oncology/tumorimmunology Lab, Radboud University Nijmegen 

Medical Centre, Nijmegen, NETHERLANDS, 2 Tumorimmunology Lab, Radboud 

University Nijmegen Medical Center, Nijmegen, NETHERLANDS, 3 Dematology, 

Radboud University Nijmegen Medical Center, Nijmegen, NETHERLANDS, 

4 

Department of Medical Oncology, Academic Medical Center, Amsterdam, 

NETHERLANDS 

Introduction: The identification of responding patients early during treatment would 

greatly improve the efficacy of novel and costly immunotherapies. Bioassays which 

accurately link preceding immune responses to clinical outcome are therefore needed. 

The mainstay of immunotherapy is to induce, enhance or sustain TAA-specific effector 

T cell immunity. Consequently, evaluation of the migratory-, antigen recognition-, as 

well as the effector function of tumor-specific cellular responses is critical. 

Methods: A large cohort of metastatic melanoma patients (n = 91) enrolled in dendritic 

cell (DC)-based vaccination protocols was retrospectively analyzed for overall survival 

(OS) in relation to skin-test infiltrating lymphocyte (SKIL) cultures characteristics. 

Increasingly stringent criteria were defined identify long-term survivors. 

Results: The presence of TAA-specific CD8 + T cells (criterion I: detection by 

tetrameric MHC-peptide complexes) in SKIL cultures associated with improved OS; 

14.1 versus 10.9 months, p = 0.055. Further analyses showed that the presence of 

multiple specificities was highly predictive for long-term survival. Tumor recognition 

by TAA-specific CD8+ T cells on peptide level (detected by specific production of 

Thelper 1 (Th1) cytokines (criterion II; e.g. IFNg and/or IL-2) or cytotoxicity and no 

Thelper 2 (Th2) cytokines) was strongly associated with improved OS; 14.2 versus 

10.2 months, p = 0.003. Recognition of naturally processed antigen by specific 

production of Th1 cytokines or cytotoxicity and no Th2 cytokines ((criterion III), 

maximized the accuracy of the test; 24.1 versus 9.9 months, p = 0.001. 

Conclusion: Our results demonstrate that analyzing SKIL cultures is a solid bioassay 

to predict overall survival in metastatic melanoma patients. This bioassay is simple, 

feasible and integrates multiple aspects of cellular functions needed for effective 

immune responses. 


1115PD A PHASE 2 RANDOMIZED STUDY OF RAMUCIRUMAB (IMC 

1121B; RAM) WITH OR WITHOUT DACARBAZINE (DTIC) 

IN PATIENTS (PTS) WITH METASTATIC MELANOMA (MM) 

(CP12-0604/NCT00533702) 

R. Carvajal 1 , J. Thompson 2 , M. Gordon 3 , K. Lewis 4 , A. Pavlick 5 , J. Wolchok 1 , 

P. Rojas 6 , J. Schwartz 7 , A. Bedikian 8 

1 Melanoma-Sarcoma Division, Memorial Sloan-Kettering Cancer Center, 

New York, NY, UNITED STATES OF AMERICA, 2 Medical L Oncology, Seattle 

Cancer Care Alliance, Seattle, UNITED STATES OF AMERICA, 3 Pinnacle 

Oncology Hematology, Oncology Research Associates, Scottsdale, AZ, UNITED 

STATES OF AMERICA, 4 Medical Oncology, University of Colorado Denver, 

Aurora, CO, UNITED STATES OF AMERICA, 5 Hematology-Oncology, New York 

University, New York, NY, UNITED STATES OF AMERICA, 6 Biostatistics, ImClone 

Systems, Bridgewater, NJ, UNITED STATES OF AMERICA, 7 Medical, ImClone 

Systems, Bridgewater, NJ, UNITED STATES OF AMERICA, 8 Melanoma Medical 

Oncology, MD Anderson Cancer Center, Houston, UNITED STATES OF AMERICA 

Background: Vascular endothelial growth factor (VEGF)-mediated angiogenesis 

contributes to MM pathogenesis. RAM is a fully human IgG1 recombinant monoclonal 

antibody that inhibits VEGF receptor-2 (VEGFR-2) ligand binding and signaling. We 

investigated RAM alone and in combination with DTIC in chemotherapy-naïve MM pts. 

Methods: Eligible pts had stage IV cutaneous MM, ECOG PS 0-1, adequate 

hematologic, hepatic, and renal function. Therapy (Rx) in Arm A: RAM (10 mg/kg) 

+ DTIC (1000 mg/m 2 ); Arm B: RAM (10 mg/kg). Rx was every (q) 3 weeks (wk); 

tumor assessments were q6 wk. The primary endpoint was progression-free survival 

(PFS); other endpoints were safety, response, overall survival (OS). 

Results: 106 pts were randomized; 102 received study Rx. Arm A (n = 52) median 

(medn) age was 63, 71% male, 37% had elevated LDH, 23% stage M1c. Arm B (n = 

50) medn age was 62, 76% male, 38% had elevated LDH, 36% stage M1c. Medn PFS 

was 2.6 months (m) Arm A and 1.7m Arm B; 6m PFS rates were 31% and 18%; 12m 

PFS rates were 24% and 16% on Arms A and B, respectively. There were 9 (17%) 

partial responses (PR) & 19 (37%) with stable disease (SD); 2 (4%) PR & 21(42%) 

SD on Arms A and B, respectively. Medn OS was 8.7m Arm A; 11m Arm 

B. Nonhematologic adverse events (AEs) considered at least possibly related to RAM 

included fatigue (50%; 4% Grade [G] ≥3), hypertension ([HTN] 21%; 15% G ≥3), 

infusion-related reactions ([IRR] 8%; 0 G ≥3), proteinuria ([PU] 8%; 4% G ≥ 3), 

headache ([HA] 10%; 2% G ≥3) on Arm A; fatigue (30%; 2% G ≥3), HTN (22%; 

14% G ≥3), IRR (14%; 6% G ≥3), PU (12%; 2% G ≥3), HA (20%; 0 G ≥3) on Arm 

B. IRR incidence was reduced following a recommendation for premedication after 

37 pts received initial Rx. Hematologic AEs were neutropenia ([NP] 33%; 19% G 

≥3), thrombocytopenia ([TP] 39%; 15% G ≥3), and anaemia ([A]14%; 4% G ≥3) on 

Arm A; NP (0%), TP (6%; 0 G ≥3) and A (2%; 0 G ≥3) on Arm B. 

Conclusions: RAM alone or in combination with DTIC was associated with 

acceptable incidence of AEs in MM. Clinical activity was modest on both arms. 

Although the study was not powered for definitive comparison between treatment 

arms, PFS appeared greater in Arm A. Biomarker analysis is ongoing. 

Disclosure: R. Carvajal: Cosulting, Novartis - money paid to me Consulting, 

Morphotek - money paid to me Grants, NIH/NCI - money paid to me Grants, 

FDA - money paid to me Grants, ASCO - money paid to me. J. Thompson: ImClone 

provided funding to the University of Washington to support this research. K. Lewis: 

Research Funding - ImClone. J. Wolchok: Consultant - Bristol Myers Squibb; Merck; 

GlaxoSmithKline Research support - Bristol Myers Squibb and GlaxoSmithKline. P. 

Rojas: I am an employee of Lilly and own Lilly stock. J. Schwartz: I am an employee 

of Lilly and own Lilly stock. All other authors have declared no conflicts of interest. 

1116PD FIVE-YEAR SURVIVAL RATES FOR PATIENTS (PTS) WITH 

METASTATIC MELANOMA (MM) TREATED WITH 

IPILIMUMAB (IPI) IN PHASE II TRIALS 

C. Lebbe1 , J.S. Weber2 , M. Maio3 , B. Neyns4 , K. Harmankaya5 , K. Chin6 , 

D. Opatt McDowell7 , L. Cykowski8 , M.B. McHenry9 , J.D. Wolchok10 1 2 

Saint-Louis Hospital, APHP University, Paris, FRANCE, Interdisciplinary 

Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, FL, 

UNITED STATES OF AMERICA, 3 Department of Oncology, Azienda Ospedaliera 

Senese - Medical Oncology and Immunotherapy Unit, Siena, ITALY, 4 Medical 

Oncology, Vrije Universiteit Brussel, Brussels, BELGIUM, 5 Department of General 

Clinical Dermatology, Medical University of Vienna, Vienna, AUSTRIA, 6 Global 

Clinical Research - Oncology, Bristol-Myers Squibb, Wallingford, CT, UNITED 

STATES OF AMERICA, 7 Global Medical, Bristol-Myers Squibb, Lawrenceville, 

NJ, UNITED STATES OF AMERICA, 8 Global Clinical Operations, Bristol-Myers 

Squibb, Wallingford, CT, UNITED STATES OF AMERICA, 9 Global Biometrics 

Sciences, Bristol-Myers Squibb, Wallingford, CT, UNITED STATES OF AMERICA, 

10 

Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, UNITED 


Purpose: Two phase III, randomized trials showed statistically significant 

improvement in overall survival (OS) in MM pts treated with IPI and data from 

phase II/III studies of IPI suggest the potential for prolonged survival (beyond 4 yrs) 

in some pts with MM. Three phase I/II studies conducted at NCI demonstrated 5-yr 


survival rates of 13-25% (Prieto et al, CCR, 2012). Evaluation of the long-term 

survival benefit of IPI for MM pts from 3 additional completed phase II studies 

continues and we now report 5-yr survival data. 

Methods: Trials included: (1) CA184-008, a single-arm study of IPI at 10 mg/kg in 

previously treated pts; (2) CA184-022, a dose-ranging study of IPI at 0.3, 3, or 10 

mg/kg in previously treated pts with crossover from lower doses to 10 mg/kg allowed 

upon disease progression; and (3) CA184-007, a study of IPI at 10 mg/kg +/prophylactic 

budesonide in treatment-naive and previously treated pts. IPI was given 

q 3 wks x 4 (induction); eligible pts could receive reinduction or maintenance IPI q 

12 wks from Week 24. The analysis reports OS with updated last known alive date or 

death based on data collected through March 2012. Safety data for these trials have 

been previously published. 

Results: Survival rates at 5 yrs ranged from 12-28% in pretreated pts and 38-50% in 

treatment-naive pts. The table summarizes median OS, previously reported yearly 

survival rates, and current 5-yr survival rates. 

Trial N 

IPI dose 

(mg/kg) 

Median 

OS, 

months 

OS rate, % 

1-yr 2-yr 3-yr 4-yr 5-yr 

008 155* 10 10.2 47.2 32.8 23.3 19.7 18.2 

022 72* 10 11.4 48.6 29.8 24.8 21.5 21.5 

72* 3 8.7 39.3 24.2 19.7 18.2 16.5 

73* 0.3 8.6 39.6 18.4 13.8 13.8 12.3 

007 57 (total) 10 + placebo 19.3 62.4 41.8 34.4 32.0 32.0 

32 † 

30.5 71.4 56.6 42.5 37.7 37.7 

25* 14.8 50.8 24.2 24.2 24.2 24.2 

58 (total) 10 + 17.7 55.9 41.1 38.7 36.2 36.2 

21 budesonide 

† 

45.0 65.9 57.7 57.7 49.5 49.5 

37* 8.5 49.9 31.6 28.4 28.4 28.4 

*Previously treated; †Treatment naive. 

Conclusions: Across studies, 5 yr OS rates appear similar to those at 4 years, 

suggesting that IPI monotherapy may result in prolonged survival in some pts with 

MM. Further research and analyses are needed to identify the pt population with 

MM most likely to achieve long term survival benefit from IPI therapy. 

Disclosure: C. Lebbe: Participation to BMS Advisory Boards. J.S. Weber: For BMS, 

only honoraria less than 10K dollars and advisory role in Ad Boards. M. Maio: Paid 

Advisor in Boards from BMS and Roche. B. Neyns: No conflict of interest to report 

with regards to this abstract. K. Harmankaya: With Regards to conflict of interest in 

this abstract, unpaid investigator on this study. K. Chin: Employed by BMS; Stock 

ownership. D. Opatt McDowell: Employed by BMS; Stock ownership. L. Cykowski: 

Employed by BMS; Stock ownership. M.B. McHenry: Employed by BMS, Stock 

OwnershipJ.D. Wolchok: I am a consultant to Bristol-Myers Squibb, Merck and 

Glaxo SmithKline. I receive research funding from Bristol-Myers Squibb. 

1117PD LONG TERM SURVIVAL AND IMMUNOLOGICAL 

CORRELATES IN METASTATIC MELANOMA TREATED 

WITH IPILIMUMAB AT 10 MGS WITHIN AN EXPANDED 

ACCESS PROGRAM 

A.M. Di Giacomo 1 , L. Calabrò 1 , R. Danielli 1 , I. Pesce 1 , E. Fonsatti 1 , E. Bertocci 1 , 

D. Giannarelli 2 , M. Biagioli 3 , M. Altomonte 1 , M. Maio 1 

1 Department of Oncology, Medical Oncology and Immunotherapy,University 

Hospital of Siena, Siena, ITALY, 2 Medical Oncology, Regina Elena National 

Cancer Institute, Roma, ITALY, 3 Department of Medicine, Dermatology, University 

Hospital of Siena, Siena, ITALY 

Background: Ipilimumab (IPI) has shown long lasting responses in metastatic 

melanoma (MM) patients (pts) in phase II/III trials (Hodi et al., NEJM 2010; Robert 

et al. NEJM 2011; Prieto et al., CCR 2012). We have previously reported a significant 

clinical efficacy of IPI in 27 heavily pre-treated MM pts enrolled within the 10 mgs 

expanded access program (EAP) available at the University Hospital of Siena; one 

and 2-years survival were 34.8% and 23.5%, respectively (Di Giacomo, et al. CII, 

2010). In spite of its clinical efficacy, no definitive predictive markers of response 

have been identified yet. We report here the survival follow-up of this cohort of MM 

pts and preliminary data on immunological correlates. 

Methods: Twenty-seven pts with stage III (2) or IV (25) MM, progressing to a 

median of 3 (1-5) systemic therapies, were treated according to the EAP with IPI at 

10 mg/Kg i.v. given at weeks (wks) 1, 4, 7, 10 during the induction phase, and every 

12 wks from W24 in the maintenance phase. Peripheral blood mononuclear cells 

were collected from 17 pts at baseline, W7, W12 and W24 and analyzed by flow 

cytometry for ICOS expression on both CD4 and CD8+ T cells. The ratio between 

absolute blood neutrophils (N) and lymphocytes (L) count was determined at 

baseline, W4, W7 and W10 for 27, 27, 24 and 23 pts, respectively. 

Results: With a median follow-up of 9.6 months the median OS was 9.6 months 

(95% CI: 4.2-16.1; range: 3.1-51.2; three and 4-years survival rates were 20.9%, with 5 

long-term survivors (>4 yrs). A significant (p < 0.05) increase in the percentage and 

absolute number of CD4 + ICOS+ and CD8 + ICOS+ circulating T cells was observed 


from W7 on. Compared to baseline, pts with a fold increase in CD4 + ICOS+ and 

CD8 + ICOS+ T cells higher than 4 at W7 and W12 experienced a clinical benefit 

(SD, PR and CR). Pts with a N/L ratio lower than median at W7 and W10 had a 

significantly better survival. 

Conclusions: ipi can induce long-term survivals in heavily pre-treated MM pts. 

Circulating ICOS+ T cells and N/L ratio in the course of treatment with ipi may 

represent predictive markers of clinical effectiveness in the daily practice. 

Disclosure: M. Maio: Advisory Board and Honoraria from Bristol-Myers Squibb and 


1118PD MULTIPLE PRIMARY MELANOMAS FROM SAME PATIENTS 

PRESENT DISCREPANT SOMATIC ALTERATIONS IN MAIN 

CANDIDATE GENES 

M. Colombino 1 , M. Sini 1 , V. De Giorgi 2 , A. Lissia 3 , D. Massi 4 , C. Rubino 5 , 

A. Cossu 3 , F. Ayala 6 , P.A. Ascierto 6 , G. Palmieri 1 

1 Unit of Cancer Genetics, Institute of Biomolecular Chemistry, CNR, Sassari, 

ITALY, 2 Department of Dermatology, University of Florence, Florence, ITALY, 

3 Institute of Pathology, University of Sassari, Sassari, ITALY, 4 Institute of 

Pathology, University of Florence, Florence, ITALY, 5 Plastic Surgery, University of 

Sassari, Sassari, ITALY, 6 Melanoma, National Tumor Institute Fondazione 

Pascale, Naples, ITALY 

Background: A series of patients with multiple primary melanoma (MPM) were 

screened for the involvement of the key-regulator genes in susceptibility (CDKN2A) 

and pathogenesis (BRAF, cKIT, CyclinD1) of such a disease. 

Methods: Genomic DNA from peripheral blood of 63 MPM patients (54 cases with 

two primary melanomas, 8 with three, and 1 with four) were screened for germline 

mutations in p16 CDKN2A and p14 CDKN2A genes by automated DNA sequencing. 

Melanoma families were identified according to standardized criteria: 9 (14%) 

patients were classified as familial cases. Paired synchronous and/or asynchronous 

MPM tissues (N = 100) from same patients (N = 46) were analyzed for somatic 

mutations in BRAF gene and FISH-based amplifications in cKIT and CyclynD1 

genes. 

Results: Overall, 6 (10%) different CDKN2A germline mutations were identified: 5 

inp16 CDKN2A and 1 inp14 CDKN2A . The age of onset was significantly lower and the 

number of primary melanomas higher in patients with mutations. CDKN2A 

mutations were significantly more frequent in patients with familial history of 

melanoma (5/9; 56%) compared with patients without (1/54; 2%) (P < 0.001), and in 

patients with more than two melanomas (3/9; 33%) compared with patients with 

only two melanomas (3/54; 6%) (P = 0.012). The debated A148T polymorphism was 

found at low level (2/54; 4%) in our series. Regarding genetic alterations at somatic 

level, BRAF mutations were identified in 36/100 (36%) primary melanoma tissues, 

whereas amplification of cKIT and CyclinD1 genes was observed in 2/88 (2%) and 

10/88 (11%) analyzed tissue samples, respectively. Considering all types of genetic 

events, paired samples presented a poorly consistent distribution of somatic 

alterations in same patients (52% consistency). 

Conclusions: Coexistence of MPM and familial recurrence of melanoma as well as 

the presence of more than two melanomas seem to be strong indications to address 

patients to CDKN2A mutational screening. The low consistency in genetic patterns 

of primary tumors from the same patients provide additional evidence that 

pathogenetic mechanisms of melanomagenesis are heterogeneous and molecularly 

different cell types may be generated in multiple primary melanoma. 


1119P ASSOCIATION OF GENETIC POLYMORPHISMS IN TUMOR 

SUPPRESSORS, ERP29 AND PTCH1, AND DNA 

TRANSCRIPTION FACTORS, IKBKAP AND ZNF415, WITH 

CUTANEOUS MELANOMA RISK 

E.F.D. Costa, G.J. Lourenço, C. Oliveira, J.A. Rinck-Junior, A.M. Moraes, 

G.A.S. Nogueira, C.S.P. Lima 

Clinical Medical, State University of Campinas, Campinas, BRAZIL 

Introduction: Recently, we found that genetic single nucleotide polymorphisms 

(SNPs) in tumor suppressors ERP29 c.293A > G, PTCH1 g.79755C > T and g.79456C 

> T, and in genes of DNA transcription IKBKAP p.Cys1072Ser and ZNF415 c.443A 

> G, alter the oropharynx cancer risk. The study was conducted using high resolution 

DNA microarrays genotyping (SNP 5.0 array, Affymetrix®) and the quantities and 

functions of the proteins encoded by distinct alleles are being examined by our 

research group. Objective: To investigate the influence of the referred SNPs in the 

risk of cutaneous melanoma (CM). 

Materials and methods: Genomic DNA from 153 CM patients and 153 controls 

were analyzed by TaqMan® genotyping assays. The differences between groups were 

analyzed by the logistic regression model. Power analysis (PA) was used to verify the 

effect of sample size on the results obtained in the study. 



Results: The frequencies of ERP29 c.293AA + PTCH1 g.79755CC (95.0 vs 80.1%, 

P= 0.006; PA= 86%), ERP29 c.293AA + PTCH1 g.79456CC (94.9 vs 79.4%, P= 0.005; 

PA= 88%), ERP29 c.293AA + ZNF415 c.443GG (56.2 vs 31.6%, P= 0.01; PA= 84%) 

combined genotypes were more common in patients than in controls. Individuals with 

the referred genotypes were under a 4.3 (95%CI: 1.61-13.43), 4.3 (95%CI: 1.63-13.49), 

and 3.05 (95%CI: 1.29-7.53) fold increased risk for CM than others. In addition, the 

frequencies of ERP29 c.293AA + PTCH1 g.79456CC + IKBKAP p.1072CysCys (98.5 vs 

83.3%, P= 0.01; PA= 86%), ERP29 c.293AA + PTCH1 g.79456CC + ZNF415 c.443GG 

(85.7 vs 44.1%, P= 0.004; PA= 96%) combined genotypes were also higher in patients 

than in controls. Individuals with the referred genotypes were under a 13.5 (95%CI: 

2.47-252.3) and 8.05 (95%CI: 2.21-39.24) fold increased risks for CM than others. 

Conclusions: Our data present for the first time that: 1) ERP29 c.293A > G, PTCH1 

g.79755C > T and g.79456C > T, IKBKAP p.Cys1072Ser, and ZNF415 c.443A > G 

SNPs are important inherited risk factors for CM and; 2) healthy individuals with 

these SNPs should receive recommendation to avoid sunlight exposition and should 

be frequently evaluated by a dermatologist to perform an early diagnosis of the 

tumor. Financial support: FAPESP and FINEP. 


1120P TIME TREND INFLUENCE OF SOCIECONOMIC STATUS 

ON SURVIVAL, BRESLOW THICKNESS, TIME FROM ONSET 

OF SYMPTOMS AND SURGICAL RESECTION IN STAGE I-II 

PRIMARY CUTANEOUS MELANOMA 

M. Mandala 1 , G. Imberti 2 , D. Piazzalunga 3 , R. Labianca 1 , G. Lucisano 4 , 

B. Merelli 1 , S. Mosconi 1 , L. Marchesi 2 , A. Gianatti 5 , C. Tondini 1 

1 Oncology and Haematology, Ospedali Riuniti di Bergamo, Bergamo, ITALY, 

2 Dermatology, Ospedali Riuniti Bergamo, Bergamo, ITALY, 3 Surgical Oncology, 

Ospedali Riuniti Bergamo, Bergamo, ITALY, 4 Epidemiology, Mario Negri Sud, 

Santa Maria Imbaro, ITALY, 5 Pathology, Ospedali Riuniti Bergamo, Bergamo, 

ITALY 

Objective: To investigate the time trend influence of socioeconomic status (SES) on 

Breslow thickness (BT) and survival in patients (pts) with stage I-II primary 

cutaneous melanoma (PCM). 

Patients and methods: Pathologic and sociodemographic characteristics of 

prospectively collected, consecutive pts diagnosed with PCM between November 1, 

1998, and July 31, 2009 were evaluated. We categorized SES into 3 levels: low 

(manual employees with primary education level), middle (non-manual employees 

with middle education level), and high (professionals, executives with tertiary 

education). We divided the representative years between 2000 and 2009 into three 

four-year (table 1). In the multilvariate analysis models the following variables were 

tested: SES, marital status, sex and age. 

Results: A total of 1274 available pts were analyzed. Overall a progressive decrease of 

BT was observed (table 1). In the first four year period gender and age correlated with 

BT and ulceration [m vs f OR (95%CI): 1.66 (1.10-1.52) and (>60 vs G, PTCH1 G.79755C > T 

AND PTCH1 G.79456C > T POLYMORPHISMS WITH 

INHERITED RISK OF CUTANEOUS MELANOMA 

G.A.S. Nogueira, G.J. Lourenço, C. Oliveira, J.A. Rinck-Junior, E.F.D. Costa, 

A.M. Moraes, C.S.P. Lima 

Clinical Medical, University of Campinas, Campinas, BRAZIL 

Background: Recently we found that SNPs alter the oropharynx carcinoma risk in 

tumor suppressor MCC c.*5077A > G, PTCH1 g.79755C > T, and PTCH1 g.79456C > 

T. This study was conducted using high-resolution large-scale DNA microarray 

genotyping (5.0 SNP array, Affymetrix ®), and the quantities and functions of the 

proteins encoded by distinct alleles of the polymorphisms are being examined by our 

research group. Objective: We aimed to verify whether the different genotypes of 

polymorphisms in MCC c.*5077A > G, PTCH1 g.79755C > T, and PTCH1 g.79456C 

> T alter the CM susceptibility. 

Materials and methods: Genomic DNA of 149 CM patients and 153 controls was 

analyzed by TaqMan genotyping (Applied Biosystems®). Statistical significance of 

differences between groups was calculated by using chi-square (χ2) and Fisher’s exact 

tests. Power analysis (PA) was used to verify the effect of sample size on the results 

obtained in the study. 

Results: Samples from patients with MC and controls were in Hardy-Weinberg 

equilibrium for MCC and PTCH1 loci. Similar frequencies of MCC and PTCH1 

genotypes were observed in patients and controls. Individuals with distinct isolated 

genotypes of the genes were under similar risks for CM. The frequencies of the 

combined genotypes MCC 5077AA + PTCH1 79755CC (90.4% versus 72.3%, P= 

0.004; PA: 99.0%), MCC 5077AA + PTCH1 79456CC (89 0% versus 71.6%, P= 0.008; 

PA: 98.0%), and MCC 5077AA + PTCH1 79755CC + PTCH1 79456CC (91.3% versus 

76.1%, P= 0.004; PA: 99.0%) were higher in patients than in controls. Individuals 

with these genotypes were at 4.44 (CI95%: 1.68 – 13.17), 3.60 (CI95%: 1.45 – .87), 

and 4.70 (CI95%: 1.75 – 14.63)-fold increased risks for CM than others, respectively. 

Conclusion: Our results suggest that combined MCC and PTCH1 polymorphisms 

are an important inherited risk factor for CM. We believe that healthy carriers with 

these genotypes deserve recommendations for protecting their skin from the harmful 

effects of UV rays to prevent tumor disease and periodic follow-up with the 

dermatologist for early tumor diagnosis. Financial support: State of São Paulo 

Research Foundation (FAPESP) and Research and Project Financing (FINEP) 


1122P INHERITED ABNORMALITIES IN GENES THAT DURING THE 

APOPTOSIS PROCESS AND CUTANEOUS MELANOMA RISK 

C. Oliveira 1 , J.A. Rinck-Junior 1 , G.J. Lourenço 1 , M.L. Cintra 2 , A.M. Moraes 1 , 

C.S.P. Lima 1 

1 Department of Internal Medicine, State University of Campinas, Distrito de 

Barão Geraldo, Campinas, São Paulo, Brazil, BRAZIL, 2 Department of 

Pathology, State University of Campinas, Distrito de Barão Geraldo, Campinas, 

São Paulo, Brazil, BRAZIL 

Background: P53 (guardian of the genome), MDM2 (p53 inhibitor), BCL2 

(anti-apoptotic) and BAX (proapoptotic) genes remove cells damaged by ultraviolet 

(UV) rays of sunlight and, therefore, are related to the origin of cutaneous melanoma 

(CM). All these genes are polymorphic in humans. The Arg wild allele of the P53 

Arg72Pro polymorphism is more efficient than the variant Pro allele at inducing 

apoptosis. The variant G and A alleles of MDM2 T309G and the BCL2 C (-948) A 

polymorphisms, and the variant A allele of the BAX G(-248)A polymorphism are 

related to higher and lower expressions of the encoded proteins, respectively, than their 

wild T, C and G alleles. This study aimed to clarify the roles of the above-mentioned 

genetic polymorphisms in the risk and clinical manifestation of the tumor. 

Material and methods: In this case-control study, genomic DNA from peripheral 

blood of 150 consecutive CM patients (75 males and 75 females, 138 Caucasians and 12 

non-Caucasians aged 20-89 years) and 150 healthy subjects, matched by age, gender and 

race, was analyzed by polymerase chain reaction followed by enzymatic digestion. 

Results: The frequencies of the P53 ArgArg and the BCL2 AA genotypes were higher in 

patients than in controls (58.7% versus 44.7%, P= 0.01) and (28.0% versus 15.3%, P= 

0.004), respectively. Carriers of these genotypes had a 1.86 and 2.87-fold increased risk for 

CM than those with the remaining genotypes, respectively. Excesses of the P53 ArgArg 

plus BCL2 AA and P53 ArgArg plus BAX AA were seen in patients when compared to 

controls (36.1% versus 16.9%, P= 0.002) and (29.5% versus 15.3%, P= 0.008). Carriers of 

these genotypes had a 3.43 and 2.71-fold increased risk for CM than others, respectively. 

Conclusions: The data suggest that P53 Arg72Pro, BCL2 C(-248)A and BAX G 

(-248)A polymorphisms, alone or combined, alter the risk for CM in our region. We 

believe that carriers of specific genotypes of the above-mentioned genes should 

receive additional recommendation to avoid exposition to sunlight, in addition to 

frequently being evaluated by a dermatologist for early disease diagnosis. Financial 

support: (FAPESP) 


1123P BRAF-V600 AND C-KIT MUTATION ANALYSIS IN 

CYTOLOGYCAL SAMPLES FROM METASTATIC MELANOMA 

T. Labiano 1 , M.D. Lozano 1 , J.I. Echeveste 1 , M. Montañana 1 , M.F. Sanmamed 2 , 

E. Castanon Alvarez 2 , N. Gómez 1 , A. Gurpide 2 , M.A. Idoate 1 , S. Martin Algarra 3 

1 Pathology, University of Navarra, Pamplona, SPAIN, 2 Medical Oncology, Clinica 

Universitaria de Navarra, Pamplona, SPAIN, 3 Medical Oncology, Clinica 

Universidad de Navarra, Pamplona, SPAIN 

Background: Vemurafenib is approved for the first-line treatment of BRAF-V600E+ 

metastatic melanoma (MM). Also, preliminary clinical experience with imatinib in 

MM patients with gene amplification or activating mutations of c-KIT, have shown 


high response rates and prolonged progression free survival. These results emphasise 

the importance of molecular information, even in those cases in which the diagnosis 

is made on small samples obtained through minimally invasive approaches. Cytology 

is an accurate and cost-effective tool for the diagnosis of MM and cytological smears 

are occasionally the only samples available from these patients. 

Methods: We have studied BRAF and c-KIT mutations in 62 cytological samples 

from MM patients. Preliminary results of 56 cases (32 men (58%) and 23 women 

(42%); median age 52 years) are included in this abstract. Diagnosis was made on 

fine needle aspiration in 41 cases, imprints in 10, direct eye touch in 1, a smear from 

cellular culture in 1, and pleural and peritoneal fluid in 3. To assure tissue quality, 

DNA was extracted directly from Papanicolau stained smears on which cytological 

diagnosis was made. BRAF and c-KIT mutations were analysed by PCR and direct 

sequencing using an ABI PRISM TM 310XL. 

Results: BRAF mutations was found in 30 cases (53.5%): V600E mutation in 26 

(86,7%) and V600K in 4 (13,3%). c-KIT mutations were studied in 18 cases. L576P 

mutation was present in 1 patient with liver metastasis from acral melanoma 

(5.56%). BRAF status did not correlated with primary melanoma histology, age at 

diagnosis, disease free survival, brain metastases rate and overall survival. 

Conclusions: The frequency of activating mutations in BRAF is 53.5% in this series. 

V600E is the most commonly observed mutations, but V600K appears in 13.3% of 

the cases. c-KIT mutations incidence is low (5.56%). Mutational analysis of BRAF 

and c-KIT using cytological samples from patients with metastatic melanoma is 

feasible and can be used to extend the benefits of targeted therapy to those patients 

from which biopsies are not available. Updated results will be presented. 

Disclosure: S. Martin Algarra: Participation in Advisory Boards of Roche. All other 


1124P AN OPEN-LABEL, MULTICENTRE SAFETY STUDY 

OF VEMURAFENIB IN PATIENTS WITH METASTATIC 

MELANOMA 

C. Blank 1 , M. Del Vecchio 2 , P.A. Ascierto 3 , P. Queirolo 4 , A. Hauschild 5 , 

A. Arance 6 ,M.Brown 7 , L. Mitchell 8 , L. Veronese 8 , J. Larkin 9 

1 Immunology, The Netherlands Cancer Institute Antoni van Leeuwenhoek 

Hospital, Amsterdam, NETHERLANDS, 2 Department of Medical Oncology, 

Instituto Nazionale dei Tumori, Milan, ITALY, 3 Unit of Medical Oncology and 

Innovative Therapy, Istituto Nazionale Tumori Fondazione G. Pascale, Naples, 

ITALY, 4 National Institute for Cancer Research, San Martino Hospital, Genova, 

ITALY, 5 Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum 

Schleswig-Holstein, Kiel, GERMANY, 6 Medical Oncology, Hospital Clinic, 

Barcelona, SPAIN, 7 Oncology, Royal Adelaide Hospital Cancer Centre, Adelaide, 

AUSTRALIA, 8 F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 9 Department 

of Medicine, Royal Marsden Hospital, London, UNITED KINGDOM 

Background: Vemurafenib, a BRAF inhibitor, is associated with improved 

progression-free survival and overall survival in patients (pts) with BRAF V600 -mutant 

metastatic melanoma (mM). Here we present findings from a safety study of 

vemurafenib in pts with unresectable Stage IIIC/IV BRAF V600 -positive mM. 

Methods: Pts with untreated or previously treated Stage IIIC/IV BRAF V600 

mutation-positive (cobas® 4800 BRAF V600 Mutation Test) melanoma were enrolled. 

Pts received continuous oral vemurafenib 960 mg bid. Primary study endpoint was 

safety; efficacy (RECIST V 1.1) was a secondary endpoint. 

Results: Of 5273 screened pts (Mar 2011–Feb 2012), 2353 (45%) were enrolled and 

2096 received ≥1dose of vemurafenib. Median age was 54 (16–95 years), 56% were 

male. Median time since first mM diagnosis was 6.4 months. Most pts were Stage IV 

(84%); 47.1% M1c, 2% Stage IIIC (stage not reported for 14% of pts). At baseline, 

87% of pts had ECOG PS 0/1, 11% ECOG PS ≥2; 24% had brain metastases and 

37% had elevated LDH. Most pts had received prior systemic therapy (60%) 

including ipilimumab (10%), MEK and BRAF inhibitors (3%). At data cut-off (29 

Feb 2012), median treatment duration was 3.1 months (10%) of any grade were arthralgia (30.7%), rash (25.6%), 

fatigue (19.6%), alopecia (15.6%), nausea (15%) and photosensitivity (11%), and were 

similar irrespective of brain metastases and ECOG PS. AEs caused treatment 

interruption in 492 (23.5%) pts. Of 774 pts (37%) who discontinued treatment, most 

withdrew due to progressive disease (71%) or death (14%) but 6% had AEs (most 

commonly general physical deterioration). Tumour assessments at Week 8 of 

treatment were available for 1356/2096 (65%) pts; 60% of pts achieved a CR or PR; 

31% had SD. 

Conclusions: In a setting representative of routine clinical practice, vemurafenib is 

well tolerated and both safety profile and activity resemble the Phase I–III data, 

although this analysis is limited by the study duration. 

Disclosure: C. Blank: Financial disclosure: Roche global steering committee, Roche 

NL presentations, conference travel, Novartis NL: conference travel, advisory board; 

MedImmune: research grant; BMS: advisory board, clinical research funding. M. Del 

Vecchio: Consultant or Advisory Role: Merck/Schering-Plough (U); Research 

Funding: Celgene, Novartis, Roche. P.A. Ascierto: Consultant for MSD; Advisory role 

for BMS, MSD, Roche-Genetech, GSK, Amgen, Celgene, Medimmune, Novartis; 


received honoraria from BMS, MSD, and Roche-Genentech. P. Queirolo: Advisory 

Board of Bristol Myers Squibb, Roche-Genentech, GSK, MSD and received honoraria 

from Brystol Myers Squibb and Roche-Genentech. A. Hauschild: Honoraria for adboard 

membership, and payments for lectures/speakers bureaus from Amgen, 

AstraZenica, Biovex, BMS, Boehringer, Ingelheim, Celgene, Eisai, GSK, IGEA, Lilly, 

Medac, MelaSciences, MSD?Merck, Novartis, Roche Pharma, SOBI, Vical, Janssen. A. 

Arance: Steering committee of this safety study (Roche). M. Brown: Membership 

of a Roche Melanoma Advisory Board. L. Mitchell: Full-time employee at 

F. Hoffmann-la-RocheL. Veronese: Full-time employee at F. Hoffmann-la-Roche. 


1125P OPEN-LABEL PILOT STUDY OF VEMURAFENIB IN 

PREVIOUSLY TREATED METASTATIC MELANOMA (MM) 

PATIENTS (PTS) WITH SYMPTOMATIC BRAIN METASTASES 

(BM) 

R. Dummer 1 , S. Goldinger 2 , C. Turtschi 2 , N. Eggmann 2 , O. Michielin 3 , 

L. Mitchell 4 , L. Veronese 4 , P.R. Hilfiker 5 , J.D. Rinderknecht 2 

1 Department of Dermatology, Universitätsspital Zürich, Zürich, SWITZERLAND, 

2 Department of Dermatology, University Hospital of Zurich, Zurich, 

SWITZERLAND, 3 Melanoma Clinic, Multidisciplinary Oncology Center, Lausanne, 

SWITZERLAND, 4 F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 5 Radiology, 

MRI Bethanien, Zurich, SWITZERLAND 

Background: The BRAF inhibitor vemurafenib has shown high response rates and 

improved progression-free and overall survival in mM harbouring V600-mutated 

BRAF. BMs are often observed with mM and indicate a poor prognosis. The aim of 

this preliminary investigation is to determine the feasibility of vemurafenib therapy 

in mM with BM. 

Methods: 24 evaluable pts with BRAF V600 mutation positive (cobas® 4800 BRAF V600 

Mutation Test) mM and BMs, requiring corticosteroids for symptom control, were 

enrolled (Nov 2010–Nov 2011). Pts received twice-daily vemurafenib 960 mg. Primary 

endpoint is safety; secondary endpoint is best overall response rate (RECIST v1.1). 

Results: All pts were white, median age 47 (24–70) years. Median baseline number of 

BMs was 3.5 (1–20). Median time since BM diagnosis was 3.2 (0–64) months. Other 

lesion sites included skin, lung, liver, bone, lymph nodes, colon/large intestine, 

stomach, breast and adrenal. All pts had prior treatment for BM: radiotherapy 83% 

(58% whole brain, 25% precision), 2 pts had surgery and 83% of pts had systemic 

therapy. As of clinical data cut-off (15 Dec 2011), median treatment duration was 

117 (3–304) days. 9 pts are ongoing; 15 (63%) discontinued treatment because of 

progression of disease (PD), 8 of whom died because of PD. 22 pts (92%) reported 

≥1 adverse event (AE), which were mainly mild or moderate. Most common AEs 

were arthralgia (33%), photosensitivity (21%) and seizures (20%, pre-existing). 3 pts 

reported 1 of each of the following grade 3 AEs: epilepsy, cutaneous squamous cell 

carcinoma (cuSCC), increased amylase, elevated γ-glutamyltransferase and ileus with 

perforation. Overall, cuSCC occurred in 3 pts (12.5%), skin papilloma in 3 pts 

(12.5%) and keratoacanthoma in 1 pt (4.2%). 7/24 pts (29%) had a confirmed partial 

response: 9 pts (38%) had stable disease, 3 (12%) PD and 5 (21%) were not evaluable 

for response. Median duration of response was 3.8 (0.8–4.7) months. 

Conclusions: Vemurafenib therapy is feasible in advanced melanoma patients with 

symptomatic BM. Interpretation of efficacy is currently limited because of a short 

follow-up time, but there are strong indications of vemurafenib activity in BM. 

Disclosure: R. Dummer: Research funding: Astra Zeneca, Novartis, Cephalon, MSD, 

Transgene, BMS, Roche, GlaxoSmithKline, Bayer. Ad-board: Astra Zeneca, Novartis, 

Cephalon, MSD, Transgene, Genta, Bayer, Roche, BMS, GSK, Spirig. L. Mitchell: 

Full-time employee of F. Hoffmann-la-Roche. L. Veronese: Full time employee at 

F. Hoffmann-la-Roche. All other authors have declared no conflicts of interest. 

1126P PHASE II STUDY OF IPILIMUMAB PLUS TEMOZOLOMIDE 

IN PATIENTS WITH METASTATIC MELANOMA 

S. Patel 1 , R. Bassett 2 ,W.Hwu 1 , K. Kim 1 , N. Papadopoulos 1 ,P.Hwu 1 , 

A. Bedikian 1 

1 Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, 

UNITED STATES OF AMERICA, 2 Biostatistics, MD Anderson Cancer Center, 


Background: Ipilimumab (Ipi) alters the immune system balance by inhibiting the 

suppression of T-cell function. In two Phase III trials, Ipi has shown an overall 

survival benefit alone and in combination with dacarbazine in previously treated and 

treatment-naïve patients (pts) with metastatic melanoma (MM), respectively. We 

performed a single-institution, Phase II clinical trial of Ipi plus temozolomide (Tem) 

in pts with MM. 

Methods: Pts between the ages of 18 and 75 with previously untreated unresectable 

Stage III or Stage IV MM and an ECOG Performance Status (PS) of 0 to 1 were 

enrolled in a Phase II trial of Ipi plus Tem. Induction phase consisted of Ipi 10mg/kg 

intravenous on Day 1 and oral Tem 200 mg/m 2 on Days 1 – 4 every 3 weeks for 4 

doses. Maintenance consisted of Ipi 10 mg/kg intravenous on Day 1 starting week 12 

and repeated every 12 weeks and oral Tem 200 mg/m 2 on Days 1 – 5 starting week 



12 and repeated every 4 weeks until disease progression or unacceptable toxicity 

occurred. The primary endpoint was progression-free survival (PFS) rate at 6 

months. Responses were evaluated using immune-related response criteria. 

Results: Sixty-four pts were enrolled and received at least one dose of study drug. All 

pts were included in the analysis. With a median follow-up of 51 weeks, the PFS rate 

at 6 months was 45%, exceeding the proposed rate of 30%, and the median PFS was 

22 weeks. There were 10 (15.6%) confirmed complete responses and 10 (15.6%) 

confirmed partial responses. To date, median overall survival has not been reached. 

Among many variables including age, gender, ECOG PS, and stage, there was a 

statistically significant difference in PFS in the group of patients with bone metastasis 

and those without bone metastasis. 

Conclusion: At a median follow-up of 51 weeks, the overall response rate in this 

study is 31%. Ipi at 10 mg/kg in combination with Tem given in an induction 

followed by maintenance fashion is safe, well-tolerated, and efficacious in MM. The 

primary endpoint of 6-month PFS has been reached and exceeded. 

Factors Associated with PFS 

No. of Pts 

Median PFS 

(weeks) 

Univariate 

P-Value 

Hazard 

Ratio 95% CI 

Bone Mets 

No 57 24 — 1.00 — 

Yes 7 12 0.01 2.73 1.20 – 6.20 

Disclosure: S. Patel: Research funding from Bristol-Myers Squibb. W. Hwu: Research 

funding from Merck Research funding from Bristol-Myers Squibb. K. Kim: Research 

funding from Bristol-Myers Squibb Advisory board, honoraria from Bristol-Myers 

Squibb. All other authors have declared no conflicts of interest. 

1127P FOUR-YEAR SURVIVAL UPDATE FOR METASTATIC 

MELANOMA (MM) PATIENTS (PTS) TREATED WITH 

IPILIMUMAB (IPI) + DACARBAZINE (DTIC) ON PHASE 3 

STUDY CA184-024 

M. Maio 1 , I. Bondarenko 2 , C. Robert 3 , L. Thomas 4 , C. Garbe 5 , A. Testori 6 , 

S. Francis 7 , K. Chin 8 , J. Wolchok 9 

1 Department of Oncology, Azienda Ospedaliera Senese - Medical Oncology and 

Immunotherapy Unit, Siena, ITALY, 2 Department of Oncology, Radiodiagnosis 

and Radioth, Dnipropetrovsk Municipal Clinical Hospital #4, Dnepropetrovsk, 

UKRAINE, 3 Melanoma Unit, Institute Gustave Roussy, Villejuif, FRANCE, 

4 Department of Dermatology, Lyon 1 University Centre Hospitalier Lyon Sud, 

Villeurbanne, FRANCE, 5 Oncology, University Medical Center, Tuebingen, 

GERMANY, 6 Melanoma Division, European Institute of Oncology, Milan, ITALY, 

7 Global Biometrics Sciences, Bristol-Myers Squibb, Braine-l’Alleud, BELGIUM, 

8 Global Clinical Research - Oncology, Bristol-Myers Squibb, Wallingford, CT, 

UNITED STATES OF AMERICA, 9 Melanoma-sarcoma Division, Memorial 

Sloan-Kettering Cancer Center, New York, NY, UNITED STATES OF AMERICA 

Background: Data from clinical trials suggest a long-term survival effect (beyond 4 

yrs) of IPI therapy in some pts with MM. An analysis of 177 pts from 3 phase I/II 

IPI studies conducted at NCI demonstrated 5-yr survival rates of 13-25% (Prieto, 

et al., CCR 2012). In other phase II trials, IPI monotherapy was associated with 

long-term survival of 4+ yrs in some pts with MM (Wolchok, et al., 2011 PIM). IPI 

in combination with DTIC in previously untreated MM patients significantly 

improved OS in phase III study CA184-024 (Robert, et al, NEJM 2011). Safety data 

from study 024 has been previously published. Here we report 4-yr survival data 

from study 024, the longest IPI survival follow-up from a phase III study. 

Methods: Pts with treatment-naive MM were randomized to receive either IPI (10 

mg/kg) + DTIC (850 mg/m 2 ) or placebo + DTIC (850 mg/m 2 ) given at Wks 1, 4, 7, 

10 followed by DTIC q 3 wks through Wk 22. Pts with stable disease or better then 

received IPI or placebo q 12 wks as maintenance. This analysis reports OS with 

updated last known alive date or death date based on data collected through April 

2012. 

Results: The table summarizes median OS, previously reported survival 

rates at 1, 2, and 3 years, and current analyses for 4-year survival rates by treatment 

group. 

Table: 1127P 

Treatment 

group 

Median OS, 

months 

[95% CI] 

Overall survival rate, % [95% CI] 

Conclusions: The 4-year survival rates observed in an extended follow-up of a 

completed phase III trial suggests that IPI 10 mg/kg in combination with DTIC 

continues to demonstrate a survival benefit compared to the control arm. The 

continued survival of some patients at 4 yrs suggests that prolonged survival may 

indeed be obtained in some pts with treatment-naive MM. This observation of 

long-term survival benefit in a phase III RCT is consistent with observations from 

phase I/II studies of IPI in patients with advanced melanoma. 

Disclosure: M. Maio: Paid advisor in boards from BMS and Roche. C. Robert: 

Consultant for BMS, GSK, Roche and Novartis. C. Garbe: I received honoraria and 

research funding from BMS. S. Francis: Employed by BMS. K. Chin: Employed by 

BMS and have Stock ownership. J. Wolchok: I am a consultant to BMS, Merck and 

GSK. I receive rsearch funding from BMS. All other authors have declared no 


1128P THE EUROPEAN IPILIMUMAB EXPANDED ACCESS 

PROGRAMME (EAP): EFFICACY AND SAFETY DATA FROM 

THE ITALIAN COHORT OF PATIENTS WITH PRETREATED, 

ADVANCED MELANOMA 

P.A. Ascierto 1 , V. Chiarion Sileni 2 , M. Del Vecchio 3 , M. Altomonte 4 , F. De Galitiis 5 , 

L. Ridolfi 6 , F. Cognetti 7 , A. Testori 8 , M.G. Bernengo 9 , P. Queirolo 10 

1 Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori di 

Napoli, Napoli, ITALY, 2 U.O. Oncologia Medica, Istituto Oncologico Veneto 

IOV-IRCCS, Padova, ITALY, 3 Department of Medical Oncology, Fondazione 

IRCCS Istituto Nazionale dei Tumori Milan, Milan, ITALY, 4 Department of 

Oncology, Azienda Ospedaliera Senese - Medical Oncology and Immunotherapy 

Unit, Siena, ITALY, 5 Department of Oncology, Dermopathic Institute of the 

Immaculate IDI-IRCCS, Rome, ITALY, 6 Medical Oncology, Scientific Institute of 

Romagna for the Study and Treatment of Cancer (IRST), Meldola, ITALY, 

7 Division Medical Oncology A, Istituto Regina Elena, Roma, ITALY, 8 Melanoma 

Division, Eurpean Institute of Oncology, Milan, ITALY, 9 Institute of Dermatology, 

University Hospital St John the Baptist, Turin, ITALY, 10 National Institute for 

Cancer Research, San Martino Hospital, Genoa, ITALY 

Purpose: Ipilimumab was the first agent approved for the treatment of unresectable 

or metastatic melanoma that showed an overall survival benefit in a randomised 

phase III trial. Here, we evaluate the safety and efficacy of ipilimumab treatment 

outside of clinical trials in patients enrolled in the EAP in Italy. 

Methods: Ipilimumab was available upon physician request for patients aged ≥16 

years with unresectable stage III/stage IV melanoma who had either failed systemic 

therapy or were intolerant to ≥1 systemic treatment and for whom no other 

therapeutic option was available. Ipilimumab 3 mg/kg was administered 

intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at 

baseline and after completion of induction therapy using immune-related response 

criteria. Patients were monitored for adverse events (AEs), including immune-related 

AEs, within 3 to 4 days of each ipilimumab dose using Common Terminology 

Criteria for Adverse Events v.3.0. 

Results: In total, 848 Italian patients participated in the EAP from June 2010 to 

April 2012 across 53 centres. Of these 848 patients, data are currently available for 

563 patients. With a median follow-up of 3 months, the disease control rate among 

468 evaluable patients was 31.4%, including 7 patients with a complete response, 51 

with a partial response and 89 with stable disease. As of April 2012, median 

progression-free survival and overall survival were 3.1 months and 6.2 months, 

respectively, with 1-year survival rate of 34%. In total, 50.1% patients reported an AE 

of any grade, most of which were drug-related (36.2%). Grade 3/4 AEs were reported 

by 18.5% patients and considered drug-related in 8.5%. Eleven patients discontinued 

treatment due to toxicity. AEs were generally reversible with treatment as per 

protocol-specific guidelines. Complete data on all 848 patients, with longer 

follow-up, will be presented. 

Conclusions: Ipilimumab is a feasible treatment option for pretreated patients who 

progressed on, or were unable to tolerate previous therapies. Many patients 

experienced durable disease control. 

Disclosure: P.A. Ascierto: PA has served as a consultant for Merck Sharp & Dohme, 

and as an advisor to Bristol-Myers Squibb (BMS), Merck Sharp & Dohme, Roche, 

GlaxoSmithKline, Amgen, Celgene, Medimmune and Novartis. He has received 

honoraria from BMS, Merck Sharp & Dohme and Roche. V. Chiarion Sileni: Vanna 

Chiaron Sileni has acted as an advisor for Bristol-Myers Squibb, Roche, 

1-year 2-year 3-year 4-year 

IPI + DTIC N = 250 11.2 [9.4-13.6] 47.5% [41.2–53.8] 28.8% [23.2–34.6] 21.2% [16.1–26.5] 19.0% [14.2 - 24.2] 

Placebo + DTIC N = 252 9.1 [7.8-10.5] 36.4% [30.4–42.4] 17.8% [13.2–22.6] 12.1% [8.1–16.3] 9.6% [6.1 - 13.5] 


GlaxoSmithKline, Merck Sharp & Dohme and Schering-Plough. M.G. Bernengo: 

Maria Grazia Bernengo has acted as an advisor to Bristol-Myers Squibb, Novartis 

and Pfizer. P. Queirolo: Paola Queirolo has acted as an advisor for Roche, 

GlaxoSmithKline, Bristol-Myers Squibb and Schering-Plough and received honoraria 

from Bristol-Myers Squibb and Roche. All other authors have declared no conflicts of 

interest. 

1129P IPILIMUMAB (IPI) EXPANDED ACCESS PROGRAM (EAP) FOR 

PATIENTS (PTS) WITH STAGE III/IV MELANOMA: SAFETY 

DATA BY SUBGROUPS 

D. Lawrence 1 , D.F. McDermott 2 , O. Hamid 3 , J.S. Weber 4 , J.D. Wolchok 5 , 

J. Richards 6 , A. Amin 7 , K. Bennett 8 , A. Balogh 9 , F.S. Hodi 10 

1 Department of Medicine, Massachusetts General Hospital Cancer Center, 

Boston, MA, UNITED STATES OF AMERICA, 2 Division of Hematology/Oncology, 

Beth Israel Deaconess Medical Center, Boston, MA, UNITED STATES OF 

AMERICA, 3 Neuro-oncology Clinic, The Angeles Clinic and Research Institute, 

Los Angeles, CA, UNITED STATES OF AMERICA, 4 Department of Oncology, 

H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, FL, UNITED 

STATES OF AMERICA, 5 Medicine, Memorial Sloan-Kettering Cancer Center, 

New York, NY, UNITED STATES OF AMERICA, 6 Oncology Hematology, 

Oncology Specialists SC, Parkridge, IL, UNITED STATES OF AMERICA, 7 Levine 

Cancer Institute, Carolinas Medical Center, Charlotte, NC, UNITED STATES OF 

AMERICA, 8 Global Medical, Bristol-Myers Squibb, Plainsboro, NJ, UNITED 

STATES OF AMERICA, 9 Global Biometrics Sciences, Bristol-Myers Squibb, 

Brain-l’Alleud, BELGIUM, 10 Melanoma Center, Dana-Farber Cancer Institute, 


Background: Treatment protocol CA184-045, a component of the EAP, provides a 

large safety database for IPI. Study 045 included pts with disease characteristics 

typically excluded from registrational clinical trials such as ECOG PS of 2, 

asymptomatic brain metastases (BM) and primary ocular (OM) and mucosal (MM) 

melanoma. We now report safety data by subgroups for pts treated in the US at 3 

mg/kg from March 2010 through July 2011. 

Methods: Eligible pts had unresectable Stage III or IV melanoma that progressed on 

at least 1 systemic therapy and had no alternate treatment options. Treatment 

algorithms were used for identification and management of immune-related adverse 

events (AEs). During induction, pts received 3 mg/kg IPI iv q 3 wks up to 4 doses. 

All AEs and on-study deaths were collected. This analysis includes events through 70 

days post last induction dose. 

Results: 2017 pts were included in this analysis; 96% were Stage IV and 92% were 

ECOG 0-1. Median number of doses during induction was 4, except 3 for BM. Data 

from pts < 65 or ≥ 65 yrs and those with BM, OM, MM, or all others are 

summarized. 

Disclosure: D.F. McDermott: BMS advisory board participantO. Hamid: Speaker for 

BMS - Reimbursed Clinic reimbursed for work done on research trials. J.S. Weber: 

BMS only honoraria less thank 10K dollars and advisory role in ad boards. J.D. 

Wolchok: I am a consultant to BMS, Merck and GSK. I receive research funding 

from BMS. J. Richards: Consultant and speaker for BMS. A. Amin: Participated in 

the BMS speaker’s bureau and advisory board during the last 2 years; unpaid 

investigator on EAP. K. Bennett: Employed by BMS; Stock Ownership. A. Balogh: 

Employed by BMS. F.S. Hodi: Nonpaid consultant and received clinical trial support 

from BMS. All other authors have declared no conflicts of interest. 

Table: 1129P 

1130P EFFICACY AND SAFETY OF IPILIMUMAB IN PATIENTS WITH 

PRETREATED, MUCOSAL MELANOMA: EXPERIENCE FROM 

ITALIAN CLINICS PARTICIPATING IN THE EUROPEAN 

EXPANDED ACCESS PROGRAMME (EAP) 

M. Del Vecchio 1 , E. Simeone 2 , V. Chiarion Sileni 3 , C. Nuzzo 4 , G. Rinaldi 5 , 

A. Testori 6 , F. De Galitiis 7 , P. Queirolo 8 , R. Marconcini 9 , M. Maio 10 

1 Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 

ITALY, 2 Fondazione Pascale, Instituto Nazional per lo Studio, Napoli, ITALY, 

3 Medical Oncology II, Istituto Oncologico Veneto IRCCS, Padova, ITALY, 

4 Department of Medical Oncology, Regina Elena National Cancer Institute, 

Rome, ITALY, 5 Discipliniche Chirurgiche ed Oncologiche, Azienda Ospedaliera 

UniversitariaPoliclinico Paolo Giaccone, Palermo, ITALY, 6 Melanoma Muscle 

Cutaneous Sarcoma Division, European Institute of Oncology, Milan, ITALY, 

7 Department of Oncology, Dermopathic Institute of the Immaculate IDI-IRCCS, 

Rome, ITALY, 8 National Institute for Cancer Research, San Martino Hospital, 

Genova, ITALY, 9 Department of Oncology, University Hospital Pisa “ Gathered 

Hospitals of Santa Clara”, Pisa, ITALY, 10 Department of Oncology, Medical 

Oncology and Immunotherapy,University Hospital of Siena, Siena, ITALY 

Purpose: Mucosal melanoma is an extremely rare and aggressive malignancy 

associated with a poor prognosis. Because of its rarity and the challenges associated 

with each anatomical location, mucosal melanoma often remains undetected until it 

is at an advanced stage, when effective treatment options are limited. The EAP 

provided an opportunity to assess the activity and safety of ipilimumab in patients 

with mucosal melanoma outside of controlled clinical trials from the EAP in Italy. 


years with stage III (unresectable) or stage IV skin, ocular or mucosal melanoma, 

who had failed or did not tolerate previous treatments and for whom no therapeutic 

option was available. Patients were treated with ipilimumab 3 mg/kg every 3 weeks 

for 4 doses. Tumour assessments were conducted at baseline and after completion of 

induction therapy using immune-related response criteria. Patients were monitored 

for adverse events (AEs), including immune-related AEs, within 3 to 4 days of each 

scheduled visit using Common Terminology Criteria for Adverse Events v.3.0. 

Results: Of 848 Italian patients participating in the EAP, 70 (8.2%) had mucosal 

melanoma. Of these, data are available for 50 patients. With a median follow-up of 

2.5 months, the disease control rate among 39 evaluable patients was 23.1%, 

including one patient with a complete response, two patients with a partial response 

and six with stable disease. As of April 2012, median progression-free survival and 

overall survival among patients with mucosal melanoma were 3.9 months and 6.2 

months, respectively. In total, 40.0% patients reported an AE of any grade, most of 

which were drug-related (32.0%). Grade 3/4 AEs were reported by 18.0% patients 

and considered drug-related in 12.0%. AEs were generally manageable and most 

resolved with treatment as per protocol-specific guidelines. 

Conclusions: Results from the EAP suggest that ipilimumab is active in some 

patients with mucosal melanoma and warrants further investigation in prospective 


Disclosure: E. Simeone: Ester Simeone has received honoraria from Bristol-Myers 

Squibb. V. Chiarion Sileni: Vanna Chiaron Sileni has acted as an advisor for 

Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck Sharp & Dohme and 

Schering-Plough. P. Queirolo: Paola Queirolo has acted as an advisor for Roche, 


from Bristol-Myers Squibb and Roche. M. Maio: Michele Maio has acted as an 

advisor for Bristol-Myers Squibb and Roche. All other authors have declared no 


Age Group Melanoma Sub-type 


Total N = 2017 < 65 yrs n = 1250 ≥ 65 yrs n = 767 BM** n = 686 OM** n = 118 MM** n = 112 All others n = 1150 

Demographics, % Males < 65 yrs Received 

all 4 induction doses 

64 62 59 61 – 58 69 – 60 67 72 49 50 63 59 51 58 53 65 57 65 

Discontinuations, % Disease progression 

Study drug toxicity Adverse event 

Study terminated ‡ 93* 49 4 2 92* 52 3 1 93* 46 6 3 94* 56 4 3 93* 55 3 2 98* 55 5 2 92* 45 4 1 

Other 

21 17 

20 16 

22 16 

16 15 22 11 25 11 

23 19 

Select Grade 3/4 drug-related AEs, % 3 3 0.3


1131P EFFICACY AND SAFETY OF IPILIMUMAB REINDUCTION 

THERAPY PATIENTS WITH PRETREATED ADVANCED 

MELANOMA PARTICIPATING IN AN EXPANDED ACCESS 

PROGRAMME (EAP) IN ITALY 

J. Pigozzo 1 , L. Calabrò 2 , P.A. Ascierto 3 , F. De Galitiis 4 , P.F. Ferrucci 5 , 

P. Queirolo 6 , M.G. Bernengo 7 , M. Aglietta 8 , M. Mandala 9 , M. Del Vecchio 10 

1 U.o.oncologia Medica, Istituto Oncologico Veneto IOV-IRCCS, Padova, ITALY, 

2 Department of Oncology, Medical Oncology and Immunotherapy,University 

Hospital of Siena, Siena, ITALY, 3 Unit of Medical Oncoloty and Innovative 

Therapy, Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, ITALY, 


Rome, ITALY, 5 Melanoma and Sarcoma, Istituto Europeo di Oncologia, Milano, 

ITALY, 6 National Institute for Cancer Research, San Martino Hospital, Genova, 

ITALY, 7 Institute of Dermatology, University Hospital St John the Baptist, Turin, 

ITALY, 8 Div Oncologia ed Ematologia, Fondazione Piemontese per la Ricerca sul 

Cancro Onlus, Candiolo, ITALY, 9 Oncology and Haematology, Ospedali Riuniti di 

Bergamo, Bergamo, ITALY, 10 Department of Medical Oncology, National Cancer 

Institute, Milan, ITALY 

Purpose: In the registrational phase III trial of ipilimumab, patients who progressed 

after initially responding to ipilimumab treatment could subsequently receive 

additional ipilimumab therapy with the same treatment regimen (reinduction). Here, 

we describe efficacy and safety data from the Italian subgroup of patients in the EAP 

who received reinduction with ipilimumab outside of a clinical trial setting. 


years with life-threatening, unresectable stage III/IV melanoma who failed or did not 

tolerate previous treatments and for whom no therapeutic option was available. 

Induction therapy with ipilimumab was 3 mg/kg every 3 weeks for 4 doses. Patients 

who progressed after stable disease (SD) lasting ≥3 months or an initial partial 

response (PR) or complete response (CR) were eligible for reinduction therapy at the 

same dose/schedule. Tumour assessments were conducted at baseline and after 

completion of induction therapy using immune-related response criteria. Patients 

were monitored for adverse events (AEs), including immune-related AEs, within 3 to 

4 days of each ipilimumab dose using Common Terminology Criteria for Adverse 

Events v.3.0. 

Results: Of 848 patients participating in the EAP in Italy, 59 received reinduction 

treatment. After a median follow-up of 10 months, the disease control rate among 26 

reinduced patients with data available was 100%; comprising nine patients with a PR 

and 17 with SD. Overall, only two reinduced patients died as a result of disease 

progression, after 11 and 13 months. As of April 2012, median overall survival for 

patients that received reinduction therapy had not yet been reached. In total, 57% 

patients reported grade 1/2 AEs. Grade 3/4 AEs were reported by 15% patients, but 

were only considered drug-related in one patient. AEs were generally reversible with 

treatment as per protocol-specific guidelines. 

Conclusions: Considering available data, reinduction with ipilimumab resulted in 

durable objective responses and/or stable disease. No new types of toxicities occurred 

during reinduction and most events were mild-to-moderate. 

Disclosure: P.A. Ascierto: PA has served as a consultant for Merck Sharp & Dohme, 

and as an advisor to Bristol-Myers Squibb (BMS), Merck Sharp & Dohme, Roche, 

GlaxoSmithKline, Amgen, Celgene, Medimmune and Novartis. He has received 

honoraria from BMS, Merck Sharp & Dohme and Roche. P. Queirolo: Paola Queirolo 

has acted as an advisor for Roche, GlaxoSmithKline, Bristol-Myers Squibb and 

Schering-Plough and received honoraria from Bristol-Myers Squibb and Roche. M.G. 

Bernengo: Maria Grazia Bernengo has acted as an advisor to Bristol-Myers Squibb, 

Novartis and Pfizer. All other authors have declared no conflicts of interest. 

1132P EFFICACY AND SAFETY DATA FROM PATIENTS WITH 

ADVANCED MELANOMA AND BRAIN METASTASES 

PARTICIPATING IN THE EUROPEAN IPILIMUMAB 

EXPANDED ACCESS PROGRAMME (EAP) IN ITALY 

P. Queirolo 1 , E. Simeone 2 , F. De Galitiis 3 , L. Di Guardo 4 , A.M. Di Giacomo 5 , 

R. Marconcini 6 , V. Ferraresi 7 , F. De Rosa 8 , M. Guida 9 , S. Stragliotto 10 

1 National Institute for Cancer Research, San Martino Hospital, Genova, ITALY, 

2 Fondazione Pascale, Instituto Nazional per lo Studio, Napoli, ITALY, 


Rome, ITALY, 4 Department of Medical Oncology, National Cancer Institute, 

Milan, ITALY, 5 Medical Oncology and Immunotherapy, University Hospital of 

Siena, Siena, ITALY, 6 Department of Oncology, University Hospital Pisa 

“Gathered Hospitals of Santa Clara”, Pisa, ITALY, 7 Department of Medical 

Oncology, Regina Elena National Cancer Institute, Rome, ITALY, 8 Medical 

Oncology, Scientific Institute of Romagna for the Study and Treatment of Cancer 

(IRST), Meldola, ITALY, 9 Medical Oncology, National Institute of Cancer, Bari, 

ITALY, 10 Medical Oncology II, Istituto Oncologico Veneto IRCCS, Padova, ITALY 

Purpose: Patients with melanoma brain metastases have a very poor prognosis and 

are usually excluded from melanoma clinical trials. The EAP provided an 

opportunity to evaluate the feasibility of ipilimumab treatment in this patient 

population outside of a controlled clinical trial in Italy. 


years with unresectable stage III /IV melanoma, including those with asymptomatic 

brain metastases, who had either failed systemic therapy or were intolerant to ≥1 

systemic treatment. Induction therapy with ipilimumab was 3 mg/kg every 3 weeks 




ipilimumab dose using Common Terminology Criteria for Adverse Events v.3.0. 

Results: Of 848 patients with advanced melanoma participating in the EAP in Italy, 

144 (17%) had asymptomatic brain metastasis. Of these, data are available for 84 

patients. With a median follow-up of 3 months, the disease control rate among 74 

evaluable patients was 16.2%, comprising four patients with a partial response and 

eight with stable disease. As of April 2012, median progression-free survival and 

overall survival among patients with brain metastases were 2.5 months and 3.8 

months, respectively. In total, 50.0% patients reported an AE of any grade, most of 

which were drug-related (40.5%). Grade 3/4 AEs were reported by 28.5% patients 

and considered drug-related in 15.5%. The most common grade 3/4 drug-related 

adverse events were diarrhoea (n = 3; 3.6%) and liver dysfunction (n = 3; 3.6%). AEs 

were generally reversible with treatment as per protocol-specific guidelines. 

Conclusions: Ipilimumab shows activity in patients with advanced melanoma 

metastatic to brain, with safety results consistent to what has been previously 

reported for ipilimumab. 

Disclosure: P. Queirolo: Paola Queirolo has acted as an advisor for Roche, 


from Bristol-Myers Squibb and Roche. E. Simeone: Ester Simeone has received 

honoraria from Bristol-Myers Squibb. All other authors have declared no conflicts of 

interest. 

1133P EFFICACY AND SAFETY OF IPILIMUMAB IN PATIENTS WITH 

PRETREATED, OCULAR MELANOMA: EXPERIENCE FROM 

ITALIAN CLINICS PARTICIPATING IN THE EUROPEAN 

EXPANDED ACCESS PROGRAMME (EAP) 

M. Maio 1 , V. Chairion Sileni 2 , L. Pilla 3 , S.V.L. Nicoletti 4 , L. Di Guardo 5 , 

P. Queirolo 6 , F. De Galitiis 7 , M. Mandala 8 , M. Guida 9 , P.A. Ascierto 10 

1 Istituto Toscano Tumori, University Hospital of Siena, Siena, ITALY, 2 Department 

of Oncology, Oncology Institute of Veneto, Padova, ITALY, 3 Department of 

Oncology, San Raffaele Hospital, Milan, ITALY, 4 Department of Medical 

Oncology, Scientific Institute of Romagna for the Study and Treatment of Cancer 

(IRST), Meldola, ITALY, 5 Department of Medical Oncology, National Cancer 

Institute, Milan, ITALY, 6 National Institute for Cancer Research, San Martino 

Hospital, Genoa, ITALY, 7 Oncology, IDI-IRCCS, Rome, ITALY, 8 Oncology and 

Haematology, Ospedali Riuniti di Bergamo, Bergamo, ITALY, 9 Medical Oncology, 

National Institute of Cancer, Bari, ITALY, 10 Unit of Medical Oncology and 

Innovative Therapy, Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, 

ITALY 

Purpose: Ocular melanoma is a rare malignancy with an incidence of 5.3–10.9 cases 

per million per year (Papastefanou and Cohen; J Skin Cancer 2011). Currently, the 

treatment of metastatic ocular melanoma is limited by the lack of an effective 

systemic therapy. The EAP provided an opportunity to assess the activity and safety 

of ipilimumab in patients with ocular melanoma outside of a controlled clinical trial 

in patients from the EAP in Italy. 


years with stage III (unresectable) or stage IV skin, ocular or mucosal melanoma, 

who had failed or did not tolerate previous treatments and for whom no therapeutic 

option was available. Patients were treated with ipilimumab 3 mg/kg every 3 weeks 




scheduled visit using Common Terminology Criteria for Adverse Events v.3.0. 

Results: Of 848 Italian patients participating in the EAP, 83 (9.8%) had ocular 

melanoma. Of these 83 patients, 55 have data available. With a median follow-up of 

3 months, the disease control rate among 46 evaluable patients was 34.8%, including 

3 patients with a partial response and 13 with stable disease. As of April 2012, 

median progression-free survival and overall survival among patients with ocular 

melanoma were 2.9 months and 5.9 months, respectively. In total, 63.6% patients 

reported an AE of any grade, most of which were drug-related (47.3%). Grade 3/4 

AEs, which were reported by 20.0% patients, were only considered drug-related in 

5.4%. AEs were generally manageable and most resolved with treatment as per 

protocol-specific guidelines. 

Conclusions: Safety and early efficacy results are similar to experience in other 

melanoma populations, thus suggesting that treatment of ocular melanoma with 

ipilimumab warrants further investigation in prospective clinical trials. 

Disclosure: M. Maio: Michele Maio has acted as an advisor for Bristol-Myers Squibb 

and Roche. V. Chairion Sileni: Vanna Chiaron Sileni has acted as an advisor for 

Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck Sharp & Dohme and 

Schering-Plough. P. Queirolo: Paola Queirolo has acted as an advisor for Roche, 


from Bristol-Myers Squibb and Roche. P.A. Ascierto: PA has served as a consultant/ 


advisor for Merck Sharp & Dohme, and as an advisor to Bristol-Myers Squibb 

(BMS), Roche, GlaxoSmithKline, Amgen, Celgene, Medimmune and Novartis. He 

has received honoraria from BMS, Merck Sharp & Dohme and Roche. All other 


1134P LONG-TERM SURVIVAL OF PATIENTS WITH ADVANCED 

MELANOMA TREATED SECOND LINE WITH IPILIMUMAB 

D. Lee 1 , L. Pericleous 2 , M. Lebmeier 2 , B. Winn 1 , A. Batty 1 , T. Nikoglou 2 

1 Health Economics, BresMed, Sheffield, UNITED KINGDOM, 2 Health Economics 

and Outcomes, Bristol Myers Squibb, Uxbridge, UNITED KINGDOM 

Objective: To estimate the long-term survival of patients with advanced melanoma 

treated second-line with ipilimumab 3 mg/kg compared to no active treatment (best 

supportive care [BSC]). 

Methods: At the end of the Phase III trial (MDX010-20) 17% of patients receiving 

ipilimumab were alive compared to 4% of those receiving GP100: median follow up 

28 months, maximum 55 months. Trial data were used to model survival beyond the 

trial period. GP100 has been shown to have no impact on survival (within 

MDX010-20 and a mixed treatment comparison). GP100 arm data were used to 

model survival of patients receiving BSC. Two groups were seen: Patients who 

experience therapy benefit and enter a stable period leading to a gradual plateau of 

the KM curve; Patients whose immune systems do not respond quickly and die 

causing an initial steep drop in the KM curve Standard modelling techniques did not 

fit the available data well and underestimated the durable response of 

immunotherapy. Around 18 months the mortality hazard was shown to change in 

the ipilimumab arm meaning that different methods were required to predict survival 

before and after this time. We estimated long-term survival as follows: · ≤18 Months 

Kaplan-Meier data was used, mimicking survival within the trial · >18 Months - 5 

years (representing the maximum data available from MDX-010-20) a standard 

parametric curve was fitted to the data · >5 years 15 year registry data from Balch 

et al (2001) for Stage IV melanoma and background mortality were used to estimate 

long-term survival. 

Results: Using the three-part approach reduced the mean absolute error (MAE) 

associated with the curve fits. Those selected having an MAE of 0.003 (0.004 for 

long-term survivors) on the ipilimumab arm, and 0.008 (0.012 for long-term 

survivors) on the BSC arm. This compares to a MAE at least 7 x higher (0.06) for 

standard parametric curves. For BSC patients, the model predicts mean survival of 

1.2 years whereas those taking ipilimumab are expected to survive for a mean of 3.7 

years. This is due to more patients remaining alive beyond 5-years, after which death 

from melanoma is less likely. 

Conclusion: Treatment with ipilimumab provides a substantial increase in survival 

over BSC in the second-line treatment of advanced melanoma. 

Disclosure: D. Lee: Funding for the analysis conducted was provided to BresMed by 

BMS. I have not received any personal funding and do not have any personal interest 

in BMS or any competitor products. L. Pericleous: I have worked for BMS. Other 

than this I have not received any personal funding and do not have any personal 

interest in BMS or any competitor products. M. Lebmeier: I work for BMS. Other 

than this I have not received any personal funding and do not have any personal 

interest in BMS or any competitor products. B. Winn: Funding for the analysis 

conducted was provided to BresMed by BMS. I have not received any personal 

funding and do not have any personal interest in BMS or any competitor products. 

A. Batty: Funding for the analysis conducted was provided to BresMed by BMS. I 

have not received any personal funding and do not have any personal interest in 

BMS or any competitor products. T. Nikoglou: I work for BMS. Other than this I 

have not received any personal funding and do not have any personal interest in 

BMS or any competitor products. 

1135P SEQUENTIAL COMBINATION OF LOW DOSE 

CHEMO-MODULATING TEMOZOLOMIDE WITH 

FOTEMUSTINE IN METASTATIC MELANOMA (MM). A PHASE 

II STUDY 

M. Guida 1 , A. Cramarossa 2 , P. Petrillo 1 , A. Albano 1 , S. Pisconti 3 , M. Aieta 4 , 

M. Traversa 2 , R. Ridolfi 5 , G. Colucci 1 

1 Medical Oncology, National Cancer Research Centre, Bari, ITALY, 2 Radiology, 

National Cancer Research Centre, Bari, ITALY, 3 Medical Oncology, Ospedale 

Civile, Taranto, ITALY, 4 Medical Oncology, Department of Medical Oncology, 

National Institute of Cancer, Rionero in Vulture, ITALY, 5 Medical Oncology, 

Immunotherapy Unit, National Cancer Institute of Romagna (IRST), Meldola, 

ITALY 

Background and purpose: MM is a chemoresistant cancer with poor prognosis. 

Further progress is likely to come from novel targeted antiBRAF therapy, available 

for about 50% of pts, and from immunotherapeutic agents such as the mAb 


ipilimumab, at present available only in some countries. Preclinical and clinical 

experiences support the concept that continuous exposure to an alkilating agent can 

effectively deplete cells of the DNA repair enzyme O6-methylguanine DNA 

methyltransferare, the primary mechanism of tumor resistance to chemotherapeutic 

agents like nitrosurea analogs. Our study was finalized to verify this hypothesis using 

a sequential combination of low dose chemo-modulating TMZ and FM. Primary 

endpoints were safety and tumor response evaluation. 

Methods: 53 consecutive MM pts were enrolled in the study. The majority of them 

(80%) were enrolled before the targeted therapy. The main characteristics included: 

median age 56 years (21-79); ECOG PS 1 (0–2); number of disease sites: 1 in 30%, 2 

in 27%, >2 in 43%; M status: M1a 9%, M1b 21%, M1c 70% with 5 pts having brain 

metastases. The following schedule was used: oral TMZ 100 mg/m2 d 1 and 2; FM iv 

100 mg/m2 d 2, 4 h after TMZ. The regimen was repeated every 3 weeks for a 

maximum total of 9 cycles. Tumour assessments were conducted at baseline and 

then every 3 cycles. 

Results: 52 pts are evaluable for toxicity and 51 for clinical assessment (1 withdrew 

consent prior to starting treatment; 2 early). The median number of treatment cycles 

administered was 7 (range 2-9). There were 13 (25%) responses (1 CR and 9 PRs) 

with a median duration of 7 months, and 12 (23%) stable disease. Median 

progression-free survival was 6 months and median overall survival 11+ months 

(range 2-35+ months). Drug-related toxicities ≥ grade 3 included thrombocytopenia 

(10%), neutropenia (6%), anemia (2%), and hepatopathy (2%). Approximately 75% 

of pts were treated without dose reduction. Two patients (4%) discontinued therapy 

because of toxicities. 

Conclusions: sequential low dose TMZ and FM demonstrated a high activity in our 

patient population with an acceptable toxicity. This schedule could therefore 

represent a good alternative for patients not eligible for targeted therapy or in whom 

previous targeted therapies failed. The study of the correlation between MGMT level 

and clinical outcomes is ongoing. 


1136P 18F-FDG-PET/CT IMAGING AS SURVIVAL PREDICTOR 

IN PATIENTS WITH METASTATIC UVEAL MELANOMA 

A. Rodriguez-Vida 1 , E. Muñoz 2 , M. Ochoa de Olza 1 , S. Rossi 3 , C. Gamez 3 , 

J.M. Caminal 4 , J. Perez 1 , J. Cortes 2 , J.M. Piulats 1 

1 Medical Oncology, Institut Catala d’Oncologia L’Hospitalet, L’Hospitalet de 

Llobregat, SPAIN, 2 Medical Oncology, Hospital Valle de Hebron, Barcelona, 

SPAIN, 3 Nuclear Medicine, Hospital Universitario de Bellvitge, L’Hospitalet de 

Llobregat, SPAIN, 4 Ophthalmology, Hospital Universitario de Bellvitge, 

L’Hospitalet de Llobregat, SPAIN 

Aims: To correlate metabolic activity by 18 F-FDG-PET/CT with survival in uveal 

melanoma patients with liver metastases (LM). 

Methods: We undertook a retrospective study of 34 patients with uveal melanoma 

and LM who underwent a 18 F-FDG-PET/CT at the time of metastatic diagnosis. 

Metabolic activity of LM was measured by standardized uptake value (SUV) and by 

grouping in 18 F-FDG-PET-negative (lower or same metabolic activity in LM than in 

normal liver parenchyma (NLP) comparing to 18 F-FDG-PET-positive (higher 

metabolic activity in LM than in NLP). These measures were correlated with overall 


Results: Patients were treated in 2 institutions between 2004-2010. There were 19 

women and 15 men. Median age was 62 years (30-84). Median follow-up was 16.7 

months. Treatment of primary tumor was: 15 enucleation (44.1%), 3 resection (8.8%) 

and 16 brachytherapy (47.1%). LM were diagnosed on screening protocol and 

histologically confirmed if possible (85.3%). Median major diameter of LM was 20 

mm (9-130). Median maximum SUV of LM was 8.7 (2-25). 18 F-FDG-PET/CT was 

negative for metabolic activity in 6 patients and positive in 28 patients. All 6 patients 

with negative 18 F-FDG-PET/CT were histologically confirmed. Metastatic disease 

treatments were: chemotherapy (27 patients), liver surgery (9 patients), liver 

stereotactic radiotherapy (2 patients), liver radiofrequency ablation (1 patient). 

Median OS was 18.8 months (CI 95% 7.2-30.4). Median OS was significantly higher 

(p = 0.001) in patients with 18 F-FDG-PET-negative (median not reached) than in 

patients with 18 F-FDG-PET-positive (15.1 months, CI 95% 11.5-18.7). Assessed as a 

continuous variable, maximum SUV in the liver was correlated with OS (p = 0.002, 

HR 1.1, CI 95% 1.03-1.2). Maximum SUV greater than 5 was related with poor 

prognosis (p = 0.025). Major diameter of LM in 18 F-FDG-PET/CT was significantly 

correlated with OS (p < 0.001). LM greater than 20 mm were related with poor 

prognosis (p < 0.001). By multivariate analysis, major diameter of LM (p < 0.001) 

and 18 F-FDG-PET/CT status (p = 0.001) remained significant survival predictors. 

Conclusion: Metabolically 18 F-FDG-PET-negative liver metastases correlated with 

better OS in patients with metastatic uveal melanoma. 




1137P IMMUNO-CHEMOABLATION OF METASTATIC MELANOMA 

WITH INTRALESIONAL ROSE BENGAL 

S.S. Agarwala 1 , J.F. Thompson 2 , B.M. Smithers 3 , M. Ross 4 , B.J. Coventry 5 , 

D.R. Minor 6 , C.R. Scoggins 7 , E. Wachter 8 

1 Cancer Center, St. Luke’s Hospital & Health Network, Bethlehem, UNITED 

STATES OF AMERICA, 2 Surgery, Melanoma Institute, Sydney, AUSTRALIA, 

3 Surgery, Princess Alexandra Hospital, Woolloongabba, AUSTRALIA, 4 Surgery, 

MD Anderson, Houston, UNITED STATES OF AMERICA, 5 Surgery, Royal 

Adelaide Hospital, Adelaide, AUSTRALIA, 6 Medical Oncology, California Pacific 

Medical Center, San Francisco, UNITED STATES OF AMERICA, 7 Surgery, 

University of Louisville, Louisville, UNITED STATES OF AMERICA, 8 Drug 

Development, Provectus Pharmaceuticals, Knoxville, UNITED STATES OF 

AMERICA 

Intralesional rose bengal (PV-10) is being investigated for treatment of solid tumors, 

where it may elicit selective chemoablation of injected lesions and a tumor-specific, 

immune-mediated bystander response in untreated bystander lesions. In phase 1 

testing in 20 subjects with AJCC Stage III-IV melanoma, single-dose treatment with 

PV-10 was well tolerated, producing a durable objective response (OR) at 12-24 

weeks in 40% of subjects (20% CR + 20% PR by modified RECIST) and locoregional 

disease control (CR + PR + SD) in 75% of subjects; 15% of subjects achieved an OR 

in bystander lesions, which strongly correlated with response of their injected lesions. 

Phase 2 testing in 80 subjects with Stage III-IV metastatic melanoma (median age 

70.0 yrs, range 33-97) commenced at 7 centers in Australia and the USA in October 

2007 with final clinical evaluation completed in May 2010 (Clinical Trials ID 

NCT00521053). In this study, subjects could receive up to four courses of PV-10 to 

up to 20 cutaneous or subcutaneous lesions (median 2 courses, range 1-4). 

Preliminary study data was presented at SMR 2010 in Sydney, Australia, and showed 

that treatments were well tolerated, with adverse events predominantly mild to 

moderate, locoregional and transient, with no grade 4 or 5 AEs attributed to PV-10. 

Preliminary evaluation also showed robust response, with 24% of subjects achieving a 

CR, 25% PR and 22% SD of their target lesions. Additionally, 24% of 38 subjects 

with evaluable, untreated bystander lesions achieved CR in their bystander lesions, 

along with 13% PR and 18% SD. As observed in phase 1, response of bystander 

lesions strongly correlated with response of injected lesions. Final efficacy data will be 

presented, including response rate and time-to-event (progression free survival and 

overall survival). These data demonstrate that the safety and efficacy profile of PV-10 

compares favorably with available and emerging treatment options for this patient 

population, and serve as the basis for phase 3 testing of PV-10 in Stage III patients 

with recurrent, in-transit or satellite metastases. A randomized controlled trial to 

assess PFS against standard care is expected to commence in the second half of 2012 

at centers in Australia, the USA and the EU. 

Disclosure: S.S. Agarwala: Provectus Pharmaceuticals: advisory board, 

corporate-sponsored research. J.F. Thompson: Provectus Pharmaceuticals: 

advisory board, corporate-sponsored research. B.M. Smithers: Provectus 

Pharmaceuticals: corporate-sponsored research. M. Ross: Provectus 

Pharmaceuticals: advisory board, corporate-sponsored research. B.J. Coventry: 

Provectus Pharmaceuticals: corporate-sponsored research. D.R. Minor: Provectus 

Pharmaceuticals: corporate-sponsored research. C.R. Scoggins: Provectus 

Pharmaceuticals: advisory board, corporate-sponsored research. E. Wachter: 

Employee of sponsoring company, stock holder 

1138P CHEMOTHERPAY AND DENDRITIC CELL VACCINE IN 

PATIENT WITH METASTATIC MELANOMA: PHASE II 

PROSPECTIVE RANDOMIZED TRIAL 

I.V. Samoylenko 1 , T.N. Zabotina 2 , I.N. Mikhaylova 1 , G.Z. Chkadua 3 ,O. 

V. Korotkova 2 , K. Baryshnikov 1 , L.V. Demidov 1 

1 Tumor Biotherapy, N.N Blokhin Russian Cancer Research Center, Moscow, 

RUSSIAN FEDERATION, 2 Laboratory of Clinical Immunology, N.N Blokhin 

Russian Cancer Research Center, Moscow, RUSSIAN FEDERATION, 

3 Laboratory of Experimental Diagnostics and Tumor Biotherapy, N.N Blokhin 

Russian Cancer Research Center, Moscow, RUSSIAN FEDERATION 

Introduction: We performed a vaccine trial in metastatic melanoma patients with a 

stable disease course. 

Aim: Primary end point was 6-month progression-free survival; secondary end 

points included overall survival, progression free survival, immunological parameters. 

Patients and methods: Inclusion criteria were morphologically proven metastatic 

melanoma, ECOG status 0-2, LDH level

or cutaneous melanoma. A survival update was performed on 31 March 2011. 

CS-PHP melphalan 3.0 mg/kg ideal body weight was infused into the hepatic artery 

over 30 min with concurrent extracorporeal filtration for 60 min. Up to 6 treatments 

were given every 4–8 wks. In the BAC group, crossover to CS-PHP melphalan was 

permitted after hepatic disease progression. The primary endpoint was 

investigator-assessed hepatic progression-free survival (hPFS). An exploratory 

post-hoc analysis of pts who crossed from BAC to CS-PHP vs. BAC-only pts was 

also performed. 

Results: 93 pts were randomized to CS-PHP (n = 44) or BAC (n = 49). After hepatic 

disease progression, 28 pts crossed over to CS-PHP. Results are shown in the Table. 

The most common grade 3/4 toxicities in CS-PHP pts (n = 40) were hematological 

peri-procedural thrombocytopenia (73%) and anemia (55%) and post-procedural 

(beyond day 4 post-treatment) neutropenia (93%) or thrombocytopenia (83%). The 

safety profile in crossover pts was similar to that in pts randomized to CS-PHP 

melphalan. 

Conclusions: CS-PHP melphalan significantly prolonged hPFS compared with BAC 

in pts with liver-dominant metastatic melanoma, thereby meeting the primary study 

objective. Efficacy was similar after hepatic disease progression in BAC-CS-PHP 

crossover pts as in those randomized initially to CS-PHP. 

Median 

hPFS, Hazard ratio Median Hazard ratio 

Treatment group n mo (95% CI) OS, mo (95% CI) 

CS-PHP 44 8.0 0.35 (0.23-0.54) 9.8 1.08 (0.69-1.68) 

BAC 49 1.6 P < 0.0001 9.9 NS 

BAC only 21 1.6 0.32 4.1 0.33 

BAC → 

CS-PHP crossover 

28 8.8 15.3 


1142P THE CONCORDANCE OF HER2 STATUS IN PRIMARY 

AND METASTATIC SITES OF EXTRAMAMMARY PAGET’S 

DISEASE 

R. Tanaka 1 , Y. Sasajima 2 , H. Tsuda 2 , K. Namikawa 1 , A. Tsutsumida 1 , 

N. Yamazaki 1 

1 Division of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, 

JAPAN, 2 Pathology and Clinical Laboratory Division, National Cancer Center 


Background: HER2-targeted therapies have been introduced to treat breast and 

stomach cancers that show HER2 protein overexpression and/or HER2 gene 

amplification. However, the HER2 status of primary tumors and their corresponding 

metastatic sites is shown to be heterogeneous in less than 20% of cases. In 

extramammary Paget’s disease (EMPD), HER2 protein overexpression and gene 

amplification has been shown to occur in 5-80% of cases; however, knowledge 

regarding the concordance of HER2 status in primary and metastatic sites of EMPD 

is limited. The aim of this study was to clarify the concordance rate of HER2 status 

in the primary tumors and metastatic sites of EMPD. 

Methods: Twenty-six tissue blocks of primary tumors and corresponding lymph 

node metastases were subjected to an immunohistochemistry (IHC) analysis. The 

IHC scores were classified into four groups (0 to 3+) according to the American 

Society of Clinical Oncology/College of American Pathologists Guidelines (2007). 

When the primary tumors and lymph node metastases showed IHC scores of either 

2+ or 3 + , the presence of HER2 gene amplification was examined using 

fluorescence in situ hybridization (FISH) and dual-colored in situ hybridization 

(DISH). 

Results: mmunohistochemically, 27% (7/26) of the primary tumors and 38% (10/26) 

of the lymph node metastases showed IHC scores of either 2+ or 3+. When HER2 

protein overexpression was classified as being either positive (2 + , 3+) or negative (0, 

1+), the concordance rate of the HER2 status of the primary tumors and 

corresponding lymph node metastases was 85% (22/26). The presence of HER2 gene 

amplification was examined in six primary tumors and 10 metastatic sites. HER2 

gene was amplified in a total of seven cases (27%): four cases in both the primary 

and metastatic sites, two cases in the metastatic sites only and one case in the 

primary site only. 

Conclusion: Good concordance of HER2 protein overexpression and gene 

amplification status was seen in the primary tumors and corresponding lymph node 

metastases of patients with EMPD. Furthermore, the HER2 gene was found to be 

always amplified in cases with an IHC score of 3+ and in two cases with an IHC 

score of 2+ in the lymph node metastases, which is suitable to be targeted for 




1143P A COMPARISON OF GENERAL POPULATION AND PATIENT 

UTILITY VALUES FOR ADVANCED MELANOMA 

A. Batty 1 , B. Winn 1 , L. Pericleous 2 ,D.Rowen 3 , D. Lee 1 , T. Nikoglou 2 

1 Health Economics, BresMed, Sheffield, UNITED KINGDOM, 2 Health Economics 

and Outcomes, Bristol Myers Squibb, Uxbridge, UNITED KINGDOM, 3 School of 

Health and Related Research, University of Sheffield, Sheffield, UNITED 

KINGDOM 

Background: Health-related quality of life (HRQL) is a fundamental part of health 

technology assessment. Utility values are vital because they can be used as preference 

weights and allow the calculation of HRQL benefits. The objective of this study was 

to compare utilities calculated for patients with advanced melanoma in the Phase III 

clinical trial for ipilimumab (MDX010-20) using a generic and a condition-specific 

preference-based measure to utilities produced by vignettes for advanced melanoma. 

A secondary objective was to determine how different analyses might be used most 

appropriately within cost-effectiveness modelling. 

Methods: The trial utilities were generated using the condition-specific EORTC-8D 

(1,190 observations) and generic SF-6D (1,157 observations) preference-based 

measures. Progression-status and time-to-death analyses were conducted on the 

patient-level data and the predictive abilities were compared. Patient-level results 

were compared to the utilities derived for progression status using vignettes valued 

by the general population. 

Results: On disease progression, vignette-generated utilities showed a greater 

decrease (0.77 to 0.59) than either the generic SF-6D (0.64 to 0.619) or 

condition-specific EORTC-8D (0.801 to 0.763). SF-6D and EORTC-8D showed a 

large decrease in utility in the 180 days prior to death (from 0.826 to 0.628 and from 

0.655 to 0.505, respectively). Compared to progression status, time to death showed a 

lower Root Mean Squared Error and higher R2 when used to predict patient utility. 

Conclusion: Practitioners should carefully analyse patient level utility data prior to 

constructing economic models as standard measures, such as progression status, 

may not fully capture the patient experience. Similarly, where vignettes are valued 

to represent health states in an economic model, their applicability to the disease 

and patient population should be carefully scrutinised. The use of standard 

progression based cost-effectiveness modelling techniques may not be appropriate 

for this disease. Consequently, there are implications for the analysis of utility 

information in future studies and the methods of cost-effectiveness modelling used 

for cancer treatments. 

Disclosure: A. Batty: BresMed were funded by BMS to conduct the analysis 

presented within this paper. Other than this I have not received any personal 

funding and do not have any personal interest in BMS or any competitor products. 

B. Winn: BresMed were funded by BMS to conduct the analysis presented within 

this paper. Other than this I have not received any personal funding and do not 

have any personal interest in BMS or any competitor products. L. Pericleous: I have 

worked for BMS. Other than this I have not received any personal funding and do 

not have any personal interest in BMS or any competitor products. D. Lee: 

BresMed were funded by BMS to conduct the analysis presented within this paper. 

Other than this I have not received any personal funding and do not have any 

personal interest in BMS or any competitor products. T. Nikoglou: I work for BMS. 

Other than this I have not received any personal funding and do not have any 

personal interest in BMS or any competitor products. All other authors have 


1144 CETUXIMAB IN METASTATIC SQUAMOUS CELL CANCER 

OF THE SKIN: A CASE SERIES 

K. Conen 1 , N. Fischer 2 , G.F. Hofbauer 3 , B. Shafaeddin-Schreve 3 , 

R. Wintherhalder 4 , C. Rochlitz 5 , A. Zippelius 1 

1 Medical Oncology, University Hospital Basel, Basel, SWITZERLAND, 2 Medical 

Oncology, Kantonsspital Winterthur, Winterthur, SWITZERLAND, 

3 Dermatologische Klinik, Universitätsspital Zürich, Zürich, SWITZERLAND, 

4 Medical Oncology, Kantonsspital Luzern, Luzern, SWITZERLAND, 5 Medical 

Onkology, University Hospital Basel, Basel, SWITZERLAND 

Background: Treatment of metastatic squamous cell cancer of the skin (SCCS) is 

challenging. Only few therapeutic options including cisplatin-based combinations are 

currently available. In a recently published phase II trial, cetuximab, a monoclonal 

antibody against the epidermal growth factor receptor (EGRF), has demonstrated a 

promising clinical activity with an overall 69% disease control rate (DCR) and 28% 

response rate (RR) in patients with unresectable SCCS. Whether this treatment is 

also effective in metastatic SCCS is unclear. 

Purpose: To summarize the efficacy of cetuximab at any line in a series of patients 

with metastatic SCCS. 

Patients and methods: We performed a retrospective analysis of six patients from 

four centres in Switzerland. We collected standard baseline data by reviewing the 



patients’ records. Endpoints were DCR at 4-8 weeks, 12-14 weeks and 20-36 weeks of 

treatment. In addition, we evaluated the treatment-related toxicity. 

Results: The median age of the patients was 67 years. A total of 10 cycles in median 

were applied (range 1-21). The DCR was 67% (4 of 6 patients) at 4-8 weeks, 50% (3 

of 6 patients) at 12-14 weeks, and 33% (2 of 6 patients) at 20-26 weeks (Table 1). 

One patient showed a complete response (CR) after 4 weeks of treatment and is still 

in remission since then. Death due to sepsis occurred in one patient. 83% (5 of 6 

patients) developed Grade I-III acne-like rash around week 3 of treatment. All 

patients who had their disease controlled at 4-8 weeks showed an acne-like rash 

(4 of 6 patients), 1 patient had a rash without disease control. 

Conclusions: Cetuximab treatment in patients with metastatic SCCS achieved an 

overall DCR of 57% at 4-8 weeks of treatment. 1 of 6 patients had a CR. These data 

suggest that cetuximab may be effective in this setting. 

Response and disease control rates. 

Response at 4-8 weeks 12-14 weeks 20-36 weeks 

Variable No % No % No % 

Complete response 1 17 1 17 1 17 

Partial response 3 50 1 17 1 17 

Stable disease 0 0 1 17 0 0 

Progressive disease 2 33 1 17 1 17 

Disease control rate 67 50 33 


1145 SENSITIVE DETECTION OF BRAF MUTATIONS USING 

MUTANT-ENRICHED PCR AND REVERSE-HYBRIDIZATION 

TESTSTRIPS 

M. Novy, G. Kriegshäuser, B. Rauscher, C. Oberkanins 

Research - Development, ViennaLab Diagnostics GmbH, Vienna, AUSTRIA 

Background: BRAF plays a key role in growth factor receptor induced signalling 

pathways. Somatic BRAF mutations are involved in oncogenesis and are found in 

various types of tumors, including colorectal, thyroid and skin cancer. Activating 

BRAF mutations confer resistance to anti-EGFR monoclonal antibody therapy. 

Moreover mutated BRAF is a prominent target of the drug vemurafenib. 

Materials and methods: We have developed a reverse-hybridization StripAssay 

detecting nine BRAF mutations: c.1799T > C (V600A), c.1799_1800TG > AT 

(V600D), c.1799T > A (V600E), c.1799_1800TG > AA (V600E), c.1799T > G 

(V600G), c.1798_1799GT > AA (V600K), c.1798G > A (V600M), c.1798_1799GT > 

AG (V600R) and c.1801A > G (K601E). The test is based on mutant-enrichted PCR 

in the presence of a BRAF wild-type suppressor, followed by hybridization of PCR 

products to teststrips presenting a parallel array of allele-specific oligonucleotide 

probes. Bound sequences are visualized using streptavidin-alkaline phosphatase 

conjungate and colour substrates. The hybridization and detection steps can be 

carried out fully automated using commercially available instrumentation. 

Results: Plasmid clones served as reference DNA templates to control for specificity. 

StripAssay performance was evaluated on genomic DNA obtained from cultured cell 

lines and formalin-fixed paraffine-embedded (FFPE) tissue. Using normal DNA 

spiked with serial dilutions of DNA from the BRAF-mutant tumor cell lines HT29 or 

IGR-1, the mutations c.1799T > A (V600E) and c.1798_1799GT > AA (V600K) were 

shown to be detectable at a level of 1%. 

Conclusions: The simultaneous detection of nine different mutations with high 

sensitivity will make the StripAssay a very useful tool for the assessment of the BRAF 

mutation status of cancer patients. 


1146 INTER- AND INTRA- TUMOR HETEROGENEITY OF SOMATIC 

BRAF MUTATIONS IN MELANOMA 

S. Murray 1 , H. Linardou 2 , F. Siannis 3 , D. Bafaloukos 2 

1 Oncology, GeneKor SA, Athens, GREECE, 2 1st Department of Medical 

Oncology, Metropolitan Hospital, Athens, GREECE, 3 Department of 

Mathematics, University of Athens, Athens, GREECE 

Background: Somatic mutations of BRAF are correlated with improved outcomes in 

patients with Melanoma treated with the anti-BRAF tyrosine kinase inhibitor 

Vemurafenib (PLX4032). Heterogeneity of patient responses to Vemurafenib in 

patients harboring BRAF mutations has questioned the stability of concordance 

between and within tumors. We conducted a systematic search of the literature to 

assess such status. 

Methods: Using a broad search string including “BRAF”, “RAS”, “Melanoma”, 

“Cancer” and associated synonyms from inception through to 23/12/2011 in 

MEDLINE (PubMed) we identified articles providing information on Melanoma 

patients pertaining to concordance between synchronous (intra-) tumors; between 

primary and metastasis; and within (inter-) tumor heterogeneity. Data extraction was 

conducted by two investigators. Predictive values of testing for the presence of BRAF 

(True positive) and ‘no detectable mutation’ (True negative) were assessed and 95% 

confidence intervals calculated. Positive and Negative Predictive Values are presented 

(PPV, NPV). 

Results: Sixteen articles presented for synchronous, 13 for meta-synchronous, and 7 

for retesting (intra-tumoral analysis). Data indicates that there is a significant level 

of dis-concordance: a) between synchronous tumors (PPV = 0.70 [0.59-0.79], 

NPV = 0.46 [0.35-0.56]); b) between meta-synchronous tumors (primary versus 

metastasis (PPV = 0.68 [0.54-0.80], NPV = 0.45 [0.32-0.58]); and within (intra-) 

tumors (PPV = 0.56 [0.49-0.69], NPV = 0.40 [0.29-0.52]). 

Conclusions: Repetitive data sets indicated heterogeneity of BRAF genotype status 

between synchronous, meta-synchronous tumors, and also at the intra-tumoral 

level. PPV and NPV were worryingly high and outside of acceptable limits. 

Approximately 30% of patients may have dis-concordance in their BRAF reporting 

status. No obvious technical errors were identified to explain these differences. 

Several studies are now indicating that tumor heterogeneity may affect several 

cancer types, and this may impact on biomarker driven stratification. More data is 

eagerly awaited 


1147 BRAF MUTATIONS ARE FREQUENT IN MALIGNANT 

MELANOMA IN ISRAELI POPULATION AND PREDICTS POOR 

RESPONSE TO BIOCHEMOTHERAPY 

I. Lazarev, A. Yakobson, S. Ariad 

Department of Oncology, Soroka Medical Center, Beer-Sheva, ISRAEL 

Introduction: Malignant melanoma is a highly-aggressive form of skin cancer. 

Lesions developing in non-chronically sun-damaged skin are associated with frequent 

activating mutations in BRAF with substitution of valine for glutamic acid at position 

600 (BRAF V600E ). The prognostic significance of BRAF mutation in patients with 

metastatic melanoma (MM) treated with chemobiotherapy is uncertain. 

Patients and methods: We studied the prognostic significance of BRAF mutation in 

69 patients with MM treated with chemobiotherapy at the Soroka Medical Center, 

Beer Chemobiotherapy consisted of BCNU, DTIC, cisplatin, IL-2, alpha-interferon, 

GM-CSF, cimetidine, and tamoxifen. Samples were micro-dissected at the molecular 

lab, Hacarmel hospital, and subjected to high-resolution melting analysis using 

primers flanking codon 600 in the BRAF gene. All abnormal high-resolution melting 

traces were subjected to bidirectional DNA sequencing. 

Results: Mean age-55 years (range 25-80); Gender-male/female–41/28; Ulceration– 

30/54; Site of primary lesion: limbs/head/neck/trunk/retina/mucous membranes–12/ 

13/0/14/2/3; Depth: T1/T2/T3/T4/undetermined-3/8/24/16/4; Lymph node biopsy– 

32/54; Lymph node involvement: none/micrometastases/metastases–14/2/16. BRAF 

mutation–42/69 (61%). BRAF mutation correlated with poor response to treatment 

(P = 0.056), but had no effect on disease-free interval (DFI). DFI was affected only by 

nodal stage (P = 0.026). In Cox multivariate analysis only male gender was associated 

with worse prognosis (P = 0.03), while BRAF mutation showed a trend towards worse 

prognosis (P = 0.169). 

Conclusions: BRAF mutation in patients with MM treated with chemobiotherapy 

may predict poor response to treatment. 


1148 SAFETY AND EFFICACY OF IPILIMUMAB 10 MG/KG AMONG 

PATIENTS WITH ADVANCED MELANOMA FROM ITALY 

ENROLLED IN A EUROPEAN COMPASSIONATE USE 

PROGRAM 

M. Maio 1 , P. Queirolo 2 , A. Testori 3 , M. Altomonte 1 , M. Maur 4 , E. Bajetta 5 ,P. 

A. Ascierto 6 , V. Chiarion Sileni 7 , A.M. Di Giacomo 1 , R. Ridolfi 8 

1 Department of Oncology, Azienda Ospedaliera Senese - Medical Oncology and 

Immunotherapy Unit, Siena, ITALY, 2 Department of Oncology, National Institute 

for Cancer Research - Genova, Genova, ITALY, 3 Melanoma Muscle Cutaneous 

Sarcoma Division, European Institute of Oncology, Milan, ITALY, 4 Dept. of 

Hematology/Oncology, Ospedale Policlinico-Modena, Modena, ITALY, 5 Medical 

Oncology, Istituto di Oncologia del Policlinico di Monza, Monza, ITALY, 6 Unit of 

Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori Fondazione 

G. Pascale, Napoli, ITALY, 7 U.O.Oncologia Medica, Istituto Oncologico Veneto 

IOV-IRCCS, Padova, ITALY, 8 Immunoterapia e Terapia Cellulare Somatica, 

IRCCS-IRST Meldola, Meldola (FC), ITALY 

Purpose: Clinical studies of ipilimumab have shown improved survival and durable 

tumour responses across a spectrum of doses and schedules. Here, we evaluate the 

use of ipilimumab 10 mg/kg outside of clinical trials, in a setting similar to daily 

practice. 

Methods: Ipilimumab was available upon physician request for patients (pts) aged 

≥16 years with unresectable stage III/stage IV melanoma who had either failed 


systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other 

therapeutic option was available. Induction therapy with ipilimumab 10 mg/kg was 

given on Week (wk) 1, 4, 7 and 10 with tumour assessments conducted at baseline, 

wk 12 and q 12 wks thereafter using modified World Health Organization criteria. 

Maintenance therapy with ipilimumab was available q 12 wks from wk 24 for pts 

with evidence of clinical benefit. Pts were monitored for adverse events (AEs) using 

Common Terminology Criteria for Adverse Events v.3.0. 

Results: In total, 74 pts, including 11 with brain metastasis, received ≥1 dose of 

ipilimumab and were eligible for analysis. Of these, 43 (58.1%) completed the 

induction phase and 26 (35.1%) received maintenance therapy (median of 2 cycles; 

range: 1–13). The disease control rate was 32%, including 3 pts (4%) with a complete 

response, 6 (9%) with a partial response, and 13 (19%) with stable disease. Median 

progression-free survival (PFS) and overall survival (OS) was 3 months (mo) (95% 

CI: 2.3–3.7) and 7 mo (95% CI: 5.3–8.7), respectively. For pts with brain metastases, 

PFS and OS were 3 mo (95% CI: 2.4–3.6) and 4 mo (95% CI: 2.4–5.6). The 3-yr 

survival rate was 16.6%, with 11 long survivors pts (>3 yrs). Overall, 45 pts (61%) 

reported an AE of any grade; most commonly pruritis and diarrhoea. Eight grade 3/4 

AEs were reported, including diarrhoea (n = 2), pain (including epigastric; n = 3) and 

one case each of fever, increased liver enzymes and pancytopenia. Most AEs were 

manageable through adherence to protocol-specific guidelines. 

Conclusions: Ipilimumab is a feasible treatment option for pts who progressed on, 

or were unable to tolerate previous therapies, with approximately one-third of pts 

achieving disease control and a long-term survival benefit. 

Disclosure: M. Maio: Advisory board and honoraria from: BMS and Roche. 

P. Queirolo: Paola Queirolo served on Advisory Board of Bristol Myers Squibb, 

Roche-Genentech, GSK, MSD and received honoraria from Brystol Myers Squibb 

and Roche-Genentech. A. Testori: I have a consultant or advisory relationship to 

disclose ( BMS, GSK, AMGEM advisory boards); I have honoraria to disclose (from 

above mentioned advisory boards); I have other remuneration to discloure ( travel 

expenses from oncovision and Igea). P.A. Ascierto: Consultant or advisory 

relationship for: Brystol Myers - Squibb Merck Roche GSK Amgen. Honoraria to 

disclose from BMS, Merck, Roche. V. Chiarion Sileni: Advisory Board and/or 

Honoraria from: BMS MSD Shering & Plough Roche GSK. All other authors have 


1149 IPILIMUMAB FOR ADVANCED MELANOMA IN AN EXPANDED 

ACCESS PROGRAMME (EAP): OCULAR, MUCOSAL AND 

ACRAL SUBTYPE UK EXPERIENCE 

H. Shaw 1 , J. Larkin 2 , P. Corrie 3 , S. Ellis 4 , J. Nobes 5 , E. Marshall 6 , S. Kumar 7 , 

S. Danson 8 , R. Plummer 9 , P. Nathan 1 

1 Cancer Services, Mount Vernon Cancer Centre, Northwood, UNITED 

KINGDOM, 2 Department of Medicine, Royal Marsden Hospital, London, UNITED 

KINGDOM, 3 Oncology Centre, Cambridge University Hospitals NHS Foundation 

Trust, Cambridge, UNITED KINGDOM, 4 Department of Oncology, Southampton 

General Hospital, Southampton, UNITED KINGDOM, 5 Department of Medicine, 

Norfolk and Norwich University Hospital, Norwich, UNITED KINGDOM, 

6 Oncology, Clatterbridge Centre for Oncology, Liverpool, UNITED KINGDOM, 

7 Department of Oncology, Velindre Cancer Centre, CARDIFF, UNITED 

KINGDOM, 8 Department of Oncology, Weston Park Hospital, SHEFFIELD, 

UNITED KINGDOM, 9 Medical Oncology, Northern Institute for Cancer Research, 

University of Newcastle upon Tyne, Newcastle, UNITED KINGDOM 

Background: Ipilimumab (Ipi) is a fully human monoclonal antibody against 

CTLA-4 which acts to promote an anti-tumour immune response. Previous phase III 

randomised controlled trials showing improved overall survival (OS) in metastatic or 

unresectable cutaneous melanoma excluded those of ocular (OM) or mucosal 

(MuM) origin and provided no data for acral melanoma (AM). These patients (pts) 

were permitted Ipi treatment in the setting of the EAP. Participating UK centres were 

asked to report data relating to the outcome of Ipi treatment in pts with rare 

melanoma types. 

Methods: Patients with unresectable stage III/IV disease were treated within the Ipi 

EAP protocol at an induction dose of 3mg/kg for up to 4 cycles. RECIST criteria 

were used for response assessment at baseline, 12 weeks and every 12 weeks 

thereafter. Documentation of adverse events (AEs) and immune-related AEs (ir-AEs) 

was according to CTCAE v3.0. 

Results: 27 pts; 18 ocular (66%), 5 acral (19%) and 4 mucosal (15%); received at least 

one cycle of Ipi across 8 UK centres. All had previously received one or more lines of 

therapy for their disease. Two pts (40%) with AM had a partial response (PR), with a 

median duration of response of 22 wks (range: 20-24).One pt (25%) with MuM and 

3 pts (17%) with OM had stable disease (SD), with a further OM pt demonstrating a 

mixed response. The median progression free survival (PFS) was 12 wks for the 

single MuM case and 14.5 wks (range: 6-64) in OM. 5 episodes of G3 ir-AEs were 

reported in 4 pts (3 colitis, 2 hepatitis), and 2 G3/4 AEs of fatigue. These resolved on 

steroid therapy. 

Conclusion: Partial responses were seen in metastatic acral but not mucosal or 

ocular melanoma in this setting. Given the small sample size it is difficult to 

accurately interpret outcome data. Activity of ipilimumab in rare melanoma subtypes 

needs to be assessed in prospective studies. 


Disclosure: J. Larkin: I have received honoraria from BMS. P. Corrie: I have 

undertaken consultancy work and advisory Boards for BMS. J. Nobes: I have been 

sponsored by BMS to attend conferences. E. Marshall: I have received previous 

honoraria for serving on an advisory board for BMS. S. Kumar: I have served on the 

advisory board for BMS. R. Plummer: I have received honoraria for advisory boards 

to BMS. P. Nathan: I have received compensation for advisory board and speakers 

panel from BMS. All other authors have declared no conflicts of interest. 

1150 SPANISH MELANOMA MULTIDISCIPLINARY GROUP (GEM) 

EXPERIENCE WITH IPILIMUMAB (IPI) IN THE EXPANDED 

ACCESS PROGRAMME (EAP) 

S. Martin Algarra 1 , L. Alonso 2 , J. Valdivia 3 , A. Garcia Castaño 4 , V. Escrig 5 , 

P. Mut 6 , A. Ballesteros 7 , T. Puertolas 8 , E. Ortega 9 , A. Berrocal 10 

1 Oncology, Clinica Universitaria de Navarra, Pamplona, SPAIN, 2 Medical 

Oncology, Hospital Clínico Victoria, Málaga, SPAIN, 3 Medical Oncology, Hospital 

Virgen de las Nieves, Granada, SPAIN, 4 Hospitalmedical Oncology, Hospital 

Marqués de Valdecilla, Santander, SPAIN, 5 Medical Oncology, Hospital Clínico 

Valencia, Valencia, SPAIN, 6 Medical Oncology, Hospital Son Llazer Mallorca, 

Mallorca, SPAIN, 7 Medical Oncology, Hospital Universitario La Princesa, Madrid, 

SPAIN, 8 Medical Oncology, Hospital Miguel Servet, Zaragoza, SPAIN, 9 Medical 

Oncology, Hospital Armau de Villanova, Lérida, SPAIN, 10 Medical Oncology, 

Hospital General Universitario, Valencia, SPAIN 

Objective: Retrospective review of the IPI-EAP experience in Spain. 

Patients and methods: Demographics were provided by BMS. Response (R), survival 

(S) and toxicity (T) were collected from a questionnaire (Q) distributed by the GEM 

to EAP treating physicians. IPI dose was 3mg/kg q 3w x 4. Patients (pts) progressing 

after objective R were eligible for reinduction. 

Results: 355 EAP requests result in 288 treated pts. Median age: 59y (24-83); Male 

57%; Stage: IVa 28.8%, IVb 20%, IVc 51.2%; CNS metastases (mts) 15%, liver 37%, 

lung 21%. ECOG (PS): 0 48%, 1 41%, 2 11%; Prior treatment (thx): chemotherapy 

(chx) 94%, immunotherapy 37%, radiotherapy 28%. At the time of this report, 

information from 138 treated pts (48%), collected using the GEM Q, was available 

for a preliminary analysis Median age: 58y (24-81); Male 57.2%; CNS mts 18.8%, 

Liver 47.1%. >2 metastatic sites: 53.6%. PS 0-1: 81.8%. Prior adjuvant thx: 44.9% pts 

(79% high dose interferon). All except 2 pts, received chx (34.8% >1 line). Median 

time from metastases to 1st dose of IPI was 11.2 months (m). 60.9% pts completed 4 

doses of IPI. Reinduction was requested for 17 pts (12.1%) and 8 received 4 cycles 

(5.8%). Discontinuation was due to death or progression (P) in 87% and T in 3.7%. 

R was evaluable in 129 pts: CR: 2 (1.4%); PR: 23 (16.6%) including 11 (7.9%) with 

initial P and delayed PR; SD: 18 (13%); P: 86 (62.3%). Of the 9 non-evaluable pts, 6 

just finished thx and 3 were still on IPI. Reinduction was done in 13 pts, 8 received 4 

doses: 2 pts with prior PR achieved a new PR, 3 with prior PR had SD, and 3 with 

prior SD progressed. Median S: 6,1 m (95% CI:125.3-272.6); 1y S: 32.9%; 18 m S: 

28.8%. Prognostic factors for S were baseline lymphocytes >1000/ml (p = 0.0008) and 

LDH >1.5xULN (p = 0.003) T was mild. Skin: grade (G) I 21.7%, GII 3.6%; liver: GI 

5.8%, GII 1.4%, GIII 2.2%; diarrhoea: GI 14.5%, GII 3.6%, GIII-IV 1.7%. 9 pts had 

GIII-IV T. 

Conclusions: IPI can be safely used by trained oncologists in a non-clinical trial 

setting. In this series, activity and T profile in is similar to the phase III data. 

Although this preliminary analysis is limited by its numbers (


mg/kg, for 4 cycles. We have focused on patients aged 70 or more years with 

previously treated, advanced melanoma. 

Results: Information on 30 patients is available. Median age was 75 years (70-81), 

53.3% were males. Liver and CNS metastases were respectively present in 26.7% and 

13.3% of the patients; 53.3% had 3 or more metastatic sites, and 51.7% had elevated 

LDH. Performance status (ECOG) was 0-1 in 93.3%. Up to 26.7% of the patients had 

received previous adjuvant treatment, which consisted of high dose interferon in 

75%. All patients had received previous first line chemotherapy, including 26.7% with 

2 or more lines. Medium time from the diagnosis of metastatic disease to the first 

dose of IPI was 14.2 months. A total of 76.7% of the patients completed the 4 

intended doses of IPI. Main reasons for early discontinuation were death or 

progression in all patients, with no patient discontinuing due to toxicity. Responses 

were evaluable in 26 patients: PR: 6 (20%) -including 3 (10%) with a delayed PR 

after an initial PD; SD: 3 (10%), and PD: 17 (56.7%). Out of the 4 non-evaluable 

patients, 3 had just completed treatment and 1 was still on therapy at the time of the 

data collection. So far, reinduction treatment has not been offered to any patient. 

Estimated median survival (Kaplan -Meier) is 180 days (5.9 months) (95% CI 

119.7-240.2). One year survival rate is 21%. Prognostic factors of survival at baseline 

were peripheral blood lymphocytes > 1000 /mL (p = 0.005) and LDH > 1.5 X ULN 

(p = 0.027) The reported toxicity per patient has been mild: skin: 23.3% grade I and 

13.3% grade II; liver 6.7% grade I; and diarrhea 6.7% grade I, 3.3% grade III-IV. Only 

4 patients experienced toxicity grade III to IV. 

Conclusions: Ipilimumab efficacy in older patients, when it is used outside a clinical 

trial setting, is in line to published phase III data. There is no increase in toxicity, 

making this treatment a valid option for older patients with previously treated 

metastatic melanoma. 

Disclosure: J.A. Lopez Martin: Participation in Avisory Boards of BMS and speaker 

in educational activities of BMS. A. Berrocal: Participation in Advisory Boards and 

speaker in educational activities sponsored by BMS. All other authors have declared 


1152 IPILIMUAMB TREATMENT AFTER ELECTROCHEMOTHERAPY 

COULD BE AN EFFECTIVE SEQUENTIAL COMBINATION 

APPROACH 

E. Simeone 1 , L. Benedetto 2 , G. Gentilcore 1 , C. Caracò 1 , G. Di Monta 2 , 

U. Marone 1 , A.M. Grimaldi 1 , S. Mori 1 , N. Mozzillo 2 , P.A. Ascierto 1 

1 Oncology, National Cancer Institute, Naples, ITALY, 2 Surgical Oncology, 

National Cancer Institute, Naples, ITALY 

Backgroud: Electrochemotherapy (ECT) has shown to be effective as local treatment 

of disseminated superficial melanoma, but there is a lack of evidence of its potential 

systemic effect. Potential immunologic changes due to ECT could have an impact on 

metastatic lesions but this hasn’t been demonstrated yet. Combining ECT with new 

drugs, like ipilimumab (ipi), could be a new therapeutic strategy. T-regulatory cells 

(T-Reg) are immunosuppressive lymphocytes whose role during ipi therapy has still 

to be clarified. Our previous experience showed a reduction of T-reg cells in patients 

responder to ipi. 

Patients and methods: 20 patients with advanced melanoma (8 at stage IIIc and 12 

IV M1c) underwent ECT with bleomycine. 5 patients were treated with ECT and no 

further therapies, while 15 pts were treated with ECT first and then, after 

progression, with ipi at 3 mg/kg for 4 cycles. We collected PBMC of these patients. 

Blood draw was performed at ECT day 0-1-15-30 and during follow-up, while during 

ipi therapy, at each cycle (week 4-7-10) and at every tumor evaluation (every 12 

weeks). 

Results: 5/20 (25%) patients, all at stage IIIc, had performed only ECT and showed a 

good local response (2 CR and 3 PR). No variation of T-Reg was detected after ECT 

treatment with median value of 0.40 % (range 0.40-2.6 %). 15/20 (75%) patients had 

a low local response and developed visceral progression after ECT without significant 

reduction of T-Reg levels. The median T-reg value was of 0.7 (range 0.50-2.6%) 

During ipi treatment, we found a decrease of T-Reg of 0.10% per cycle. This result 

was consistent with our previous evidence in patients treated with ipi in Italian EAP. 

Moreover, 3/15 patients (20%) showed local CR and 2 of them also systemic PR 

lasting at 12.1 months of follow- up, with a median T-Reg value of 0.10%. 8/15 

(53%) had both local and systemic SD with a median TTP of 7.9 months and a 

median T-Reg of 0.30%. 4/15 (27%) developed a local and distant progression and 

we found a small decrease with median T-Reg of 1.8%. 

Conclusion: ECT followed by ipi in patients with metastatic melanoma, may be 

more effective than ECT and ipi alone. This combination may represent a new 

option. Anyway, further studies are necessary to verify these data. 


1153 PACLITAXEL/CARBOPLATIN CHEMOTHERAPY AS SALVAGE 

TREATMENT IN METASTATIC MELANOMA: IS 

NON-CUTANEOUS MELANOMA DIFFERENT? 

W. Chang 1 , J. Lee 1 , S.J. Lee 1 , S. Park 1 , M.K. Choi 1 , J.Y. Hong 1 , Y.S. Kim 1 , 

C.H. Maeng 2 , S. Kim 1 

1 Medicine, Samsung Medical Center, Seoul, KOREA, 2 Hematology-Oncology, 

Samsung Medical Center, SEOUL, KOREA 

Background: There is limited data on salvage chemotherapy for metastatic, 

non-cutaneous melanoma after failure to dacarbazine-based chemotherapy. Given the 

high incidence of non-cutaneous melanoma in Korea, we focused on the treatment 

outcome of paclitaxel/carboplatin as salvage chemotherapy in noncutaneous 

metastatic melanoma. 

Patients and methods: We retrospectively analyzed patients with metastatic 

melanoma who underwent paclitaxel and carboplatin (PC) chemotherapy as 

salvage treatment at Samsung Medical Center (SMC) between February 2009 

and February 2012. The treatment schedule is as follows: intravenous paclitaxel 

175 mg/m 2 plus intravenous carboplatin at area under curve 5 (AUC 5) on day 1 of a 

21-day interval. Overall response rate, overall and progression free survival were 

calculated. 

Results: Thirty two patients (median age: 54 years, range 24 – 72 years) were treated 

with PC as salvage chemotherapy. All patients were pretreated and had previously 

received a median of 2 systemic therapies. With respect to primary site, 10 patients 

(31.3%) had cutaneous melanoma, 8 (25%) had acral melanoma, 10 (31.3%) had 

mucosal melanoma, 2 (6.3%) had ocular melanoma. Of 32 patients, 7 patients 

achieved partial response (PR) (21.9%) and 11 patients were stable disease (34.4%). 

Median progression free survival (PFS) was 2.53 months for all patients. PFS was 4.3 

months for patients controlled disease (partial response and stable disease) compared 

to 1.37 months for patients with progressive disease (p = 0.0001). Median overall 

survival was 5.2 months without a significant difference between noncutaneous and 

cutaneous metastatic melanoma group (p =0.75). 

Conclusion: PC chemotherapy seems to be a reasonable therapeutic option in 

heavily pretreated metastatic melanoma patients. Especially, this combination 

chemotherapy appears to have definite and clinically meaningful activity when used 

as salvage therapy in metastatic melanoma including non-cutaneous melanoma. 



abstracts 

neuroendocrine tumors and cup 

1154O THE VEGF PATHWAY IN PATIENTS WITH PANCREATIC 

NEUROENDOCRINE TUMORS: EFFICACY OF EVEROLIMUS 

BY BASELINE MARKER LEVEL, AND PROGNOSTIC AND 

PREDICTIVE EFFECT ANALYSES FROM RADIANT-3 

J.C. Yao 1 , M. Shah 2 , A. Panneerselvam 3 , S. Stergiopoulos 4 , D. Chen 5 , T. Ito 6 , 

M. Pavel 7 

1 Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, 

UNITED STATES OF AMERICA, 2 Medical Oncology, Ohio State University, 

Columbus, OH, UNITED STATES OF AMERICA, 3 Oncology Biometrics and Data, 

Novartis Pharmaceuticals Corporation, East Hanover, NJ, UNITED STATES OF 

AMERICA, 4 Oncology, Novartis Pharmaceuticals, East Hanover, NJ, UNITED 

STATES OF AMERICA, 5 Oncology Biometrics and Data, Novartis 

Pharmaceuticals Corporation, Florham Park, NJ, UNITED STATES OF AMERICA, 

6 Medicine and Bioregulatory Science, National Cancer Center Hospital, Tokyo, 

JAPAN, 7 Dept of Gastroenterology & Hepatology, Charité Universitätsmedizin 

Berlin, Berlin, GERMANY 

Background: RADIANT-3 was a phase III study investigating the effect of the 

mammalian target of rapamycin inhibitor everolimus on progression-free survival 

(PFS) in patients with advanced pancreatic neuroendocrine tumors (pNET; Yao 

et al, NEJM, 2011). Everolimus significantly improved PFS compared with 

placebo (11 vs 4.6 months, P < .001). Here we investigate the predictive and 

prognostic effect of soluble VEGF pathway biomarkers among patients treated in 

this study. 

Methods: Baseline plasma levels of VEGF-A, PlGF, sVEGFR1, and sVEGFR2 

were determined by ELISA using multiplexed MSD platform. The optimal cutoffs 

for these markers were explored using the “survival tree analysis” method. 

Interaction of treatment and baseline marker status (< or ≥ cutoff) was analyzed 

using a Cox proportional hazards model to assess predictive effects of these 

markers. P values and hazard ratios for prognostic effects were obtained using 

stratified log rank test and Cox proportional hazards model, stratified by 

treatment. 

Results: PFS was significantly improved to a similar extent in patients receiving 

everolimus compared with patients who received placebo, regardless of baseline 

levels of markers (P < .001, all analyses; Table), suggesting that none of these 

markers are associated with the efficacy of everolimus in patients with pNET. 

However, significantly longer PFS was seen in those with lower VEGF-A, PlGF, 

and sVEGFR1 levels, suggesting these three markers are prognostic in pNET 

(Table). 

Conclusions: These exploratory analyses demonstrated consistent everolimus efficacy 

in all patients with advanced pNET irrespective of their baseline VEGF pathway 

biomarker levels. However, levels of VEGF-A, PlGP, and sVEGFR1 are potential 

prognostic factors for pNET. 

Marker 

Cutoff 

(pg/mL) 

Median PFS 


1156O RAMSETE: A SINGLE-ARM, MULTICENTER, SINGLE-STAGE 

PHASE II TRIAL OF RAD001 (EVEROLIMUS) IN ADVANCED 

AND METASTATIC SILENT NEURO-ENDOCRINE TUMOURS 

IN EUROPE: ANALYSIS BY TUMOR ORIGIN 

M. Pavel 1 , B. Wiedenmann 1 , J. Capdevila 2 , J.W. Valle 3 , W.W. De Herder 4 , 

C. Metzer 5 , R. Salazar 6 , D. Horsch 7 , K. Oberg 8 

1 Dept of Gastroenterology & Hepatology, Charité Universitätsmedizin Berlin, 

Berlin, GERMANY, 2 Medical Oncology, Hospital Vall d’Hebrón, Barcelona, 

SPAIN, 3 Medical Oncology, The Christie NHS Foundation Trust, Manchester, 

UNITED KINGDOM, 4 Endocrine Oncology, Erasmus University Medical Center, 

Rotterdam, NETHERLANDS, 5 Internal Medicine and Clinical Chemistry, 

Ruprecht-Karls-Universitat Heidelberg Medizinische Klinik und Poliklinik, 

Heidelberg, GERMANY, 6 Medical Oncology, ICO Hospital Duran i Reynals, 

Barcelona, SPAIN, 7 Gastroenterology and Endocrinology, ChA Klinik für Innere 

Medizin, Bad Berka, GERMANY, 8 Endocrine Oncology Unit, Dept of Medicine, 

Uppsala University, Uppsala, SWEDEN 

Background: Everolimus is an oral inhibitor of the mammalian target of 

rapamycin and approved for treatment of advanced pancreatic neuroendocrine 

tumors (pNET). Its efficacy in nonsyndromic, nonpancreatic NET is unknown. 

Here we report a secondary exploratory post hoc analysis by tumor origin of the 

RAMSETE trial. 

Methods: RAMSETE include patients (pts) with advanced, progressive, 

nonsyndromic, nonpancreatic NET who received everolimus (10 mg/day) 

monotherapy. Primary endpoint was objective response rate (per RECIST v1.0) by 

central radiologic review. Secondary endpoints included progression-free survival 

(PFS). 

Results: Database lock was Dec 1, 2011, and included 73 pts with median everolimus 

treatment of 193 days. In the total population, the best response was stable disease 

(55%) with a median PFS of 185 days (95% CI: 158-255). 22 (30.1%) pts had 

primary tumor origin in the lung, thymus, bronchus, or mediastinum; 34 (46.6%) pts 

had primary tumor origin other than the lung, bronchus, or mediastinum (the 

largest subsets included small bowel/ileum [n = 16], rectum [n = 4], and caecum [n = 

2]); and 17 (23.3%) pts had unknown primary tumor origin. Tumor characteristics 

and efficacy by tumor origin site are detailed in the Table. Everolimus was associated 

with a high proportion of stable disease along with a favorable PFS in pts with 

nonsydromic, nonpancreatic NET. 

Conclusions: These results provide evidence that everolimus may be effective in 

nonsyndromic, nonpancreatic NET with diverse tumor origin sites and in pts with 

high tumor grade. These data support previous results from phase III trials that 

indicate everolimus is effective in pancreatic NET (RADIANT-3) and in NET 

associated with carcinoid syndrome (RADIANT-2). 

Characteristic and 

Endpoint 

Lung, thymic, bronchial, 

mediastinal (n = 22) 

Other than 

lung (n = 34) 

Unknown 

(n = 17) 

Well differentiated, % 40.9 97.0 82.3 

Moderately 

differentiated, % 

59.0 2.9 17.6 

Ki67 >10%, % 62.5 42.8 50.0 

Stable disease, % 63.2 42.9 69.2 

Progressive disease, % 36.8 57.1 30.8 

Median PFS, days 

(95% CI) 

189 (84–321) 174 (118–245) 316 (126–337) 

Disclosure: M. Pavel: Honoraria for presentations and participation in advisory 

board meetings for Novartis, Ipsen, Pfizer; Research grant from Novartis. B. 

Wiedenmann: Honoraria from and consultancy with Novartis, Ipsen, Pfizer, and 

Lexicon. J.W. Valle: Consultant/advisory relationship with Novartis; Honoraria from 

Novartis. W.W. De Herder: Consultant/advisory relationship with Novartis; 

Honoraria from Novartis. R. Salazar: Research funding from Novartis; Honoraria from 

Novartis. D. Horsch: Consultant or advisory role with Pfizer, Novartis, and IPSEN; 

honoraria from Pfizer and Novartis; research funding from Novartis, Ipsen, MDS, 

Nordion, Covidien, Eckart and Ziegler. K. Oberg: Consultant/advisory relationship with 

Novartis; Honoraria from Novartis. All other authors have declared no conflicts of 

interest. 

1157O PAZONET: A PHASE II TRIAL OF PAZOPANIB AS A 

SEQUENCING TREATMENT IN PROGRESSIVE METASTATIC 

NEUROENDOCRINE TUMORS (NETS) PATIENTS (PTS), ON 

BEHALF OF THE SPANISH TASK FORCE FOR NETS (GETNE) 

E. Grande 1 , D. Castellano 2 , R. García-Carbonero 3 , A. Teulé 4 , I. Durán 5 , 

J. Fuster 6 , I. Sevilla 7 , P. Escudero 8 , J. Sastre 9 , O. Casanovas 10 , L. Ortega 11 , 

J. Earl 12 , J.J. Díez 13 , G. de Velasco 2 , F. Longo 1 , A. Navarro 14 , V. Pachón 1 , 

A. Carrato 1 , R. Salazar 4 , J. Capdevila 14 

1 Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, 

SPAIN, 2 Medical Oncology Department, Doce de Octubre University Hospital, 

Madrid, SPAIN, 3 Medical Oncology Department, Virgen del Rocío University 

Hospital, Seville, SPAIN, 4 Medical Oncology Department, Catalan Institute of 

Oncology, Barcelona, SPAIN, 5 Medical Oncology Department, Centro Integral de 

Oncología Clara Campal, Madrid, SPAIN, 6 Medical Oncology Department, Som 

Espases Hospital, Mallorca, SPAIN, 7 Medical Oncology Department, Virgen de la 

Victoria University Hospital, Malaga, SPAIN, 8 Medical Oncology Department, 

Hospital Clínico Universitario Lozano Blesa, Zaragoza, SPAIN, 9 Medical 

Oncology Department, Hospital Clínico San Carlos, Madrid, SPAIN, 10 Tumor 

Angiogenesis Group, Translational Research Laboratory, Catalan Institute of 

Oncology, Barcelona, SPAIN, 11 Pathology Department, Hospital Clínico San 

Carlos, Madrid, SPAIN, 12 Medical Oncology Laboratory, Ramon y Cajal 

University Hospital, Madrid, SPAIN, 13 Endocrinology Department, Ramón y Cajal 

University Hospital, Madrid, SPAIN, 14 Medical Oncology Department, Vall 

D’Hebrón University Hospital, Barcelona, SPAIN 

Background: Pazopanib is an oral tyrosine kinase inhibitor of the VEGFR, PDGFR 

and KIT with demonstrated clinical activity in NETs. The aims of our study were to 

assess efficacy, safety and potential predictive biomarkers of pazopanib in pts with 

NETs who may have received previous antiangiogenic or mTOR inhibitor treatment. 

Methods: All pts had pancreatic or extra-pancreatic metastatic NET disease 

documented as progressive. Pazopanib 800 mg was given daily until disease 

progression (DP) or unacceptable toxicity. Primary endpoint was Clinical Benefit 

Rate (CBR) at 6 months (m) defined as Complete Response (CR) plus Partial 

Response (PR) plus Stable Disease (SD) by RECIST-V-1.0. Optimal two-stage Simon 

design was utilized with H1 and H0 set at 70 % and 50 % respectively, Kaplan-Meier 

estimates were used for the analysis of time-to-event variables: 95% CI. 

Results: 41 evaluable pts for response per protocol. 53.7% males, mean age 59.2 ± 

10.3 years. At 6 months, 3 pts had PR (7.36%), 32 SD (78.0%), and 6 DP (14.6%), 

thus the CBR was 85.4%. Global median PFS 48,3 (13.9-82.7) weeks (w). By 

subgroups, CBR at 6 m and median PFS were 100% and 25.7 w in pts with no 

previous targeted therapy (9 pts), 88.9% and 48.3 w in pts with previous mTOR 

inhibitors (9 pts), 83.3% and 50.3 w in pts with previous antiangiogenics (16 pts) 

and 71.4% and 20.6 w in pts with previous antiangiogenics and mTOR inhibitors (7 

pts) respectively. The sum of the longest diameter of target lesions had a decrease > 

10% in 32.5 % of pts (37.5% without previous biological treatment, 22.2 % with 

previous mTOR inhibitor, 31.3% with prior multitarget inhibitor, and 42.9% with 

previous multitarget and mTOR, p = 0.506). Most frequent toxicities at of any grade 

were: asthenia (75%), diarrhoea (63%), nausea (42%). Translational studies on 

angiogenesis and inmunohistochemistry biomarkers and CTCs are ongoing. 

Conclusions: Pazopanib 800 mg daily has promising activity in advanced NET 

regardless of previous treatment with other targeted therapies. This trial suggests the 

role that treatment sequencing with novel targeted agents may have in NETs. 


1158P KI-67 INDEX VARIABILITY IN NEUROENDOCRINE TUMORS 

J. Craig 1 , M. Cheung 2 ,C.Law 3 , S. Singh 1 

1 Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 

Toronto, ON, CANADA, 2 Hematology, Odette Cancer Centre, Sunnybrook 

Health Sciences Centre, Toronto, ON, CANADA, 3 Surgical Oncology, Odette 

Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, CANADA 

Introduction: The Ki-67 labeling index is now well recognized as an integral factor 

in the identification and treatment of neuroendocrine tumors (NETs) from both a 

prognosis and treatment perspective. In 2010, the WHO endorsed a grading system 

of NETs dividing tumors into G1 (Ki-67 

20%) classes. Previous studies have associated higher Ki-67 scores with greater 


morbidity, with G3 tumors behaving particularly aggressively, often requiring 

cytotoxic chemotherapy. Currently Ki-67 is determined from a single biopsy in a 

majority of cases. Little is known about the variability of the Ki-67 labeling index 

during the disease course or between primary and metastatic deposits, and there are 

no consensus guidelines on taking multiple biopsy specimens throughout the disease 

course. AIMS: To compare Ki-67 labeling among multiple biopsy samples in 

individual patients to examine for variability. 

Methods: The Sunnybrook Odette NETs database (n = 327) was retrospectively 

reviewed for patients with a confirmed diagnosis of NET and multiple ( > = 2) biopsy 

or surgical pathologic specimens, either at variable times in their disease course or 

biopsies of both the primary and metastasis. All but 2 cases were reviewed by our 

expert local neuroendocrine pathologist. Changes in WHO classification between 

multiple specimens in individual patients were determined. 

Results: 43 patients were identified for inclusion in the analysis. 39 patients had 

pathology on their primary tumor as well as a metastatic focus, while 4 had 

pathology on multiple metastatic foci only. 16/43 patients (37.2%) were identified 

who had enough variability between Ki-67 indices resulting in differing WHO 

classification grades. Twelve cases of 43 (27.9%) resulted in a second sample that 

increased the WHO grade by at least one level. Seven of 43 (16.3%) resulted in a new 

WHO classification of G3. 

Conclusions: The Ki67 labeling index in neuroendocrine tumors may change 

throughout the disease course, may differ between primary tumor and metastases, 

and may behave more aggressively later in the disease. Given the reliance on this 

index for management decisions, multiple biopsies of both the primary and 

metastatic tumor as well as through the disease course may be required to effectively 

treat these heterogeneous malignancies. 


1159P A PHASE II TRIAL OF BEVACIZUMAB COMBINED WITH 

CHEMOTHERAPY IN PATIENTS WITH METASTATIC 

WELL-DIFFERENTIATED DUODENO-PANCREATIC 

ENDOCRINE TUMORS (BETTER STUDY) 

J. Seitz 1 , D. Smith 2 ,D.O’Toole 3 , C. Lepère 4 , C. Dromain 5 , A. Gorana 6 , E. Mitry 7 , 

M.P. Ducreux 8 

1 Oncologie Digestive, Hôpital de la Timone, Marseille, FRANCE, 2 Oncologie 

Digestive, Hôpital Saint André, Bordeaux, FRANCE, 

3 Gastroentérologie-Pancréatologie, Hôpital Beaujon, Clichy, FRANCE, 

4 Hépato-Gastro Entérologie et Oncologie Digestive, Hôpital Européen Georges 

Pompidou, Paris, FRANCE, 5 Radiodiagnostic, Institut Gustave Roussy, Villejuif, 

FRANCE, 6 Pharmacovigilance, Laboratoires Roche, Boulogne-Billancourt, 

FRANCE, 7 Oncologie Médicale, Institut Curie, Paris, FRANCE, 8 Oncologie 

Digestive, Institut de Cancérologie Gustave Roussy, Villejuif, FRANCE 

Background: We assessed bevacizumab (Bv), a monoclonal antibody targeting 

VEGF, in combination with chemotherapy in duodeno-pancreatic NET, in a 

multicenter, open-label, non-randomized, two-group phase II trial. Demographics 

and primary endpoint (PFS) will be presented at ASCO 2012 (abstract # 4036). Here 

we emphasize on response centralized review, PP analysis and safety data. 

Methods: Patients (pts) with progressive, metastatic, well-differentiated 

duodeno-pancreatic NET (WHO 2000), ECOG PS ≤2 and Ki 67 index < 15% were 

treated with Bv (7.5 mg/kg IV on day 1, every 3 weeks) and 5-FU (400 mg/m 2 /d)/ 

Streptozocin (500 mg/m 2 /d IV, d1-5/ every 42 days), during 6 months and up to 24 

months. Efficacy, safety and quality of life were assessed. 

Results: In the ITT population (n = 34), 22 (64.7%) pts were men, median age 55.3 

years (37.0-77.6), ECOG-PS was 0/1 in 33 pts (97.1%). Ki-67 proliferative index was 

between 3 - 15% in 75.0% of pts. After a maximum of 24 months of follow-up per 

patient, median PFS assessed by investigators was 23.7 months [95%CI: 13.1; not 

reached] based on 18 events. Centralized review of tumor control rate was 100% (n= 

33; 1 missing) including partial response in 17 (51.5%) pts and stable disease in 16 

(48.5%) pts; similarly to investigators assessments. Survival rate at 24 months was 

88%. Median OS was not reached. All efficacy results were comparable in the ITT 

and PP populations. All patients experienced at least one adverse event (AE). CTC 

grade 3/4 AEs occurred in 23 (67.6%) of pts, mainly digestive 5 (14.7%) pts 

(abdominal pain, 4 pts). G3/4 AEs of special interest to BV were hypertension in 7 

(20.6%) pts and thromboembolism in 3 (8.8%), all venous. No grade 3/4 proteinuria 

was observed. Five patients died (4 of disease progression and 1 of thromboembolic 

event). 

Conclusions: Efficacy results of Bv and 5-FU/stz, a novel approach in 

duodeno-pancreatic NET, are encouraging. The toxicity profile of the combination of 

Bv with streptozocin is acceptable and did not induce any unexpected events. These 

results warrant to be confirmed in a phase III study. 

Disclosure: M.P. Ducreux: Consultant: Roche, Merck Serono Honoraries: Roche, 

Merck Serono, Amgen, Bayer, Fresenus, Pfizer, Sanofi Clinical research project: 

Pfizer, Chugai, Merck Serono. J. Seitz: Consultant: Keocyt Honoraries: Roche, Pfizer. 

C. Dromain: Consultant: Roche Honoraries: Roche. A. Gorana: Employment: Roche. 

E. Mitry: Honoraries: Roche. All other authors have declared no conflicts of interest. 


1160P A PHASE II TRIAL OF BEVACIZUMAB WITH CAPECITABINE 

IN PROGRESSIVE, METASTATIC WELL-DIFFERENTIATED 

DIGESTIVE ENDOCRINE TUMORS (BETTER STUDY) 

T.A. Walter 1 , E. Baudin 2 , J.E. Kurtz 3 , P. Ruszniewski 4 , L. Bengrine-Lefevre 5 , 

G. Cadiot 6 , S. Dominguez-Tinajero 7 , S. Kraemer 8 , M.P. Ducreux 9 , E. Mitry 10 

1 Oncologie Médicale, Hôpital Edouard Herriot, Lyon, FRANCE, 2 Oncologie, 

Institut Gustave Roussy, Villejuif, FRANCE, 3 Oncologie et Hématologie, Hôpitaux 

Universitaires, Strasbourg, FRANCE, 4 Gastro-Entérologie, Hôpital Beaujon, 

Clichy, FRANCE, 5 Oncologie Médicale, Hôpital Saint-Antoine, Paris, FRANCE, 

6 Gastro-Entérologie et Hépatologie, Hôpital Robert Debré, Reims, FRANCE, 

7 Oncologie - Pathologie Digestive, Centre Oscar Lambret, Lille, FRANCE, 

8 Biostatistique, Laboratoires Roche, Boulogne-Billancourt, FRANCE, 9 Oncologie 

Digestive, Institut de Cancérologie Gustave Roussy, Villejuif, FRANCE, 

10 Oncologie Médicale, Institut Curie, Paris, FRANCE 

Background: We assessed bevacizumab (Bv), a monoclonal antibody directed against 

VEGF, combined with capecitabine (CAP) in neuroendocrine digestive tumors 

(NET) known to be highly vascularized neoplasms Demographics and primary 

endpoint (PFS) will be presented at ASCO 2012 (abstract#4071). Here we emphasize 

on response (central review), PP analysis and safety data. 

Methods: BETTER is a multicenter, open-label, non-randomized, two-group phase II 

trial. Patients (pts) with progressive, metastatic well-differentiated digestive tract 

endocrine tumors (WHO 2000 classification), ECOG-PS ≤2, Ki 67 index < 15%, no 

prior systemic chemotherapy were treated with Bv (7.5 mg/m 2 on d1/3 weeks) and 

CAP (1000 mg/m 2 twice daily, orally d1-14, resumed on day 22). Pts were treated for 

≤6 months, up to 24 months. Efficacy (PFS, overall survival [OS], response rate), 

safety and quality of life were assessed. 

Results: In the ITT population (n = 49), 26 (53.1%) pts were men; median age 60.3 

years (41.2-82.3); ECOG-PS was 0/1 in 46 (93.9%) pts. Primary tumor site was 

mainly small intestine 40 (81.6%) pts. Ki-67 proliferative index was 0-2% in 17 

(35.4%) pts and 3-14% in 31 (64.6%). After a maximum of 24 months of follow-up 

per patient, median PFS assessed by investigators was 23.4 months [95%CI: 13.2; not 

reached] based on 26 events. Centrally reviewed tumor control rate was 93.8% (n = 

45) including partial response in 6 (12.5%) pts and stable disease in 39 (81.3%) pts 

(1 missing and 3 not evaluable), comparable to investigators assessment. Survival rate 

at 24 months was 85%. Median OS was not reached. All efficacy results were similar 

in the ITT and PP populations. CTC grade 3/4 Adverse Events (AEs) occurred in 41 

(83.7%) pts, mainly digestive 14 (28.6%) pts. Main G3/4 AE of special interest to BV 

was hypertension in 15 (30.6%) pts. Eight patients died: 3 of disease progression, 2 of 

AEs (stroke, peritonitis) and 3 for other reasons (Parkinson disease, liver 

transplantation/septicemia, cardiac arrest). 

Conclusions: In this phase II study assessing Bv and CAP in a chemotherapy 

resistant tumor; such encouraging results suggest that this combination may become 

a good alternative in the treatment of ileal NET. 

Disclosure: E. Mitry: Honoraries: Roche. E. Baudin: Honoraries: Scientific committee 

of BETTER Trial. P. Ruszniewski: Consultant: Ipsen, Novartis, Pfizer Honoraries: 

Ipsen, Novartis, Pfizer. Clinical research project: Ipsen, Novartis, Pfizer. G. Cadiot: 

Honoraries: Novartis, Ipsen, Pfizer Other financing (please detail): Novartis, Ipsen, 

Pfizer. S. Kraemer: Employment: Roche. M.P. Ducreux: Consultant: Roche, Merck 

Serono Honoraries: Roche, Merck Serono, Amgen, Bayer, Fresenus, Pfizer, Sanofi 

Clinical research project: Pfizer, Chugai, Merck Serono. All other authors have 


1161P TREATMENT OF ADVANCED NEUROENDOCRINE TUMOURS: 

FINAL RESULTS OF THE UKINETS AND NCRI RANDOMISED 

PHASE 2 NET01 TRIAL 

T. Meyer 1 , M. Caplin 2 , N. Reed 3 , W. Qian 4 , S. Lao-Sirieix 4 , G. Armstrong 4 , 

J. Valle 5 , D. Tablot 6 , D. Cunningham 7 , P. Corrie 8 

1 Ucl Cancer Institute, University College London, London, UNITED KINGDOM, 

2 Royal Free Hampstead Nhs Trust, Royal Free Hampstead NHS Trust, London, 

UNITED KINGDOM, 3 Beatson Oncology Centre, Gartnavel General Hospital, 

Glasgow, UNITED KINGDOM, 4 Cambridge Cancer Trials Centre, Cambridge 

University Hospitals NHS foundation Trust, Cambridge, UNITED KINGDOM, 

5 Histopathology, The Christie NHS Foundation Trust, Manchester, UNITED 

KINGDOM, 6 Cancer Medicine, University of Oxford, Oxford, UNITED KINGDOM, 

7 The Royal Marsden, The Royal Marsden, London, UNITED KINGDOM, 

8 Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, 

Cambridge, UNITED KINGDOM 

Background: Chemotherapy is widely used for advanced, unresectable 

neuroendocine tumours (NETs) but only four randomised trials are published. The 

first combined streptozocin (strep) and 5fluorouracil (5FU), reporting 63% response 

rate (RR), but subsequent retrospective studies had lower RRs (6-45%). Cisplatin has 

been combined with strep + 5FU in a retrospective study with promising activity in 



NETs and capecitabine (cap) has been effectively substituted for 5FU in many 

tumours. The NET01 trial was designed to investigate whether cap + strep ± cisplatin 

warrant further evaluation. 

Methods: Patients (pts) with histologically confirmed, unresectable, advanced and/or 

metastatic NETs of foregut, pancreatic or unknown primary site were randomised 

(1:1) to 6 cycles of 3-weekly cap 625 mg/m 2 po bd daily (D1-21), strep 1.0g/m 2 IV 

(D1), with cisplatin 70mg/m 2 IV (D1) (Cap-strep-cist) or without (Cap-strep). The 

primary outcome measure was RR using RECIST criteria. 84 pts were required to test 

a RR of 60% with a significance level of 5% and 80% power in each arm. 

Central pathology review and 10% of central radiology review were performed. 

Results: 86 pts (58% male, median age 59 years) were randomised (44 Cap-strep, 42 

Cap-strep-cist) with primary site – foregut 20%, pancreatic 48% and unknown 33%. 

The grade was low 12 (17%), intermediate 43 (62%) and high 14 (20%). Baseline 

characteristics were balanced between the 2 arms. 59% Cap-strep and 33% 

Cap-strep-cist pts received ≥6 cycles. 18 Cap-strep and 26 Cap-strep-cist pts 

experienced grade ≥3 toxicities. Outcome results are summarised in the table. 

Cap-strep-cist Cap-strep 

Response PR SD PD n = 38 13% 61% 26% n = 40 8% 73% 20% 

PFS No. progressions/deaths, 

n(%) Median (mo) 

n = 42 35 (83%) 9.7 n = 44 34 (77%) 10.2 

OS No. deaths, n(%) Median 

(mo) 

n = 42 22 (52%) 27.5 n = 44 25 (57%) 26.7 

Conclusions: The novel Cap-strep ± cisplatin regimens were associated with overall 

disease control and survival durations consistent with published studies. Cap-strep 

was better tolerated than Cap-strep-cist. Further prospective randomised trials are 

needed to determine optimal NET chemotherapy. 

Disclosure: D. Cunningham: Research Funding: Amgen, Roche. Astra Zeneca Expert 

testimony: Amgen (Uncompensated) Honoraria: None Advisory: Amgen Roche 

(Uncompensated). All other authors have declared no conflicts of interest. 

1162P PHASE 1 STUDY OF EVEROLIMUS COMBINED WITH 

LUTETIUM-177 OCTREOTATE RADIOPEPTIDE THERAPY OF 

ADVANCED LOW-GRADE NEUROENDOCRINE TUMOURS 

P. Claringbold 1 , J.H. Turner 2 

1 Oncology, Fremantle Hospital and Health Service, Fremantle, WA, AUSTRALIA, 

2 Nuclear Medicine, Fremantle Hospital, Fremantle, WA, AUSTRALIA 

Background: Recent clinical trials of mTOR inhibitors have shown benefit from 

everolimus treatment of advanced low-grade neuroendocrine tumours (NETs). 

Targeting of NET somatostatin receptors with radiopeptides is another effective 

therapeutic option. This phase I study investigates the safety of combining 

everolimus with lutetium-177 octreotate. 

Methods: Patients with biopsy proven low-grade NETs (Ki 67 index < 5%), positive 

on gallium 68-octreotate PET scan were studied. All patients received fixed dose 7.8 

GBq lutetium-177 octreotate each 8 weeks for 4 cycles, combined with everolimus. 

Successive cohorts received escalating doses of everolimus in groupings of 5, 7.5 and 

10 mg given as a daily oral dose for the 24 weeks of radiopeptide therapy. Dose 

limiting toxicities were established by standard NCI common toxicity criteria 

(CTCAE v 4.03). 

Results: Eleven patients have been treated, 4 patients at the 5 mg everolimus dose 

level and 3 each at the 7.5 mg and 10 mg levels. Full dose lutetium-177 octreotate 

for 4 cycles was possible in 6 of 7 patients in cohorts 1 and 2, whilst only 1 of 

3 patients completed all cycles at the 10 mg dose level. Patients at 5 mg and 7.5 

mg doses of everolimus received 85% of the total planned dosage over 24 weeks. 

All patients required dose reduction or complete cessation of everolimus at the 

10 mg level because of unacceptable toxicities. The commonest reasons for dose 

reductions in cohorts 1 and 2 were grade 2 or 3 neutropenia and 

thrombocytopenia. Unexpected reversible grade 2 nephrotoxicity caused significant 

reductions in creatinine clearance levels of 40-50% baseline in 2 of 3 patients in 

the 10 mg cohort, not seen in the lower dose levels. Tumour responses have been 

observed at each dose level. 

Conclusion: Everolimus can be combined safely with lutetium-177 octreotate to treat 

low-grade NETs. Toxicities were observed at all dosage levels of everolimus but 

appear manageable and reversible. The maximum tolerated dose (MTD) of 

everolimus was 7.5 mg daily in combination with 7.8 GBq lutetium-177 octreotate in 

a 4 cycle course over 24 weeks. 

Disclosure: P. Claringbold: Dr Claringbold has acted on an advisory panel and 

received financial support from Novartis Pharmaceuticals. J.H. Turner: Dr Turner 

has acted on an advisory panel and received financial support from Novartis 

Pharmaceuticals. 

1163P RESPONSE EVALUATION USING RECIST AND CHOI 

CRITERIA IN PATIENTS WITH WELL-DIFFERENTIATED 

PANCREATIC NEUROENDOCRINE TUMORS (PNET) 

TREATED WITH SUNITINIB OR EVEROLIMUS 

C. Dreyer 1 , O. Hentic 2 , M. Zappa 3 , P. Hammel 2 , M. Bouattour 1 , C. Mateescu 1 , 

S. Faivre 1 , P. Ruszniewski 2 , E. Raymond 4 

1 Oncology Department, Beaujon University Hospital, Clichy, FRANCE, 

2 Gastroenterology, Beaujon, Clichy, FRANCE, 3 Radiology, Beaujon, Clichy, 

FRANCE, 4 Department of Medical Oncology, Beaujon University Hospital, Clichy, 

FRANCE 

Background: Despite low response rate by RECIST, sunitinib and everolimus 

improved the progression-free survival of patients (pts) with well-differentiated 

pNET in two large phase III controlled trials. RECIST being a poor surrogate 

endpoint for PFS, this study aimed evaluating the value of CHOI criteria in PNET 

pts. 

Methods: Data for this analysis were collected from pts with well-differentiated 

PNET treated consecutively with sunitinib or everolimus in our center between 

10-2006 and 11-2010. All pts had tumor progression within 12 months (m) prior to 

treatment. Pts were considered evaluable if CT-scans were performed within 6 weeks 

prior treatment and

pts. Poorly differentiated endocrine carcinoma (PDEC). Age (median) 54 a. (r 

18-84). Primary Location: small intestine 40, pancreas 26 pts. Appendix 9 pts., 

Stomach 8, rectum 6, unknown 6, colon 4, and esophagus 1 pte. Metastatic disease 

76 pts., Localized disease in 24 pts. The expression of SSTR was: Subtype 2 (positive 

80 pts.) and subtype 5 (positive 46 pts.). Ki 67 was less than or equal to 2% in 36 

pts., between 3 and 15%, 49 pts. and more than 15% in 12 pts. 26/100 pts. had 

functioning tumors. The analysis included 55 pts. with SSTR 2 / 5 pos. Ki 67 less 

than or equal to 2% (Group 1), 38 pts. with SSTR 2 / 5 pos and Ki 67 more than 2% 

(Group 2), 5 pts. with SSTR 2 / 5 neg. Ki 67 less than or equal to 2% (Group 3) and 

2 pts. with SSTR 2 / 5 neg and Ki 67 more than 2% (Group 4). Univariate analysis 

showed significant differences for the expression of SSTR 2 (p. 009), and Ki 67 

(p. 001). Survival was higher in Group 1 versus Group 2, median OS was 97 months 

vs 49 months, and 36 to 23 months, in groups 3 and 4 respectively (p. 0001). 

Conclusions: In this population of pts with GEP-NET we could identify a subgroup 

of better prognosis associated with expression of SSTR 2 / 5 and Ki 67 less than or 

equal to 2%. The assessment of SSTR 2 and 5 in tissue, and proliferative index are 

useful tools for evaluating prognosis in this setting. 


1165P EFFICACY AND SAFETY OF SOMATULINE AUTOGEL IN 

COMBINATION WITH MOLECULAR TARGETED THERAPIES 

(MTT) IN NEUROENDOCRINE TUMORS (NETS) 

J. Capdevila 1 , I. Sevilla 2 , V. Alonso 3 , L. Anton-Aparicio 4 , P. Jimenez Fonseca 5 , 

E. Grande 6 , J.J. Reina 7 , J.L. Manzano 8 , J. Alonso-Jara 9 , P. García Alfonso 10 


2 Medical Oncology, Virgen de la Victoria University Hospital, Malaga, SPAIN, 

3 Medical Oncology, Miguel Servet University Hospital, Zaragoza, SPAIN, 

4 Medical Oncology, Complejo Hospitalario A Coruña, A Coruña, SPAIN, 5 Medical 

Oncology, Hospital Universitario Central de Asturias, Oviedo, SPAIN, 6 Medical 

Oncology, Ramon y Cajal University Hospital, Madrid, SPAIN, 7 Medical 

Oncology, Virgen de la Macarena University Hospital, Sevilla, SPAIN, 8 Medical 

Oncology, ICO Hospital Germans Trias i Pujol, Barcelona, SPAIN, 9 Medical 

Oncology, Virgen de la Arrixaca University Hospital, Murcia, SPAIN, 10 Medical 

Oncology, Gregorio Marañón University Hospital, Madrid, SPAIN 

Background: Analysis of the mechanisms of action of somatostatin analogs (SSAs) 

and mTOR inhibitors or multiple tyrosine kinase inhibitors have suggested that they 

may provide synergistic effects when used in combination for the treatment of 

patients with NETs. 

Methods: This is a Spanish Multicenter cohort of patients (pts) with NETs treated 

with the SSAs lanreotide (LAN) and MTTs at 35 Spanish Medical Oncology 

Departments. The data of 159 combined treatments (133 pts) was retrospectively 

collected in order to evaluate the efficacy and safety of such combinations out of trials. 

Results: 133 pts (52,6% Male) with a mean age of 59,4 years; ECOG 0/1/2/3: 34%/ 

49%/16%/1%; Lung/Pancreas/Gastrointestinal//Unknown(UK)origin: 9%/48% /32%/ 

11%; G1/G2/G3/UK: 41%/32%/1%/26%; Non Functioning/ Functioning (69%/31%) 

received treatment with MTT + LAN for synergistic antiproliferative purpose in 85% 

of the cases, hormonal control (13,5%) or both objectives (1,5%). 115 pts received 

just one and 18 pts received between 2 (12 pts) and 5 (1 pt) combination treatments. 

LAN was administrated in combination with everolimus (46%), sunitinib (38%), 

bevazucimab (6%), sorafenib (5%) and pazopanib (5%). The reported toxicity was 

determined by the MTT profile with no significant additional severe adverse events 

related to the combination with LAN. The median progression-free survival (mPFS) 

for the two main groups was 31.9 months for those pts who received LAN and 

sunitinib (n = 50) and 21.9 months for those pts who received LAN and everolimus 

(n = 56). 

Conclusions: The combination of LAN and MTT treatments, mainly everolimus and 

sunitinib, is widely used in clinical practice without unexpected toxicities. Although 

studies are not directly comparable mPFS observed in the two main groups were 

higher than data showed by phase III studies with sunitinib, everolimus or SSAs 

alone raising the hypothesis of enhanced antitumor efficacy combining SSAs and 

MTT that should be confirmed in randomized prospective clinical trials. 

Tumor Response (%) 

Nº PD SD PR CR Not evaluated 

61 Sunit +LAN 4.9 68.9 14.8 1.6 9.8 

73 Evero +LAN 12.3 67.0 15.1 0 5.5 

9 Bevac +LAN 0 88.9 11.1 0 0 

8 Soraf +LAN 0 100.0 0 0 0 

8 Pazop +LAN 12.5 75.0 12.5 0 0 



1166P AWARENESS OF THE CLINICAL PRESENTATION AND 

DIAGNOSIS OF NEUROENDOCRINE TUMOURS IN AN 

AUSTRALIAN GENERAL PHYSICIAN POPULATION 

J.C. Leyden 

Anaesthesia, Royal North Shore Hospital, St Leonards, NSW, AUSTRALIA 

Background: Neuroendocrine Tumours (NETs) are a rare group of malignancies 

where the correct diagnosis is often delayed for many years resulting in local and 

distant spread of the disease and mean 5 year survival rate of 30%. The diagnosis 

of NETs is challanging and requires the expertise of many medical specialists and 

diagnostic modalities. The General Physician (GP) is pivotal for early recognition, 

referral and management of this disease. The Unicorn Foundation, Australia’s only 

charity directed to NET patient support, advocacy and research conducted a 

survey of Australian Physicians to determine knowledge of NETs. A secondary 

objective of the survey was to raise awareness of the disease in a broad medical 

population. 

Methods: 9952 registered medical practitioners received an introductory email 

requesting participation in the online “NET Awareness Survey”. The questions were 

presented as ‘best answer’ multiple choice format with the ability to choose ‘not sure’ 

as an option. 26 questions covering basic NET epidemiology, clinical pathology and 

presentation, diagnosis and referral pattern were included. 

Results: The survey was open from July 2011 until December 2011. A population of 

9552 registered medical practitioners received the email; 38% (3630) ‘opened’ the 

email and 7% (655) completed the survey. Of the survey respondants, 65% (425) 

were General Physicians. The results of the survey indicated a lack of awareness/ 

knowledge regarding NET epidemiology; pathology; spectrum of disease (including 

metastatic potential) and use of Chromogranin A as a biomarker of the disease. The 

majority of the respondants acknowledged the difficulties of diagnosis; the myriad 

presenting symptoms and association of NETs with familial syndromes. 

Conclusion: The survey results showed that a significant proportion of General 

Physicians had minimal knowledge of Neuroendocrine Tumours (NETs) and their 

behaviour and there was a general misunderstanding of appropriate investigations to 

facilitate diagnosis. Improved awareness of the NETs and investigative strategies to 

improve diagnosis are needed amongst medical practitioners especially those in 

general practice. 

Disclosure: J.C. Leyden: This research project has been supported by unrestricted 

educational grant from Novartis Oncology, Ipsen Pharmaceutical and Pfizer 

Pharmaceutical. 

1167P NEUROENDOCRINE TUMORS: A REVIEW OF THE 

SUNNYBROOK ODETTE CANCER CENTRE DATABASE 

J. Craig 1 , M. Cheung 2 ,C.Law 3 , S. Singh 4 

1 Medical Oncology, Sunnybrook Odette Cancer Center, Toronto, ON, CANADA, 

2 Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 

Toronto, ON, CANADA, 3 Surgical Oncology, Odette Cancer Centre, Sunnybrook 

Health Sciences Centre, Toronto, ON, CANADA, 4 Medical Oncology, Odette 

Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, CANADA 

Background: Neuroendocrine tumors (NETs) are an uncommon and heterogeneous 

group of malignancies. A number of reviews have been published attempting to 

better identify factors of important prognostic significance in predicting overall 

survival, however these studies are often limited by small sample size and were 

published before new therapy options came into widespread use. AIMS: We reviewed 

our experience at our NETs multidisciplinary reference centre in the management of 

NETs to attempt to identify important patient and tumor characteristics associated 

with improved overall survival. 

Methods: The Sunnybrook Odette Cancer Centre NETs Database was retrospectively 

reviewed. All patients with a pathologically confirmed diagnosis of NET were 

included in the analysis. Patient characteristics, tumor markers and pathology, 

treatment, and response to treatment were recorded. Univariate and multivariate 

Cox-regression analyses were performed. 

Results: A total of 327 patients were included in the analysis. Mean age at presentation 

was 55.6 years. A total of 159 (48.6%) patients were male. The most common primary 

site was small bowel (34.3%), followed by pancreas (21.1%) and large bowel/rectum/ 

anus (11.9%). In univariate analysis, factors associated with improved overall survival 

included local/regional disease at presentation (p < 0.001), lower Ki67 index 

(p < 0.001), normal chromogranin A at presentation (p = 0.008), urinary 

5-Hydroxyindoleacetic acid drop following treatment (p = 0.024), symptom response to 

treatment (p < 0.001), surgery on the primary tumor (p < 0.001), surgery on metastases 

(p = 0.003), having multiple surgeries (p < 0.001), and treatment with long-acting 

somatostatin (LAS) (p = 0.029). In multivariate analysis, treatment with LAS (p < 

0.001, HR 0.141, 95%CI 0.064-0.31) and having multiple surgeries (p = 0.045, HR 

0.591, CI 0.354-0.988) were shown to be independent predictors of improved overall 

survival. 



Conclusions: Treatment with long-acting somatostatin and having multiple surgeries 

were shown to be independent predictors of improved overall survival in NETs. This 

data further supports the use of aggressive medical and surgical intervention in a 

multi-modal approach for advanced NETs. This may be best achieved in the setting 

of NETs multidisciplinary reference centres. 


1168P DOES SPECIALIST CENTRE HISTOPATHOLOGY REVIEW 

OF GASTROINTESTINAL NEUROENDOCRINE TUMOURS 

AFFECT CLINICAL MANAGEMENT? 

S.C. Bowen Jones, L. Foster, J. Valle, W. Mansoor, R. Hubner, B. Chakrabarty 

Histopathology, The Christie NHS Foundation Trust, Manchester, 


Introduction: Gastroenteropancreatic Neuroendocrine Tumours (GEP NET) are 

uncommon tumours occurring at all sites within the gastrointestinal tract. The 

behaviour of these tumours is difficult to predict and they have been subject to 

numerous changes in classification and grading systems. In the UK the National 

Institute for Clinical Excellence recommends centralised histopathology review of 

these tumours by a member of the NET tumour board. We aimed to determine the 

frequency of discrepancies between local and central histopathology that could 

impact clinical management. 

Methods: We identified 86 cases of suspected GEP NET referred for specialist 

histopathology review at the regional network centre from January 2010 to April 

2012. Cases were identified by a SnoMed search for cases coded under various 

endocrine tumour designations and by cross referencing with patient lists from 

multidisciplinary team meetings. Details of the local and network centre pathology 

reports were compared. The reports were also judged for compliance with the UK 

Royal College of Pathologists minimum dataset. 

Results: There was complete diagnostic agreement in 54 cases (63%). Discrepancies 

occurred in the remaining 32 cases (37%), including, 18 differences in grade or 

proliferation index score (21%), 16 differences in nomenclature (19%), 6 differences 

in stage (7%) and 5 differences in assessment of perineural or vascular invasion (6%). 

In 9 cases (10%) an original diagnosis of endocrine tumour was changed to a 

different type of tumour without endocrine differentiation or vice versa following 

review. Twenty-six of the overall discrepancies (30% of the total cases) had the 

potential to meaningfully impact on clinical management. In addition, neither 

tumour grade nor proliferation index were recorded in 15 local pathology reports 

(17%), which would necessitate additional pathological analysis prior to clinical 

decision making. There was full adherence to the minimum dataset in only 19 cases 

(42% of resections). 

Conclusions: This study highlights the importance of specialist centre histopathology 

review of GEP NET to ensure these patients receive the appropriate clinical 

management. 


1169P NOVEL INFLAMMATION-BASED PROGNOSTIC 

DETERMINANTS IN PATIENTS WITH CARCINOMA 

OF UNKNOWN PRIMARY 

Z. Mohamed, D.J. Pinato, R. Sharma 

Division of Experimental Medicine, Imperial College London, Hammersmith 

Hospital, Hammersmith, UNITED KINGDOM 

Background: Carcinomas of unknown primary (CUP) incorporate tumours with 

heterogeneous biology and invariably poor prognosis. There is a lack of validated 

prognostic indices in this context. The presence of a cancer related systemic 

inflammatory reaction is both pathogenic and prognostic in advanced cancer. We 

aimed to assess whether a panel of inflammatory indices including the 

modified-Glasgow Prognostic Score (mGPS), neutrophil/lymphocyte ratio (NLR) and 

platelet/lymphocyte ratio (PLR) could predict prognosis and response to therapy in 

CUP. 

Methods: Consecutive patients diagnosed with histologically proven CUP at the 

Imperial College oncology unit (1996-2011) were considered. Demographic, 

treatment, disease status and bloods were collected. The effect of candidate 

prognostic factors on overall survival (OS) was determined using Kaplan-Meier 

curves followed by multivariate Cox regression analysis. Normalisation of the NLR 

following 1 cycle of epirubicin cisplatin and capecitabine (ECX) chemotherapy was 

tested for its impact on OS in a subgroup of patients receiving ECX chemotherapy 

(n = 14). 

Results: 60 patients were included: median age 61 (range: 33-86); 51% men; median 

OS 5.9 months (0.7-42.9); 88% had metastasatic disease. On univariate analysis NLR 

> 5 (p = 0.009) and mGPS (p = 0.027) correlated with OS, unlike PLR > 300 (p = 0.5). 

Multivariate analysis confirmed mGPS (Hazard Ratio (HR); 1.52, 95%CI 1.0-2.3 p = 

0.029) and NLR > 5 (HR 2.02 95%CI 1.0-4.1, p = 0.043) as independent predictors of 

OS. NLR normalisation post 1 cycle of ECX was associated with improved OS (8.6 

months vs 4.6 months, p = 0.014). Results from an independent validation set will be 

presented. 

Conclusion: Inflammatory indices are independent prognostic predictors in patients 

with CUP. Additionally, correction of NLR appears to reflect successful disease 

modulating effects of chemotherapy and may be used to predict survival benefit from 

treatment. External validation of these scores is ongoing. 


1170P PROGNOSTIC AND PREDICTIVE SIGNIFICANCE OF 

PHARMACOGENETIC ANALYSIS IN PATIENTS WITH 

CARCINOMAS OF UNKNOWN PRIMARY (CAUP) 

C. Papadaki 1 , G. Pentheroudakis 2 , A. Cervantes Ruiperez 3 , E. Lagoudaki 4 , 

D. Petrakis 2 , J. Souglakos 5 , E.R. Braun 6 , V. Georgoulias 7 , D. Mavroudis 5 , 

N. Pavlidis 8 

1 Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, 

Heraklion, GREECE, 2 Medical Oncology, University General Hospital of Ioannina, 

Ioannina, GREECE, 3 Serv. Hematologia y Oncologia Medica, Hospital Clinico 

Universitario de Valencia, Valencia, SPAIN, 4 Laboratory of Pathology, School of 

Medicine, University of Crete, Heraklion, GREECE, 5 Medical Oncology, University 

General Hospital of Heraklion, Crete, GREECE, 6 Hematology and Medical 

Oncology, INCLIVA University of Valencia, Valencia, SPAIN, 7 Medical Oncology, 

University Hospital of Heraklion, Heraklion, GREECE, 8 Dept. Medical Oncology, 

University of Ioannina, Ioannina, GREECE 

Purpose: To investigate the prognostic/predictive significance of the expression of 

BRCA1, ERCC1, RRM1, TOPO-I, TOPO-IIa, TOPO-IIb, TXR1 TYMS and HIF1a 

mRNA in patients with Carcinomas of Unknown Primary (CaUP). 

Material and methods: Ninety-three patients with CaUP and available tumoral 

samples diagnosed in three institutions were included in the study. The mRNA levels 

of the target genes were determined by quantitative real-time PCR from 

microdissected cells derived from patients’ tumoral specimens. β-actin and PGK1 

were used as reference genes. 

Results: Successful amplification of at least one gene was achieved in all samples. 

BRCA1, ERCC1, HIF1a and TXR1 were amplified in all samples, while RRM1, 

TOPO-I, TOPO-IIa, TOPO-IIb were amplified in 88 samples and TYMS in 86 of 

them. Patients’ characteristics were: median age 68 (28-84) years; 53 (57%) males; 

ECOG-PS 0 in 23 (25%), 1 in 33 (35%) and ≥ 2 in 37 (40%) patients. The 

histological type was: 47 (50%) adenocarcinomas, 18 (19%) squamous cell 

carcinomas, 14 (15%) undifferentiated carcinomas, 8 (9%) carcinomas with 

neuroendocrine features and 6 (6%) clear cell carcinomas. Forty-one (47%) 

patients received a platinum analog as 1 st line treatment, while 21 (24%) were 

treated with taxane-based chemotherapy. Patients with high ERCC1 mRNA levels 

presented increased median overall survival compared with those with low 

ERCC1 expression (mOS: 16.5 versus 8.3 months; p = 0.034). Also, high 

compared to low expression of TXR1 or TOPO-I was significantly correlated with 

decreased survival (4.5 months vs. 22.6 months; p = 0.015 and 5.9 months vs. 

16.5 months; p = 0.042, respectively). A statistical trend for increased survival was 

also observed in patients with low HIF1a expression (p = 0.07), while the 

expression of the other genes did not show significant prognostic correlation. No 

predictive significance of any gene was observed in patients treated with a 

platinum analog. 

Conclusions: The ERCC1, TXR1, TOPO-IA and HIF1a expression may be used as 

prognostic markers in patients with CaUP. The predictive significance of these genes 

was not confirmed in the small subgroup of patients treated with platinum analogs. 


1171P THE IMPACT OF PERFORMANCE STATUS AT DIAGNOSIS 

ON PROGRESSION-FREE SURVIVAL AFTER SECOND-LINE 

CHEMOTHERAPY IN UNFAVORABLE-RISK CANCER OF 

UNKNOWN PRIMARY PATIENTS 

T. Shimoi, E. Sasaki, M. Kudo, T. Shimoyama, Y. Omuro, R. Okamoto, 

Y. Maeda, T. Sasaki 

Chemotherapy, Cancer and Infectious Diseases Center Komagome Hospital, 

Bunkyo-ku, Tokyo, JAPAN 

Introduction: Cancer of unknown primary (CUP) patients classified as an 

unfavorable-risk group generally have a poor prognosis. Moreover, there are no 

well-defined studies of the efficacy of second-line chemotherapy in unfavorable-risk 

CUP patients. Unfavorable-risk CUP patients who had second-line chemotherapy 

were retrospectively reviewed, and the characteristics predictive of better 

progression-free survival (PFS) after second-line chemotherapy were examined. 

Methods: A total of 117 CUP patients was diagnosed in our hospital between May 

2002 and April 2012, and 97 patients had more than first-line chemotherapy. A total 

of 34 patients (46% of unfavorable-risk patients) received second-line chemotherapy. 

Results: Among 34 patients, there were 21 female patients (62%). The median age 

was 60 (range, 39–74) years. The majority of patients had PS 1 (75%). 


Adenocarcinoma was present in 25 patients. The median number of primary 

metastatic sites was 2.5 (range, 1–8) sites, with 3 (range, 1–9) metastatic sites before 

second-line chemotherapy. For the first-line chemotherapy regimen, 28 patients (82%) 

had a platinum-based combination regimen. For second-line chemotherapy, 12 patients 

received platinum-based combination chemotherapy, 12 patients had non-platinum-based 

combination chemotherapy, and 10 patients had non-platinum-based monotherapy. 

Response to second-line chemotherapy; 7 (21%) patients showed an objective partial 

response, and 16 (47%) showed stable disease. The median overall survival in 34 

unfavorable-risk CUP patients who could receive second-line chemotherapy was 46 

months (median survival time not reached). The median PFS after second-line 

chemotherapy was 1.8 (range, 0.23–25) months. Multivariate Cox analysis showed that PS 

0 or 1 relative to PS 2 at initial diagnosis was related to better PFS (Hazard Ratio, 0.033; 

95% confidence interval, 0.00053-0.61) (p = 0.022). 

Conclusion: The results of this retrospective study showed that 21% of 

unfavorable-risk patients responded to second-line chemotherapy. The data suggest 

that PS 0 or 1 may be associated with better PFS after second-line chemotherapy. 


1172 LONG ACTING OCTREOTIDE IN PTS WITH DISSEMINATED 

NEUROENDOCRINE TUMORS 

A. Markovich, G. Emelianova, V. Gorbounova, V. Bruzgin, N. Orel 

Dept. of Chemotherapy, N.N. Blokhin Russian Cancer Research Center of Ramn, 

Moscow, RUSSIAN FEDERATION 

Objectives: To evaluate the effectiveness of long acting octreotide at the doses 30 - 

40 mg per month in heavily pretreated pts (pts) with disseminated neuroendocrine 

tumors (NET). 


Patients and methods: 31 pts with disseminated NET, progressing on different 

treatment regimens. We used long acting octreotide: Sandostatin-LAR, 

Octreotide-Depo, Octreotide-LONG. Origin of the tumor were: pancreas (3 pts, 

9.7%), intestines (15 pts, 48.4%), lung (1 pt, 3.2%), kidney (1 pt, 3.2%), or unknown 

(11 pts, 35.5%).Tumor grades were as follows: G1 - 8 (25.8%), G2 - 14 (45.2%), G3 

-1 (3.2%), unknown - 8 (25.8%). Isolated liver metastases were found in 15 pts 

(48.4%). 12 pts (38.7%) had liver metastases in combination with other sites of 

involvement. Carcinoid syndrome along with high levels of serum chromogranin A, 

serotonin and 5-OIAA were present in 29 pts (93.5%). Initially, 29 pts received long 

acting octreotide 20 mg for an average of 20 months (range, 3-60). The reasons for 

dose escalation were disease progression in 19 pts (61.3%), increase in markers and 

lack of control of carcinoid syndrome in 12 pts (38.7%). In 18 pts (58%) the dose 

was 30 mg, in 13 pts (42%) — 40 mg. 14 pts received long acting octreotide only 

(45.1%), 6 pts (19.4%) — in combination with α-interferon, 11 pts (35.5%) - in 

combination with chemotherapy. 

Results: In 14 pts receiving long acting octreotide only, objective responses were not 

observed; 11pts (78.6%) had stable disease (SD), 3 pts (21.4 %) progressed. Median 

time to progression was not reached. The pts were followed for a median of 13.5 

months. 5 pts (35.7%) are still receiving the treatment after 20 months. In the total 

group PR (partial response) was observed in 1 pts (3.2%), receiving octreotide with 

chemotherapy, SD — in 25 pts (80.7%), PD — in 5 pts (16.1%). Control of tumor 

growth was achieved in 83.9% of cases, these pts got a biochemical response and 

obtained symptom relief. In the total group the median time to progression was 18 

months. Median survival was not reached. Tolerability of long-acting octreotide in a 

dose of 30-40 mg was satisfactory for all pts. 

Conclusion: long acting octreotide at doses of 30-40 mg, alone or in combination 

with other types of drug treatment, controls the growth of disseminated tumors in 

most pts progressing on a lower dose, and has a good tolerability. 



new diagnostics 

1173P A HIGHLY SENSITIVE IMMUNOHISTOCHEMICAL ASSAY TO 

DETECT BRAF V600E MUTATIONS IN PATIENTS WITH 


J. Desai 1 ,F.Day 2 , A. Muranyi 3 , S. Singh 3 , K. Shanmugam 3 , T. Grogan 3 , 

P. Gibbs 4 , D. Williams 2 , O. Sieber 2 , P. Waring 5 

1 Medical Oncology, Ludwig Institute for Cancer Research, Royal Melbourne 

Hospital, Peter MacCallum Cancer Centre, Parkville, AUSTRALIA, 2 LCCI, Ludwig 

Institute for Cancer Research, Parkville, AUSTRALIA, 3 Ventana, Ventana Medical 

Systems, Tucson, AZ, UNITED STATES OF AMERICA, 4 LCCI, Ludwig Institute 

for Cancer Research, Royal Melbourne Hospital, Parkville, VIC, AUSTRALIA, 

5 Pathology, University of Melbourne, Parkville, AUSTRALIA 

Background: The BRAF V600E mutation is a well-validated negative prognostic 

biomarker in metastatic colorectal cancer (mCRC), and is a highly attractive drug 

target. Barriers to the development of agents targeting BRAF V600E in mCRC are 

the low rate of mutations (approximately 10%) and reliance on to sequencing-based 

technologies, which are not routinely available outside of large cancer centres. A 

simple immunohistochemistry (IHC) test, more suited to routine pathology practice, 

would provide much broader access to patient (pt) identification, and would also 

enable studies of tumor heterogeneity. Aims: To validate an IHC-based method of 

detecting the BRAF V600E mutation in a large cohort of community-based CRC 

patients. 

Methods: Tissue microarrays, comprising matched normal and tumor paraffin 

embedded tissue samples obtained from colectomy specimens from a community 

cohort of 505 pts with stage I–IV CRC, were tested with 2 antibodies (Ab): pBR for 

total BRAF and VE1 for BRAF V600E, using the Ventana UltraView and OptiView 

kits, respectively. IHC was assessed independently by 2 blinded pathologists, and 

results compared to BRAF V600E status determined by Sanger sequencing (SS). pBR 

negative samples were considered non - evaluable. Nine discordant cases were 

re-tested with a BRAF V600E SNaPshot assay. 

Results: Demographic features were evenly matched. SS was evaluable in 504/505; 

IHC in 477/505; with both evaluable in 476/505 pts. 56/476 (11.8%) pts had V600E 

mutations detected by SS, 65/476 (13.7%) by IHC. The positive predictive value was 

84.6% (55/65). 1 pt was negative by IHC and positive on SS and SNaPshot; resulting 

in a negative predictive value of 99.8% (410/411 cases). There was 100% concordance 

between SS and SNaPshot. Further validation is ongoing, and outcome data will be 

available at the time of presentation. 

Conclusions: We have conducted a comprehensive analytical and clinical validation 

and feasibility analysis of an IHC-based method to detect the BRAF V600E mutation 

in a large community-based population of pts with CRC. Shown to be highly 

sensitive, we are planning to adopt this approach as our initial screening step in an 

upcoming prospective combination trial targeting BRAF V600E in pts with mCRC. 

Disclosure: J. Desai: Research Support: Roche, Ventana Medical Systems, 

A. Muranyi: Employee: Ventana Medical Systems, K. Shanmugam: Employee and 

Shareholder, Ventana Medical Systems, T. Grogan: Shareholder and Chief Scientific 

Officer, Ventana Medical Systems, P. Gibbs: Research Support, Ventana Medical 

Systems, P. Waring: Research Support: Ventana Medical Systems, All other authors 


1174P DIAGNOSTIC AND PROGNOSTIC SIGNIFICANCE OF THE 

ALTERNATIVELY SPLICED ACTN4 VARIANT IN HIGH-GRADE 

NEUROENDOCRINE PULMONARY TUMOURS 

A. Miyanaga 1 , K. Honda 1 , K. Tsuta 1 , M. Masuda 1 , H. Tsuda 2 , H. Asamura 3 , 

A. Gemma 4 , T. Yamada 1 

1 Division of Chemotherapy and Clinical Research, National Cancer Center 

Research Institute, Tokyo, JAPAN, 2 Pathology and Clinical Laboratory Division, 

National Cancer Center Hospital, Tokyo, JAPAN, 3 Division of Thoracic Surgery, 

National Cancer Center Hospital, Tokyo, JAPAN, 4 Internal Medicine, Nippon 

Medical School, Tokyo, JAPAN 

Background: High-grade neuroendocrine tumours (HGNTs) of the lung manifest a 

wide spectrum of clinical behaviour, but no method of predicting their outcome has 

been established. 

Materials and methods: We newly established a monoclonal antibody specifically 

recognizing the product of the alternatively spliced ACTN4 transcript (namely, 

variant actinin-4), and used it to examine the expression of variant actinin-4 



immunohistochemically in a total of 609 surgical specimens of various histological 

subtypes of lung cancer. 

Results: Variant actinin-4 was expressed in 55% (96/176) of HGNTs, but in only 

0.8% (3/378) of non-neuroendocrine lung cancers. Expression of variant actinin-4 

was significantly associated with unfavorable overall survival in HGNT patients 

(P = 0.00021, log-rank test). Multivariate analysis using the Cox proportional hazards 

model showed that expression of variant actinin-4 was the most significant 

independent negative predictor of survival in HGNT patients (hazard ratio, 2.18; 

P = 0.000714) after the presence of lymph node metastasis (hazard ratio, 2.30; 

P = 0.00012). 

Conclusions: Expression of variant actinin-4 is an independent prognostic factor for 

patients with HGNTs. This protein has high affinity for filamentous actin polymers 

and likely promotes aggressive behaviour of cancer cells. The present clinical findings 

clearly support this notion. 


1175P CLINICAL FEASIBILITY STUDY OF A NOVEL 

CYTOMETRY-BASED SYSTEM FOR THE DETECTION OF 

CIRCULATING TUMOR CELLS IN PATIENTS WITH LUNG 

CANCER 

Y. Koh 1 , M. Watanabe 1 , T. Sawada 2 , Y. Uehara 2 , Y. Fujimura 3 , T. Tamura 4 , 

F. Koizumi 2 

1 Division of Drug Discovery and Development, Shizuoka Cancer Center, 

Sunto-gun, JAPAN, 2 Shien-Lab, National Cancer Center Hospital, Tokyo, 

JAPAN, 3 R&D, On-Chip Biotechnologies Co., Ltd, Koganei, JAPAN, 4 Division of 

Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN 

Background: The presence and number of circulating tumor cells (CTCs) in the 

peripheral blood of solid tumor patients are predictive of clinical outcome. To date 

the CellSearch system has been the only FDA-cleared CTCs enumeration system for 

advanced breast, prostate and colon cancers. However, low prevalence of CTCs and 

lack of capability as an application platform for molecular analysis have limited the 

use of CTCs in the clinic. To overcome these shortcomings, innovative and emerging 

technologies with easier access to further molecular analysis are under development 

worldwide. 

Methods: We have developed a flow cytometry-based CTCs detection system 

independent of EpCAM expression level of tumor cells with cytokeratin and 

vimentin-staining after the depletion of CD45-expressing cells. In a preclinical study, 

various cancer cell lines were spiked into blood from healthy donors and the 

sensitivity in detection was evaluated at two different sites (Shizuoka Cancer Center 

and National Cancer Center Tokyo). Then clinical feasibility study was conducted in 

patients with lung cancer. 

Results: Enumeration of the spiked cancer cells (10 to 1000 cells in 4 ml of blood) 

was linear, with a recovery rate of over 90%. A significantly higher recovery rate was 

observed with our system (90 to 102%) than that with CellSearch system (0%) 

particularly when EpCAM-negative PC-14 non-small lung cancer cells were spiked 

in, suggesting a superior sensitivity of our system in capturing EpCAM-negative 

tumor cells. In 22 blood samples from lung cancer patients, CTCs were detected with 

numbers ranging from 0 to 16 CTCs (median, 6.5) per 4 ml of blood with our 

system and in 72.7% (17/23) of the patients, 4 CTCs or more per 4 ml of blood were 

detected. On the other hand with CellSearch system, 2 CTCs or more per 7.5 ml of 

blood were detected in only 27% of the patients. 

Conclusions: The preclinical study and the results of the clinical feasibility study 

suggested superior sensitivity of our flow cytometry-based detection method than 

CellSearch system. Cell sorting device under development will be combined with this 

system for isolation and collection of CTCs for molecular analysis with 

next-generation sequencing. 


1176P EBUS-TBNA GIVES ADEQUATE TISSUE INFORMATION ON 

CELL TYPE IN LUNG CANCER 

M.K. Wong, M.S. Ip, D.C. Lam, J.C.M. Ho 

Medicine, Queen Mary Hospital, Hong Kong, HONG KONG 

Introduction: In formulating systemic treatment in patients with advanced stage 

lung cancer, it is now considered imperative to know the cell type such as squamous 

carcinoma, adenocarcinoma and large cell carcinoma as chemotherapeutic agents 

would be tailored to treat different cell type. 



abstracts

Method: Endobronchial ultrasound guided transbronchial needle aspiration 

(EBUS-TBNA)was performed under local anaesthesia in patients presented with 

mediastinal abnormality suspected of or confirmed lung cancer for diagnosis and 

staging purpose. Once malignancy was confirmed from the pathological materials, 

exact cell type, origin of tumour, differentiation were recorded. In the later phase of 

the study period, molecular profiling was also deployed to confirm the EGFR 

mutation and ALK translocation status. 

Results: Over the study period of 4 years and 4 months, there were 269 EBUS-TBNA 

performed in 258 patients. Of the 209 patients confirmed having malignancy as their 

final diagnosis, EBUS-TBNA was able to detect extrathoracic malignancy in 

23 (11.0%) and primary lung cancer in 133 (63.6%). Among those 133 patients 

confirmed having primary lung cancer, 116 (87.2%) had exact cell type delineated. 

For those 40 patients who had molecular profiling performed, patients with adequate 

tissue for EGFR mutation and/or ALK translocation were obtained in 38 (95.0%). Of 

the 157 patients confirmed to have malignancy by EBUS-TBNA, only 22 (14%) had 

revealed NSCLC without knowing the exact cell type, differentiation of the tumour, 

EGFR status or primary origin of the tumour. In the 220 patients with final 

diagnosis of malignancy, the sensitivity was 89.0% and negative predictive value was 

65.0% 

Conclusion: EBUS-TBNA is effective in subtyping of tumour cells and molecular 

profiling in patients with lung cancer. 


1177P VARIATIONS OF DISCORDANCE OF THE CLINICAL TNM 

STAGE WITH THE PATHOLOGICAL TNM STAGE BETWEEN 

JAPANESE DESIGNATED CANCER HOSPITALS 

F. Nakamura 1 , T. Higashi 2 , Y. Emori 3 , H. Nishimoto 3 

1 Healthcare Epidemiology, Kyoto University Graduate School of Medicine and 

Public Health, Kyoto, JAPAN, 2 Department of Public Health/Health Policy, The 

University of Tokyo Graduate School of Medicine, Tokyo, JAPAN, 3 Cancer 

Surveillance Division, National Cancer Center, Tokyo, JAPAN 

Introduction: Previous studies showed that TNM stages that were clinically 

determined before surgery were not often concordant with pathological TNM stages. 

However, no previous studies have examined variations of discordance of the clinical 

TNM stage with the pathological TNM stage among hospitals. We aimed to examine 

the discordance of the clinical and pathological stages among Japanese designated 

cancer hospitals using compiled data from the hospital-based cancer registry 

submitted from 286 designated cancer care hospitals in Japan. 

Methods: The registry data had UICC TNM stages before and after surgery for 

stomach, colorectal, lung and breast cancer patients treated in these hospitals. We 

excluded patients who received adjuvant chemotherapy or radiotherapy, patients who 

received care from facilities with less than 10 patients, male breast cancer and 

patients whose stages were unknown from the analysis. We also calculated 

discordance of stages that could have theoretically resulted in changes in surgical 

procedures or treatment choice. Discordance was also calculated after excluding stage 

IV patients as sensitivity analysis. 

Results: In total, 145,726 patients (38,692 stomach, 47,304 colorectal, 19,643 lung 

and 40,096 breast cancer patients) were included in the analysis. Patients’ mean age 

and clinical TNM stage varied across hospitals. The facility-level discordance between 

clinical and pathological stages ranged from 4% to 52% in stomach cancer, 3% to 


57% in colorectal cancer, 0% to 50% in lung cancer and 1% to 45% in breast cancer. 

TNM stages before surgery were lower than after surgery in more than half of the 

cases. The multi-level logistic regression model showed that variance in facilities 

existed after adjustment for age, sex and clinical TNM stage. Discordance of stages 

that could lead to changes in the surgical procedures or treatment choice ranged 

from 4% to 58% in stomach cancer, 4% to 63% in colorectal cancer, 0% to 5% in 

lung cancer, and 5% to 52% in breast cancer. Sensitivity analysis yielded similar 

results. 

Conclusion: We can confirm variations of discordance of TNM stages before and 

after surgery. 


1178TiP PROSPECTIVE EVALUATION OF PLANAR BONE 

SCINTIGRAPHY, SPECT/CT, 18F NAF PET/CT AND WHOLE 

BODY 1.5T MRI FOR DETECTION OF BONE METASTASES 

IN HIGH RISK BREAST AND PROSTATE CANCER PATIENTS 

A.K. Kuisma 1 , I. Jambor 2 , R. Huovinen 1 , M. Sandell 2 

1 Oncology and Radiotherapy, University Hospital of Turku, Turku, FINLAND, 

2 Radiology, University Hospital of Turku, Turku, FINLAND 

Purpose: The aim of the study was to compare the diagnostic accuracy of 99mTc 

methylene-diphosphonate planar bone scintigraphy (99mTc-MDP BS), 99mTc 

methylene-diphosphonate single photon emission tomography/computed 

tomography (99mTc-MDP SPECT/CT), 18F NaF positron emission tomography/ 

computed tomography (PET/CT) and whole body 1.5 Tesla magnetic resonance 

imaging (1.5T MRI) for the detection of bone metastases in high risk breast and 

prostate cancer patients. 

Materials and methods: Twenty breast cancer patients and eight prostate cancer 

patients at high risk of bone metastases prospectively underwent 99mTc-MDP BS, 

99mTc-MDP SPECT/CT, 18F NaF PET/CT and whole body 1.5T MRI using spine 

and surface coils. Four independent reviewers interpreted each individual modality 

without the knowledge of other imaging findings. The final metastatic status was 

based on the consensus reading of all imaging modalities. The findings were 

compared on patient and region basis. In the region based analysis, the skeleton was 

divided into five regions. 

Results: Based on the consensus reading, 13 (46%) patients and 42 (30%) regions 

had presence of bone metastases while 15 patients and 98 regions were free of bone 

metastases. 99mTc-MDP BS was false negative in four patients. In the patient/region 

based analysis, the sensitivity for 99mTc-MDP BS, 99mTc-MDP SPECT/CT, 18F 

NaF PET/CT and whole body 1.5T MRI was 69%/44%, 77%/76%, 92%/90% and 

77%/71%, respectively, while the accuracy was 86%/82%, 89%/92%, 96%/97% and 

86%/91%, respectively. 

Conclusions: 99mTc-MDP SPECT/CT, 18F NaF PET/CT and whole body MRI 

including diffusion weighted imaging demonstrated higher sensitivity and accuracy in 

detection of bone metastasis compared to planar bone scintigraphy. Observed 

difference between imaging modalities might potentially affect the patient 

management. Clinical relevance statement: 99mTc-MDP SPECT/CT, 18F NaF PET/ 

CT and whole body MRI including diffusion weighted imaging showed higher 

sensitivity for detecting bone metastases in high risk breast and prostate cancer 

patients to planar bone scintigraphy. 



non-small cell lung cancer, early stage 

1179O THE EUROPEAN THORACIC ONCOLOGY PLATFORM 

LUNGSCAPE PROJECT: A WAY TO BRIDGE NON-SMALL 

CELL LUNG CANCER MOLECULAR CHARACTERISTICS 

AND CLINICAL DATA 

S. Peters 1 , O. Dafni 2 , L. Bubendorf 3 , P. Meldgaard 4 ,K.O’Byrne 5 , A. Wrona 6 , 

W. Weder 7 , M. Canela 8 , S. Malatesta 9 , J. Vansteenkiste 10 , A-M. Dingemans 11 , 

M. Nicolson 12 , S. Savic 13 , P. Baas 14 , R. Peck 15 ,S.Lu 16 ,E.Smit 17 , 

E. Jantus-Lewintre 18 , R. Rosell 19 , R.A. Stahel 20 

1 Multidisciplinary Oncology Center, Lausanne Cancer Center, Centre Hospitalier 

Universitaire Vaudois, Lausanne, SWITZERLAND, 2 Frontier Science 

Foundation-Hellas, Athens, GREECE, 3 Division of Cytology, Institute for 

Pathology, University Hospital Basel, Basel, SWITZERLAND, 4 Department of 

Oncology, Aarhus University Hospital, Aarhus, DENMARK, 5 HOPE Directorate, 

St James’s Hospital, Dublin, IRELAND, 6 Department of Oncology and 

Radiotherapy, Medical University of Gdansk, Gdansk, POLAND, 7 Division of 

Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 8 Surgery, 

Vall d’Hebron University Hospital, Barcelona, SPAIN, 9 Anatomia Patologica, 

Ospedale Clinicizzato, Chieti, ITALY, 10 Respiratory Oncology, University Hospital 

Leuven, Leuven, BELGIUM, 11 Pulmonology, Maastricht University Medical 

Centre, Maastricht, NETHERLANDS, 12 Medical Oncology, Aberdeen Royal 

Infirmary, Aberdeen, UNITED KINGDOM, 13 Pathology, Institute for Pathology, 

University Hospital Basel, Basel, SWITZERLAND, 14 Department of Thoracic 

Oncology, The Netherlands Cancer Institute, Amsterdam, NETHERLANDS, 

15 University Hospital South Manchester and The Christie NHS Foundation Trust, 

Manchester, UNITED KINGDOM, 16 Shanghai Lung Tumor Clinic Center, 

Shanghai Chest Hospital, Shanghai, CHINA, 17 Pulmonology, Vrije Universiteit 

Medical Center, Amsterdam, NETHERLANDS, 18 Fundación para la Investigación 

del Hospital General Universitario de Valencia, Valencia, SPAIN, 19 Medical 

Oncology Service, Catalan Institute of Oncology, Badalona (Barcelona), SPAIN, 

20 Clinic of Oncology, University Hospital Zurich, Zurich, SWITZERLAND 

Background: The Lungscape project aims at building a virtual biobank to facilitate 

an international high-quality analysis of large numbers of tumors for molecular 

alterations linked to clinical and biological characteristics captured in the iBiobank. 

Methods: Retrospective radically resected stage I-III non-small cell lung cancer cases 

from 15 ETOP centers, with mandatory comprehensive clinical annotations 

including at least 2 years of FU have been reviewed and captured. 

Results: This first set of 1614 cases was enriched in adenocarcinoma (61.8%), with 

28.8% of squamous and 4.9% of large cell histologies. Median age is 65 yrs, 37.6% 

are women, and respectively 13.9%, 33.5% and 49.6% are never, current and former 

smokers. Stage distribution is: IA 23.7%, IB 25.8%, IIA 16.4%, IIB 11.6%, IIIA 20.8%, 

IIIB 1.7%. At last FU, 52.8% of patients were still alive, with a median FU of 5.3 yrs. 

PFS 

No. of 

patients 5 years (95% C.I.) 

Median (mos) 

(95% C.I.) 

TOTAL 1614 46 (43.3, 48.6) 49.0 ( 43.9, 55.2) 

Stage Ia 382 64.5 (59.1, 60.5) NR 

Ib 417 55.4 (50.3, 60.5) 78.0 

IIa 264 44.8 (38.4, 51.3) 46.9 

IIb 187 39.2 (31.6, 46.8) 33.7 

IIIa 335 20.0 (15.2, 24.8) 17.5 

IIIb 28 11.9 (0.0, 25.3) 10.1 

OS 1614 52.0 (49.3, 54.7) 64.2 (57.3, 76.9) 

Stage Ia 382 70.0 (64.9, 75.2) NR 

Ib 417 60.6 (55.5, 65.7) NR 

IIa 264 50.5 (43.8, 57.1) 62.2 

IIb 187 43.7 (36.0, 51.4) 43.3 

IIIa 335 29.3 (23.9, 34.7) 29.0 

IIIb 28 10.3 (0.0, 27.1) 20.2 

Conclusion: This is the first large-scale series based on 7th TNM classification 

reporting on OS and PFS in the context of European standards of care. These data 

confirm the discriminative capacity of the 7 th TNM with a potentially somewhat 

superior outcome. Histologies other than adenocarcinoma are currently actively 

being captured. Complete data including PFS and TTP - never reported before - as 

well as OS based on the expected 2400 patients correlated to stage, gender, smoking 

status, histology and age will be provided. This complete clinical dataset will be 



invaluable to investigate the impact of molecular characteristics on outcome. It will 

allow building future hypothesis for prospective evaluation of new treatment 

strategies and help in the development of a molecularly refined TNM. 


1180PD EXPRESSION OF HYPOXIA-INDUCED FACTOR 1α AND 

GLUCOSE TRANSPORTER 1 CORRELATES WITH 

[18F]-FLUORO-2-DEOXY-GLUCOSE UPTAKE ON 

POSITRON EMISSION TOMOGRAPHY AND TUMOR 

AGGRESSIVENESS IN DIFFERENT HISTOLOGIC SUBTYPES 

OF LUNG ADENOCARCINOMAS 

Y. Miyata, T. Furukawa, Y. Tsutani, T. Mimae, K. Misumi, T. Yoshiya, Y. Ibuki, 

M. Okada 

Surgical Oncology, Hiroshima University, Hiroshima, JAPAN 

Background: High maximal standardized uptake values (SUVmax) on 

[18F]-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) are 

associated with inferior survival in lung adenocarcinoma. However, the exact 

mechanisms are unknown. Here, we investigated the biological mechanisms 

underlying FDG uptake in different subtypes of adenocarcimomas. 

Methods: This retrospective study included 287 patients with adenocarcinoma (166 

with Stage IA). The patients underwent systematic tumor resection at Hiroshima 

University Hospital from January 2007 to December 2011, at the latest, 4 weeks after 

FDG-PET. The SUVmax values for primary lesions were calculated based on FDG 

uptake. Tumors were subdivided according to each morphologic growth pattern. The 

expression of hypoxia-inducible factor 1α (HIF1α) and glucose transporter 1 (GLUT1) 

was evaluated in 70 patients with 147 histologic subtypes using immunostaining. 

Results: There were significant differences in SUVmax and disease-free survival 

(DFS) among different histologic subtypes. Mean SUVmax and 5-year DFS were 0.90 

and 100% in is situ (n = 41), 1.1 and 100% in minimally invasive (n = 5), 1.8 and 

94.3% in lepidic (n = 66), 3.9 and 75.2% in papillary (n = 136), 5.4 and 91.7% in 

acinar (n = 26), and 7.6 and 71.6% in solid (n = 13) predominant subtypes. HIF1α 

and GLUT1, and GLUT1 and SUVmax were significantly correlated (p < 0.001 for 

both) in adenocarcinoma. Moreover, the expressions of HIF1α and GLUT1 

correlated with various clinicopathological factors relating to malignancy, such as 

pathological stage (I vs. II + III; p = 0.014), lymph node metastasis (p = 0.037), 

pleural invasion (p = 0.0093), lymphatic invasion (p < 0.001), and venous invasion 

(p < 0.001). GLUT1 and SUVmax were jointly associated with DFS (p = 0.0098 and 

p < 0.001, respectively in adenocarcinoma). There were significant differences in 

HIF1α and GLUT1 expression among different histologic subtypes. Mean HIF1α and 

GLUT1score were 0 and 0.15 in is situ (n = 13), 0.03 and 0.11 in lepidic (n = 36), 

0.19 and 1.0 in papillary (n = 52), 0.47 and 1.2 in acinar (n = 34), 0.11 and 1.6 in 

micropapillary (n = 9), and 2.3 and 3.0 in solid (n = 3) subtypes. 

Conclusions: In different histologic subtypes of lung adenocarcinomas, 

HIF1α-induced GLUT1 expression might explain high FDG uptake on PET and 

correlate with poor prognosis. 


1181PD RANDOMIZED PHASE II STUDY OF ADJUVANT 

CHEMOTHERAPY WITH S-1 VERSUS CDDP + S-1 IN 

RESECTED STAGE II-IIIA NON-SMALL-CELL LUNG 

CANCER (WJOG4107) 

H. Yoshioka1 , Y. Iwamoto2 , S. Ito3 , T. Yamanaka4 , H. Tada5 , M. Yoshimura6 , 

I. Okamoto7 , I. Yoshino8 , K. Nakagawa7 , Y. Nakanishi9 1 2 

Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, JAPAN, Medical 

Oncology, Hiroshima City Hospital, Hiroshima, JAPAN, 3 Department of Thoracic 

Surgery, Aichi Cancer Center Hospital, Nagoya, JAPAN, 4 Clinical Research 

Center, National Cancer Research Center, East Hospital, Kashiwa, JAPAN, 

5 

General Thoracic Surgery, Osaka City General Hospital, Osaka, JAPAN, 

6 7 

Thoracic Surgery, Hyogo Cancer Center, Akashi, JAPAN, Medical Oncology, 

Kinki University School of Medicine, Osakasayama, JAPAN, 8 General Thoracic 

Surgery, Chiba University Graduate School of Medicine, Chiba, JAPAN, 

9 

Research Institute for Diseases of The Chest, Kyushu University Hospital, 

Fukuoka, JAPAN 

Background: Postoperative cisplatin doublet chemotherapy benefits patients with 

completely resected stage II-IIIA non-small-cell lung cancer (NSCLC). S-1 is an oral 

fluorinated pyrimidine formulation that combines tegafur (FT), 5-chloro-2, 

4-dihydroxypyridine (CDHP), and potassium oxonate in a molar ratio of 1:0.4:1 and 



abstracts

widely used by single agent or platinum doublet for advanced NSCLC in Japan. This 

phase II trial assessed the efficacy and safety of S-1 and cisplatin plus S-1 for 

adjuvant chemotherapy. 

Methods: From September 2007 to Dec 2009, 200 patients with completely resected 

stage II and IIIA (exclude multi-station N2 cases) NSCLC were randomized to 

receive either oral S-1 (40 mg/m2 twice per day) for consecutive 2 weeks repeated 

every 3 weeks for 1 year or cisplatin (60 mg/m2 day1) plus oral S-1 (40 mg/m2 twice 

per day) for consecutive 2 weeks repeated every 3 weeks for 4 cycles within 8 weeks 

after surgery. Main inclusion criteria were no prior chemotherapy or radiotherapy, 

ECOG PS 0-1, an age of less than 75 years, and an adequate organ function. 

Stratification factors included histology, stage and institutions. Primary endpoint was 

relapse free survival rate on 2 years and secondary endpoints were overall survival 

(OS) and toxicity. 

Results: Patient demographics were well balanced between the arms in terms of 

sex, age, histologic type and stage. 52.6% of patients in S-1 arm and 76.7% in 

cisplatin plus S-1 arm were completed planned administration. Relapse free 

survival rate on 2 years was 65.6% (95% confidence interval, 55.3-74.0%) in the 

S-1 arm and 58.1% (95% confidence interval, 47.7-67.2%) in the cisplatin plus S-1 

arm. OS were not matured in the both arms. Though the rates of leukopenia or 

neutropenia of grade 3/4, febrile neutropenia, nausea, and vomiting were more 

frequent in the cisplatin plus S-1 arm, there were no treatment related deaths in 

the both groups. 

Conclusion: Both S-1 monotherapy and cisplatin plus S-1 are feasible as adjuvant 

chemotherapy for completed resected NSCLC. 

Disclosure: I. Yoshino: Research Funds from Taiho Pharmaceutical Co. and Chugai 

Pharmaceutical Co.All other authors have declared no conflicts of interest. 

1182P IMMUNOGENICITY AND SAFETY OF THE PRAME CANCER 

IMMUNOTHERAPEUTIC IN NON-SMALL CELL LUNG 

CANCER (NSCLC): PHASE I DOSE ESCALATION STUDY 

J. Pujol 1 ,T.DePas 2 , A. Rittmeyer 3 , B. Kubisa 4 , E. Vallieres 5 , E. Levchenko 6 , 

B. Salaun 7 , N. Vanhoutte 8 , M. Debois 8 , V. Brichard 9 

1 Thoracic Oncologic Unit, Montpellier Academic Hospital, Hospital Arnaud De 

Villeneuve, Montpellier, Montpellier, FRANCE, 2 Medical Oncology, European 

Institute of Oncology, Milan, ITALY, 3 Lungenfachklinik Immenhausen, 

Lungenfachklinik Immenhausen, Immenhausen, GERMANY, 4 Thoracic Surgery, 

Pomeranian Medical University, Szczecin, POLAND, 5 Thoracic Oncology, 

Swedish Cancer Institute, Seattle, WA, UNITED STATES OF AMERICA, 6 Thoracic 

Oncology, Petrov Research Institution of Oncology, St. Petersburg, RUSSIAN 

FEDERATION, 7 R&D DAP Cancer, GlaxoSmithKline Biologicals, Rixensart, 

BELGIUM, 8 Immunotherapeutics, GlaxoSmithKline Biologicals, Rixensart, 

BELGIUM, 9 Immunotherapeutics BU, GlaxoSmithKline Biologicals, Rixensart, 

BELGIUM 

Introduction: Adjuvant chemotherapy (CT) is the standard treatment for stage II– 

IIIA NSCLC, but is debated for stage IB. As not all patients (pts) are eligible for CT 

and many of them relapse, alternative therapies are needed. The PRAME tumor 

antigen, expressed frequently in NSCLC and at lower levels in few normal cells, offers 

an attractive target for active immunization. Moreover, while most NSCLC tumors 

expressing the antigen MAGE-A3 are PRAME positive, 45% of PRAME-expressing 

NSCLC do not express MAGE-A3. This dose-escalation phase I open study aimed at 

determining the optimal dose of the PRAME cancer immunotherapeutic (PRAME 

recombinant protein (recPRAME) with AS15 immunostimulant) by evaluating its 

safety and immunogenicity in NSCLC pts. 

Methods: Pts with PRAME-positive resected stage IB-IIIA NSCLC were enrolled in 3 

consecutive cohorts to receive up to 13 injections of recPRAME (20 µg, 100 µg, and 

500 µg) with AS15 (fixed dose) over approximately 2 years. Adverse events (AEs), 

including pre-defined dose-limiting toxicity (DLT), were recorded throughout the 

study. The anti-PRAME humoral and cellular responses were assessed post-dose 4 by 

ELISA and flow cytometry (PRAME-specific T-cells producing both IFNγ and 

TNFα), respectively. 

Results: 60 pts were treated in the study (18, 18, 24 pts received 20, 100, 500 µg 

recPRAME, respectively). AEs were mostly grade 1/2. No grade 3/4 AEs considered 

by the investigator to be causally related were reported. One grade 2 serious AE 

causally related to PRAME administration was reported. No DLTs were reported. 

Immunogenicity results are shown in the table. 

Conclusions: The PRAME cancer immunotherapeutic was well-tolerated and elicited 

similar humoral responses in all 3 cohorts. A trend for an increased cellular response 

was observed with increasing dose of recPRAME. Thus, the highest dose was selected 

for further clinical development. 

Immunogenicity post-dose 4 (ATP population). 


Cohort (recPRAME dose) 1 (20 µg) 2 (100 µg) 3 (500 µg) 

Humoral responders, n/N* 10/10 11/11 19/19 



N, number of patients enrolled into each group; * number of patients with pre and 

post-vaccination results; n, number of responders; ATP, according-to-protocol 

Funding: GSK Biologicals 

Disclosure: J. Pujol: Honorarium study coordination as only conflict of interest. B. 

Kubisa: I am the Principal Investigator of this study at my institution. E. Vallieres: I 

am a consultant for GLAXOSMITHKLINE BIOLOGICALS and a member of the 

PRAME NSCLC Global Development Advisory Board. B. Salaun: Currently 

employed by GSK Vaccines as a scientist. N. Vanhoutte: Employee of 

GlaxoSmithKline Biologicals. M. Debois: Employee of GlaxoSmithKline Biologicals. 

V. Brichard: GSK employee. All other authors have declared no conflicts of interest. 

1183P USE OF ADJUVANT CHEMOTHERAPY (CT) AND 

RADIOTHERAPY (RT) IN INCOMPLETELY RESECTED (R1) 

EARLY STAGE NON-SMALL CELL LUNG CANCER (NSCLC): A 

EUROPEAN SURVEY CONDUCTED BY THE EUROPEAN 

SOCIETY FOR MEDICAL ONCOLOGY (ESMO) YOUNG 

ONCOLOGISTS COMMITTEE 

R. Califano, on behalf of the Young Oncologists Committee of the European 

Society for Medical Oncology 

Department of Medical Oncology, The Christie NHS Foundation Trust & 

University Hospital of South Manchester NHS Foundation Trust, Manchester, 


Background: Early stage NSCLC is potentially curable with radical surgery. 

Cisplatin-based adjuvant CT improves survival and is recommended in the ESMO 

guidelines for stage II-III completely resected NSCLC. There is limited evidence to 

guide the use of adjuvant CT and RT in incompletely resected (R1) early stage NSCLC. 

Design and objective: A European survey of oncologists treating lung cancer was 

conducted to evaluate the use of adjuvant CT and RT for R1-resected NSCLC and to 

identify factors influencing treatment decisions. Demographics were collected and 

outcomes such as clinical stage, regimens, cycles planned, radiotherapy site, 

multidisciplinary management and discussion about inconclusive evidence with the 

patient were analyzed. Logistic regression model was used to detect statistical association 

and to estimate Odds Ratio; Cochrane-Armitage test was used to detect trend. 

Results: 768 surveys were collected from 41 European countries between January to 

April 2012. 82.9% of participants were medical oncologists; 49.3% ESMO members; 

37.1% based in a University Hospital; 32.6% practicing oncology for more than 15 

years and 81.4% active in research. 91.4% of participants prescribed adjuvant CT. 

Prescription according to stage: IA/IB/IIA/IIB/IIIA = 13.3%/44.8%/83.9%/90.5%/ 

94.5%, respectively. Most common CT regimens were: Cisplatin/Vinorelbine (81.2%), 

Cisplatin/Gemcitabine (42.9%), Carboplatin/Vinorelbine (31.6%), Carboplatin/ 

Paclitaxel (31%) and Carboplatin/Gemcitabine (26.7%). Number of cycles planned: 3/ 

4/6 = 7.5%/78.1%/14.5%, respectively. 85% discussed limited clinical evidence with 

the patient. 48.3% of participants prescribed adjuvant RT. Among these, RT to the 

surgical bed and for pN2 disease was prescribed by 85.1% and 84.8%, respectively. 

Most common RT regimens for surgical bed: 60 Gy in 30 fractions (Fx) (45.6%), 54 

Gy in 27-30 Fx (29.6%), 50 Gy in 20 Fx (23.4%) and 52.5 Gy in 20 Fx (3.6%). Most 

common RT regimens for pN2 disease: 60 Gy in 30 Fx (35.2%), 54 Gy in 27-30 Fx 

(34.1%), 50 Gy in 20 Fx (24.1%) and 50 Gy in 25 Fx (4.8%). 

Conclusions: This European survey indicates that adjuvant CT and RT for 

incompletely resected (R1) NSCLC are commonly used in clinical practice despite 

limited evidence. Prospective trials for R1-resected NSCLC are necessary to clarify 

optimal management. 

Acknowledgments: ESMO Young Oncologists Committee: R. Califano, The Christie 

NHS Foundation Trust, Manchester, United Kingdom; E. Martinelli, Second 

University of Naples, Naples, Italy; V. Guarneri, University of Modena and Reggio 

Emilia, Modena, Italy; S. Banerjee, Royal Marsden Hospital, London, United 

Kingdom; D. Olmos Hidalgo, National Cancer research Centre (CNIO), Madrid, 

Spain; S. Postel-Vinay, Institute of Cancer Research ICR, London, United Kingdom; 

K. Jordan, University Hospital of Halle, Halle, Germany; M. Karamouzis, School of 

Medicine, University of Athens, Athens, Greece; K. Kamposioras, University Hospital 

of Larissa, Larissa, Greece; M. Preusser, Medical University of Vienna, Vienna, 

Austria; E. de Azambuja, Institute Jules Bordet, Brussels, Belgium; M. Hutka, Royal 

Marsden Hospital, London, United Kingdom. 



Medical Statistics: V. Torri, Istituto di Ricerche Farmacologiche “Mario Negri”, 

Milan, Italy; L. Porcu, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, 

Italy 

ESMO project management team: K. Fumasoli, L. Kristoffersen, M. Cogo, 

Viganello-Lugano, Switzerland 


1184P PROGNOSTIC FACTORS IN EARLY STAGE NON-SMALL CELL 

LUNG CANCER (NSCLC): THE IMPORTANCE OF NUMBER OF 

RESECTED LYMPH NODES AND VASCULAR INVASION 

M. Caramanti 1 , R. Berardi 1 , A. Santinelli 2 , A. Brunelli 3 , A. Savini 1 , P. Mazzanti 1 , 

C. Pompili 3 , M. Salati 3 , C. Pierantoni 1 , S. Cascinu 4 



Riuniti Ancona Università Politecnica delle Marche, Ancona, ITALY, 3 Thoracic 

Surgery, AOU Ospedali Riuniti Ancona, Ancona, ITALY, 4 Dipartimento di 

Medicina Clinica e Biotecnologie A, University of Ancona, Ancona, ITALY 

Introduction: Despite an appropriate surgical treatment, half of early-stage NSCLC 

patients will die due to lung cancer. The number of resected lymph-nodes and 

vascular invasion have proved to be a prognostic factor in other solid tumors, as well 

as breast and colorectal cancer. Here we evaluate their prognostic impact in the 

largest mono-centric series of resected NSCLC patients. 

Methods: Clinical and pathological characteristics and prognostic outcomes of 439 

consecutive patients undergoing radical surgical resection for NSCLC at our 

Institution were evaluated. 

Results: The multivariate analysis showed that number of resected lymph nodes, 

vascular invasion and sex had a prognostic impact on overall survival. The optimal 

cut-off number of lymph nodes with the highest sensitivity and specificity for 

estimating the outcome was set at 10 after Receiver Operating Characteristics (ROC) 

curve analysis. Removing 10 lymph nodes in our study represents a cut-off with a 

significant prognostic impact particularly in resected stage II NSCLC. 

Conclusions: Similarly to other cancer types (i.e. colorectal cancer), our results suggest 

that an adequate classification of NSCLC should always include an adequate lymph 

nodes clearance, particularly in stage II NSCLC. Again vascular invasion resulted an 

independent prognostic factors for overall survival (H.R. 0.82, CI 0.68-0.96, p = 0.042). 

Therefore the number of resected lymph nodes, together with vascular invasion, may 

also drive the selection of NSCLC patients for adjuvant treatment. 


1185P PROGNOSTIC ROLE OF ERBB FAMILY RECEPTORS, MYC 

AND MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) IN 

PATIENTS WITH EARLY-STAGE NON SMALL-CELL LUNG 

CANCER 

V. Ludovini 1 , G. Bellezza 2 , F. Bianconi 3 , R. Chiari 1 , C. Bennati 1 , F.R. Tofanetti 1 , 

J. Vannucci 4 , F. Puma 4 , A. Sidoni 2 , L. Crinò 1 

1 Medical Oncology Division, S. Maria della Misericordia Hospital, Perugia, ITALY, 

2 University of Perugia, Institute of Pathological Anatomy and Histology, University 

of Perugia, Perugia, Italy, Perugia, ITALY, 3 Department of Surgical and Medical 

Specialties & Public Health, University of Perugia, Perugia, ITALY, 4 Department of 

Thoracic Surgery, University of Perugia, Perugia, ITALY 

Background: EGFR deregulation has been extensively studied in non small-cell lung 

cancer (NSCLC), but the expression and the role of other ErbB receptors and their 

downstream signal transductions remains still unclear. MYC and MAPK are key 

downstream components of the EGFR pathway and have significant roles in cell 

survival, proliferation, and growth. This study evaluates the prognostic role of EGFR, 

ErbB2, ErbB3, ErbB4, MYC and MAPK by immunohistochemistry (IHC) in early 

stage NSCLC. 

Methods: One-hundred nine NSCLC patients were evaluated: median age was 67 

years (range 40–84); Male/Female: 93/16; squamous (SCC)/adenocarcinoma (ADC)/ 

BAC/other: 52/36/3/18; smoker/never smoker:100/9, and stage I/II/III:67/17/25. IHC 

results were evaluated by two independent observers and the tumors with ≥10% 

positive cells were classified positive, further confirmed by Receiver Operating 

Characteristic (ROC) analysis. Kaplan-Meier estimates of survival and time to 

recurrence were calculated for clinical and biologic variables using Cox model for 

multivariate analysis. 

Results: EGFR was expressed in 55.9%, ErbB2 in 24.7% ErbB3 in 33.9%, ErbB4 in 

27.5%, Myc in 23.8% and MAPK in 27.5 % of patients, respectively. EGFR and 

ErbB3 were associated with SCC (p < 0.0001 and p = 0.004, respectively) whereas 

ErbB2 and MYC with ADC (p = 0.004 and p < 0.0001, respectively). EGFR and 

ErbB3 were significantly associated (p = 0.003), as well as MAPK and ErbB4 

(p = 0.02). At a median follow-up of 75 months the contemporary over-expression of 

EGFR, ErbB2 and MAPK was associated with shorter disease free survival (DFS) 

(HR = 5.4, p = 0.002) and overall survival (OS) (HR = 8.9, p < 0.0001). At multivariate 

analysis adjusting for stage, the co-expression of EGFR, ErbB2 and MAPK was an 

independent predictor for worse DFS and OS (HR = 5.7, p = 0.004; HR = 8.67, 

p < 0.001, respectively). 

Conclusions: Our results suggest that in early stage NSCLC the co-expression of 

EGFR, ErbB2 and MAPK predicted a worse prognosis. Such features may have 

important implications for future targeted therapies. We thank Italian Association for 

Cancer Research (AIRC) for supporting the study. 


1186P GENE AMPLIFICATION OF ACTN4 IN LUNG CANCER: A 

NOVEL PROGNOSTIC INDICATOR FOR STAGE I 

ADENOCARCINOMA OF THE LUNG 

K. Honda 1 , R. Noro 2 , N. Miura 1 , K. Tsuta 3 , G. Ishii 4 , H. Tsuda 3 , A. Gennma 2 , 

H. Asamura 5 , K. Nagai 6 , T. Yamada 1 

1 Division of Chemotherapy and Clinical Research, National Cancer Center 

Research Institute, Tokyo, JAPAN, 2 Department of Internal Medicine, Division of 

Pulmonary Medicine, Infectious Diseases and Oncology, Nippon Medical School, 

Tokyo, JAPAN, 3 Pathology and Clinical Laboratory Division, National Cancer 

Center Hospital, Tokyo, JAPAN, 4 Department of Pathology, National Cancer 

Center Hospital East, Kashiwa, JAPAN, 5 Division of Thoracic Surgery, National 

Cancer Center Hospital, Tokyo, JAPAN, 6 Department of Thoracic Oncology, 

National Cancer Center Hospital East, Kashiwa, JAPAN 

Background: Even if detected at an early stage, a substantial number of lung cancers 

relapse after surgery. Patients with such tumors are likely to benefit from adjuvant 

therapy, but methods for identifying such patients have yet to be established. 

Methods: We retrospectively analyzed multiple cohorts totaling 1744 patients who 

underwent resection of lung adenocarcinoma. Expression of actinin-4 protein in 

tumors was evaluated immunohistochemically, and copy numbers of the actinin-4 

(ACTN4) gene were determined by fluorescence in situ hybridization. 

Results: Amplification of the ACTN4 gene correlated significantly with smoking 

history (P = 0.02), pathological stage (P = 0.002), and histological differentiation 

(P < 0.001, chi-squared test). Overall survival was significantly worse for patients with 

stage I lung adenocarcinoma harboring ACTN4 gene amplification than for those 

with tumors showing no such gene amplification (P < 0.001, log-rank test). 

Multivariate analysis revealed ACTN4 gene amplification in stage I lung 

adenocarcinoma as an independent factor associated with higher risk of death 

(hazard ratio, 6.78; 95% confidence interval, 2.59-17.7; P < 0.001, Cox regression 

analysis). The 5-year survival rate of patients with stage I lung adenocarcinoma 

showing increased actinin-4 protein expression and ACTN4 gene amplification was 

58%, compared to 87% for patients with tumors lacking gene amplification and 95% 

for patients with tumors lacking actinin-4 protein expression. The former group 

showed significantly worse overall survival than either of the latter (P < 0.001). 

Conclusions: Amplification of the actinin-4 gene defines a subset of stage I lung 

adenocarcinoma with distinctly poor outcomes. 


1187P THE ROLE OF MUTATIONS OF EGFR, K-RAS, EML4-ALK, 

AND B-RAF GENES IN RESECTED PATHOLOGICAL STAGE I 

LUNG ADENOCARCINOMA 

G. Toyokawa 1 , T. Ohba 1 , K. Sugio 2 , Y. Morodomi 1 , T. Takenaka 1 , 

M. Yamaguchi 1 , F. Hirai 1 , K. Taguchi 3 , T. Seto 1 , Y. Ichinose 2 

1 Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, 

JAPAN, 2 Department of Thoracic Oncology, Clinical Research Institute, National 

Kyushu Cancer Center, Fukuoka, JAPAN, 3 Clinical Research Center, National 

Kyushu Cancer Center, Fukuoka, JAPAN 

Background: The mutations of EGFR, K-ras, EML4-ALK and B-RAF genes are an 

early event during oncogenesis of NSCLC. This study retrospectively assessed the 

mutations of these genes and their clinical significance in resected adenocacinomas. 

Methods: A total of 256 patients with resected stage I lung adenocarcinoma were 

retrospectively included in this study. The mutations of EGFR and K-ras were determined 

using PCR-based fragment analysis and direct sequencing. The EML4-ALK fusion gene 

was assayed by immunohistochemistry and multiplex RT-PCR. The mutation of B-RAF 

gene was determined using direct sequencing. The DFS for prognostic value and the OS 

for predictive value of treatment after recurrence were evaluated. 

Results: In 256 tumors, the mutations of EGFR, K-ras, EML4-ALK, and B-RAF 

genes were detected in 114 (44.5%), 14 (5.5%), 7 (2.7%), and 3 (1.2%). One patient 

with the EML4-ALK fusion gene harbored the mutation of EGFR, and double 

mutations of EGFR and B-RAF were also observed in one patient. The incidence of 

EGFR mutations was significantly higher in females than males (41.2% vs. 54.4%, p 

< 0.05). The incidence of K-ras mutations was higher in males than females and 

older patients than younger patients (not significant). The EML4-ALK fusion gene 

was detected in younger patients (4.2 vs. 0%). The DFS and OS of K-ras mutant 

group were significantly inferior than those of EGFR mutant group, EML4-ALK 

fusion gene group, and wild-type group. Twenty-four of 41 patients with recurrent 


disease after surgery were treated by EGFR-TKI and 17 patients were treated by other 

cytotoxic agents. In the patients treated by EGFR-TKI, the MST in patients with 

EGFR mutation (n = 15) was 53.4 months, which was significantly superior than that 

in patients without EGFR mutation (n = 9) of 20.1 months. In patients treated by 

cytotoxic agents, there was no difference in OS between EGFR-mutation positive and 

negative groups. Six of 7 patients with EML4-ALK fusion gene are alive without 

recurrent disease. However, the evaluation of prognostic value of EML4-ALK and 

B-RAF was difficult because of the small number of patient with mutation. 

Conclusion: In patients with stage I adenocarcinoma, the mutation of K-ras gene 

was a poor prognostic factor for recurrence, and the mutation of EGFR was a 

predictive factor for EGFR-TKI treatment after recurrence. 


1188P EXAMINATION OF PATHOLOGICAL STAGE IB NON-SMALL 

CELL LUNG CANCER—ADEQUACY OF PLEURAL 

INFILTRATION ASSESSMENT 

R. Nakahara 1 , H. Suzuki 1 , S. Igarashi 2 , H. Matsuguma 1 

1 Division of Thoracic Surgery, Tochigi Cancer Center, Utsunomiya, JAPAN, 

2 Division of Pathology, Tochigi Cancer Center, Utsunomiya, JAPAN 

Background: In January 2010, the TNM classification of lung cancer was revised 

(7th version). The T factor was more closely divided, and lung cancer with 3 cm or 

less in greatest dimension and infiltration of visceral pleura was classified as the T2a 

group. 

Purpose: We examined whether the evaluation of visceral pleural infiltration in the 

new TNM classification is appropriate. 

Methods: Among patients with non-small cell lung cancer who underwent radical 

surgery in our hospital between October 1986 and December 2006, pathological T1 

to T3N0M0 tumors were detected in 625. Of these, we performed survival analysis in 

197 with T2aN0M0 (stage IB) tumors using gender, age, pleural infiltration (p), 

lymph vessel invasion (ly), and vascular infiltration (v) as prognostic factors. 

Furthermore, the stage-IB patients were divided into 3 groups based on the tumor 

diameter (s) and visceral pleural infiltration (p): Group A: s ≤ 3 cm, p1,2 (n = 49), 

Group B: 3 cm < s ≤ 5 cm, p0 (n = 101), and Group C: 3 cm < s ≤ 5 cm, p1,2 (n = 47). 

We compared the survival rate among the 3 groups, and investigated differences from 

the survival rates in the IA to IIB groups. 

Results: Concerning the clinical background of the 197 stage-IB patients, the mean 

age was 68 years (37 to 87), and the number of males was 128 (65%). The number of 

patients with adenocarcinoma was 125 (63%), and that of patients with squamous 

cell carcinoma was 61 (31%). Univariate analysis showed that advanced age, male 

gender, p(+), and v(+) were significant prognostic factors. On multivariate analysis, 

age (p = 0.0002) and p factor (p = 0.0007) alone were regarded as independent 

prognostic factors. The 5-year survival rates in Groups A, B, and C were 61, 82, and 

57%, respectively. There were significant differences between Groups A and B 

(p = 0.0074), as well as between Groups B and C (p = 0.0058). In the p(+) factor 

group, the prognosis was significantly less favorable than in the p(-) factor group. 

The survival rates in Groups A and C were similar to the 5-year survival rate in 

T2bN0M0 (stage IIA) patients (64%). 

Discussion: In this study, p(+) patients showed an unfavorable prognosis regardless 

of the tumor diameter. When selecting the T factor, it should be evaluated as higher 

in p(+) patients. 


1189P IMPACT OF ADENOCARCINOMA VERSUS 

SQUAMOUS-CELL-CARCINOMA HISTOLOGY ON SURVIVAL 

OF RESECTED STAGE I-II NON-SMALL CELL LUNG CANCER 

(NSCLC) IN A COHORT OF 509 PATIENTS 

J. Bosch-Barrera 1 , X. Baldo 2 , M. Rubio 2 , M. Buxó 3 , L. Vilardell 3 , R. Porta 1 , 

E. Marmol 2 , N. Basté 1 , A. Izquierdo 1 , F. Sebastian 2 

1 Oncology, Catalan Institute of Oncology, Girona, SPAIN, 2 Thoracic Surgery, 

Hospital Universitari de Girona Dr. Josep Trueta, Girona, SPAIN, 3 Epidemiology 

Unit and Cancer Registry of Girona, Oncology Planning, Department of Health, 

Girona Biomedical Research Institute, Girona, SPAIN 


Background: Histology is a prognostic and predictor of the response factor in 

advanced non-small cell lung cancer (NSCLC). Adenocarcinoma (ADC) has a better 

prognosis in advanced NSCLC whereas it is considered that resected patients (pts) 

with squamous-cell-carcinoma (SqCC) have a better outcome. We have analyzed our 

experience of resected stage I-II NSCLC pts to determine the impact of ADC vs 

SqCC histology in this setting. 

Methods: From 1996 to 2010, 289 stage I pts and 220 stage II pts were treated by 

surgery. Chemotherapy (CT) was administered in 19 (6.6%) pts with stage I disease 

and 94 (42.7%) pts with stage II disease. Overall survival (OS) and cause-specific 

survival (CSS) curves were estimated by Kaplan-Meier analysis and differences were 

assessed with the log-rank test or the Peto and Peto modification of the 

Gehan-Wilcoxon test. 

Results: Most pts (92.9%) were men. Median age was 68 years and mean follow-up 

was 37.4 months. Median OS for pts with stage I NSCLC was 68 mo (IC 95: 55-123) 

for ADC and 55 mo (IC 95: 47-67) for SqCC (p = 0.0604) with an estimated OS at 5 

years of 54.1% vs 48%. Median CSS were not achieved in the two histology groups, 

with an estimated CSS at 5 years of 78.3% for ADC versus 71.5% for SqCC (p = 0. 

626). For pts in stage II disease, the median OS was 31 mo (IC 95: 21-45) for ADC 

and 24 mo (IC 95: 18-34) for SqCC (p = 0.515) with an estimated OS at 5 years of 

20.5% vs 29.6%. Median CSS were 45 mo (IC 95: 31-NA) for ADC and 93 mo (IC 

95: 39-NA) for SqCC (p = 0.462), with an estimated CSS at 5 years of 44.8% vs 

54.3%. 

Conclusions: A trend for better OS of ADC was observed in stage I compared to 

SqCC but it disappeared for CSS. Thus, no statistically significant differences in OS 

nor CSS were observed in resected stage I-II NSCLC patients between ADC vs SqCC 

histology. 


1190P SPECIFICITIES OF LUNG CANCER IN NEVER-SMOKING 

WOMEN 

J. Mazieres 1 , I. Rouquette 1 , B. Lepage 1 , J. Milia 1 , P. Validire 2 , P. Hofman 3 , 

M. Beau-Faller 4 , L. Brouchet 1 , P. Fouret 5 

1 Thoracic Oncology, CHU Toulouse - Hôpital Larrey, toulouse, FRANCE, 

2 Pathology, Institut Mutualiste Montsouris, Paris, FRANCE, 3 Pathology, CHU 

Nice, Nice, FRANCE, 4 Pathology, CHU Strasbourg, Strasbourg, FRANCE, 

5 Pathologie, APHP-La Salpetrière, PAris, FRANCE 

Introduction: Based on epidemiological, clinical, and preclinical data, lung 

carcinogenesis can be distinctive in women. No clear data is available to help us 

understand the high rate of tobacco-independent lung cancer in women. We 

hypothesize that genetic events or hormonal factors might be partly involved in these 

tobacco-independent lung cancers. 

Method: We thus aimed to compare clinical, pathological and biological 

characteristics of lung cancer in two cohorts of smoking and never smoking women. 

A population of 140 women (63 never-smokers and 77 former or current smokers) 

carrying adenocarcinoma issued from our centre and a national collection has been 

included in this study. 

Results: The non-smoking population was characterized by a higher age (67yrs 

vs 58.7, p < 0.0001) and a higher frequency of a lepidic component (60.3% vs 

37.7 %, p = 0.008) than the smoking patients. We observed a differential genetic 

alteration repartition in women according to their tobacco status: 50.8% of 

never-smokers displayed EGFR mutation vs. 10.4% of smokers (p < 0.001). At 

the opposite KRas mutation was more frequently mutated in smokers (33.8%) 

than in never-smokers (9.5%, p = 0.001). We also observed a higher percentage 

of ERα (p = 0.03 by using the breast cancer score) and ERβ expression (p = 0.02) 

for non-smoking patients compared with smoking ones. We found no significant 

differences for progesterone receptors. Lastly ER expression was correlated with 

EGFR mutation. 

Conclusion: This study suggests that lung cancer occurring in never-smoking 

women is more frequently associated with EGFR mutation and ER expression, 

with a correlation between both markers. These findings underline the possibility 

of therapy in non-smoking-women targeting both hormonal factors and genetic 

abnormalities. 



non-small cell lung cancer, locally 

advanced 

1191PD CLINICAL ACTIVITY OF CRIZOTINIB IN PATIENTS WITH 

ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC) 

HARBORING ROS1 GENE REARRANGEMENT 

S.I. Ou 1 , D.R. Camidge 2 , J. Engelman 3 , J. Clark 4 ,L.Tye 5 , K. Wilner 6 , 

P. Stephenson 6 , M. Varella-Garcia 7 ,A.Iafrate 4 , A.T. Shaw 4 

1 Cancer Centre, Chao Family Centre, Irvine, CA, UNITED STATES OF AMERICA, 

2 School of Medicine, University of Colorado, Denver, UNITED STATES OF 

AMERICA, 3 Cancer Research, Massachusetts General Hospital, Charlestown, 

MA, UNITED STATES OF AMERICA, 4 Cancer Center, Massachusetts General 

Hospital, Boston, UNITED STATES OF AMERICA, 5 Oncology, Pfizer, CA, 

UNITED STATES OF AMERICA, 6 Chapel Hill, Rho, Inc., NC, UNITED STATES OF 

AMERICA, 7 School of Medicine, University of Colorado, CO, UNITED STATES 

OF AMERICA 

Background: Chromosomal rearrangements in the receptor tyrosine kinase (RTK) 

ROS1 define a new molecular subset of NSCLC. ALK inhibitors can inhibit ROS1 

kinase activity in cell lines. We examined the efficacy and safety of crizotinib, a small 

molecule inhibitor of two other RTKs, MET and ALK, in patients with advanced, 

ROS1-rearranged NSCLC. 

Methods: Patients with advanced NSCLC harboring ROS1 rearrangement, as 

determined using a break-apart FISH assay, were recruited into an expansion cohort 

of the original phase 1 study of crizotinib. Patients were treated with crizotinib at the 

standard oral dose of 250 mg BID. The objective response rate (ORR) was 

determined based on RECIST v1.0. The disease control rate (DCR; stable disease 

[SD] + partial response [PR] + complete response [CR]) was evaluated at weeks 

8 and 16. 

Results: At the time of data cut-off on April 19, 2012, 15 patients with ROS1 NSCLC 

had received crizotinib and 14 were evaluable for response. The median age was 54 

years (range 31–72). Fourteen patients were never-smokers and all had 

adenocarcinoma histology. All patients were confirmed negative for ALK 

rearrangement. The median number of prior treatments was 1 (range 0–6). The first 

ROS1 patient received crizotinib on October 19, 2010. To date, the ORR is 57% 

(8/14; 95% CI 28.9–82.3), with 7 PR and 1 CR. There were 4 SD, one of which was 

unconfirmed as PR at the time of data cut-off. The DCR at 8 weeks was 79% (11/14). 

Median duration of treatment was 25.7 weeks (range 0.1 + to 65.3 + ), and 12 patients 

continue on study. The pharmacokinetics, antitumor activity and safety profile of 

crizotinib in this group of patients were similar to those observed in patients with 

ALK-positive NSCLC. 

Conclusions: Crizotinib is associated with clinically significant antitumor activity in 

patients with ROS1 NSCLC. Similar to ALK, ROS1 rearrangement defines another 

unique molecular subset of NSCLC patients for whom crizotinib therapy may be 

highly effective. Importantly, this study represents the first clinical investigation of 

ROS1 as a driver mutation and therapeutic target in cancer. 

Disclosure: S.I. Ou: Advisory role: Pfizer, Genentech. Compensated Honoraria: 

Pfizer, Genentech, Lilly. Myself Research funding: Pfizer. Myself (institution). D.R. 

Camidge: Advisory role: Pfizer. Myself. Honoraria: Pfizer. Myself. L. Tye: 

Employment: Pfizer. Clinician. Myself. Stock Ownership; Pfizer. Myself. K. Wilner: 

Emplyement: Pfizer. Senior Director. Myself. Compensated. Stock ownership: Pfizer. 

Myself. M. Varella-Garcia: Honoraria: Abbott Molecular. Myself. funding for the trial 

provided by NIH - yes. A.T. Shaw: Advisory role: Pfizer, Ariad, Chugai, Novartis, 

Daiichi-sankyo. Myself. Compensated Research funding: Astra Zeneca, Novartis. 

Myself. All other authors have declared no conflicts of interest. 

1192PD LACE-BIO POOLED ANALYSIS OF THE PROGNOSTIC AND 

PREDICTIVE VALUE OF TP53 MUTATIONS IN COMPLETELY 

RESECTED NON SMALL CELL LUNG CANCER (NSCLC) 

P. Hainaut 1 ,X.Ma 2 , B. Lacas 3 , M. Tsao 4 , J. Douillard 5 , V. Rousseau 6 , 

A. Dunant 6 , L. Seymour 7 , M. Filipits 8 , S. Graziano 9 

1 Research, International Prevention Research Institute, Lyon, FRANCE, 2 Jinan 

Central Hospital, Shandong University, Jinan, CHINA, 3 Meta-Analysis Unit, 

Institut Gustave-Roussy, Villejuif, FRANCE, 4 Hematology and Oncology, Princess 

Margaret Hospital, Toronto, CANADA, 5 Medical Oncology, Centre René 

Gauducheau, Saint-Herblain, FRANCE, 6 Biostatistics, Institut Gustave Roussy, 

Villejuif, FRANCE, 7 NCIC Clinical Trials Group, Queen’s University, Kingston, 

CANADA, 8 Medicine, Medical University of Vienna, Vienna, AUSTRIA, 



9 Hematology and Internal Medicine, SUNY Upstate Medical University Hospital, 

Syracuse, UNITED STATES OF AMERICA, on behalf of the LACE-Bio Study 

Group 

Background: Mutations in the Tumour Suppressor Gene TP53 occur in about 50% 

of Stage II-III NSCLC. However, prognostic and predictive value of survival after 

adjuvant therapy not defined. We report here on the pooled analysis of 4 

randomized trials of platinum-based Adjuvant ChemoTherapy (ACT) or observation. 

Methods: Trials included IALT, JBR10, CALGB-9633 and ANITA. Mutations in 

exons 5-8 of TP53 (encompassing hotspots and over 90% of known mutations) were 

detected by PCR/sequencing in DNA extracted from formalin-fixed 

paraffin-embedded NSCLC. Mutations were classified into 3 structure/function 

groups: non-missense; missense outside DNA Binding Notifs (missense non-DBM); 

missense DBM. Main endpoint was overall survival (OS). Hazard ratio (HR) and 

95% confidence interval (CI) were estimated with a Cox model stratified on trial and 

adjusted on gender, age and clinico-pathological variables. 

Results: 1209 NSCLC patients (pts) (5.5 years median follow-up) were analysed. 

Mutations were detected in 434 pts (36%; IALT: 42%; JBR10: 28%; CALGB-9633: 

39%; ANITA: 30%). Mutant TP53 had a borderline significant prognostic effect (HR 

for OS, mutation vs. wild-type (WT): 1.19; CI [1.00-1.41]; p = 0.05). Missense 

non-DBM mutations, likely to alter p53 protein structure, had a marginally worse 

prognostic effect (HR for OS, missense non-DBM vs. WT: 1.38; CI [1.08-1.75]), but 

effects in the 3 function groups were not significantly different (p = 0.23). Among pts 

with WT TP53, OS was better in the ACT group (HR for OS, ACT vs. no ACT: 0.77; 

CI [0.62-0.96]; p = 0.02), whereas ACT had no effect among pts with mutation. 

Conversely, in the ACT group, OS was significantly shorter in pts with TP53 

mutation than in WT pts (HR for OS, Mutant vs. WT TP53: 1.39; CI [1.09-1.77]; p 

= 0.008), whereas TP53 had no prognostic effect in the control group. The ACT effect 

in the mutated and WT groups and the prognostic effect in the ACT and control 

groups were not different (interaction test p = 0.07). 

Conclusion: TP53 mutation status had a borderline prognostic effect and was not 

predictive of adjuvant chemotherapy effect on OS in NSCLC. Supported by French 

Ligue against Cancer (LNCC) and by unrestricted grant from Sanofi Aventis. XM 

was supported by a fellowship from International Agency for Research on Cancer 


1193P ONCOGENIC DRIVER MUTATIONS IN CHINESE NON-SMALL 

CELL LUNG CANCER (NSCLC) 

J. He 1 , H. Yang 2 , Q. Deng 3 ,P.He 2 , J. Jiang 1 , M. Zhao 2 ,X.Gu 4 , L. Zheng 5 , 

H. Pang 1 , J.X. Zhou 6 

1 Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, 

Guangzhou, CHINA, 2 Thoracic Oncology, The First Affiliated Hospital of 

Guangzhou Medical University, Guangzhou, CHINA, 3 The Center for Translational 

Medicine, The First Affiliated Hospital of Guangzhou Medical University, 

Guangzhou, CHINA, 4 Pathology, The First Affiliated Hospital of Guangzhou 

Medical University, Guangzhou, CHINA, 5 The Center for Translational Medicine, 

Xiamen University, Xiamen, CHINA, 6 Pathology, Ningbo University School of 

Medicine, Ningbo, CHINA 

Background: Oncogenic driver mutations are responsible for both the initiation and 

maintenance of cancers including NSCLC. Elucidation of driver mutation occurrence 

in NSCLC and its relationship with clinical outcome are imperative to personalized 

treatment of NSCLC. 

Methods: Tumor tissues from a total of 488 Chinese NSCLC patients at various 

stages were enrolled in this retrospective study. Mutations were assessed using 

amplification-refractory mutation system (ADx-ARMSTM)-PCR and verified using 

direct sequencing. ERCC1 levels were measured using immunohistochemistry 

method. The relationship between tumor gene mutation status and patient’s 

disease-free survival (DFS) was analyzed. 

Results: Of the 488 NSCLC tumors, 28 had EML4-ALK fusions (5.7%). Female 

(10.38%), young age (

stage IIIA NSCLC, EML4-ALK fusion-positive patients had poorer DFS than those 

EML4-ALK fusion-negative patients (P = 0.0057). Moreover, multivariate Cox 

proportional hazard analysis indicated that in stage IIIA NSCLC EML4-ALK fusion 

was the only significant predictor for poor DFS (HR = 4.4, 95% CI 2.0-9.7, P < 0.001). 

We further found that ERCC1 was highly expressed in EML4-ALK fusion-positive 

tumors. 

Conclusion: Oncogenic driver mutations define molecular subsets of Chinese 

NSCLC patients with distinct clinicopathological characteristics. EML4-ALK fusion 

might be a significant prognostic biomarker for locally advanced stage NSCLC. 


1194P TISSUE AND SERUM BIOMARKER RESULTS FROM THE 

PHASE II INNOVATIONS STUDY IN NON-SMALL CELL LUNG 


N. Reinmuth 1 , S.J. Scherer 2 , R. Penzel 3 , P. Schnabel 4 , M. Meister 1 , 

J. Kiemle-Kallee 5 , A. Reuss 6 , J.R. Fischer 7 , M. Wolf 8 , M. Thomas 1 

1 Department of Thoracic Oncology, Thoraxklinik Heidelberg, University of 

Heidelberg, Heidelberg, GERMANY, 2 Pharma Development Department, 

F. Hoffmann-La Roche Ltd/Genentech, San Francisco, CA, UNITED STATES OF 

AMERICA, 3 Institute of Pathology, University of Heidelberg, Heidelberg, 

GERMANY, 4 Department of Pathology, University of Heidelberg, Section for 

Thoracic Pathology, Heidelberg, GERMANY, 5 Pharma AG, Roch Pharma AG, 

Grenzach, GERMANY, 6 Coordinating Center for Clinical Trials, Phillips-University 

Marburg, Marburg, GERMANY, 7 Department of Medical Oncology, Klinik 

Löwenstein, Löwenstein, GERMANY, 8 Division of Haematology and Oncology, 

Klinikum Kassel, Kassel, GERMANY 

Background: The phase II INNOVATIONS study was a randomised trial of 224 

patients (pts) with advanced non-squamous NSCLC who received 1 st -line treatment 

with either erlotinib (E) plus bevacizumab (B) or cisplatin (P) plus gemcitabine (G) 

plus B. PGB was superior to EB for progression-free survival (PFS). Pts with EGFR 

mutation-positive NSCLC were most likely to benefit from EB [1]. This abstract 

reports exploratory analyses from the optional biomarker (BM) sub-study for a 

number of candidate BMs commonly examined in previous NSCLC bevacizumab 

trials. 

Methods: Tissue (t) markers were determined by immunohistochemistry H-score. 

Serum (s) markers were analysed on day 0 and 43 using a novel protein array/ELISA. 

Median baseline values were used to dichotomise pts (low vs high BM) and to 

correlate BMs with PFS/overall survival (OS) (Cox model). Analyses were not 

adjusted for multiple testing. 

Results: BM population represented 88% of the intent-to-treat population; baseline 

characteristics were well balanced. Tissue (n = 198) and serum samples (day 0, n = 

184; day 43, n = 151) were provided for BM analysis. Soluble VEGFA was not 

assessed; only serum samples were available. Serum analyses: PFS was longer for the 

BM population with low baseline IL8 and FLT4 (HR = 0.55, p < 0.05 and HR = 0.50, 

p < 0.05, respectively); the trend was consistent in EB and PGB treatment arms. 

Similar results were seen for day 43 analyses (PFS/OS). Low baseline FLT1 was 

associated with longer PFS in PGB pts (HR = 0.53, p < 0.05). Low ICAM levels were 

associated with better clinical outcomes (PGB arm). Tissue analyses: None of the 

three tumour markers tested showed significant association with PFS/OS (p > 0.05). 

Significant correlations (p < 0.05) were observed between tumour and serum 

markers: tVEGFR1 and tVEGFR2/tVEGF; tVEGFR2 and tVEGF; sFLT1 and sTie2; 

sKDR and sICAM; sFLT4 and sICAM. 

Conclusion: Several serum baseline candidate BMs showed a statistically significant 

correlation with OS/PFS, in particular FLT4/IL8. The choice of treatment partner 

(E/PG) for bevacizumab may influence the value of BMs. Further examination of the 

data from this and other bevacizumab trials may provide greater insight. [1] Thomas 

et al. J Clin Oncol 2011;29:7504 

Disclosure: N. Reinmuth: Advisory Board, Lilly Corporate sponsored research, F. 

Hoffmann-La Roche Ltd. S.J. Scherer: Currently employed by Roche/Genentech. J. 

Kiemle-Kallee: Currently employed by Roche. M. Thomas: Attended advisory boards 

for Roche and Lilly. Received research funding from Roche and Lilly. All other 


1195P DETECTION OF ANAPLASTIC LYMPHOMA KINASE (ALK) 

GENE REARRANGEMENT IN NON-SMALL CELL LUNG 

CANCER (NSCLC): A GLANCE AT “BORDERLINE” CASES 

M. von Laffert 1 , E. Berg 1 , D. Lenze 1 , P. Lohneis 1 , M. Hummel 1 , M. Dietel 2 

1 Institue of Pathology Charité, Charite Berlin Mitte, Berlin, GERMANY, 2 Surgical 

Pathology, Charité, Humboldt-Universität zu Berlin, Berlin, GERMANY 

Background: Lung cancer is the leading cause of cancer related mortality in men 

and women. In ∼5% [range: 0.9-13] of NSCLC a genomic EML4-ALK fusion has 

been described, showing therapeutically sensitivity for ALK-inhibitors. Although 

much has been reported about clinical and histological data of this NSCLC subtype 

(young patients, non-smokers, solid/mucinous adenocarcinomas), the parameters for 


FISH-based (e.g. threshold of positive cells, signal distance) diagnosis vary among the 

different studies. 

Material and methods: We performed retrospective screening (tissue microarray 

based) of 488 NSCLC (336 adenocarcinomas, 152 squamous cell carcinomas) for 

ALK-expression (IHC-intensity: 0-3) using immunohistochemistry (Novocastra) and 

ALK-breaks using FISH (Abbott, ALK break-apart with positivity if split signals or 

single red signals were detectable in ≥15% per 100 cells). The evaluation of the IHC 

and FISH data was performed independent from each other. Since various thresholds 

for ALK-break positivity have been reported in the literature, special attention was 

given to cases with ALK-breaks in the range of 12%-20%. 

Results: 95.7% (467/488) of the cases were ALK-break-negative (


harboring EGFR activating mutations. However, almost all patients eventually acquire 

resistance to EGFR-TKIs within several years. The major mechanisms of acquired 

resistance including 2 nd mutation of T790M and amplification of MET have been 

identified. However, the mechanisms of other resistance remain unclear. In this 

study, we established novel erlotinib-resistant NSCLC cells and examined their 

resistant mechanisms. 

Methods: NSCLC HCC827 cells have an EGFR Exon 19 deletion and gene 

amplification and are highly sensitive to erlotinib. The resistant cells were established 

by continuously exposing HCC827 cells to 0.1, 1 or 10 µM of erlotinib in 96 well 

plates for three months. The resistant mechanisms were determined by direct 

sequence analysis and EGFR FISH analysis. 

Results: The fourteen and three resistant cells were established by 0.1 µM and 1 µM 

of erlotinib exposure, respectively. No resistant cells appeared in the wells of 10 µM 

of erlotinib. The IC50 values of these resistant cells were more than 25-fold higher 

than that of parental cells. No 2 nd mutation of T790M was detected in any of the 

resistant cells and MET gene amplification was detected in only one resistant cells. 

Instead, we found that 13/17 resistant cells were dominated by EGFR not amplified 

cells and one of resistant cells B10 consisted of more than 99.9% of EGFR not 

amplified cells, and that the parental cells consisted of only 2.5% of EGFR not 

amplified cells and 97.5% of EGFR amplified cells. EGFR not amplified clone 4D8 

isolated from parental cells and showed resistance to erlotinib comparable to the 

resistant cells B10. Furthermore, we found that EGFR not amplified cells were 

constantly emerged from EGFR amplified clone isolated from parental cells under 

normal cell culture condition. 

Conclusion: Loss of amplified EGFR gene with mutation causes acquired resistance 

in HCC827 cells when exposed to relatively low concentration of erlotinib while high 

concentration of erlotinib deprives HCC827 cells of the chance of emergence of 

resistant cells. 


1198P A RANDOMIZED PHASE (PH) 2 STUDY WITH EXPLORATORY 

BIOMARKER ANALYSIS OF FICLATUZUMAB (F) A 

HUMANIZED HEPATOCYTE GROWTH FACTOR (HGF) 

INHIBITORY MAB IN COMBINATION WITH GEFITINIB (G) 

VERSUS G IN ASIAN PATIENTS (PTS) WITH LUNG 

ADENOCARCINOMA (LA) 

T.S.K. Mok 1 , K. Park 2 , S.L. Geater 3 , S. Agarwal 4 , M. Han 5 , M. Credi 4 , 

K. McKee 6 , N. Kuriyama 7 , W. Slichenmyer 4 , E.H. Tan 8 

1 Department of Clinical Oncology, Chinese University of Hong Kong Prince of 

Wales Hospital, Shatin, Hong Kong, CHINA, 2 Division of Hematology/Oncology, 

Department of Medicine, Sungkyunkwan University, School of Medicine, Seoul, 

KOREA, 3 Oncology, Prince of Songkla University Faculty of Medicine, Songkla, 

THAILAND, 4 Clinical Research, AVEO Pharmaceuticals, Inc, Cambridge, MA, 

UNITED STATES OF AMERICA, 5 Preclinical Development, AVEO 

Pharmaceuticals, Inc, Cambridge, MA, UNITED STATES OF AMERICA, 6 Clinical 

Operations, AVEO Pharmaceuticals, Inc, Cambridge, MA, UNITED STATES OF 

AMERICA, 7 Biostatistics, AVEO Pharmaceuticals, Inc, Cambridge, MA, UNITED 

STATES OF AMERICA, 8 Medical Oncology, National Cancer Institute, Singapore, 

SINGAPORE 

Background: HGF/cMet pathway activation has been implicated in EGFR TKI 

resistance in LA. F is an HGF IgG1 inhibitory MAb that prevents cMet receptor 

activation by blocking its only known ligand, HGF. This study compared FG with G 

in treatment naïve pts with high incidence of sensitizing EGFR mutation (SM + ), 

and explored other biomarkers. 

Methods: This was a multicenter, open-label, randomized Ph 2 Study in Asian pts 

with LA. Pts received either G (250 mg daily) or F (20 mg/kg IV q 2 wks) plus G 

(250 mg daily). Pts on G were allowed to cross over to FG upon disease 

progression. Primary endpoint was ORR. The secondary endpoints included PFS 

and correlation of biomarkers with clinical activity. Biomarker analysis included 

EGFR mutation status, cMet and HGF expression, EGFR and cMet gene copy 

number. 

Results: 188 pts were randomized, 94 (19M/75F) to FG or G, respectively; mean 

age (FG: 59, G: 60) yrs; ECOG-PS was balanced between arms. Tumor tissue 

samples were analyzed from 144 of 188 subjects. Table 1 shows efficacy by 

biomarker subset and includes results for overall population. Notable difference 

was seen in low cMet group, ORR (41 v 22%) and mPFS (7.3 v 2.8 m), favoring 

FG. The difference can be mostly attributed to the SM + /cMet low subset ORR 

(70 v 44%) and mPFS (11.0 v 5.5 m) favoring FG. The low cMet group may 

identify a subgroup in SM + that had worse outcome by G (mPFS 5.5 v 7.4 m in 

SM + overall) and benefited from FG treatment (11.0 m). There is also a trend in 

OS favoring FG in several biomarker subsets. FG demonstrated a manageable 

toxicity profile. 

Conclusions: FG was well tolerated and showed clinical activity in biomarker subsets. 

However, the study results did not reach statistical significance. FG appears to 

improve treatment outcome in a subset of pts with SM + and low cMet expression. 

These observations warrant further evaluation. 

FG G 

N PFS, m ORR,% N PFS, m ORR,% 

Overall Population 94 5.6 43 94 4.7 40 

Biomarker Subset N PFS, m ORR,% N PFS, m ORR,% 

SM + 33 9.2 58 38 7.4 61 

SM- 24 1.8 25 30 1.9 10 

cMet Low 22 7.3 41 23 2.8 22 

cMet High 34 7.4 44 44 5.5 30 

SM + /cMet Low 10 11.0 70 9 5.5 44 

SM-/cMet Low 9 1.3 0 13 2.3 0 

Disclosure: S. Agarwal: Employed by AVEO Pharmaceuticals, Inc. Involved in the 

design, execution, data analysis, and interpretation, of this trial. M. Han: Employed 

by AVEO Pharmaceuticals, Inc. Involved in the design, execution, data analysis, and 

interpretation, of this trial. K. McKee: Employed by AVEO Pharmaceuticals, Inc. 

Involved in the design, execution, data analysis, and interpretation, of this trial. M. 

Credi: Employed by AVEO Pharmaceuticals, Inc. Involved in the design, execution, 

data analysis, and interpretation, of this trial. N. Kuriyama: Employed by AVEO 

Pharmaceuticals, Inc. Involved in the design, execution, data analysis, and 

interpretation, of this trial. W. Slichenmyer: Employed by AVEO Pharmaceuticals, 

Inc. Involved in the design, execution, data analysis, and interpretation, of this trial. 


1199P A RANDOMISED PHASE II STUDY OF CETUXIMAB (C) IN 

COMBINATION WITH TWO CISPLATIN-BASED CONCURRENT 

CHEMORADIOTHERAPY REGIMENS IN PATIENTS (PTS) WITH 

STAGE III NON-SMALL CELL LUNG CANCER (NSCLC). FINAL 

RESULTS OF THE GFPC 08-03 TRIAL 

L. Greillier 1 , I. Martel-Lafay 2 , D. Arpin 3 , N. Pourel 4 , S. Chabaud 5 , R. Lamy 6 , 

A. Madroszyk 7 , P. Fournel 8 

1 Multidisciplinary Oncology & Therapeutic Innovations, Aix-Marseille Univ, 

Assistance Publique-Hôpitaux de Marseille, Marseille, FRANCE, 2 Radiotherapy, 

Centre Leon Berard, Lyon, FRANCE, 3 Pulmonology, Centre Hospitalier de 

Macon, Macon, FRANCE, 4 Radiotherapy, Institut Sainte Catherine, Avignon, 

FRANCE, 5 UBET, Centre Leon Berard, Lyon, FRANCE, 6 Pulmonology, Centre 

Hospitalier de Bretagne Sud, Lorient, FRANCE, 7 Medical Oncology, Institut Paoli 

Calmettes, Marseille, FRANCE, 8 Département d’Oncologie Médicale, Institut de 

Cancérologie Lucien Neuwirth, Saint-Priest en Jarez, FRANCE 

Background: This non-comparative randomised trial (EUDRACT 2008-005013-21) 

aimed to assess the feasibility of combining cetuximab (C) with cisplatin (P) + vinorelbine 

(V) + radiotherapy (R) or with P + etoposide (E) + R in selected stage IIIA/B NSCLC PTS. 

Methods: Eligibility criteria included age

1200P CONCOMITANT CHEMORADIATION GIVES SIGNIFICANT 

SURVIVAL AND HRQOL BENEFITS IN PATIENTS WITH 

LOCALLY ADVANCED STAGE III NON SMALL CELL LUNG 

CANCER (NSCLC) NOT ELIGIBLE FOR RADICAL 

TREATMENT: A RANDOMIZED TRIAL BY THE NORWEGIAN 

LUNG CANCER STUDY GROUP 

H.H. Strøm 1 , S. Sundstrøm 2 , N. Helbekkmo 3 , R. Bremnes 3 , U. Aasebø 4 

1 Medical Department, Helgelands Hospital, Sandnessjøen, NORWAY, 

2 Oncology, St.Olavs Hospital, Trondheim, NORWAY, 3 Oncology, University 

Hospital of Northern Norway, Tromsø, NORWAY, 4 Medical, University Hospital of 

Northern Norway, Tromsø, NORWAY 

Background: In patients with locally advanced, inoperable NSCLC and negative 

prognostic factors, treatment will be of palliative intent. Platinum-based 

chemotherapy and thoracic radiation are both well documented, but the role of 

chemoradiation has not been established. Objective: Will concomitant radio- and 

chemotherapy (chemoradiation), when compared to chemotherapy alone, be superior 

with respect to survival and health-related quality of life (HRQOL) in patients with 

incurable NSCLC stage III (negative prognostic factors)? 

Methods: Stage III NSCLC patients, not eligible for curative radiotherapy due to 

tumor size ≥ 8 cm or performance status 2 or weight loss ≥ 10 % during the last 6 

months, were randomized to receive either chemoradiation or chemotherapy alone. 

Chemotherapy consisted of 4 cycles of carboplatin iv day 1 and vinorelbine po day 1 

and 8, with 3-week intervals. Patients in the chemoradiation arm also received 

radiotherapy with fractionation 42 Gy/2.8 Gy, starting at the 2nd chemo course. The 

primary endpoint was overall survival. Secondary endpoints were HRQOL and 

toxicity. 

Results: 191 patients from 25 Norwegian hospitals were randomized from Nov 2006 

until Nov 2011, when enrollment was terminated due to slow accrual. Median age 

was 67 years and 20% had PS 2. In the chemotherapy versus the concomitant arm, 

the median overall survival was 9.7 and 13.3 months, respectively (p < 0.01).1-year 

survival 31.9 % and 51.1%, respectively (p < 0.01). Following a minor decline in 

global QOL during treatment, patients in the chemoradiation arm improved over the 

subsequent months, while those in the chemotherapy only arm reported gradual 

deterioration. In the chemoradiation arm, there were more hospital admissions 

related to side effects (p < 0.01) as 31.5 % of these patients reported esophagitis grade 

3, but none grade 4. 

Conclusions: Of the 2 investigated treatment regimens; chemoradiation was superior 

to chemotherapy alone with respect to both survival and global HRQOL, at the 

expense of more hospital admissions due to toxicity. 


1201P 18F-FDG-PET RESPONSE DURING THE SECOND WEEK OF 

CONCURRENT OR SEQUENTIAL CHEMO-RADIOTHERAPY 

SIGNIFICANTLY CORRELATES WITH 2-YEAR SURVIVAL IN 

NSCLC PATIENTS 

W. van Elmpt 1 , M. Öllers 1 , A.C. Dingemans 2 , P. Lambin 1 , D. De Ruysscher 1 

1 Department of Radiation Oncology (Maastro), GROW, Maastricht University 

Medical Centre, Maastricht, NETHERLANDS, 2 Pulmonology, Maastricht 

University Medical Center (MUMC), Maastricht, NETHERLANDS 

Purpose/Objective: Assessment early during the course of treatment could identify 

prognostic groups, allowing treatment individualisation at a time when therapy 

changes are possible and before major toxicity occurred. We hypothesised that 

FDG-PET/CT imaging during the second week of chemo-radiotherapy would 

correlate with 2-year overall survival (OS). 

Methods: We performed FDG-PET/CT imaging at two time points: One 4D PET/ 

CT was performed prior to the start of radiotherapy, and a second 4D PET/CT 

during the second week of radiotherapy, sequential or concurrently with 

cisplatin-vinorelbine. In total 34 consecutive patients with NSCLC were successfully 

imaged. Images were analysed both for CT-based characteristics (volume of the 

primary tumour and, if present, involved lymph nodes), PET characteristics included 

the average, maximum and peak SUV (SUVmean, SUVmax, SUVpeak, resp.). The 

difference in these parameters between both time points were correlated to the 2-year 

overall survival. 

Results: The change in FDG-uptake (SUVmean) of the primary tumour was 

significantly different (p = 0.007) between the group surviving more than 2 years 

(-20.2 ± 20.5%) compared to the group not surviving two years ( + 2.1 ± 21.9%). 

Using the EORTC criteria for partial response (decrease in signal of 15%), a 

sensitivity of 63% and a specificity of 93% in this population was found that 

separated the survival curves (p = 0.001). CT-based early response parameters were 

not associated with prediction of survival. 

Conclusions: Decrease in FDG-uptake already in the second week of (chemo-) 

radiotherapy is correlated with overall survival in NSCLC. This opens avenues for 

individualized and optimized treatment based on early treatment response analysis. 

A prospective trial including 120 patients has just been terminated. 


1202P OUTCOMES OF AGGRESSIVE CONCURRENT 

CHEMOTHERAPY IN SEPTUAGENARIANS WITH STAGE IIIB 

NON-SMALL CELL LUNG CARCINOMA 

E. Topkan 1 , C. Parlak 1 , S. Topuk 1 , O. Ozyilkan 2 




Background: Aim of the study was to retrospectively assess the feasibility of radical 

chemoradiotherapy in terms of tolerability and survival outcomes in medically fit 71 

to 79 years old stage IIIB NSCLC patients. 

Materials and methods: From the hospital records, 78 medically fit, septuagenerians 

with stage IIIB lung carcinoma were evaluated. Patients should have performance of 

ECOG 0-1, body mass index of ≥20kg/m 2 , and weight loss of


Results: Out of the 230 patients, 227 were eligible for analysis. With a median FU of 

23 months the median PFS was 15 months (95% CI 12-21 months), and a 2 years 

overall survival of 55% (95% CI 48%-64%). At the time of analysis 134 PFS events 

had occurred. The primary factors associated with PFS were tumor volume and SCC, 

with the pairwise interactions between SCC and both gender and histology also being 

potentially important. A full Cox regression model including the interactions and a 

reduced model only including only SCC and tumor volume were constructed. In 

both models a difference in PFS at 24 months of roughly 40% was observed between 

the high-and low risk groups. 

Conclusion: A model prognostic for PFS using SCC and tumor volume, was 

developed that identified stage II-III patients at high risk for progressive disease after 

CCRT. Validation of this model is ongoing. 


1204P PHASE III STUDY COMPARING SECOND- AND 

THIRD-GENERATION REGIMENS WITH CONCURRENT 

THORACIC RADIOTHERAPY IN UNRESECTABLE STAGE III 

NON-SMALL CELL LUNG CANCER: AN ADDITIONAL 

ANALYSIS BY THE HISTOLOGICAL TYPE IN THE 

WJTOG0105 STUDY 

M. Satouchi 1 , Y. Chiba 2 , N. Yamamoto 3 , Y. Nishimura 4 , K. Tsujino 5 , Y. Fujisaka 6 , 

S. Kudoh 7 , T. Hida 8 , S. Atagi 9 , K. Nakagawa 6 

1 Thoracic Oncology, Hyogo Cancer Center, Hyogo, JAPAN, 2 Clinical Reserch 

Center, Kinki University, Osakasayama, JAPAN, 3 Thoracic Oncology, Shizuoka 

Cancer Center, Shizuoka, JAPAN, 4 Radiation Oncology, Kinki University Faculty 

of Medicine, Osakasayama, JAPAN, 5 Radiation Oncology, Hyogo Cancer center, 

Akashi, JAPAN, 6 Medical Oncology, Kinki University Fuculty of Medicine, Osaka, 

JAPAN, 7 Respiratory Medicine, Osaka City University, Osaka, JAPAN, 8 Thoracic 

Oncology, Aichi Cancer Center, Nagoya, JAPAN, 9 Thoracic Oncology, 

Kinki-chuo Chest Medical Center, Osaka, JAPAN 

Background: The WJTOG0105 study was conducted to compare third-generation 

regimen (irinotecan/carboplatin [IC], paclitaxel/carboplatin [PC]) and 

second-generation regimen (mitomycin/vindesine/cisplatin [MVP]) with concurrent 

thoracic radiotherapy (TRT) in patients with unresectable stage III non-small-cell 

lung cancer (J Clin Oncol. 2010; 28: 3739-45). We conducted an additional analysis 

by the histological type (Squamous [Sq] vs. Non-squamous [Non-sq]) to closely 

examine differences of efficacy between more frequent radiosensitizing doses and 

systemic doses of chemotherapy. 

Materials and methods: Patients received the following treatments: MVP, mitomycin 

(8 mg/m2 on day 1, 29), vindesine (3 mg/m2 on day 1, 8, 29, 36), and cisplatin (80 

mg/m2 on day 1, 29) with concurrent TRT (60 Gy), followed by 2 courses of MVP; 

IC, weekly irinotecan (20 mg/m2)/carboplatin (AUC 2) for 6 weeks with concurrent 

TRT (60 Gy), followed by 2 courses of irinotecan (50 mg/m2)/carboplatin (AUC 5); 

PC, weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks with concurrent 

TRT (60 Gy), followed by 2 courses of paclitaxel (200 mg/m2)/carboplatin (AUC 5). 

Overall survival (OS), progression free survival (PFS), and patterns of initial failure 

were compared by the histological type. 

Results: The median OS and PFS were 20.3, 9.0 months in Sq and 20.5, 8.1 months 

in Non-sq. The Hazard ratio (HR) for OS and PFS in Non-sq were 0.996 (P = 0.973) 

and 1.199 (P = 0.079). Although there was no statistically significant difference 

between Sq and Non-sq, the out-field recurrence rate in Non-sq (51.1%) was higher 

than Sq (26.1%) and the PFS in Sq tended to be longer than Non-sq. The efficacy of 

PC was compared with MVP in each histological type. For Sq, the median OS and 

PFS were 22.0, 10.4 months in PC and 19.7, 9.3 months in MVP. The HR for OS 

and PFS in PC were 0.957 (P = 0.822) and 0.871 (P = 0.459). For Non-sq, the median 

OS and PFS were 21.3, 8.1 months in PC and 21.8, 7.6 months in MVP. The HR for 

OS and PFS in PC were 1.083 (P = 0.662) and 0.996 (P = 0.984). Therefore no 

statistically significant difference was found between PC and MVP in each 

histological type. Furthermore, the patterns of initial failure were similar between PC 

and MVP. 

Conclusion: Weekly PC with concurrent TRT showed similar efficacy to MVP with 

concurrent TRT, with no relation to the histological type. 


Table: 1205P 

1205P PHASE II STUDY OF TWO ERIBULIN REGIMENS IN 

COMBINATION WITH ERLOTINIB IN PATIENTS (PTS) WITH 

PREVIOUSLY TREATED ADVANCED NON-SMALL CELL LUNG 


S.L. Geater 1 , N. Ianotti 2 , S. Thongprasert 3 , A. Spira 4 , D. Smith 4 , V. Lee 5 , 

W-T. Lim 6 , P. Gopalakrishna 7 , C. Reynolds 8 , T.S.K. Mok 9 

1 Medical Oncology, Songklanagarind Hospital, Hatyai Songkhla, THAILAND, 

2 Medical Oncology, Hematology Oncology Associates, Port Saint Lucie, FL, 

UNITED STATES OF AMERICA, 3 Department of Medicine, Maharaj Nakorn 

Chiang Mai Hospital, Faculty of Medicine, Chiangmai, THAILAND, 4 Medical 

Oncology, US Oncology Research, Houston, TX, UNITED STATES OF 

AMERICA, 5 Medical Oncology, Queen Mary Hospital, Hong Kong, Hong Kong, 

CHINA, 6 Medical Oncology, National Cancer Centre, Singapore, SINGAPORE, 

7 Medical Oncology, Eisai Ltd, Hatfield, UNITED KINGDOM, 8 Oncology, Ocala 

Oncology Center and US Oncology Research, Houston, TX, UNITED STATES 

OF AMERICA, 9 Clinical Oncology, Chinese University of Hong Kong, Hong Kong, 

CHINA 

Background: Eribulin, a microtubule dynamics inhibitor, is approved for pts with 

locally advanced/metastatic breast cancer that progressed after ≥2 chemotherapeutic 

regimens for advanced disease. Prior therapy should have included an anthracycline 

and taxane unless not suitable. This randomized, multicenter study compared 

efficacy and tolerability of two eribulin regimens administered sequentially with 

erlotinib in pts with advanced NSCLC to establish an optimal dosing schedule. 

Methods: Pts (ECOG ≤2; ≥1 prior anti-cancer therapy for advanced NSCLC 

including ≥1 platinum-based therapy) received 2.0 mg/m 2 eribulin mesilate (2-5 min 

IV) on Day (D) 1 and 150 mg oral erlotinib on D2-16 (21D cycle), or 1.4 mg/m 2 

eribulin mesilate on D1 and D8 and 150 mg erlotinib on D15-28 (28D cycle). 

Primary endpoint was objective response rate (ORR); secondary endpoints were 

progression-free survival (PFS), overall survival (OS), disease control rate (DCR), 

safety, pharmacokinetics and biomarker (BM) assessment. 

Results: 123 pts were treated (63 pts 21D cycle, 60 pts 28D cycle). Median age was 

63 years (range 35-87), 53.7% male, 75.6% smokers, 65.9% stage IV disease and 

91.1% ≥2 prior therapy for advanced NSCLC. ORR was 12.7% (21D) and 16.7% 

(28D); other efficacy parameters were also greater with the 28D cycle. Concomitant 

administration of erlotinib did not affect eribulin exposure and was well tolerated 

with no unexpected toxicities. BM analysis supported overall results. 

Conclusions: Both regimens were associated with moderate activity in this heavily 

pre-treated population. The 28D regimen appears to have greater activity and less 

toxicity than the 21D. 

Disclosure: S. Thongprasert: The author declares the following conflicts of interest: 

consultant/advisory role (Novartis/Pfizer/Eli Lilly), honoraria (AstraZeneca/Roche), 

and research funding (Novartis/Pfizer/Roche). D. Smith: The author declares the 

following conflicts of interest: research funding (Eisai). P. Gopalakrishna: The author 

declares the following conflicts of interest: employee (Eisai Ltd. C. Reynolds: The 

author declares the following conflicts of interest: honoraria/speakers bureau (Eisai). 

T.S.K. Mok: Consultant/advisory role (AstraZeneca /Pfizer/Eli Lilly/Roche/Merck 

Serono/Eisai/BMS/BeiGene/AVEO/Taiho/BI), honoraria (AstraZeneca/Roche Pfizer/ 

Eli Lilly/ Merck Serono/Eisai/BMS/BeiGene/AVEO /Taiho/BI), research funding 

(AstraZeneca). All other authors have declared no conflicts of interest. 

1206P PEMETREXED (PEM) COMBINATION THERAPY WITH 

CARBOPLATIN (CB) FOLLOWED BY PEM MAINTENANCE IN 

JAPANESE PATIENTS (PTS) WITH NONSQUAMOUS 

NON-SMALL CELL LUNG CANCER (NSCLC): SUBGROUP 

ANALYSIS OF ELDERLY PTS 

N. Nogami 1 , R. Sekiguchi 2 , S. Enatsu 2 , K. Nakagawa 3 , T. Tamura 4 

1 Dept of Thoracic Oncology, NHO Shikoku Cancer Center, Matsuyama, JAPAN, 

2 Development Center of Excellence, Eli Lilly Japan K.K., Kobe, JAPAN, 3 Medical 

Oncology, Kinki University School of Medicine, Osaka, JAPAN, 4 Division of 

Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, 

Tokyo, JAPAN 

Objectives: This subgroup analysis evaluated the efficacy and safety of Pem 

combination therapy with Cb followed by Pem maintenance in Japanese elderly 

NSCLC pts. 

21D 28D 

Median no. cycles (range) Pts completing ≥6 cycles, % 3 (1-31) 36.5 4 (1-23) 36.7 

ORR a Partial response (PR) b Stable disease (SD) b DCR 

(Complete response + PR + SD) a 

12.7 (5.6, 23.5) 8 (12.7) 22 (34.9) 47.6 (34.9, 60.6) 16.7(8.3, 28.5 ) 10 (16.7) 28 (46.7) 63.3 (49.9, 75.4) 

PFS c OS c 

3.5 (1.9, 4.7) 7.6 (6.3,12.1) 3.8 (3.3, 5.5) 8.5 (6.2,13.1) 

Adverse events of interest (grade ≥3), % Diarrhea Neutropenia 

Peripheral neuropathy Rash 

6.3 44.4 3.2 6.3 1.7 38.3 0 1.6 

a % (95% CI) b n (%) c median, months (95% CI). 


Patients and methods: The study was a multicenter, prospective post-marketing 

study which assessed the safety and efficacy of Cb AUC 6 and Pem 500 mg/m 2 on 

Day 1 of each 21-day cycle for 4 cycles as induction therapy followed by Pem 

maintenance therapy. For this subgroup analysis 109 advanced nonsquamous 

NSCLC pts with good PS (ECOG 0-1) were grouped by age (elderly: ≥70 years, 

younger: 60years (22% vs 9%, p > 0.05). 

Histology also significantly effected the development of brain metastasis (43.2% in 

adenocarcinoma, 16.4% in epidermoid carcinoma, p = 0.004). On multivariate 

analysis, only age was found to be significant prognostic factor (p = 0.01) 

Conclusion: Age and histology significantly effects development of brain metastasis 

in locally advanced NSCLC. Younger age was the only significant variable for brain 

metastasis. 


1208 ANAPLASTIC LYMPHOMA KINASE (ALK) GENE 

REARRANGEMENT IN NON-SMALL CELL LUNG CANCER 

(NSCLC): RESULTS OF THE FIRST INTERN ROUND ROBIN 

PANEL TESTING (8 INSTITUTES FROM GERMANY AND 

SWITZERLAND) 

M. von Laffert 1 , P. Schirmacher 2 , H. Kreipe 3 , R. Büttner 4 , I. Petersen 5 , 

W. Jochum 6 , M. Dietel 7 , M. Hummel 1 

1 Institute of Pathology Charité, Charite Berlin Mitte, Berlin, GERMANY, 

2 Pathology, University of Heidelberg, Heidelberg, GERMANY, 3 Pathology, MHH 

(University of Hannover), Hannover, GERMANY, 4 Pathology, University of 

Cologne, Köln, GERMANY, 5 Pathology, University of Jena, Jena, GERMANY, 

6 Pathology, Kantonspital St Gallen, St.Gallen, SWITZERLAND, 7 Surgical 

Pathology, Charité, Humboldt-Universität zu Berlin, Berlin, GERMANY 

Background: The reliable identification of NSCLC patients with breaks in the gene 

of the anaplastic lymphoma kinase (ALK) is crucial for the induction of therapy with 


inhibitors (e.g. Crizotinib) against the ALK activity. The implementation of round 

robin tests is essential to certificate institutes of pathology which are capable to 

perform ALK-testing with high reliability. 

Material and methods: Tissue microarrays consisting of 10 NSCLC cases (all 

adenocarcinomas; 3 cores for each case) were independently tested for 

ALK-expression by immunohistochemistry (IHC) and genomic ALK-breaks by FISH 

in 8 institutes of pathology (listed authors on behalf of the group: Universities of 

Berlin, Heidelberg, Hannover, Köln, München, Jena, St. Gallen and Wiesbaden). 5 

cases were ALK-break positive (one case with a low percentage of ALK-break positive 

cells; 20%) whereas the remaining 5 cases were clearly ALK-break negative as 

determined by blinded testing independently performed in Berlin and Heidelberg. 

RT-PCR was carried out to confirm the presence of an EML4-ALK fusion in the 

ALK-break positive cases. 

Results: All 8 participants identified the 5 ALK-break negative cases correctly (IHC 

and FISH) and 4 of the FISH-positive cases were detected by all but one of the 

participants (FISH). The remaining ALK-break positive case with a low number of 

affected tumour cells was scored negative by 3 of the 8 participants. IHC for the 

detection of ALK-expression revealed heterogeneous results in the ALK-break 

positive cases whereas ALK-break negative cases were consistently scored negative by 

all participants. 

Conclusion: Our round robin test for ALK-testing demonstrates that 

unequivocal ALK-break negative NSCLC cases were consistently scored negative 

by all participants by means of FISH and IHC. In contrast ALK-IHC 

(ALK-expression) with currently available antibodies clearly failed to detect all 

ALK-translocation positive lung cancers. Thus, application and validation of 

more reliable ALK-antibodies is required before IHC screening can be 

recommended. ALK-break positivity appears to be reliably detectable (FISH) in 

cases with a high percentage of affected tumour cells. Cases with low numbers 

of ALK-break positive tumour cells (between 15% and 20%) remain a 

diagnostic challenge. 


1209 DETECTING EGFR MUTATION AND ITS LIGANDS 

EXPRESSION IN ADVANCED NON-SMALL CELL LUNG 


S. Wang 1 , X. Han 2 ,J.Li 1 ,X.Hu 1 , X. Wang 1 , L. Gui 1 , L. Zhao 1 , Y. Sun 1 ,Y.Shi 1 

1 Medical Oncology, Cancer Hospital-China Academy of Medical Sciences Chao 

Yang District CAMS and PUMC, Beijing, CHINA, 2 Clinical Laboratory, Cancer 

Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union 

Medical College, Beijing, CHINA 

Background: Epidermal growth factor receptor (EGFR) mutations testing for 

advanced non–small cell lung cancer (NSCLC) patients were found to be predictive 

of response to EGFR tyrosine kinase inhibitor (TKI). The aim of our study was to 

explore whether expression levels of ligands of EGFR measured in plasma were 

predictive of response to EGFR-TKIs. 

Methods: 134 cases of formalin-fixed and paraffin-embedded tumor tissues and 

paired plasma from advanced NSCLC patients treated by EGFR-TKIs were collected, 

EGFR mutations were assessed by Scorpions and ARMS using real time PCR. 

Amphiregulin, transforming growth factor-alpha (TGFa) and TGFb were assessed 

using enzyme-linked immune-sorbent assay (Elisa). We evaluated the relationship 

between the EGFR mutation status, concentrations of ligands and response to 

EGFR-TKIs therapy. 

Results: 68 (50.7%) of 134 advanced NSCLC patients were detected EGFR somatic 

mutations. The effect of EGFR-TKIs treatment on progression-free survival (PFS) 

and overall survival (OS) showed a significant difference by EGFR mutation 

(p 0.05, respectively). EGFR mutation rate was found to be higher in women than 

in men (p < 0.05), and there was no difference between mutation rates with other 

clinical characteristics. Also, there was no difference between expression levels of 

ligands with clinical characteristics. 

Conclusions: EGFR somatic mutations appear to occur frequently in China, 

Scorpions and ARMS technology is a sensitive method to detect EGFR mutation and 

is suitable for screening patients who would like to accept EGFR-TKIs therapy. 

Ligands of EGFR measured in plasma could not be predictive of response to 

EGFR-TKIs therapy. 




1210 LONG-TERM EFFICACY AND SAFETY OF L-BLP25 VACCINE 

IN A MULTI-CENTRE OPEN-LABEL STUDY OF PATIENTS 

WITH UNRESECTABLE STAGE III NSCLC 

C. Butts 1 , R.N. Murray 2 , C.J. Smith 3 , P.M. Ellis 4 , K. Jasas 5 , A. Maksymiuk 6 , 

G. Goss 7 , M. Falk 8 , A.H. Loos 9 , D. Soulières 10 

1 Department of Oncology, Cross Cancer Institute, Edmonton, AB, CANADA, 

2 Department of Medical Oncology, Vancouver Cancer Centre, Vancouver, BC, 

CANADA, 3 Department of Oncology, Tom Baker Cancer Centre, Calgary, 

CANADA, 4 Department of Oncology, Juravinski Cancer Centre, Hamilton, ON, 

CANADA, 5 Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, 

AUSTRALIA, 6 Department of Oncology, CancerCare Manitoba, Winnipeg, MB, 

CANADA, 7 Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, 

CANADA, 8 Global Clinical Development Unit, Merck KGaA, Darmstadt, 

GERMANY, 9 Global Biostatistics / Oncology, Merck KGaA, Darmstadt, 

GERMANY, 10 Departement of Medicine, CHUM Hôpital Notre-Dame, Montreal, 

QC, CANADA 

Introduction: L-BLP25 (Stimuvax®) is an antigen-specific cancer immunotherapeutic 

agent targeting the mucin 1 tumour-associated antigen. Phase IIb data suggest 

prolonged overall survival with L-BLP25 when administered after completion of 

chemoradiotherapy for locally advanced non-small-cell lung cancer (NSCLC; 

non-significant). This study was initiated in April 2005 to obtain safety data when 

modifications of the adjuvant component of the immunotherapeutic were performed. 

Here we report an updated analysis of long-term data based on the cut-off date 18 

May 2011. 

Methods: The primary objective of this open-label phase II study was to evaluate the 

safety of the new formulation of L-BLP25 in patients with unresectable stage IIIA/B 

NSCLC, with a secondary objective of assessment of survival time. Following 

completion of initial chemoradiotherapy, patients with stage III NSCLC received 

treatment with L-BLP25 starting with weekly injections over 8 weeks, followed by 

injections given every 6 weeks from week 13 onwards until disease progression. A 

single low dose of intravenous cyclophosphamide 300 mg/m 2 (maximum 600 mg) 

was given 3 days before first vaccination. 

Results: Twenty-two patients were enrolled. After a median follow-up of 70.3 

months (median treatment duration 9.9 months [range, 1–73]), median survival time 

was 51.9 months (95%CI, 17.5, not estimable [NE]) and median progression-free 

survival was 31.4 months (95%CI, 5.7, NE). Five-year survival was 50% (95%CI, 29– 

71%); previously reported 1- and 2-year survival rates, 82% (95%CI, 66–98%) and 

64% (95%CI, 44–84%), respectively. Four patients survived more than 72 months. 

Safety findings were consistent with previous reports; adverse events (AEs) consisted 

mainly of fatigue (59%), injection-site reactions (55%) and mild-to-moderate 

influenza-like illness. Two serious treatment-emergent AEs were assessed as being 

treatment-related: cholecystitis and pneumonia. 

Conclusions: Long-term follow-up of this small patient population provides 

encouraging survival data for L-BLP25 maintenance therapy in stage III NSCLC. 

Long-term safety data were consistent with previous reports and did not reveal any 

new safety issues. 

Disclosure: C. Butts: Charles Butts has provided consultancy and served on Speakers’ 

Bureaux for Merck Serono. A. Maksymiuk: Andrew Maksymiuk has some stock 

shares in Merck Canada (

months (95% CI:13-25). The PFS and OS at 1/2 years were 59%/38% and 85%/46% 

respectively. A total of 43 cycles of D-C induction chemotherapy were given; main 

toxicities (NCI-CTC 3.0) per p Grade (g) 1-2/3-4 (%) were as follows: neutropenia 

2.3/13.9; anemia 13.9/0; nausea/vomiting 23.2/2.3; diarrhea 25.5/2.3; febrile 

neutropenia, 2 p. Main toxicities per p in CChRT (D-C doses: 147, 3.4 per p; mean 

doses RT: 63,4 Gys) were g1-2/3 (%): neutropenia 25.5/6.9; anemia 43.9/0; nausea/ 

vomiting 18.6/0; fatigue 37.2/4.6; esophagitis 46.5/2.3 and pneumonitis 39.5/0; there 

were three episodes of hospitalization: febrile neutropenia, 2 p and g3 esophagitis, 

1p. 

Conclusions: CChRT with bi-weekly Docetaxel and Cisplatin and thoracic 

radiotherapy is a feasible treatment option for inoperable locally advanced stage III 

NSCLC, showing good clinical efficacy and tolerability with promising survival. 


1213 ACUTE TOXICITY OF FULL-DOSE CISPLATIN-ETOPOSIDE 

CONCURRENTLY WITH HIGH-DOSE HYPOFRACTIONATED 

CHEST RADIOTHERAPY FOR STAGE III NON-SMALL CELL 

LUNG CANCER: SUBSET ANALYSIS OF NON-RANDOMISED 

PATIENTS IN THE PET-BOOST PHASE II TRIAL 

(NCT01024829) 

D. De Ruysscher 1 , W. van Elmpt 1 , R. Wanders 1 , A. van Baardwijk 1 ,A. 

C. Dingemans 3 , B. Reymen 1 , G. Bootsma 4 , P. Lambin 2 , J. Sonke 5 , 

J. Belderbos 5 

1 Maastro Clinic, Maastricht University Medical Center (MUMC), Maastricht, 

NETHERLANDS, 2 Department of Radiation Oncology (maastro), Grow, 

Maastricht University Medical Centre, Maastricht, NETHERLANDS, 

3 Pulmonology, Maastricht University Medical Center (MUMC), Maastricht, 

NETHERLANDS, 4 Pulmonology, Atrium Medical Center Heerlen, Heerlen, 

NETHERLANDS, 5 Radiation Oncology, Netherlands Cancer Institute, 


Background: Full-dose concurrent platinum-based doublet chemotherapy and 2 Gy/ 

day radiotherapy is the first choice treatment for most patients with stage III NSCLC. 

No prospective data are available on the acute toxicity of full-dose chemotherapy and 

high-dose hypofractionated accelerated radiotherapy. Here we report on a subset of 

patients included in the PET-boost trial that could not be randomised because dose 

escalation to the primary tumour over 72 Gy/ 24 fractions was not possible because 

of OAR constraints. 

Methods: Patients received cisplatin 80 mg/m2 on day 1 and etoposide 100 mg/m2 

on days 1-3 every 21 days for a total of three cycles. At day 1 of the second 

chemotherapy cycle, radiotherapy to the primary tumour and the involved lymph 

nodes was delivered (66 Gy /24 QD fractions of 2.75 Gy). Toxicity was evaluated 

weekly and scored according to CTCAE3.0. We considered the treatment safe when 

at maximum 5/12 developed G3 acute toxicity, reversible in at least 4/5 within 8 

weeks post-therapy. 

Results: 12 patients, 10 males, 2 females, mean age 66.9 years with stage III NSCLC 

were included. Mean PTV dose: 64.9 Gy. Mean fractions: 23.6. Mean OTT: 32.6 days. 

Mean MLD: 19.2 Gy, mean mean oesophageal dose 30.7 Gy, mean max oesophageal 

dose 60.4 Gy. Median follow-up: 9.9 months (range 3.3-15.1). G2 dyspnea: 1 (8.3 %). 

Maximal oesophagitis: G1: 2 (16.7 %), G2: 6 (50.0 %), G3: 4 (33.3 %), all recovering 

to G0 within 6 weeks post-treatment. 

Conclusions: Full-dose cisplatin-etoposide was safely combined with high-dose 

hypofractionated accelerated radiotherapy. 


1214 A PHASE II CLINICAL TRIAL OF TUMOR TREATING FIELD 

(TTF) THERAPY CONCOMITANT TO PEMETREXED FOR 

ADVANCED NON-SMALL CELL (NSCLC) LUNG CANCER 

M. Pless 1 , D. Betticher 2 , C. Droege 3 , M. Salzberg 4 , R. von Moos 5 

1 Tumorcenter, Kantonsspital Winterthur, Winterthur, SWITZERLAND, 2 Medical 

Oncology, Fribourg Cantonal Hospital, Fribourg, SWITZERLAND, 3 Medical 

Oncology, Spital Maennedorf, Maennedorf, SWITZERLAND, 4 Medical Affairs, 

Medpace Inc., Cincinatti, UNITED STATES OF AMERICA, 5 Medizinische 

Onkologie und H, Cantonal Hospital Graub, Chur, SWITZERLAND 

Background: TTF therapy is a novel, non-invasive treatment modality for solid 

tumors recently approved by FDA for recurrent GBM. It uses intermediate frequency 

alternating electric fields to inhibit tumor growth, by mitotic spindle and plasma 

membrane integrity disruption during cytokinesis. Pemetrexed is a folate 

antimetabolite used as a first/second line and as a maintenance therapy for 

non-squamous NSCLC patients. Preclinical studies in NSCLC models demonstrated 

that TTF therapy and pemetrexed had additive efficacy, with no increase in toxicity. 

The current trial tested TTF therapy concomitant to pemetrexed in NSCLC patients. 

Methods: A single arm, multi-center, prospective trial was performed in 42 stage 

IIIB (with pleural effusion) and IV NSCLC patients, following progression after at 

least one prior chemotherapy. Patients received continuous 150 KHz TTF therapy 


(12 h/day) using the NovoTTF-100L system (NovoCure, Israel), concomitant to 

pemetrexed (Alimta, Eli Lilly) q3w, until progression. Pemetrexed was in use for 

squamous histology when the study opened. 

Results: The trial included 35 patients with non-squamous histology and 7 patients 

with squamous histology. TTF Therapy was well tolerated by all patients enrolled in the 

trial, with high compliance (11 h/day). No TTF-related adverse events were reported 

apart from dermatitis caused by the application of transducer arrays. Median 

progression free survival was 22.7 and 10.3 weeks for non-squamous and squamous 

histology, respectively. Seven patients who initially had in-field-only disease (including 

squamous histology) had distant metastases before progressing in-field. Median overall 

survival was 12.4 and 13.8 months for nonsquamous and squamous histology, 

respectively. One- and two- year-survival was 53% and 27%, respectively. 

Conclusions: TTF therapy concomitant to pemetrexed was well tolerated and safe 

for patients with advanced NSCLC, of all histologies. Efficacy indices are 

promising, in view of the poor outcome previously reported for similar 

populations. This first clinical trial involving TTF as a treatment for NSCLC 

patients suggests that it should be further studied in larger clinical trials for 

squamous and nonsquamous NSCLC 

Disclosure: M. Salzberg: Medpace Inc. is a contracted Contract Research Organization 

(CRO) for Novocure Ltd. All other authors have declared no conflicts of interest. 

1215 PHASE I TRIAL OF COMBINATION CHEMOTHERAPY OF 

PEMETREXED PLUS CISPLATIN AND CONCURRENT 

THORACIC RADIOTHERAPY IN PATIENTS WITH LOCALLY 

ADVANCED NON-SQUAMOUS NON-SMALL-CELL LUNG 

CANCER: POST-HOC ANALYSIS FOR SURVIVAL AND 

RECURRENT SITES 

S. Niho 1 , H. Nokihara 2 , K. Nihei 3 , T. Akimoto 3 , M. Sumi 4 , Y. Ito 4 , I. Sekine 2 , 

K. Kubota 1 ,Y.Ohe 1 , T. Tamura 2 

1 Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, 

JAPAN, 2 Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, 

JAPAN, 3 Division of Radiation Oncology, National Cancer Center Hospital East, 

Kashiwa, JAPAN, 4 Division of Radiation Oncology, National Cancer Center 


Background: Combination chemotherapy of pemetrexed (PEM) plus cisplatin 

(CDDP) is established as a standard treatment for advanced non-squamous 

(Non-Sq) non-small-cell lung cancer (NSCLC). PEM has radiosensitizing potential 

when evaluated in vitro in combination with platinum-containing compounds and 

radiation. Our previous phase I trial demonstrated that combination chemotherapy 

of PEM plus CDDP with concurrent thoracic radiotherapy (TRT) at a total dose of 

66Gy was well tolerated in patients with locally advanced Non-Sq NSCLC, and the 

response rate was 83% (The European Multidisciplinary Cancer Congress 2011, 

#9060). We conducted a post-hoc analysis of progression-free survival (PFS) and 

recurrent sites in those patients who were enrolled in the phase I trial. 

Methods: Patients received PEM 500mg/m2 plus CDDP 75mg/m2 on day 1 of a 21-day 

interval for 3 cycles and concurrent TRT of 60Gy (n = 6) or 66Gy (n = 12) followed by 

consolidation PEM 500mg/m2 of a 21-day interval for 3 cycles. We reviewed the medial 

records to collect data on progression, recurrent sites, late toxicity and survival. 

Results: Between November 2008 and December 2010, 20 patients were enrolled in 

this study, and 18 patients received the protocol treatment. No late radiation 

morbidity was observed. 12 patients had progressed, and recurrence included distant 

metastases (n = 7), local (n = 7) (in the radiation field (n = 6), out of the radiation 

field (n = 2), and both (n = 1)), and local plus distant sites (n = 2). Median PFS was 

10.5 months (95% confidence interval: 8.7-12.3), and 2-year PFS rate was 32%. 

Median follow-up time for censored cases was 21.8 months (range: 17.2-35.6 

months). Overall survival data will be presented. 

Conclusions: Median PFS in our study was comparable with that in historical 

controls of chemoradiotherapy. 


1216 CT BASED QUANTIFICATION OF RADIATION INDUCED LUNG 

DAMAGE (RILD) AND THE INTERACTION WITH 

CHEMOTHERAPY AND CETUXIMAB 

H. Sharifi 1 , W. van Elmpt 1 , R. Vandendries 1 , A.C. Dingemans 2 , M. Das 3 , 

G. Nalbantov 1 , M. Oellers 1 , P. Lambin 1 , J. Belderbos 4 , D. De Ruysscher 1 

1 Department of Radiation Oncology (Maastro Clinic), GROW - School for 

Oncology and Developmental Biology, Maastricht University Medical Centre, 

Maastricht, NETHERLANDS, 2 Pulmonology, Maastricht University Medical Center 

(MUMC), Maastricht, NETHERLANDS, 3 Radiology, Maastricht University Medical 

Center (MUMC),GROW - School for Oncology and Developmental Biology, 

Maastricht University Medical Centre, Maastricht, NETHERLANDS, 4 Radiation 

Oncology, Netherlands Cancer Institute, Amsterdam, NETHERLANDS 

Purpose: Radiation-induced lung damage (RILD) is one of the most important 

dose-limiting toxicities in the treatment of lung cancer patients. Prediction models 



are still unsatisfactory, partly because dyspnea as an endpoint is influenced by 

many other parameters than RILD and is difficult to quantify. Interactions 

between drugs and radiotherapy (RT) are thus difficult to assess. We therefore 

evaluated RILD more objectively, quantitatively and on a continuous scale 

measuring the changes of lung density per voxel before and after chemo-RT and 

with or without cetuximab. 

Methods: CT scans from 55 stage III NSCLC patients were evaluated. Deformable 

registration was used to register the 3 month follow-up scans to the baseline 

scans. Changes in CT density in the lungs were correlated to the RT dose 

delivered in every part (i.e. voxel) of the lungs. Four different treatments were 

included: sequential chemo-RT (N = 9), concurrent chemo-RT (N = 17), concurrent 

chemo–RT with cetuximab (N = 19) from phase I trial (NCT00522886) and 

patients from the randomized phase II PET-boost trial (NCT01024829) receiving a 

higher radiation dose per fraction than the other groups (2.75 Gy) (N = 10). 

Patients with an increase of over 0.5 Hounsfield Units (HU) per Gy dose in each 

voxel of the lungs were considered as ‘responders’, i.e. showing susceptibility for 

RILD. 

Results: Patients received a mean dose of 64.14 Gy(range 55-86 Gy) to the tumor, 

with a standard deviation of 11.3. The number of responders in patients treated in 

cetuximab was 16/19 (85%), in the concurrent chemo-RT group 11/16 (69 %), 7/10 

(70 %) in the PET-boost patients and 4/9 (56 %) in the sequential chemo-RT group. 

The average increase in density was 2.6 HU per Gy for responders and 0.01 HU per 

Gy for non-responders. 

Conclusion: CT density changes allow quantitative non-invasive assessment of RILD, 

giving complementary information to clinical endpoints. Large individual variability 

in the susceptibility for RILD could be shown by CT as well as treatment modality 

related differences. 


1217 MODIFIED FRACTIONATION RADIOTHERAPY VERSUS 

CONVENTIONAL RADIOTHERAPY FOR UNRESECTED 

NON-SMALL CELL LUNG CANCER PATIENTS: A 

COST-EFFECTIVENESS ANALYSIS 

D. De Ruysscher 1 , B.L.T. Ramaekers 2 , M.A. Joore 3 , B. Lueza 4 , J. Bonastre 4 , 

A. Mauguen 4 , J. Pignon 4 , C. Le Pechoux 5 , J.P. Grutters 2 , on behalf of The 

Mar-LC Collaborative Group 4 

1 Department of Radiation Oncology (Maastro Clinic), GROW - School for 

Oncology and Developmental Biology, Maastricht University Medical Centre, 

Maastricht, NETHERLANDS, 2 Department of Health Services Research (HSR), 

Caphri - School for Public Health and Primary Care, Maastricht University, 

Maastricht, NETHERLANDS, 3 Clinical Epidemiology and Medical Technology 

Assessment (KEMTA), Maastricht University, Maastricht, NETHERLANDS, 

4 Biostatistics and Epidemiology, Institut de Cancérologie Gustave-Roussy, 

Villejuif, FRANCE, 5 Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE 

Background: Modified fractionation radiotherapy (RT), delivering multiple fractions 

per day or shortening the overall treatment time, improves overall survival for 

non-small cell lung cancer (NSCLC) patients over conventional fractionation RT 

(CRT). However, its cost-effectiveness is unknown. Objective: To examine and 

compare the cost-effectiveness of different modified RT schemes and CRT in the 

curative treatment of unresected NSCLC patients. 

Methods: A probabilistic Markov model was developed based on individual patient 

data from the Meta-Analysis of Radiotherapy in Lung Cancer (MAR-LC) with 10 

randomized trials (N = 2000). Costs (Dutch healthcare perspective), quality-adjusted 

life years (QALYs) and net monetary benefits (NMB) were compared between 2 

accelerated RT schemes (very accelerated (VART) and moderately accelerated 

(MART)), 2 hyperfractionated RT schemes (using an identical total treatment dose 

as CRT (HRT I ) and higher total treatment dose as CRT (HRT H )) and CRT. The 

NMB was calculated by multiplying the number of QALYs by the ceiling ratio (what 

society is willing to pay per QALY) of €80,000 per QALY and subtracting the total 

costs. The treatment strategy with the highest NMB can be considered as the most 

cost-effective treatment. 

Results: All modified fractionations were more effective and costly than CRT (1.179 

QALYs, €24,341). VART and MART were most effective (1.360 and 1.383 QALYs) 

and costed €25,735 and €26,194 respectively. HRT I and HRT H yielded less QALYs 

than the accelerated schemes (1.327 and 1.202 QALYs), and costed €26,187 and 

€29,688 respectively. MART had the highest NMB (€84,427; 95%CI 

€41,708-€139,698) and was thus the most cost-effective treatment followed by VART 

(€83,071; CI €69,785-€97,619). CRT had the second lowest NMB (€69,997; CI 

€59,684-€80,786). Uncertainty was considerable: MART had the highest probability 

of being cost-effective (43%), followed by VART (31%), HRT I (24%), HRT H (2%) 

and finally CRT (0%). 

Conclusion: Implementing accelerated RT is almost certainly more efficient than 

current practice (CRT) and should be recommended as standard RT for the curative 

treatment of unresected NSCLC patients. 

Disclosure: J. Pignon: Unrestricted grants from Roche for a meta-analysis of 

bevacizumab in advanced NSCLC. All other authors have declared no conflicts of 

interest. 

1218 PROSPECTIVE, SINGLE-ARM, POST-MARKETING CLINICAL 

STUDY OF PEMETREXED (PEM) AND CARBOPLATIN 

COMBINATION FOLLOWED BY MAINTENANCE PEM IN 

CHEMO-NAïVE JAPANESE PATIENTS WITH NON-SQUAMOUS 

NON-SMALL CELL LUNG CANCER (NSCLC): 24 MONTH 

FOLLOW-UP OS RESULTS 

K. Hotta 1 , K. Kiura 1 , K. Kubota 2 , H. Yoshizawa 3 , S. Enatsu 4 , R. Sekiguchi 4 , 

K. Nakagawa 5 , T. Tamura 2 

1 Department of Respiratory Medicine, Okayama University Hospital, Okayama, 

JAPAN, 2 Division of Internal Medicine and Thoracic Oncology, National Cancer 

Center Hospital, Tokyo, JAPAN, 3 Bioscience Medical Research Center, Niigata 

University Medical and Dental Hospital, Niigata-City, JAPAN, 4 Development 

Center of Excellence, Eli Lilly Japan K.K., Kobe, JAPAN, 5 Medical Oncology, 

Kinki University School of Medicine, Osaka, JAPAN 

Background: Platinum doublet chemotherapy is standard first-line treatment for 

advanced NSCLC, however, further studies are required to establish the effectiveness 

of maintenance therapy. The aim of this study was to evaluate the efficacy and safety 

of Pem/Carboplatin (Cb) followed by Pem in Japanese patients (pts) with advanced 

non-squamous NSCLC. This study is sponsored by Eli Lilly Japan K.K. 

(ClinicalTrials.gov: NCT01020786). 

Patients and methods: Pts were chemo-naïve with unresectable stage IIIB, IV or 

postoperative recurrent non-squamous NSCLC, and a PS (ECOG) of 0-1. Pts 

received Cb AUC 6 and Pem 500 mg/m 2 on Day 1 of each 21-day cycle for 4 cycles 

as induction therapy. Pts who achieved non-PD at the end of the 4-cycle induction 

therapy could continue Pem as maintenance therapy until PD. The primary endpoint 

was PFS, and it was assumed that the threshold and the expected values for the 

median PFS were 5 and 7 months, respectively. 

Results: A total of 111 pts were enrolled. Of the 109 treated pts, 75 pts (69%) 

completed induction therapy and 60 pts (55%) entered maintenance therapy; 15 pts 

(14%) discontinued in the 4th cycle due to PD (8 pts), AE (4 pts), and investigator 

or subject decision (3 pts). Pts (n = 109): median age 63 years, stage IV/others (66%/ 

34%), PS 0/1 (34%/66%), EGFR-mutant/wild-type/unknown (22%/58%/20%). 

Among the 109 pts, 38 pts (35%) achieved PR, 41 pts (38%) SD, and 21 pts (19%) 

PD. Median PFS and MST from enrollment was 5.6 months (95% CI: 4.3, 7.2) and 

20.2 months (95% CI: 16.7, incalculable), respectively. The MST for EGFR (-) pts 

was 19.4 months; MST could not be calculated for EGER ( + ) pts (17 pts [71%] 

censored). The most common Gr 3/4 toxicities in the induction and maintenance 

phases were neutropenia (57%), thrombocytopenia (41%), anemia (31%), whereas Gr 

3 febrile neutropenia occurred in 1 pt without any regimen-related deaths. 

Conclusions: PFS as the primary endpoint was not better than expected, but other 

endpoints seemed favorable. Hematologic toxicities were frequently observed. 

Updated data including MST will be presented at the congress. 

Disclosure: S. Enatsu: An employee of Eli Lilly Japan K.K. R. Sekiguchi: An 

employee of Eli Lilly Japan K.K. All other authors have declared no conflicts of 

interest. 

1219 COST-UTILITY ANALYSIS OF MAINTENANCE THERAPY WITH 

EITHER GEMCITABINE OR ERLOTINIB VERSUS 

OBSERVATION WITH PREDEFINED SECOND-LINE 

TREATMENT AFTER CISPLATIN-GEMCITABINE INDUCTION 

CHEMOTHERAPY IN ADVANCED NSCLC: IFCT-GFPC 

0502-ECO PHASE III STUDY 

I. Borget 1 , M. Perol 2 , D. Perol 3 , A. Lavole 4 , L. Greillier 5 , R. Gervais 6 , G. Zalcman 7 , 

S. Chabaud 8 , A. Vergnenegre 9 , C. Chouaid 10 

1 Biostatistics and Epidemiology, institut Gustave Roussy, Villejuif, FRANCE, 

2 Medical Oncology, Centre L, Lyon Cedex, FRANCE, 3 Biostatistics Unit, Centre 

L, Lyon Cedex, FRANCE, 4 Pneumology, Hopital Tenon, Paris, FRANCE, 

5 Multidisciplinary Oncology & Therapeutic Innovations, Aix-Marseille Univ, 

Assistance Publique-Hôpitaux de Marseille, Marseille, FRANCE, 6 Pneumology, 

Centre François Baclesse, Caen, FRANCE, 7 Service de Pneumologie, C.H.U. de 

Caen, Caen Cedex, FRANCE, 8 UBET, Centre Leon Berard, Lyon, FRANCE, 

9 Service de Pneumologie, Hopital du CluzeauCHU Dupuytren, Limoges Cedex, 

FRANCE, 10 Pulmonology, Hopital Saint-Antoine, Paris, FRANCE 

Rationale: The IFCT–GFPC 0502 phase III reported prolongation of progression-free 

survival with maintenance with either gemcitabine or erlotinib versus observation 

after cisplatin-gemcitabine chemotherapy in advanced NSCLC. Their incremental 

cost-effectiveness ratio (ICER) was assessed in global population and in pre specified 

sub-groups. 

Methods: A cost-utility analysis was performed to evaluate ICER of maintenance 

therapy with either gemcitabine or erlotinib, compared to observation. Direct 

medical costs (drugs costs, hospitalization, examinations, second-line treatments and 

palliative costs) were prospectively collected per patient alongside the trial, until 

death, from the third party payer perspective. Utility were extracted from literature. 

Sensitivity analyses were performed. 

Results: ICER for maintenance therapy with gemcitabine and erlotinib were 

respectively 76 625 and 184 733 €/quality-adjusted life years (QALY). Gemcitabine 


maintenance therapy had favourable ICER in patients with PS = 0 (52 213 €/QALY), 

in responders to induction chemotherapy (64 296 €/QALY) and in patients with 

adenocarcinoma (62 292 €/QALY); erlotinib had favourable ICER if PS = 0 (94 908 

€/QALY), in patients with adenocarcinoma (97 160 €/QALY) and objective response 

to induction (101,186 €/QALY), but it is not cost-effective in patients with PS = 1, 

other histology or if stable disease. 

Conclusion: Gemcitabine and erlotinib maintenance therapy have acceptable ICER 

but with wide variation, function of histology, PS and response to the first line 


Disclosure: I. Borget: Honoraria from Roche for set up a class in health economy 

(no relation with the present study). M. Perol: consultant or advisory board with 

Roche, Lilly (myself) Honoraria from Lilly, Roche, Pfizer, Boehringer Ingelheim 

(myself) Research funding from Lilly, Roche (myself). D. Perol: Honoraria : Roche 

(myself). G. Zalcman: Honoraria from Lilly, Roche Research funding from Lilly, 

Roche. A. Vergnenegre: honoraria and research funding from Roche. C. Chouaid: 

Honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffman la 

Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis and Amgen Research funding 

from AstraZeneca, Lilly, Novartis and Amgen. All other authors have declared no 


1220 DOUBLET VERSUS SINGLE CYTOTOXIC AGENT AS 

FIRST-LINE TREATMENT FOR ELDERLY PATIENTS WITH 

ADVANCED NON-SMALL-CELL LUNG CANCER: A 

SYSTEMATIC REVIEW AND META-ANALYSIS 

W. Qi 1 , Y. Yao 2 , Z. Shen 2 ,A.He 2 ,F.Lin 2 

1 Oncology, The Sixth People Hospital, Shanghai Jiao Tong University, Shanghai, 

CHINA, 2 Dept. of Oncology, The Sixth People’s Hospital Shanghai Jiaotong 

University, Shanghai, CHINA 

The standard treatment for elderly patients with advanced non-small cell lung cancer 

(NSCLC) is still debated. As a result, we performed a meta-analysis of all 

randomized controlled trials comparing the efficacy of doublet versus single 

third-generation cytotoxic agent in the elderly patients with advanced NSCLC. 

Finally, eight eligible trials involved 2108 patients were identified. The intention to 

treatment (ITT) analysis demonstrated that doublet therapy significantly improved 

OS (HR0.85 95%CI 0.72-1.00, p = 0.048), PFS (HR 0.72, 95%CI 0.55-0.93, p = 0.012), 

1-year SR (RR 1.18, 95%CI 1.02-1.36, p = 0.027) and ORR (RR1.65,95%CI 1.36-1.99, 

p = 0.000), compared with single cytotoxic agent. Sub-group analysis also favored 

platinum-based doublet therapy in terms of OS, PFS/TTP, 1-year SR and ORR. 

Though gemcitabine-based doublet significantly increased ORR compared with 

single agent (RR1.51, 95%CI 1.21-1.87, p = 0.000), it did not translate into increase in 

survival benefits in terms of OS, PFS and 1-year SR. More incidences of grade 3 or 4 

hematologic toxicities were observed in doublet therapy group. With respect to grade 

3 or 4 non-hematologic toxicities, equivalent frequencies were found between groups 

excluding more incidence of neutrotoxicity in doublet therapy group. Our data 

indicated that doublet therapy was superior to single third-generation cytotoxic agent 

for elder patients with advanced NSCLC. The optimal drug dosage and treatment 

schedule of platinum-based doublet should be investigated in future prospective 

clinical trials. Gemcitabine-based doublet could be considered for elderly patients 

who were not suitable for platinum-based chemotherapy. 


1221 WEEKLY PACLITAXEL VERSUS THE STANDARD 3-WEEKLY 

SCHEDULE IN PATIENTS WITH NON-SMALL CELL LUNG 

CANCER 

I. Abdel Halim 1 , M. El-Ashry 2 , W. El-Sadda 1 , S. Temraz 1 

1 Clinical Oncology & Nuclear Medicine, Mansoura University Hospital School of 

Medicine, Mansoura, EGYPT, 2 Clinical Oncology, Mansoura University 

HospitalSchool of Medicine, Mansoura, EGYPT 

Background: Paclitaxel is one of the active drugs in non-small cell lung cancer 

(NSCLC). Weekly paclitaxel seems less toxic and more effective compared to 

paclitaxel every three weeks (possibly because of the proapoptotic and angiogenic 

activity) the dose intensity is quiet higher with tolerable toxicities. The purpose of 

the study is to compare the efficacy of weekly paclitaxel to the every three weeks 

schedule in terms of response, toxicity profile, PFS and OS. Patients 

Methods: Between Sep 2007 & Sep 2009, eighty patients were enrolled in the study, 

40 in each group. Eligibility criteria were chemo-naiive patients, stage III & IV 

histologically proven NSCLC, WHO PS 0-1, adequate bone marrow, kidney & liver 

functions. Patients were randomized for 6-8 cycles of either weekly paclitaxel 80 mg/ 

m 2 D1,8,15 (1 hour IV infusion) and paraplatin AUC = 5 D1 (30 min IV infusion ) 

every 4 weeks (Group A) or paclitaxel 175 mg/m 2 and paraplatin AUC = 5 every 3 

weeks (Group B). Prophylactic growth factor support was allowed if indicated in 

Group B. Response was assessed every 2 cycles, patients who showed objective 

response (CR, PR, or SD) had continued to 8 cycles. 

Results: All patients were evaluable for response, toxicity, and survival. The median 

age was 56 years (range 42-64) in both groups. Median WHO PS 1. Male to female 


ratio was 4:1. Stage III 60% & 62.5%, stage IV 40% & 37.5% in groups A & B 

respectively. The overall response rates ware 60% (CR 10%, PR 50%) & 40% (CR 5%, 

PR 35%) in groups A & B respectively. No grade IV toxicities were observed in either 

group. In group A & B; grade II anemia occurred in 15 & 25% of patients, grade III 

neutropenia was noted in 10 & 30% of patients, and grade II neuropathy occurred in 

10 & 50% of patients in group A & B respectively. Median time to progression and 

median survival were 10 & 7 months and 14 & 11 months respectively. 

Conclusion: Weekly paclitaxel is more effective than the every 3 weeks 

administration in the treatment of advanced NSCLC with higher RR, TTP, OS and 

better toxicity profile. 


1222 ERLOTINIB IN SECOND AND THIRD LINE THERAPY IN 

ADVANCED NSCLC (STAGE IIIB AND IV), RELATION WITH 

CHEMOTHERAPY AND SCHEDULE OF ADMINISTRATION 

(A RETROSPECTIVE STUDY) 

A. Grigorescu, I. Turtoi, S.E. Boeru 

Medical Oncology, Institute of Oncology Bucharest, Bucharest, ROMANIA 

Background: Is now very well known that Erlotinib (E) has an impact in progression 

free survival and in some study in overall survival in second or third line therapy for 

advanced non small -cell lung cancer (NSCLC). Aims of the study: This study try to 

provide data which sustain the use of E in second and third line and the fact that 

mono-chemotherapy could be active and after treatment with E for some patients 

(Pt) with advanced NSCLC. In addition we try to find data supporting the use of E 

for senior adults. 

Materials and method: The data from 90 case report forms of Ps with Stage IIIB 

and IV NSCLC treated with E in Institute of Oncology Bucharest between March 

2010 and March 2012 were analyzed regarding clinical benefit, survival and relation 

with monochemotherapy in second or third line. In particular we purposed to 

point out the benefit of senior adults treated with E and the possible benefit of 

chemotherapy with a single agent after failure of treatment with E. Main symptoms 

were evaluated by Edmonton scale. Statistical analysis was perform by Caplan Meyer 

curve and X2 test. 

Results: 86 Pt were valuable, 17 with stage IIIB and 69 stage IV. The overall survival 

for the Pt included in this study was 17 month. The survival in second line therapy 

with E was 7 month (CI: 3.6 – 10.3) and the survival after third line chemotherapy 

was 3 month (CI:2.1-3.8). On the whole the clinical benefit was 90% of Pt. The 

response rate for chemotherapy in third line after E was 8% but symptomatic benefit 

was in 15% of Pt. As a function of waiting time to receive E in second line it was a 

higher response rate in Ps who received E without waiting time, toxicity of E was 

represented by rash grade I 80%, diarrhea 10%, dizziness 3%, ocular dysfunctions 

2%. Grade III of toxicity was observed only in 3% of patients. Toxicity for senior 

adults treated by E. was similar with younger Pt. 

Conclusions: Despite the limits of a retrospective study we can conclude that E is 

useful in second and third line treatment for advanced lung cancer, chemotherapy 

could have benefit in third line after E, and senior adults have about the some 

response and benefit from E. Toxicity was reduced for all Pt treated with E. 


1223 HYPERBARIC OXYGENATION AND EP (CISPLATIN AND 

ETOPOSIDE) CHEMOTHERAPY IN TREATMENT OF PATIENTS 

WITH ADVANCED NON SMALL CELLS LUNG CANCER 

(NSCLC) 

M.V. Kopp 1 , I.A. Koroleva 1 , S.V. Kozlov 2 , L.V. Shaplygin 3 , M.E. Popova 1 , 

J.G. Kutyreva 1 

1 Chemotherapy, Samara Regional Clinical Oncology Dispensary, Samara, 

RUSSIAN FEDERATION, 2 Oncological, Samara State Medical University, 

Samara, RUSSIAN FEDERATION, 3 Samara Oncology Center, Samara, RUSSIAN 

FEDERATION 

Background: By the time of diagnosis more than 75% of all lung cancer patients 

have locally advanced or metastatic process. According to WHO, at different stages 

of treatment to 80% of lung cancer patients need chemotherapy. Malignant neoplasm 

lead to the development of tissue oxygen deficiency or directly related to acute or 

chronic hypoxia. Hypoxia of normal tissue is one of the reasons of chronic anemia 

in patients with advanced NSCLC. We conducted an analysis of toxicity of 

chemotherapy in patients with advanced NSCLC by means of chemotherapy 

concurrently with hyperbaric oxygenation. 

Materials and methods: Between October 2010 and March 2012 63 patients with 

advanced NSCLC were treated with EP chemotherapy regimen (Cisplatin 75mg/m2 

on day 1 + Etoposide 120mg/m2 in 1, 3, 5 days). Cycles repeated every 21 days. We 

used two hyperbaric pressure chamber: BLKS 303MK and BLKS-307 Khrunichev. 

Hyperbaric oxygenation procedures are held under pressure 1.3 atm for 40 minutes, 

1 time a day every day for 5 consecutive days. All the patients were divided into 2 

groups. 28 patients received chemotherapy only. 35 patients received chemotherapy 



simultaneously with hyperbaric oxygen therapy. Patients were not given any 

prophylaxis of neutropenia. Toxicity was evaluated with Common Toxicity Criteria, 

Version 3.0. 

Results: Grade 2 anemia was reported in 29% patients treated with chemotherapy 

and hyperbaric oxygenation and in 43% patients treated with chemotherapy only. 

The beneficial effect of hyperbaric oxygenation was also demonstrated by a quick 

recovery of hemoglobin level than in control. We evaluated the dose intensity of 

chemotherapy. Dose reductions and increased periods between cycles of 

chemotherapy are associated with poor outcomes of chemotherapy. Dose intensity in 

patients received chemotherapy with hyperbaric oxygenation was 91%, but in the 

group of chemotherapy only dose intensity was 79%. We did not observed any 

specific side effects of hyperbaric oxygenation. 

Conclusions: The results show that hyperbaric oxygenation procedures with 

the chemotherapy n reduced grade of anemia in patients with advanced 

NSCLC. 



abstracts 

non-small cell lung cancer, metastatic 

1225O A RANDOMIZED PHASE 2 STUDY OF ERLOTINIB PLUS 

PEMETREXED VS ERLOTINIB OR PEMETREXED ALONE AS 

SECOND-LINE TREATMENT FOR NEVER-SMOKER 

PATIENTS WITH NON-SQUAMOUS ADVANCED NON-SMALL 


D.H. Lee 1 , J.S. Lee 1 , S.W. Kim 1 , J. Rodrigues Pereira 2 , B. Han 3 , X.Q. Song 4 , 

J. Wang 5 , H-K. Kim 6 , T. P. Sahoo 7 , R. Digumarti 8 , X. Wang 9 , S. Altug 10 , 

M. Orlando 11 

1 Asan Medical Center, Seoul, KOREA, 2 Grupo de Assistencia Médica, Sao 

Paulo, BRAZIL, 3 Shanghai Chest Hospital, Shanghai, CHINA, 4 Affiliated Cancer 

Hospital of Guangxi Medical University, Nan Ning, CHINA, 5 Beijing Tumor 

Hospital, Beijing, CHINA, 6 St. Vincent Hospital, Suwon, KOREA, 7 Chirayu 

Medical College and Hospital, Bhopal, INDIA, 8 Nizam’s Institute of Medical 

Sciences, Hyderabad, INDIA, 9 Eli Lilly and Company, Shanghai, CHINA, 10 Eli Lilly 

and Company, Istanbul, TURKEY, 11 Eli Lilly and Company, Buenos Aires, 

ARGENTINA 

Background: Erlotinib (E) and Pemetrexed (P) are approved second-line treatments 

in patients (pts) with relapsed NSCLC and may be effective in combination. This 

randomized phase 2 study compared the efficacy and safety of E + P vs either agent 

alone, as second-line treatment in never-smoker pts with advanced non-squamous 

NSCLC. 

Methods: From Nov 2007 to Jul 2010, never-smoker NSCLC, ECOG Performance 

Status (PS) ≤2 pts who had failed 1 prior chemotherapy regimen were enrolled 

and randomized to either: E 150 mg daily, P 500 mg/m 2 day 1, or P 500 mg/m 2 

day 1 plus E 150 mg daily on days 2 to 14 of a 21-day cycle, continued until 

discontinuation criteria were met. The primary endpoint of progression-free 

survival (PFS) was analyzed using a sequential approach. A multivariate Cox 

model was used to perform a global comparison across the 3 arms with pairwise 

comparisons between treatments using contrasts within the model. If the global 

null hypothesis was rejected at a 2-sided 0.2 significance level (SL), then 2 

pairwise comparisons of E + P vs E or P were conducted. Statistical significance 

was claimed if both pairwise and global null hypotheses were rejected at a 

2-sided 0.05 SL. 

Results: A total of 240 non-squamous pts (Male, 34.6%; East Asian, 55.4%; ECOG 

PS 0-1, 92.9%) were included. A statistically significant difference in PFS was found 

across the 3 arms (global p = 0.003), with E + P significantly better than both single 

agents (HR (95% CI) for E + P vs E was 0.57 (0.40, 0.81), p = 0.002; for E + P vs P 

was 0.58 (0.39, 0.85), p = 0.005). Median PFS (95% CI) was 7.4 months (4.4, 12.9) in 

E + P, 3.8 (2.7, 6.3) in E and 4.4 (3.0, 6.0) in P. Safety analyses showed a higher 

number of pts with ≥1 TEAE with CTCAE grade 3/4 toxicity in E + P (n = 45; 

60.0%) than in P (n = 10; 28.9%) or E (n = 22; 12.0%), the majority being 

neutropenia, anemia, rash and diarrhea. 

Conclusions: Erlotinib + Pemetrexed significantly improved PFS compared to either 

agent alone in this clinically selected population. E + P had more toxicity, but was 

clinically manageable. Further analysis of the EGFR mutational status will help to 

understand and predict which pts will benefit most from this approach. 

Disclosure: X. Wang: I am employee of Eli Lilly and Company. S. Altug: I am 

employee of, and hold stock/stock options in, Eli Lilly and Company. M. Orlando: “I 



am employed by and hold stock in Eli Lilly & Company”. All other authors have 


1226O BIOMARKER ANALYSES AND OVERALL SURVIVAL (OS) 

FROM THE RANDOMIZED, PLACEBO-CONTROLLED, PHASE 

3, FASTACT-2 STUDY OF INTERCALATED ERLOTINIB WITH 

FIRST-LINE CHEMOTHERAPY IN ADVANCED 

NON-SMALL-CELL LUNG CANCER (NSCLC) 

T.S.K. Mok 1 , J.S. Lee 2 , L. Zhang 3 ,C.Yu 4 , S. Thongprasert 5 , G.E.I. Ladrera 6 , 

V. Srimuninnimit 7 , M.I. Truman 8 , B. Klughammer 9 ,Y.Wu 10 

1 Department of Clinical Oncology, Chinese University of Hong Kong, Prince of 

Wales Hospital, Hong Kong, HONG KONG, 2 Research Institute and Hospital, 

National Cancer Center, Goyang, KOREA, DEMOCRATIC PEOPLE’S REPUBLIC 

OF, 3 Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, 

CHINA, 4 Department of Internal Medicine, National Taiwan University Hospital, 

Taipei, TAIWAN, 5 Faculty of Medicine, Chiang Mai University, Chiang Mai, 

THAILAND, 6 Department of Pulmonary Medicine, Lung Center of the Philippines, 

Quezon City, PHILIPPINES, 7 Department of Medicine, Siriraj Hospital, Mahidol 

University, Bangkok, THAILAND, 8 Department of Biometrics, F. Hoffmann-La 

Roche Ltd., Sydney, AUSTRALIA, 9 Pharmaceutical Division, F. Hoffmann-La 

Roche Ltd., Basel, SWITZERLAND, 10 Guangdong Lung Cancer Institute, 

Guangdong General Hospital & Guangdong Academy of Medical Sciences, 


Background: FASTACT-2 is a randomized, placebo-controlled, phase 3 study in 

first-line advanced NSCLC, which met its primary endpoint of significantly 

prolonged PFS with intercalated erlotinib and chemotherapy: median 7.6 vs 6.0 

months; HR = 0.57; p < 0.0001 (Mok et al. ASCO 2012). We report OS results and 

correlations of biomarkers with PFS for this study. 

Methods: Patients (pts) with untreated stage IIIB/IV NSCLC and ECOG PS 0/1 

received up to 6 cycles of gemcitabine (1,250 mg/m 2 on d1 & 8) plus platinum 

(carboplatin AUC = 5 or cisplatin 75 mg/m 2 on d1) q4w, with either intercalated 

erlotinib (150 mg/day on d15–28; GC-E; n = 226) or placebo (GC-P; n = 225). Pts 

without progression received maintenance erlotinib or placebo until progression, 

unacceptable toxicity or death. Provision of tumour samples was encouraged; 

tests were conducted at a central laboratory and prioritized as follows: EGFR 

mutation; KRAS mutation (both by PCR-based test [COBAS]); ERCC1 expression 

by immunohistochemistry (IHC; median cut-off); EGFR gene copy number by 

fluorescence in-situ hybridization (FISH); and EGFR IHC. 

Results: OS data are not fully mature yet (45.1% and 52.4% of pts in GC-E and 

GC-P arms with event, respectively, in Oct 2011), but a trend towards prolonged OS 

with GC-E vs GC-P was observed: HR = 0.78 (95% CI 0.60–1.02); p = 0.0686; median 

18.3 vs 14.9 months. Updated OS data with June 2012 cut-off will be presented. A 

total of 283/451 pts (62.7%) provided samples for biomarker analyses. The table 

shows correlations with PFS for the overall biomarker populations and the EGFR 

wild-type (WT) subgroup. 

Conclusions: As expected, the EGFR mutation-positive (Mut+) subgroup had the 

strongest PFS benefit with intercalated erlotinib and first-line chemotherapy. ERCC1 

IHC+ status was also associated with longer PFS with GC-E vs GC-P, even in pts 

with known EGFR WT status. 




Biomarker subgroup 

HR for PFS 

(95% CI) 

Median PFS 

with GC-E vs 

GC-P, months p-value 

EGFR Mut+ (n = 97) 0.21 (0.12–0.35) 15.6 vs 6.9

Ingelheim, GSK Biologicals (compensated). Received honoraria from all the above. 

Research funding from AstraZeneca. J. O’Connell: Employed by Pfizer as Senior 

Director. Holds Pfizer stock. S. Ou: Advisory relationship with Pfizer and Genentech 

(compensated). Honoraria from Pfizer, Genentech and Eli Lilly. Research funding 

from Pfizer. I. Taylor: Employed by Pfizer as a Senior Director. Holds Pfizer stock. 

H. Zhang: Employed by Pfizer as a Senior Manager. Holds Pfizer stock. 

1229PD LUX-LUNG 3: SYMPTOM AND HEALTH-RELATED QUALITY 

OF LIFE RESULTS FROM A RANDOMIZED PHASE III STUDY 

IN 1ST-LINE ADVANCED NSCLC PATIENTS HARBOURING 

EGFR MUTATIONS 

L.V. Sequist 1 , M. Schuler 2 , N. Yamamoto 3 , K.J. O’Byrne 4 , V. Hirsh 5 , T.S. 

K. Mok 6 , J. Lungershausen 7 , M. Shahidi 8 , M. Palmer 9 , J.C. Yang 10 

1 Medicine, Massachusetts General Hospital, Boston, MA, UNITED STATES OF 

AMERICA, 2 Medicine, West German Cancer Center, University Duisburg-Essen, 

Essen, GERMANY, 3 Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, 

JAPAN, 4 Oncology, St James’s Hospital, Dublin, IRELAND, 5 Oncology, McGill 

University Health Centre, Montreal, QC, CANADA, 6 Department of Clinical 

Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong, CHINA, 

7 Health Economics, Boehringer Ingelheim, Ingelheim, GERMANY, 8 Clinical 

Research / Management, Boehringer Ingelheim, Bracknell, UNITED KINGDOM, 

9 Statistics, Keele University, Keele, UNITED KINGDOM, 10 Oncology, National 

Taiwan University Hospital, Taipei, TAIWAN 

Background: Afatinib (A) is an oral, irreversible ErbB family blocker. LUX-Lung 3 

compared A with cisplatin/pemetrexed (CP) in patients with EGFR mutation positive 

lung adenocarcinoma. The primary analysis demonstrated significant improvement 

in progression-free survival (PFS), with a median PFS of 11.1 months for A and 6.9 

months for CP (HR = 0.58, p = 0.0004). Here, we present patient-reported 

Health-related Quality of Life (HRQoL) data. 

Methods: 345 patients were randomized (2:1) to receive A or CP. Symptoms and 

HRQoL were measured using EORTC questionnaires (QLQ-C30/LC13) at baseline 

and q3w until progression. Changes of ≥10 points were considered clinically 

significant. Analyses of cough, dyspnoea and pain symptoms were pre-specified. 

Time to deterioration (1st 10-point worsening from baseline) was analyzed using a 

stratified log rank test. Percentage improved/worsened by ≥10 points or stable was 

determined. Mean scores over time were estimated using longitudinal (mixed-effects 

growth curve) models. 

Results: Compliance with questionnaires was >85% over time and all patients had 

low baseline symptom burden. Compared to CP, therapy with A significantly delayed 

time to deterioration for cough (HR = 0.60; p = 0.0072) and dyspnoea (HR = 0.68; p 

= 0.0145); results for pain trended toward A (HR = 0.82; p = 0.1913). A higher 

proportion of A-treated patients had ≥10 point improvements in cough (67% vs 

60%; p = 0.2444), dyspnoea (64% vs 50%; p = 0.0103) and pain (59% vs 48%; p = 

0.0513), compared to CP, particularly among patients with baseline symptoms. Mean 

scores over time for cough and dyspnoea also significantly favoured A. Consistent 

with the safety profile of A, a higher proportion of A-treated patients had significant 

worsening of symptoms of diarrhoea, sore mouth and dysphagia compared to CP. 

Reported fatigue, nausea, and vomiting were significantly worse on CP. Overall, 

therapy with A improved global HRQoL, physical, role and cognitive functioning 

compared to CP (p < 0.05). 

Conclusion: In LUX-Lung 3, prolongation of PFS on A was associated with 

significant HRQoL improvement and delay of deterioration of lung cancer-related 

symptoms compared to CP. 

Disclosure: L.V. Sequist: Paid consultancy/advisory relationship with: Boehringer 

Ingelheim, Daiichi-Sankyo, Merrimack, Clovis and Celgene; Research funding from: 

Boehringer Ingelheim. M. Schuler: Paid consultancy/advisory relationship with: 

Boehringer Ingelheim; Research funding from: Boehringer Ingelheim; Travel support 

from: Lilly. K.J. O’Byrne: Paid consultancy/advisory relationship with: Boehringer 

Ingelheim, Lilly Oncology; Honoraria from Boehringer Ingelheim, Lilly Oncology; 

Research funding from Boehringer Ingelheim; Other remuneration from Boehringer 

Ingelheim, Lilly Oncology. V. Hirsh: Honoraria from the Boehringer Ingelheim 

Advisory Board. T.S.K. Mok: Paid consultancy/advisory relationship with and 

honoraria from: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, 

AVEO, Pfizer, Taiko, Boehringer Ingelheim; Research funding from: AstraZeneca. J. 

Lungershausen: Employee of Boehringer Ingelheim. M. Shahidi: Employee of 

Boehringer Ingelheim. M. Palmer: Consulting fee, honorarium, travel support, fees 

for reviews, and payment for writing or reviewing the manuscript via N Zero 1 Ltd; 

Board membership of N Zero 1 Ltd and consultancy, travel/accommodation/meeting 

costs unrelated to activities listed. J.C. Yang: James Chih-Hsin Yang has received 

honorarium for speech and advisory roles from Astrazeneca, Roche, Pfizer, OSI. He 

was the advisor for Boehringer Ingelheim and Eli Lilly without payment. All other 


1230PD UPDATED RESULTS OF A GLOBAL PHASE II STUDY WITH 

CRIZOTINIB IN ADVANCED ALK-POSITIVE NON-SMALL 


D. Kim 1 , M. Ahn 2 ,P.Yang 3 , X. Liu 4 ,T.DePas 5 , L. Crinò 6 , S. Lanzalone 7 , 

A. Polli 7 , A. Shaw 8 

1 Internal Medicine, Seoul National University Hospital, Seoul, KOREA, 2 Division of 

Hematology/Oncology, Department of Medicine, Sungkyunkwan University 

School of Medicine Samsung Medical Center, Seoul, KOREA, 3 Department of 

Internal Medicine, National Taiwan University College of Medicine, Taipei, 

TAIWAN, 4 Cancer Center, 307 Hospital of the Academy of Military Medical 

Sciences, Beijing, CHINA, 5 Medical Oncology Unit of Respiratory Tract and 

Sarcomas, European Institute of Oncology, Milano, ITALY, 6 Department of 

Medical Oncology, Ospedale Santa Maria della Misericordia, Perugia, ITALY, 

7 Oncology, Pfizer, Milano, ITALY, 8 Hematology/Oncology, Department of 

Medicine, Massachusetts General Hospital, Boston, MA, UNITED STATES OF 

AMERICA 

Background: Anaplastic lymphoma kinase (ALK) is a known oncogenic driver in 

NSCLC, and approximately 5% of patients harbor ALK gene rearrangements. 

Crizotinib is a first-in-class, selective small-molecule ALK inhibitor with 

demonstrated clinical activity in ALK-positive NSCLC. PROFILE 1005 is a global, 

multicenter, open-label, single-arm phase II study evaluating the safety and 

efficacy of crizotinib in previously treated patients with ALK-positive advanced 

NSCLC. 

Methods: Crizotinib 250 mg was administered BID to patients with ALK-positive 

advanced NSCLC who had received ≥1 chemotherapy for locally advanced/ 

metastatic disease, including those with treated brain metastases. Most patients had 

centrally confirmed ALK-positivity by break-apart fluorescence in-situ hybridization, 

defined as ≥15% of tumor cells with split signals. Disease response was evaluated by 

RECIST 1.1 every 6 weeks. 

Results: As of January 2012, 901 patients had been dosed. The first 261 patients 

who had enrolled and started crizotinib by February 2011, with a median 

duration of treatment of 48 weeks, were considered to be the mature population. 

Demographic, exposure, and efficacy results in both the overall and mature 

populations are provided in the table. Among all 901 patients, 15% discontinued 

treatment due to adverse events (AEs) and 10% had a dose reduction due to an 

AE. The most frequent AEs of any cause were vision disorder (54%), nausea 

(51%), diarrhea (44%), vomiting (44%), and constipation (37%), which were 

mostly grade 1/2. 

Conclusions: Crizotinib demonstrated a high response rate that was durable, with a 

median progression-free survival of 8.1 months. Crizotinib has a favorable tolerability 

profile. These findings continue to provide strong evidence for crizotinib as a 

standard of care for advanced ALK-positive NSCLC. 

Overall population Mature population 

Total no. of patients, n 901 261 

Response-evaluable patients, n 803 259 

Demographics: 

Median age, years 

Male/female, % 

ECOG PS 0/1, % 


53 

52 

43/57 

46/54 

82 

83 

Adenocarcinoma, % 

92 

94 

Duration of treatment (weeks), median 

(range) 

20 (


1231PD IMPACT OF CRIZOTINIB TREATMENT ON 

PATIENT-REPORTED SYMPTOMS AND QUALITY OF LIFE 

(QOL) IN ADVANCED ALK-POSITIVE NON-SMALL CELL 

LUNG CANCER (NSCLC) 

F.H. Blackhall 1 , T.L. Evans 2 , J. Han 3 , R. Salgia 4 , D. Moro-Sibilot 5 , S. Gettinger 6 , 

L. Crino 7 , K. Wilner 8 , A. Reisman 9 ,S.Iyer 10 


KINGDOM, 2 Medical Oncology, University of Philadelphia, Philadelphia, PA, 

UNITED STATES OF AMERICA, 3 Center for Lung Cancer, National Cancer 

Center, Goyang, KOREA, 4 Department of Medicine, Section of Hematology/ 

Oncology, University of Chicago, Chicago, IL, UNITED STATES OF AMERICA, 

5 Department of Lung Cancer, CHU De Grenoble - Hôpital A. Michalon, 

Grenoble, FRANCE, 6 Thoracic Oncology, Yale University School of Medicine, 

New Haven, CT, UNITED STATES OF AMERICA, 7 Medical Oncology, S. Maria 

della Misericordia Hospital, Perugia, ITALY, 8 Reseach and Development, Pfizer 

Oncology, La Jolla, CA, UNITED STATES OF AMERICA, 9 Medical Oncology, 

Pfizer Inc, New York, NY, UNITED STATES OF AMERICA, 10 Medical Oncology, 

Pfizer Oncology, New York, NY, UNITED STATES OF AMERICA 

Background: Crizotinib is a potent, selective, ATP-competitive ALK inhibitor 

demonstrating a high response rate in advanced ALK-positive NSCLC. The effect of 

crizotinib on patient-reported symptoms, functioning and QOL from PROFILE 1005 

is presented. 

Methods: PROFILE 1005 is an ongoing global, multicenter, open-label, single-arm, 

phase II study evaluating the safety and efficacy of crizotinib (250 mg BID in 3-week 

cycles) in previously treated patients with advanced ALK-positive NSCLC. 

Patient-reported outcomes (PROs) were assessed as secondary endpoints using the 

European Organisation for Research and Treatment of Cancer questionnaire 

(EORTC-QLQ-C30) and lung cancer module (QLQ-LC13) at baseline, Day 1 of each 

cycle and at end of treatment. Functioning, symptoms and global QOL were assessed 

and scored on scales of 0–100. Higher scores indicate higher symptom severity or 

higher functioning/QOL. Change from baseline was assessed for statistical and 

clinical significance (defined as ≥10-point change from baseline). 

Results: As of Jan 2012, 901 patients were evaluable for safety and 797 (88%) of 

these patients had completed the entire questionnaire at baseline. The majority of 

patients was female (57%), never smokers (66%), and had adenocarcinoma (92%), 

with a median age of 52 years. A clinically meaningful (≥10-point) improvement 

from baseline was observed early and maintained in patient-reported symptoms of 

cough (Cycle 2 onwards), pain (Cycles 2 to 19), dyspnea from QLQ–C30 (Cycles 3 

to 19), pain in chest (Cycles 3 to 20 except for Cycle 18), pain in arm and shoulder 

(Cycles 3 to 16) and fatigue (Cycles 4 to 21). Clinically significant deterioration was 

observed for constipation (Cycles 2 and 3) and diarrhea (Cycle 2 to 6, 9 and 10). 

Clinically meaningful improvements were observed for physical functioning (Cycle 8 

and 9), role functioning (Cycles 9 and 10), social functioning (Cycles 4 to 15, except 

Cycle 12) and global QOL (Cycles 3 to 15, except Cycle 11). 

Conclusion: Treatment with crizotinib in pretreated patients with advanced 

ALK-positive NSCLC showed an overall positive impact on patient-reported lung 

cancer symptoms and global QOL. 

Disclosure: F.H. Blackhall: Advisory relationship with Pfizer. Honoraraia, research 

funding and other remuneration received from Pfizer. D. Moro-Sibilot: Honoraria 

received from Pfizer. K. Wilner: Employed by Pfizer as a Senior Director and has 

stock ownership with Pfizer. A. Reisman: Employed by Pfizer and has stock 

ownership with Pfizer. S. Iyer: Employed as a Director (Global Outcomes Research) 

by Pfizer. All other authors have declared no conflicts of interest. 

1232PD LUNG CANCER HARBORING HER2 MUTATION: 

EPIDEMIOLOGICAL CHARACTERISTICS AND 

THERAPEUTIC PERSPECTIVES 

J. Mazieres 1 , S. Peters 2 , A. Cortot 3 , B. Besse 4 , F. Barlesi 5 , M. Beau-Faller 6 , 

T. Urban 7 , D. Moro-Sibilot 8 , J. Milia 1 , O. Gautschi 9 

1 Department of Pneumology, CHU Toulouse - Hôpital Larrey, Toulouse, 

FRANCE, 2 Oncology, Centre Hospitalier Universitaire Vaudois - CHUV, 

Lausanne, SWITZERLAND, 3 Pneumology, CHU Lille, Lille, FRANCE, 4 Thoracic 

Group, INSERM U981, Institut Gustave Roussy, Villejuif, FRANCE, 5 Service 

d’Oncologie Multidisciplinaire et Innovations Thérapeutique, Hôpital Nord, 

Marseille, FRANCE, 6 Hôpitaux Universitaires de Strasbourg et INSERM U682 

Hôpital De Hautepierre Laboratoire de Biochimie et de Biologie Moléculaire, 

Strasbourg Cedex, E/M Laboratoire de Biochimiee et de Biologie Moléculaire, 

Hôpitaux Universitaires de Strasbourg et INSERM U682 Hôpital de Hautepierre, 

Strasbourg, FRANCE, 7 Oncology Department, CHU Anger, Anger, FRANCE, 

8 Cancérologie, Hôpital A. Michallon - CHU Grenoble, Grenoble, FRANCE, 

9 Medizinsiche Onkologie, Luzerner Kantonsspital, Luzern, SWITZERLAND 

Introduction: HER2 oncogene is a member of the EGFR family, encoding a 

transmembrane receptor that drives and regulates cell proliferation. HER2 mutations 

are identified in about 2% of non small cell lung cancer (NSCLC), mainly located in 

exon 20, and appear to be critical for lung cancer carcinogenesis. Very scarce data 

are available to define a clinical profile of the patients harboring HER2 mutated 

NSCLC. We aimed to study clinicopathological characteristics and therapeutic 

outcomes of patients harboring HER2 mutation in a large European series. 

Results: We retrospectively identified 46 NSCLC patients diagnosed with HER2 exon 

20 mutation. HER2 mutation was mainly exclusive as only one concomitant KRas 

mutation was described. Our population was characterized by a median age of 60 yr 

(31 to 86 yr), a high proportion of women (30 vs. 16 men, 65%), and of never 

smokers (24, 52%). All tumors were adenocarcinomas (two with lepidic features). 

Half of the patients had stage IV disease at the time of diagnosis. HER2 targeted 

treatment was delivered after conventional chemotherapy. A total of 20 anti-Her2 

treatments were evaluable. We observed 4 progressive diseases, 7 disease stabilizations 

and 9 partial responses according to RECIST 1.1 (overall response rate ORR = 45%; 

disease control rate DCR = 80%). Specifically, we observed a DCR of 92% for 

trastuzumab-based therapies (n = 14), 100 % for afatinib (n = 3) but no response to 

lapatinib (n = 2) and to a multiTKI (n = 1). Median survival was of 68.2 months and 

22.9 months for respectively early stage and stage IV patients. 

Conclusion: This study, the largest to date dedicated to HER2 mutated NSCLC, 

reinforces the importance of an HER2 screening strategy in lung adenocarcinomas. 

HER2-targeted drugs should be tested further, ideally within large collaborative 



1233PD EFFICACY AND PATIENT (PT)-REPORTED OUTCOMES 

(PROS) WITH SELUMETINIB (AZD6244, ARRY-142866; 

SEL) + DOCETAXEL (DOC) IN KRAS-MUTANT ADVANCED 

NON-SMALL CELL LUNG CANCER (NSCLC): A 

RANDOMIZED, PHASE II TRIAL 

P.A. Janne 1 , A.T. Shaw 2 , J.R. Pereira 3 , G. Jeannin 4 , J.F. Vansteenkiste 5 , 

C. Barrios 6 , F.A. Franke 7 , L. Grinsted 8 , I. Smith 8 , L. Crino 9 

1 Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA, 

UNITED STATES OF AMERICA, 2 Hematology/Oncology, Massachusetts General 

Hospital, Boston, MA, UNITED STATES OF AMERICA, 3 Depto de Pneumologia, 

Grupo de Assistencia Médica, Sao Paulo, BRAZIL, 4 Service de Pneumologie, 

Hôpital Gabriel Montpied, Clermont- Ferrand, FRANCE, 5 Respiratory Oncology 

Unit (Pulmonology), University Hospital Gasthuisberg, Leuven, BELGIUM, 

6 Oncology, Hospital Sao Lucas da PUC de Porto Alegre, Porto Alegre, BRAZIL, 

7 Cacon, Hospital de Caridade de Ljui, Ljui, BRAZIL, 8 Oncology, Astra Zeneca, 

Alderley Park, UNITED KINGDOM, 9 Department of Oncology, Hospital Santa 

Maria della Misericordia, Perugia, ITALY 

Objectives: This randomized, double-blind, placebo (PBO)-controlled, phase II trial 

evaluated the efficacy and safety of SEL + DOC as second-line treatment for pts with 

KRAS-mutant advanced NSCLC. Assessment of the prevalence, severity, and change 

over time of lung cancer symptoms was an exploratory objective. 

Methods: Pts with stage IIIB-IV, second-line KRAS-mutant advanced NSCLC, 

received iv DOC 75mg/m 2 , and po SEL 75mg or PBO BD. PROs were assessed using 

the Lung Cancer-Specific Symptom Questionnaire (LSSQ), which includes the Lung 

Cancer Subscale (LCS) plus items relating to symptoms and functional activities 

from the FACT-L. Pts completed the questionnaire on Day 1, and every 3 weeks 

until discontinuation from study treatment, and at discontinuation. 

Results: 422 pts were screened across 67 centers in 12 countries; 87 were randomized 

(SEL + DOC, 44; PBO + DOC, 43). Baseline characteristics were reasonably balanced. 

OS was longer for SEL + DOC vs PBO + DOC (9.4 vs 5.2 mo), but not statistically 

significant (HR 0.80; 80% CI 0.56–1.14) and hazards were non-proportional. All 

secondary endpoints, including response rate (37% vs 0%; p < 0.0001) and PFS (5.3 

vs 2.1 mo; HR 0.58; 80% CI 0.42–0.79), were significantly improved for SEL + DOC 

vs PBO + DOC. Most frequent grade 3/4 AEs were neutropenia and febrile 

neutropenia. Compliance for completion of the LSSQ at baseline and at least 1 

follow-up visit was 85.5%. There was a numerical improvement in the change from 

baseline in the LSSQ scores with SEL + DOC compared with PBO + DOC, 

throughout the assessment period. In a post-hoc analysis, the % pts with a clinically 

meaningful improvement in LCS score was greater for SEL + DOC (44%) than PBO 

+ DOC (24%; OR 2.50; 80% CI 1.34–4.77; 1-sided p = 0.029). The time to 

deterioration of LCS score was also in favor of SEL + DOC (HR 0.33; 80% CI 0.22– 

0.49; 1-sided p = 0.0002). 

Conclusions: This is the first prospective study to demonstrate a clinical benefit of 

targeted therapy (SEL + DOC) for pts with KRAS-mutant cancer of any type. In a 

post-hoc analysis, more pts experienced clinically meaningful improvements in lung 

cancer symptoms with SEL + DOC than PBO + DOC. 

Disclosure: P.A. Janne: I have served as a consultant to Astra Zeneca and have been 

compensated. A.T. Shaw: Research funding from Astra Zeneca and funding for costs 

of clinical trials. J.F. Vansteenkiste: Dr. Vansteenkiste is the holder of the Astra 

Zeneca Chair in personalized lung cancer care which provides research funding. L. 

Grinsted: Lynda Grinsted is an employee of Astra Zeneca and receives stock shares. I. 

Smith: Ian Smith is an employee of Astra Zeneca and receives stock. All other 



1234PD RANDOMIZED PHASE III TRIAL OF S-1 PLUS CISPLATIN 

VERSUS DOCETAXEL PLUS CISPLATIN FOR ADVANCED 

NON-SMALL-CELL LUNG CANCER (TCOG0701) 

H. Sakai 1 , A. Gemma 2 , K. Kubota 2 , M. Nishio 3 , H. Okamoto 4 , A. Inoue 5 , 

H. Isobe 6 , K. Kobayashi 7 , M. Takeuchi 8 , S. Kudoh 9 

1 Thoracic Oncology, Saitama Cancer Center, Saitama, JAPAN, 2 Internal 

Medicine, Nippon Medical School, Tokyo, JAPAN, 3 Thoracic Oncology Center, 

The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 

Tokyo, JAPAN, 4 Department of Respiratory Medicine, Yokohama Municipal 

Citizen’s Hospital, Yokohama, JAPAN, 5 Department of Respiratory Medicine, 

Tohoku University, Sendai, JAPAN, 6 Clinical Oncology, KKR Sapporo Medical 

Center, Sapporo, JAPAN, 7 Respiratory Medicine, Saitama International Medical 

Center, Saitama, JAPAN, 8 Biostatistics and Pharmaceutical Medicine, Kitasato 

University School of Pharmacy, Tokyo, JAPAN, 9 Respiratory Medicine, Fukujuji 


Background: Quality of life (QOL) should be an explicit priority throughout the 

course of care for patients with advanced non-small-cell lung cancer (NSCLC). 

Docetaxel plus cisplatin (DP) is the only third-generation regimen that has 

demonstrated statistically significant improvements in overall survival and QOL by a 

head-to-head comparison with a second-generation regimen (vindesine plus 

cisplatin) in patients with advanced NSCLC. S-1 plus cisplatin (SP) has shown 

activity and good tolerability in phase II settings. 

Method: Patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 

0-1 and adequate organ functions were randomly assigned to receive either oral S-1 

80 mg/m 2 /day (40 mg/m 2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m 2 on day 8 

every 5 weeks or docetaxel 60 mg/m 2 on day 1 plus cisplatin 80 mg/m 2 on day 1 

every 3 weeks, both up to 6 cycles. The primary endpoint was overall survival (OS). 

A non-inferiority study design was employed; the upper confidence interval (CI) 

limit of the hazard ratio (HR) was


1236PD TUMOUR BIOMARKER AND PLASMA TIME COURSE DATA 

FROM ABIGAIL, A PHASE II STUDY OF 1ST-LINE 

BEVACIZUMAB + CHEMOTHERAPY IN ADVANCED 

NON-SQUAMOUS NON-SMALL-CELL LUNG CANCER 

(NS-NSCLC) 

M. Reck 1 , V.A. Gorbunova 2 , E. Juhasz 3 , B. Szima 4 , S. Orlov 5 ,C.Yu 6 , 

C. Pallaud 7 , S.J. Scherer 8 , V. Archer 9 , T.S.K. Mok 10 

1 Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, 

GERMANY, 2 Department of Chemotherapy, Russian Research Oncology Center 

n.a. N. N. Blokhin Russian Cancer Research Center, Moscow, RUSSIAN 

FEDERATION, 3 Pulmonology Department XIV, Országos Korányi TBC és 

Pulmonologiai Intézet, Budapest, HUNGARY, 4 Department of Oncoradiology, 

Markusovszky Hospital, Szombathely, HUNGARY, 5 Laboratory of Thoracic 

Oncology, St Petersburg State Medical University, St Petersburg, RUSSIAN 

FEDERATION, 6 Department of Internal Medicine, National Taiwan University 

Hospital, Taipei, TAIWAN, 7 Pharma Development Oncology Department, 

F. Hoffmann-La Roche Ltd., Basel, SWITZERLAND, 8 Pharma Development 

Department, Genentech, San Francisco, CA, UNITED STATES OF AMERICA, 

9 Clinical Development (oncology), Roche Products Ltd., Welwyn Garden City, 

UNITED KINGDOM, 10 Department of Clinical Oncology, Chinese University of 

Hong Kong, Prince of Wales Hospital, Hong Kong, HONG KONG 

Background: BO21015 (NCT00700180) is a phase II, randomized, multicentre study 

exploring correlation between biomarkers (BMs) and best overall response (BOR) to 

bevacizumab with carboplatin/gemcitabine (CG) or carboplatin/paclitaxel (CP) in 

chemonaïve patients with advanced/recurrent NSCLC. Efficacy, safety and correlation 

of 7 baseline (BL) plasma BM (bFGF, E-selectin, ICAM, PLGF, VEGFA, VEGFR-1 

and VEGFR-2) with BOR and progression-free survival (PFS) have been reported. 1 

This abstract presents BM analysis for tumour tissue, plasma time course and clinical 

outcome. 

Methods: 303 eligible patients were randomized 1:1 to receive bevacizumab 7.5 mg/ 

kg or 15 mg/kg until disease progression (PD) or unacceptable toxicity (with 6 cycles 

of CG or CP, at investigators’ discretion). Consented patients provided blood 1 and 

tumour samples for BM analysis. Pre-specified exploratory analyses examined 

correlation between BL plasma BM and overall survival (OS) and changes in plasma 

BM levels from BL to PD, cycles 2, 4 and 6. Plasma BM levels were measured by 

ELISA. IHC analyses of 5 tumour BMs (VEGFR-1, MVD, VEGFA, VEGFR-2 and 

NRP1) were assessed for correlation with BOR, PFS and OS, and with BL plasma 

BM levels. 

Results: \Further exploratory analyses adjusting for BL prognostic factors and 

accounting for multiple testing showed a correlation of high BL VEGFA levels 

( 3 median) with shorter OS (n = 280; 19.8 vs 11.1 mos; p = 0.0042). No other 

BL plasma BMs correlated with OS. No significant changes in plasma BM 

levels were seen between baseline and PD, and/or cycles 2, 4 or 6 for any of 

the BMs. The only correlation between tumour and plasma markers was for 

tumour VEGFR1 expression and VEGFA plasma BL (p = 0.025, 0.26). No 

significant correlation was seen between tumour BM level and BOR, PFS or 

OS. 

Conclusions: Exploratory analysis showed high plasma BL VEGFA significantly 

correlated with shorter OS, consistent with previously reported data on PFS. No 

other BL plasma BMs correlated with OS. BL plasma VEGFA levels correlated with 

tumour VEGFR1 expression. None of the investigated tumour BMs significantly 

correlated with clinical outcome. 1 Mok et al. ESMO 2011 

Disclosure: M. Reck: Attended advisory boards for Roche, Lilly, BMS, AstraZeneca 

and Daiichi Sankyo. Received honoraria for lectures from Roche, Lilly, Daiichi 

Sankyo and AstraZeneca. V.A. Gorbunova: Attended advisory boards with Novartis 

and Pfizer. Honoraria for lectures from Roche and Bayer. B. Szima: Received 

funding for research. C. Yu: Attended advisory boards for Roche, AstraZeneca, 

Pfizer and Takeda. C. Pallaud: Owns stock in Roche. Currently employed by Roche. 

S.J. Scherer: Currrently employed by Roche/Genentech. V. Archer: Currently 

employed by Roche. T.S.K. Mok: Advisory boards: AstraZeneca, Roche, Eli Lilly, 

Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, BI, GSK Biologicals. On 

the IASLC board of directors. Received research funding from AstraZeneca. 

Employed by The Chinese Uinversity of Hong Kong. All other authors have 


1237PD CLINICAL ACTIVITY AND SAFETY OF ANTI-PROGRAMMED 


PATIENTS (PTS) WITH ADVANCED NON-SMALL CELL LUNG 


S. Gettinger 1 , L. Horn 2 , S.J. Antonia 3 , D. Spigel 4 , L. Gandhi 5 , L.V. Sequist 6 ,J. 

M. Wigginton 7 , G. Kollia 8 , A. Gupta 9 , J.R. Brahmer 10 

1 Thoracic Oncology, Yale University School of Medicine, New Haven, CT, 

UNITED STATES OF AMERICA, 2 Thoracic Oncology Program, Vanderbilt-Ingram 

Cancer Center, Nashville, TN, UNITED STATES OF AMERICA, 3 Thoracic 

Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 

UNITED STATES OF AMERICA, 4 Oncology, Sarah Cannon Research Institute/ 

Tennessee Oncology PLLC, Nashville, TN, UNITED STATES OF AMERICA, 

5 Oncology, Dana-Farber Cancer Institute, Boston, MA, UNITED STATES OF 

AMERICA, 6 Oncology, Massachusetts General Hospital Cancer Center, Boston, 

MA, UNITED STATES OF AMERICA, 7 Discovery Medicine-Clinical Oncology, 


8 Biostatistics and Data Management, Bristol-Myers Squibb, Princeton, NJ, 

UNITED STATES OF AMERICA, 9 Discovery Medicine, Immuno-Oncology, 


10 Melanoma Program, Sidney Kimmel Cancer Center at Johns Hopkins 

University, Baltimore, MD, UNITED STATES OF AMERICA 

Purpose: BMS-936558 is a fully human monoclonal antibody that blocks the PD-1 

co-inhibitory receptor expressed by activated T cells. We report here the activity and 

safety of BMS-936558 in pretreated pts with advanced NSCLC, a tumor not 

previously considered responsive to immunotherapy. 

Methods: BMS-936558 was administered IV q2wk to pts with various solid tumors 

at 1 − 10 mg/kg during dose escalation and/or cohort expansion. Pts with advanced 

NSCLC previously treated with at least 1 prior line of therapy were eligible. Pts 

received up to 12 cycles (4 doses/cycle) of treatment or until unacceptable toxicity, 

confirmed progressive disease, or complete response. Clinical activity was assessed by 

RECIST v1.0. 

Results: As of Feb 24, 2012, 122 NSCLC pts had received BMS-936558 at 1 (n = 31), 

3 (n = 33), or 10 mg/kg (n = 58). ECOG performance status was ≤1 for 117/122 pts; 

67/122 pts had received ≥3 prior therapies. Median duration of therapy was 12 

weeks (range 2 − 101.3 wks). Common drug-related AEs in NSCLC pts were fatigue 

(18%), decreased appetite (10%), anemia (8%), and nausea (7%). The incidence of 

grade 3–4 related AEs was 8%. There were 2 drug-related deaths from pneumonitis. 

Of 76 evaluable pts, 14 had a partial response (PR) (Table); all 14 were treated ≥24 

wk, and 8 had responses of ≥24 wk. 5 Five pts had stable disease (SD) lasting ≥24 

wk. Additionally, 3 pts had a persistent decrease in target lesion tumor burden in the 

presence of new lesions and were not categorized as responders. 

Conclusions: BMS-936558 had an acceptable risk: benefit profile in previously 

treated, advanced NSCLC. Activity in squamous NSCLC was particularly intriguing. 

Additional long-term follow-up data will be reported. 

Dose, mg/kg No. pts a 

ORR, 

No. pts (%) 

[95% CI] 

PFSR at 

24 wks, % 

[95% CI] 

1 18 1 (6) [0.1 − 27] 16 [0 − 34] 

3 19 6 (32) [13 − 57] 41 [18 − 64] 

10 39 7 (18) [8 − 34] 24 [11 − 38] 

All 76 b 

14 (18) [11 − 29] 26 [16 − 36] 

All–Nonsquamous 56 7 (13) [5 − 24] 22 [11 − 34] 

All–Squamous 18 6 (33) [13 − 59] 33 [12 − 55] 

a Response-evaluable pts dosed by 07/01/2011 b Includes 2 pts with unknown 

histology, 1 with PR ORR = objective response rate ([{CR + PR} ÷ n] × 100); PFSR = 

progression-free survival rate 

Disclosure: L. Horn: Consultant or Advisory Role: OSI/Astellas (myself, 

uncompensated). D. Spigel: Consultant or Advisory Role: Bristol-Myers Squibb 

(myself, uncompensated). L.V. Sequist: Consultant or Advisory Role: Clovis, Celgene, 


GlaxoSmithKline (myself, compensated); Daiichi-Sankyo, Merrimack (myself, 

uncompensated). J.M. Wigginton: Employment or Leadership Role: Bristol-Myers 

Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb 

(myself). G. Kollia: Employment or Leadership Role: Bristol-Myers Squibb 


(myself). A. Gupta: Employment or Leadership Role: Bristol-Myers Squibb 


(myself). All other authors have declared no conflicts of interest. 

1238PD ACTIVE SPECIFIC IMMUNOTHERAPY WITH 

RACOTUMOMAB IN THE TREATMENT OF ADVANCED 

A. Macías 1 , S. Alfonso 2 , E. Santiesteban 3 , C. Viada 1 , I. Mendoza 4 , P.P. Guerra 4 , 

R.E. Gómez 5 , M.L. Ardigo 5 , A.M. Vázquez 1 , R. Pérez 1 

1 Clinical Department, Center of Molecular Immunology, Havana, CUBA, 

2 Oncology Unit, University Hospital “Celestino Hernánez Robau”, Las Villas, 

CUBA, 3 Oncology Unit, Hospital “José Ramón Tabranes”, Matanzas, CUBA, 

4 Project Management and Monitoring, National Clinical Trial Coordinator Center, 

Havana, CUBA, 5 Clinical Research, Elea Laboratories, Buenos Aires, ARGENTINA 

Background: Gangliosides, especially NeuGc-GM3, are an attractive target for cancer 

immunotherapy. They do not express in normal human cells but are overexpressed 

in several solid tumors including NSCLC and are involved in tumor development 

and growth. Racotumomab is therapeutic vaccine which induces a cellular and 

humoral immune response against NeuGc-GM3 expressed in tumors. Phase I and II 

trials in melanoma, breast and lung cancer have shown the low toxicity and high 

immunogenicity of racotumomab. 

Methods: Multicenter, randomized, placebo controlled, double blind clinical trial in 

patients with advanced (IIIB and IV) NSCLC who had an ECOG status ≤ 2 and had 

achieved partial or complete response or disease stabilization after completion of 

onco-specific treatment. 176 patients were randomized 1:1 to placebo or 

racotumomab. Initially 1 dose was administered every 14 days (induction period, 5 

doses in total), followed by 1 dose every 28 days (maintenance period) until patient 

refusal or worsening of ECOG status. 

Results: Safety: The most common adverse events were expected mild reactions at the 

injection site (pain and itching). No differences were observed between both groups. 

Overall Survival (OS): Intent to Treat Analysis (ITT): Survival since inclusion was 15.7 

months (mean) and 8.3 months (median) in the racotumomab arm and 10.6 months 

(mean) and 6.3 months (median) in the placebo arm (log rank test, p= 0.02). OS rate 

(%) at 12 and 24 months was 38 % and 17 % in the racotumomab arm and 24 % and 

7 % in the placebo arm. Per Protocol Population Analysis (PPP): Includes patients 

who received ≥ 5 doses of racotumomab/ placebo (135/174 patients, 77% of the patient 

population). Survival since inclusion was 18.9 months (mean) and 10.9 (median) in 

the racotumomab arm and 11.4 months (mean) and 6.9 months (median) in the 

placebo arm (log rank test, p= 0.002). OS rate (%) at 12 and 24 months: 48 % and 22 

% in the racotumomab arm and 28 % and 8 % in the lacebo arm. 

Conclusions: Immunization with racotumomab is safe. There is an OS benefit for 

racotumomab, both in the ITT and PPP analyses. Survival benefit appears to be 

increased when the patient’s clinical condition allows completion of the induction 

period of vaccination. 

Disclosure: R.E. Gómez: Is a full time employee at Elea Laboratories. M.L. Ardigo: Is a full 

time employee at Elea Laboratories. All other authors have declared no conflicts of interest. 

1239P CLINICAL GENOTYPING AND EFFICACY OUTCOMES: 

EXPLORATORY BIOMARKER DATA FROM THE PHASE II 

ABIGAIL STUDY OF 1ST-LINE BEVACIZUMAB + 

CHEMOTHERAPY IN NON-SQUAMOUS NON-SMALL-CELL 

LUNG CANCER (NS-NSCLC) 

C. Pallaud 1 , M. Reck 2 , E. Juhasz 3 , B. Szima 4 ,C.Yu 5 , O. Burdaeva 6 , S. Orlov 7 , 

S.J. Scherer 8 , V. Archer 9 , T.S.K. Mok 10 

1 Pharma Development Oncology Department, F. Hoffmann-La Roche Ltd, Basel, 

SWITZERLAND, 2 Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, 

GERMANY, 3 Pulmonology Department Xiv, Országos Korányi TBC és 

Pulmonológiai Intézet, Budapest, HUNGARY, 4 Pulmonology Department, 

Markusovszky Hospital Oncoradiology, Szombathely, HUNGARY, 5 Department of 

Internal Medicine, National Taiwan University Hospital, Taipei, TAIWAN, 

6 Chemotherapy Department, Arkhangelsk Regional Oncology Center, 

Arkhangelsk, RUSSIAN FEDERATION, 7 Laboratory of Thoracic Oncology, St 

Petersburg State Medical University, St. Petersburg, RUSSIAN FEDERATION, 

8 Pharma Development Department, Genentech, San Francisco, CA, UNITED 

STATES OF AMERICA, 9 Clinical Development (oncology), Roche Products Ltd., 

Welwyn Garden City, UNITED KINGDOM, 10 Department of Clinical Oncology, 

Chinese University of Hong Kong Prince of Wales Hospital, Shatin, Hong Kong, CHINA 

Background: ABIGAIL (BO21015; NCT00700180) is a phase II, randomized, 

multicentre study exploring correlation between biomarkers (BMs) and best overall 

response (BOR) to bevacizumab with carboplatin/gemcitabine (CG) or carboplatin/ 

paclitaxel (CP) in chemonaïve patients with advanced/recurrent ns-NSCLC. 


ABIGAIL efficacy, safety and plasma baseline results have been reported. This 

abstract presents exploratory clinical genotyping data from this study. 

Methods: 303 patients with untreated advanced/recurrent ns-NSCLC were 

randomized 1:1 to receive bevacizumab 7.5 mg/kg or 15 mg/kg until progression or 

unacceptable toxicity (with 6 cycles of CG or CP). Patients who consented provided 

blood and tumour samples for BM analysis. Exploratory analyses were conducted to 

assess whether genetic variants in the VEGFA pathway may act as biomarkers for 

efficacy and safety. Here we report data from DNA analysis for 12 single-nucleotide 

polymorphisms (SNPs) across 3 genes: VEGFA (5 SNPs), VEGFR-1 (3 SNPs) and 

VEGFR-2 (4 SNPs). SNPs were identified using specific individual genotyping assays. 

Results: VEGFA: c. + 405/c.-634 (CG), VEGFA: c.-460T > C; c. -1498T > C (CT) and 

VEGFA: c.-2578 C > A (AC) were all associated with >50% higher odds of 

responding to treatment. VEGFR-1 rs9554316 (GT) was associated with >30% higher 

risk of progression and >40% higher risk of death. VEGF: c. + 936 C > T (CT) was 

associated with higher incidence of hypertension. When p-values were adjusted for 

treatment and prognostic factors, no SNPs were associated with significantly higher 

risk of hypertension. 

Conclusions: One SNP was associated with increased risk of progression/death, while 

3 others were associated with increased BOR. However, adjustment for multiple 

testing would no longer result in statistically significant p-values. SNPs analysed in 

this study have been previously reported as showing potential predictive value in 

other studies: VEGFA SNPs in breast cancer (E2100) and NSCLC (E4599); VEGFR1 

SNP in pancreatic cancer (AVITA). More exploratory analyses from this and other 

trials of bevacizumab may provide further insight. 

Disclosure: C. Pallaud: Own stock in and currently employed by F. Hoffmann-La 

Roche Ltd. M. Reck: Attended advisory boards for Roche, Lilly, BMS, AstraZeneca 

and Daiichi Sankyo. Received honoraria for lectures from Roche, Lilly, Daiichi 

Sankyo and AstraZeneca. B. Szima: Received funding for research. C. Yu: Attended 

advisory boards for Roche, AstraZeneca, Takeda and Pfizer. S.J. Scherer: Currently 

employed by Roche/Genentech. V. Archer: Currently employed by Roche. T.S.K. 

Mok: Attended advisory boards for AstraZeneca, Roche, Eli Lilly, Merck Serono, 

Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, BI and GSK Biologicals. On the IASLC 

board of directors. Received research funding from AstraZeneca. All other authors 


1240P CIRCULATING ENDOTHELIAL CELLS (CEC), CIRCULATING 

ENDOTHELIAL PROGENITORS (CEP) AND CIRCULATING 

TUMOUR CELLS (CTC) AS MARKERS FOR RESPONSE TO 

BEVACIZUMAB/CARBOPLATIN/PACLITAXEL (B + CP) OR 

BEVACIZUMAB/ERLOTINIB (B + E) IN ADVANCED 

NON-SQUAMOUS NON-SMALL-CELL LUNG CANCER 

(NS-NSCLC) 

F. Farace 1 , S. Le Moulec 2 , J. Mazieres 3 , H. Senellart 4 , E. Dansin 5 , 

A. Madroszyk 6 , X. Quantin 7 , H. Berard 8 , B. Besse 9 


2 Department of Oncology, Hôpital d’Instruction des Armées du Val-de-Grâce, 

Paris, FRANCE, 3 Department of Thoracic Oncology, Hôpital De Larrey, Toulouse, 

FRANCE, 4 Department of Medical Oncology, Institut de Cancérologie de l’Ouest 

Site René Gauducheau, Nantes, FRANCE, 5 Department of Medical of Oncology, 

CLCC Oscar Lambret, Lille, FRANCE, 6 Department of Medical Oncology, Institut 

Paoli Calmettes, Marseille, FRANCE, 7 Department of Thoracic Oncology, Hôpital 

Arnaud de Villeneuve, CHU de Montpellier, Montpellier, FRANCE, 8 Department 

of Pnuemology, Hôpital d’Instruction des Armées Sainte Anne, Toulon, FRANCE, 

9 Departement of Medicine, Institute Gustave Roussy, Villejuif, FRANCE 

Background: The phase II, open-label BRAIN study (ML21823; NCT00800202) is 

the first to assess the efficacy/safety of bevacizumab combined with chemotherapy in 

patients (pts) with ns-NSCLC and untreated CNS metastases. Investigation of CEC, 

CEP or CTC levels as potential markers of response to bevacizumab was undertaken. 

Methods: In the B + CP arm, blood samples were taken before treatment on day 1 

(d1) of cycle 1 (C1) (and 6 hrs after [C1 + 6h] treatment at one centre only), and on 

d1 of C2 and C3, i.e. 4 samples in total. Samples were taken for the B + E arm on d1 

of C1, C2 and C3 (3 samples total). CEC and CTC levels were measured with 

CellSearch (Immunicon, Veridex). CEP were measured using four-colour flow 

cytometry after enrichment of progenitor cells using Miltenyi Biotec EPC 

enumeration and enrichment kit. Cut-offs were 15 cells/4mL for CEC, 2 cells/7.5mL 

for CTC and median for CEP. Relation between marker levels and 6-month 

progression-free rate (PFR) and best overall response (BOR) was examined. 

Results: CEC and CTC were analysed in 69/91 (76%) pts, and CEP in 32/91 (35%) 

pts; baseline (BL) characteristics were similar to the overall population. CEC, CTC 

and CEP were detected at BL in 94%, 94% and 100% of these pts. In the B + CP 

group, CEC levels were increased at C1 + 6h, possibly reflecting the antivascular effect 

of chemotherapy. Furthermore, in the B + CP group, pts with higher BL CTC and no 

peak in CEC levels at C1 + 6h progressed at 6 months. Analysis of association of 

markers with BOR and PFR for the two regimens is ongoing. 

Conclusions: Measuring CEC, CTC and CEP is feasible in NSCLC. Detailed analyses 

will be presented. The clinical value of these markers for predicting response to 

bevacizumab in advanced ns-NSCLC patients warrants further investigation. 



CEC (cells/4mL) 

Median (range) 

C1 

cells/4mL 

C1 + 6h 

cells/4mL change 

from BL 

C2 


from BL 

C3 


from BL 

CTC (cells/7.5mL) 

n (%) 

C1 

< 2 cells/7.5mL 

≥ 2 cells/7.5mL 

C2 



C3 



CEP (133+ CEP/ 

1000 CD34+) 

Median (range) 

B + CP B + E 

Progression/death at 6 

Progression/death at 6 months months 

No 

(n = 28) 

(n = 27) 

24 (4–464) 

(n = 9) 

104 (12–632) 36 

(-336–72) 

(n = 24) 

24 (8–308) 

(n = 23) 

0 (-376–268) 

(n = 26) 

34 (0–228) 

(n = 25) 

4 (-440–208) 

No 

(n = 28) 

(n = 28) 

24 (85.7%) 

4 (14.3%) 

(n = 24) 

21 (87.5%) 

3 (12.5%) 

(n = 25) 

22 (88.0%) 

3 (12.0%) 

No 

(n = 12) 

C1 (n = 12) 

1.8 (0.0–4.3) 

C1 + 6h (n = 8) 

1.5 (0.0–7.8) 

C2 (n = 12) 

0.3 (0.0–5.8) 

C3 (n = 12) 

1.2 (0.0–8.7) 

Yes 

(n = 19) 

(n = 18) 

32 (0–184) 

(n = 7) 

28 (0–120) -16 

(-172–100) 

(n = 15) 

20 (0–216) 

(n = 14) 

-4 (-176–196) 

(n = 10) 

30 (0–464) 

(n = 10) 

10 (-172–444) 

Yes 

(n = 19) 

(n = 17) 

8 (47.1%) 

9 (52.9%) 

(n = 16) 

10 (62.5%) 

6 (37.5%) 

(n = 11) 

7 (63.6%) 

4 (36.4%) 

Yes 

(n = 9) 

(n = 9) 

1.6 (0.0–5.9) 

(n = 6) 

0.0 (0.0–0.5) 

(n = 7) 

0.0 (0.0–3.3) 

(n = 4) 

0.0 (0.0–1.5) 

No 

(n = 13) 

(n = 12) 

28 (8– 

108) 

– – 

(n = 12) 

34 (4– 

180) 

(n = 11) 

-4 (-72– 

160) 

(n = 11) 

28 (0–76) 

(n = 10) 

0 (-100– 

52) 

Yes 

(n = 8) 

(n = 8) 

44 (4–96) 

(n = 8) 

34 (0– 

356) 

(n = 8) 

-4 (-76– 

316) 

(n = 7) 

76 (0– 

244) 

(n = 7) 

28 (-20– 

No 

192) 

Yes 

(n = 13) (n = 8) 

(n = 12) (n = 8) 

10 7 (87.5%) 

(83.3%) 

2 (16.7%) 

1 (12.5%) 

(n = 11) (n = 8) 

9 (81.8%) 5 (62.5%) 

2 (18.2%) 3 (37.5%) 

(n = 12) (n = 6) 

12 (100%) 4 (66.7%) 

0 (0%) 2 (33.3%) 

No Yes 

(n = 7) (n = 4) 

(n = 7) 

0.0 (0.0– 

2.1) 

– – 

(n = 6) 

0.4 (0.0– 

3.2) 

(n = 7) 

0.7 (0.0– 

3.7) 

(n = 4) 

5.0 (0.2– 

7.1) 

(n = 4) 

0.3 (0.0– 

1.1) 

(n = 3) 

1.8 (0.0– 

3.4) 

Disclosure: H. Senellart: Financial Interest: Advisory Board. E. Dansin: Attended 

advisory boards for Roche, Lilly and Boehringer-Ingelheim. B. Besse: Received 

research grants from Roche. All other authors have declared no conflicts of interest. 

1241P A PLASMA PROTEOMIC SIGNATURE PREDICTS OUTCOMES 

IN A PHASE 3 STUDY OF GEMCITABINE (G) + CISPLATIN (C) 

± SORAFENIB IN FIRST LINE STAGE IIIB OR IV NSCLC 

J.F. Vansteenkiste 1 , L. Paz-Ares 2 , T.Q.G. Eisen 3 , D. Heigener 4 , W. Eberhardt 5 , 

M. Thomas 6 , C. Zhou 7 , A. Santoro 8 , C. Lathia 9 , H. Roder 10 

1 Respiratory Oncology Unit (Pulmonology), University Hospital Gasthuisberg, 

Leuven, BELGIUM, 2 Instituto de Investigaciones Biomédicas de Sevilla, 

University Hospital Virgen del Rocío, Seville, SPAIN, 3 Oncology, University of 

CambridgeAddenbrooke’s Hospital, Cambridge, UNITED KINGDOM, 4 Medical 

Oncology, Krankenhaus Großhansdorf, Grosshansdorf, GERMANY, 5 Department 

of Medical Oncology, West German Cancer Center, University Hospital Essen, 

Essen, GERMANY, 6 Department of Thoracic Oncology, University of Heidelberg, 

Heidelberg, GERMANY, 7 Lung Cancer Institute, Shanghai Pulmonary Hospital, 

Shanghai, CHINA, 8 Medical Oncology, Istituto Clinico Humanitas, Rozzano, 

ITALY, 9 Clinical Sciences, Bayer HealthCare Pharmaceuticals, Montville, NJ, 

UNITED STATES OF AMERICA, 10 Research and Development, Biodesix, Inc, 

Boulder, CO, UNITED STATES OF AMERICA 

Introduction: Previously presented results from NExUS, a Phase 3 study of sorafenib 

in combination with G + C (GC) vs placebo + GC in first line NSCLC patients, showed 

no improvement in overall survival (OS) and a small statistically significant 

improvement in progression free survival (PFS) for sorafenib + GC. VeriStrat® (V), 

a proteomic test using Matrix Assisted Laser Desorption/Ionization Time of Flight 

Mass Spectrometry (MALDI-TOF MS), was used in the present study to classify 

baseline plasma samples from NExUS patients into V Good (VG) and V Poor 

(VP) categories based on a pre-specified 8-peak mass spectral signature. The 

overall objective was to determine if V status was predictive of sorafenib + GC 

clinical activity. 

Methods: Patients with Stage IIIB or IV NSCLC, ECOG PS = 0 or 1, were 

randomized 1:1 to receive G (1250 mg/m 2 on Days 1 and 8) and C (75 mg/m 2 on 

Day 1) for up to six 21-day cycles, in combination with sorafenib 400 mg bid or 

placebo. V status was determined for 403 of 774 non-squamous patients. Analyses 

were performed blinded to clinical outcomes. PFS was compared between treatment 

arms within VP and VG groups. Hazard ratios (HR) and Kaplan-Meier curves were 

evaluated and multivariate analyses performed. 

Results: Consistent with previous reports, approximately 30% of subjects had VP 

status. PFS and HRs in treatment arms in patients with and without assigned V 

status were similar. VG status was associated with a longer PFS in placebo + GC 

patients (HR = 0.51, log-rank p

1243P IDENTIFICATION OF MICRORNA (MIRNA) SIGNATURES FOR 

RESPONSE AND SURVIVAL IN NON-SMALL CELL LUNG 

CANCER (NSCLC) PATIENTS (PTS) TREATED WITH 

CISPLATIN-VINORELBINE (CV): A ELCWP STUDY 

I. Cstoth 1 , T. Berghmans 1 , L. Willems 2 , M. Paesmans 3 , L. Ameye 3 , J. Lafitte 4 , 

A. Scherpereel 4 , A. Cortot 4 , C. Mascaux 1 , J. Sculier 5 

1 Thoracic Oncology, Institut Jules Bordet, Brussels, BELGIUM, 2 Molecular and 

Cellular Biology Laboratory, Gemboux Agro-Bio Tech, Gembloux, BELGIUM, 

3 Data Centre, Institute Jules Bordet, Brussels, BELGIUM, 4 Pneumology, CHU 

Lille, Lille, FRANCE, 5 Intensive Care and Thoracic Oncology, Institut Jules 


Background: Clinical variables, like stage and performance status (PS), have 

predictive and prognostic values in advanced NSCLC pts treated with chemotherapy, 

but not on an individual basis. As a secondary aim of a prospective study, we 

assessed the predictive (for response) and prognostic (for survival) values of miRNA 

expression in NSCLC pts treated by C (60 mg/m 2 D1) and V (25 mg/m 2 , D1 + 8) in 

1 st line chemotherapy. 

Methods: During the diagnostic bronchoscopy, a tumour biopsy was lysed into 

Tripure Isolation Reagent (Roche Diagnostics) on ice, snap frozen and stored at -80° 

C. miRNA expression was assessed using TaqMan Low Density Arrays (756 human 

miR panel, Applied Biosystems) and normalized using the delta delta CT method to 

RNU48 (SNORD48) CT value for every sample. Survival was measured from the 

registration date and response by WHO criteria. 

Results: From 180 pts screened between 04/2009 and 11/2011, 38 pts were eligible 

including 27 males, 26 pts with Karnofsky PS of 80-100, 20 adenocarcinomas and 30 

stage IV. Sixteen partial responses (43%) were observed. After stepwise selection, a 

two miRNA (miR-149 and miR-375) predictive signature for response to CV (AUC 

0.90, sensitivity 88%, negative predictive value 89%) which was related to 

progression-free survival (medians 12 and 17 months (ms), respectively, p = 0.047). 

Using a linear combination of the miRNA CT values with Cox’s regression 

coefficients as weights, a prognostic score for survival including 4 miRNA (miR-200c, 

miR-424, miR-29c and miR-124) was identified. The signature distinguished pts with 

good (n = 18) and poor (n = 20) prognosis with median survival of 47.3 months 

(95% CI 29.8-52.4) and 15.5 months (95% CI 9.1-22.8), respectively (p C SNP, 3R G > C SNP) and 

methylenetetrahydrofolate reductase (MTHFR) (C677T, A1298C). Progression-free 

survival (PFS) and overall survival (OS) were evaluated according to each genotype. 

Results: 103 patients with stage III-IV NSCLC (47% adenocarcinoma, 41% 

squamous cell carcinoma, 12% NOS) receiving platinum-based chemotherapy were 

eligible (14 patients with stage I-II were excluded). The median PFS was significantly 

longer in patients with C/T or T/T genotypes in codon 118 in ERCC1: 13 months 

(m) and 10 m, respectively, as compared to 6 m for the C/C patients (p = 0.034). 

Patients with ERCC1 C/T or T/T genotypes had a trend to longer median OS (20 m) 

than those C/C (10.5 m; p = 0.1). Subgroup analysis revealed that ERCC1 C/T or T/T 

genotypes were associated with increased PFS in male (p = 0.005), smokers (p = 


0.036) and age


1246P RANDOMISED PHASE II STUDY OF AXITINIB OR 

BEVACIZUMAB COMBINED WITH PACLITAXEL/ 

CARBOPLATIN (PAC/CARB) AS FIRST-LINE THERAPY FOR 

PATIENTS (PTS) WITH ADVANCED NON–SMALL CELL LUNG 


C. Twelves 1 , E. Chmielowska 2 ,L.Havel 3 , S. Popat 4 , A. Swieboda-Sadlej 5 , 

P. Sawrycki 6 , P. Bycott 7 , A. Niethammer 8 , P. De Besi 9 , J.H. Schiller 10 

1 Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine & St 

James’s Institute of Oncology, Leeds, UNITED KINGDOM, 2 Onkologii, Oddzial 

Kliniczny Onkologii Centrum Onkologii Bydgoszcz, Bydgoszcz, POLAND, 

3 Pneumology- Budinova 2, Fakultni Nemocnice Na Bulovce, Phaha, CZECH 

REPUBLIC, 4 Department of Medicine, Royal Marsden HospitalNHS Foundation 

Trust, London, UNITED KINGDOM, 5 Oncology, Samodzielny Publiczny Centralny 

Szpital Kliniczny, Warsaw, POLAND, 6 Oddzial Chemioterapii Nowotworow, 

Wojewodzki Szpital Zespolony, Torun, POLAND, 7 Biostatistics, Pfizer Oncology, 

San Diego, UNITED STATES OF AMERICA, 8 Pfizer Global Research and 

Development, Pfizer Oncology, San Diego, UNITED STATES OF AMERICA, 9 Clinical 

Oncology, Pfizer Italia Srl, Milano, ITALY, 10 Hematology/Oncology, University of 

Texas Southwestern Medical Center, Dallas, UNITED STATES OF AMERICA 

Background: Axitinib is a potent and selective second-generation inhibitor of 

vascular endothelial growth factor receptors 1, 2, and 3, with promising single-agent 

activity in advanced NSCLC. This study evaluated the efficacy and safety of axitinib 

+ pac/carb vs bevacizumab + pac/carb in advanced non-squamous NSCLC. 

Methods: Pts with stage IIIB with pleural effusion or stage IV non-squamous 

NSCLC without prior systemic therapy (except adjuvant therapy >12 mo prior to 

enrolment) were stratified by prior adjuvant therapy and gender, and randomised 1:1 

to receive axitinib (5 mg twice daily) or bevacizumab (15 mg/kg every 3 wks [q3w]) 

plus pac/carb (200mg/m 2 /AUC 6 mg/mL x min q3w). The primary endpoint was 

progression-free survival (PFS). 

Results: Pt baseline characteristics in the axitinib (n = 58) and bevacizumab (n = 60) 

arms were well balanced: 38% were female, 31% vs 30% were current smokers, 

respectively. Median PFS (95% confidence interval [CI]) was 5.7 mo (4.1–7.5) in the 

axitinib vs 6.1 mo (4.2–8.7) in the bevacizumab arms (hazard ratio [HR] 1.09, 95% CI 

0.68–1.76; 1-sided stratified P = 0.64). Median overall survival (95% CI) was 10.6 mo (7.5– 

16.4) and 13.3 mo (10.4–17.6), respectively, in the axitinib vs bevacizumab arms (HR 

1.12, 95% CI 0.74–1.69; 1-sided stratified P = 0.70). Objective response rates (95% CI) 

were 29.3% (18.1–42.7) and 43.3% (30.6–56.8) and duration of response was 4.4 and 7.0 

mo for the axitinib and bevacizumab arms, respectively. Common treatment-emergent 

all-causality adverse events (AEs) with axitinib + pac/carb vs bevacizumab + pac/carb, 

respectively, were diarrhoea (47% vs 34%), alopecia (36% vs 46%), hypertension (43% vs 

42%), decreased appetite (43% vs 22%), fatigue (34% vs 39%), nausea (36% vs 32%), and 

neutropenia (31% vs 27%). Neutropenia was the most common grade 3/4 AE in both 

treatment arms. More pts in the axitinib arm discontinued treatment due to AEs than in 

the bevacizumab arm (41% vs 31%, respectively). 

Conclusions: Axitinib + pac/carb did not improve efficacy compared with bevacizumab 

+ pac/carb, and was less well tolerated in pts with advanced non-squamous NSCLC. 

Disclosure: C. Twelves: I am an advisor/board member for Pfizer and Genentech/ 

Roche, received honorarium from Pfizer, and honorarium from Speaker’s Bureau 

from Genentech/Roche. S. Popat: I am a consult for Roche and Pfizer and received 

honoraria from Roche and Pfizer. P. Bycott: I am a full-time employee of Pfizer Inc 

and own Pfizer stocks. A. Niethammer: I am a full-time employee of Pfizer and own 

Pfizer stocks. P. De Besi: I am a conusltat for Pfizer Italia Srl. J.H. Schiller: I am a 

consultant for Pfizer and Genentech and received grants/research support from 

Pfizer and Genentech. All other authors have declared no conflicts of interest. 

1247P RANDOMISED PHASE II TRIAL OF ORAL VINORELBINE (N) 

AND CISPLATIN (P) OR PEMETREXED AND C (PC) IN FIRST 

LINE ADVANCED NON SQUAMOUS (NSCC) NON SMALL 

CELL LUNG CANCER (NSCLC) PATIENTS (PTS). 

NAVOTRIAL01: FINAL RESULTS 

E.H. Tan 1 ,L.Havel 2 , M.J. Krzakowski 3 , J. Kollmeier 4 , R. Gervais 5 , E. Dansin 6 , 

M. Serke 7 , S. Malassé 8 , F. Biville-Hedouin 9 , J. Bennouna 10 

1 Medical Oncology, National Cancer Institute, Singapore, SINGAPORE, 

2 Pneumology- Budinova 2, Fakultni Nemocnice Na Bulovce, Phaha, CZECH 

REPUBLIC, 3 Lung & Thoracic Tumors Dept, MSC Memorial Cancer Centre and 

Institute Maria Sklodowska Curie, Warsaw, POLAND, 4 Oncology/pneumology, 

Helios Clinic Emil von Behring, Berlin, GERMANY, 5 Pneumology, Centre François 

Baclesse, Caen, FRANCE, 6 Pneumology, Centre Oscar Lambret, Lille, FRANCE, 

7 Pneumology, Lungenklinik Hemerdes Deutschen 

Gemeinschafts-Diakonieverbandes GmbH, Hemer, GERMANY, 8 Statistical 

Department, Institut de Recherche Pierre Fabre, Boulogne Billancourt, FRANCE, 

9 Medical Affairs Oncology, Institute de Recherche Pierre Fabre, Boulogne 

Billancourt Cedex, FRANCE, 10 Oncology/ Pneumology, Institut de Cancerologie 

de l’Ouest-site René Gauducheau, Nantes, FRANCE 

Background: Individualized treatments in NSCLC are now based on molecular 

and/or histological data. This randomized trial (2/1) was set up to assess the 

efficacy of NC compared to PC for pts with nSCC. The primary end-point was 

disease control rate (DCR) including overall response rate (ORR) and stable 

disease (SD). 

Methods: Pts received N60-80 mg/m 2 D1, D8 + C80 mg/m 2 D1 or P500 mg/m 2 + 

C75 mg/m 2 D1 for 4 cycles q3w; pts with DCR received single agent continuation 

maintenance (CM) until progression or toxicity. 

Results: From 10/09 to 02/11, 151 pts were treated with NC or PC. 

ITT = 151 

NC 

n = 100 

PC 

n=51 

Male/Stage IV (%) 62.0/87.0 64.7/88.2 

Median age (y, range) 61.0 (38.4-75.1) 63.8 (40.3-75.5) 

Combination: (%) ITT(95% CI) 

DCR 75.0 (65.3-83.1) 74.5 (60.4-85.7) 

ORR 21.0 (13.5-30.3) 23.5 (12.8-37.5) 

Combination + CM:(%) ITT (95% CI) n= 53 n = 33 

DCR 75 (65.3-83.1) 76.5 (62.5-87.2) 

ORR 24 (16.0-33.6) 31.4 (19.1-45.9) 

Median PFS ITT (m,range) 4.2 (3.6-4.7) 4.2 (3.2-5.6) 

PFS ITT at 6/12/18m (%) 33.0/10.3/5.5 27.5/7.4/2.5 

Median OS ITT (m,range) 10.6 (7.8-12.1) 10.8 (7.0-14.5) 

Related toxicities G3/4 (%pts) NC/PC during Combination: anemia 9.0(G3)/8.2, 

leucopenia 26.0/10.2, neutropenia 44.0/18.3, febrile neutro 2.0/2.0, thrombocytopenia 

0/6.1, fatigue(G3) 7.0/3.9, hyperglycemia 4.0/7.8, nausea(G3) 5.0/0, vomiting(G3) 7.0/ 

2.0, stomatitis(G3) 0/2.0, pneumonia(G3) 0/2.0, deep vein thrombosis(G3) 0/2.0, 

pulmonary embolism(G4) 0/2.0. During Maintenance: anemia 5.0/4.1, leucopenia 

2.0/10.2, neutropenia 11.0/20.4, febrile neutro 3.8/0, fatigue (G3) 3.8/0, stomatitis 

(G3) 1.9/ 3.0, pain 3.8/6.0, Respiratory disorders 0/4.0, deep vein thrombosis (G3)0/ 

2.0. Deaths potentially related to CT 2/1. 

Conclusions: NC and PC had similar efficacy. In the present economic context, the 

acquisition cost of the two platinum based doublets should be considered in the 

treatment decision making of pts with advanced nSCC NSCLC. 

Disclosure: S. Malassé: Statistician of the study Employment for the sponsor. F. 

Biville-Hedouin: Medical Project Manager of the study Employment for the sponsor. 


1249P FINAL RESULTS OF A RANDOMIZED, DOUBLE-BLIND 

PHASE II STUDY TO COMPARE NITROGLYCERIN (N) PLUS 

ORAL VINORELBINE (NVBO) PLUS CISPLATIN (C) WITH 

PLACEBO (P) PLUS NVBO PLUS C IN PATIENTS (PTS) WITH 

STAGE IIIB/IV NON-SMALL CELL LUNG CANCER (NSCLC) 

M. Reck 1 , A. Meyer 2 , D. Hartwigsen 3 , C. Schaeper 4 , R. Skock-Lober 5 , A. Bier 6 , 

G. Huebner 7 , U. Gereke 8 , C. Rose 9 , C.P. Held 10 

1 Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, GERMANY, 2 Klinik 

Fuer Pneumologie, Kliniken Maria Hilf Moenchengladbach, Moenchengladbach, 

GERMANY, 3 Medizinische Klinik I, Malteser Krankenhaus St. Franziskus - 

Hospital Flensburg, Flensburg, GERMANY, 4 Klinik fuer Innere Medizin B, 

Universitaetsmedizin Greifswald, Greifswald, GERMANY, 5 Klinik fuer 

Pneumologie, Helios Klinikum Schwerin, Schwerin, GERMANY, 6 Zentrum fuer 

Innere Medizin, Abteilung fuer Pneumologie, Universitaetsklinikum Rostock, 

Rostock, GERMANY, 7 Klinik Oldenburg, Klinik fuer Innere Medizin, Sana Kliniken 

Ostholstein, Oldenburg, GERMANY, 8 Klinik fuer Haematologie und Onkologie, 

Hanse-Klinikum Stralsund, Stralsund, GERMANY, 9 Onkologie, Pierre Fabre 

Pharma GmbH, Freiburg, GERMANY, 10 Clinical Science, GMIHO mbH, Berlin, 

GERMANY 

Background: Yasuda (JCO 2006) reported increased ORR, TTP and OS when adding 

N to the combination of i.v. vinorelbine (NVBiv) + C in pts with stage IIIB/IV 

NSCLC probably due to better drug delivery based on changed vascular tonus. 

NVBo and NVBiv have comparable efficacy with a more convenient administration 

of the oral form. Main study objective was the confirmation of the Asian results in a 

Caucasian population. 

Methods: In the experimental arm pts received N 25 mg D-3 to D2 + NVBo (60) 80 

mg/m 2 D1, D8 + C 80 mg/m 2 D1, q3w; in the control arm pts received P D-3 to D2 

+ NVBo (60) 80 mg/m 2 D1, D8 + C 80 mg/m 2 D1, q3w. Treatment continued until 

PD, unacceptable toxicity (tox) or pts wish to discontinue treatment. The primary 

endpoint was ORR, secondary endpoints included OS, PFS and safety. To show an 

ORR-increase from 40 to 70% with a power of 0.80 and a two-side alpha of 0.05 the 

planned sample size was 100 pts. 

Results: From 10/07 to 05/10, 68 pts were randomised to the N-arm (35 pts) or 

P-arm (33 pts). 66 pts were treated (N-arm: 34 pts, P-arm: 32 pts). The study was 

stopped prematurely due to lack of recruitment. 


N-arm 

n=34 

P-arm 

n=32 

All 

n=66 

Male (%) 76.5 68.8 72.7 

Median age 

(y, range) 

63.0 (36-82) 62.5 (33-73) 62.5 (33-82) 

Median Karnofsky 

(%, range) 

90 (70-100) 90 (70-100) 90 (70-100) 

Smoker (%) 

non/former/current 

8.8/41.2/50.0 15.6/40.6/43.8 12.1/40.9/47.0 

Squamous/adeno (%) 55.9/44.1 46.9/34.4 51.5/39.4 

IIIB/IV/local relapse (%) 32.4/64.7/2.7 34.4/65.6/0 33.3/65.2/1.5 

Median N cycles 

(n, range) 

4.5 (1-8) 4.0 (1-6) 4.0 (1-8) 

ORR ITT (%) 

35.3 18.8 27.3 

95%CI 

(19.7-53.5) 

p = 0.171 

(7.2-36.4) 

ORR eval (%) 

37.5 22.2 30.5 

95%CI (n = 32/27/59) 

(21.1-56.3) 

p = 0.262 

(8.6-42.3) 

DCR ITT (%) 61.8 53.1 57.6 

Median TTP (mo) 4.7 5.0 4.8 

Median OS (mo) 11.0 12.1 11.5 

Tox G3-4 >5% (%pts): N-arm: neutropenia 32.3, leucopenia 20.6, anemia 14.7, nausea 

8.8 (G3), fatigue 5.9 (G3), pneumonia 5.9 (G3). P-arm: neutropenia 43.8, leucopenia 

25.0, fatigue 9.4 (G3), nausea 9.4 (G3), anemia 6.3, vomiting 6.3. 1 case of febrile 

neutropenia G3 (N-arm). 2 deaths potentially related to chemotherapy (1 per arm). 

Conclusions: The oral formulation of Vinorelbine + C achieved in both arms a high 

level of efficacy (all pts: ORR 27.3, DCR 57.6, TTP 4.8, OS 11.5). Despite the 

premature discontinuation and low sample size per group, the results seem to 

confirm previous data reported in Asian patients, with an ORR numerically higher in 

the N-arm but without significance. 

Disclosure: M. Reck: Honoraria for lectures: Lilly, Roche, AstraZeneca, 

Daiichi-Sankyo Advisory Board: Lilly, Roche, AstraZeneca, Daiichi-Sankyo, BMS, 

Pfizer, Genentech. C. Rose: Employed by Pierre Fabre Pharma GmbH. All other 


1250P DISRUPT: A RANDOMIZED PHASE 2 TRIAL OF OMBRABULIN 

(AVE8062) COMBINED WITH A TAXANE-PLATINUM REGIMEN 

IN THE FIRST-LINE TREATMENT OF METASTATIC 

NON-SMALL CELL LUNG CANCER (NSCLC) 

J. von Pawel 1 , V. Gorbounova 2 , M. Reck 3 , D. Kowalski 4 , A. Allard 5 , M. Chadjaa 6 , 

A. Rey 6 , J. Bennouna 7 , F. Grossi On Behalf of The Disrupt Investigators 8 

1 Department of Medicine III, Asklepios Fachkliniken, Muenchen, GERMANY, 

2 Oncology, Cancer Research Centre, Moscow, RUSSIAN FEDERATION, 

3 Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, GERMANY, 

4 Oncology, Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, 

POLAND, 5 Bio Stats, Sanofi, Chilly-Mazarin, FRANCE, 6 Clinical, Sanofi, 

Vitry-sur-Seine, FRANCE, 7 Medical Oncology, Institut de Cancérologie de 

l’Ouest, Herblain, FRANCE, 8 Lung Cancer Unit, National Institute for Cancer 

Research, Genova, ITALY 

Introduction: Ombrabulin is a vascular disrupting agent and analogue of 

combretastatin A4 that damages established tumor vasculature, which causes tumor 

necrosis and regression. DISRUPT (NCT01263886) evaluated whether adding 

ombrabulin to a taxane-platinum doublet in the first-line setting improves outcomes 

in patients with metastatic NSCLC. 

Methods: Patients (≥18 yrs of age, ECOG PS 0–1, stage IV) were randomized 1:1 to 

either ombrabulin 35 mg/m 2 or placebo (Pbo) on day 1 followed by a taxane-platinum 

regimen on day 2 (docetaxel 75 mg/m 2 + cisplatin 75 mg/m 2 or paclitaxel 200 mg/m 2 

+ carboplatin AUC 6), every 3 weeks. Randomization was stratified by histology 

(squamous/nonsquamous) and taxane-platinum regimen. Treatment was continued 

up to 6 cycles, or until unacceptable toxicity, disease progression, or consent 

withdrawal. The primary endpoint was progression-free survival (PFS) (stratified 

log-rank analysis; one-sided significance level 0.2). The study had 92% power to detect 

a 33% risk reduction in the hazard rate for progression (HR 0.67). Secondary 

endpoints included overall survival (OS), response rate (RR), and safety. 

Results: From February 2011 to January 2012, a total of 176 patients were 

randomized (n = 88 in each group). Groups were balanced in terms of baseline 

characteristics. Overall, the median age was 62 yrs (range, 32 – 84), 76% were male, 

66% were nonsquamous and 34% squamous, 52% received paclitaxel-carboplatin and 

48% docetaxel-cisplatin. PFS was analyzed after 124 events (61 ombrabulin; 63 Pbo); 

median follow-up was 8 months. PFS was not significantly improved in the 

ombrabulin group versus Pbo (median 5.7 vs 5.5 months, respectively; HR 0.95; 60% 

CI 0.81–1.11; one-sided p = 0.39). Overall RR were similar (ombrabulin 32%; Pbo 

31%). Median OS was 11.0 months in both arms. Safety profiles were comparable; 

rates of grade 3-4 adverse events were 57% for ombrabulin and 52% for Pbo. 


Conclusions: This randomized phase 2 trial of ombrabulin combined with a 

platinum-taxane regimen did not meet the primary endpoint of improving PFS 

compared with Pbo in the first-line treatment of metastatic NSCLC. Study sponsored 

by Sanofi. 

Disclosure: J. von Pawel: Member of Sanofi Steering Committee. V. Gorbounova: 

Member of advisory board: Novartis and Pfizer Honoraria for lectures: Hoffman La 

Roche. M. Reck: Ad board membership: Lilly, Hoffmann-La Roche, Daiichi-Sankyo, 

Pfizer, AstraZeneca, BMS Honoraria for lectures: Lilly, Hoffmann-La Roche, 

Daiichi-Sankyo, AstraZeneca. A. Allard: Sanofi employee. M. Chadjaa: Sanofi employee 

and stock holder. A. Rey: Sanofi employee and stock held. J. Bennouna: Advisory 

board: Sanofi-Aventis. F. Grossi On Behalf of The Disrupt Investigators: Membership 

on advisory board: Sanofi. All other authors have declared no conflicts of interest. 

1251P FRONT-LINE CHEMOTHERAPY WITH OR WITHOUT 

NGR-HTNF IN NON-SMALL CELL LUNG CANCER (NSCLC) 

V. Gregorc 1 , N. Zilembo 2 , F. Grossi 3 ,T.DePas 4 , F. Pietrantonio 2 , M. Giovannini 4 , 

G. Rossoni 1 , A. Bulotta 1 , A. Lambiase 5 , C. Bordignon 5 

1 Oncologia, IRCCS San Raffaele, Milano, ITALY, 2 Department of Oncology, 

IRCCS Fondazione Istituto Nazionale dei Tumori, Milan, ITALY, 3 Lung Cancer 

Unit, Istituto Nazionale per la Ricerca sul Cancro, Genoa, ITALY, 4 Unit of 

Respiratory Tract and Sarcomas, Istituto Europeo di Oncologia, Milan, ITALY, 

5 Clinical Development, MolMed, Milan, ITALY 

Background: NGR-hTNF (asn-gly-arg-human tumor necrosis factor) is a selective 

vascular targeting agent able to improve intratumoral chemotherapy uptake. 

Methods: After stratification by histology (nonsquamous or squamous) and PS (0 or 

1), previously untreated patients (pts) with advanced NSCLC were randomly 

assigned to receive cisplatin 80 mg/m 2 /d1 plus either pemetrexed 500 mg/m 2 /d1 

(nonsquamous) or gemcitabine 1,250 mg/m 2 /d1 + 8 (squamous) q3w for 6 cycles 

with (arm A) or without (arm B) NGR-hTNF 0.8 µg/m 2 /d1 q3w given until 

progression. Progression-free survival (PFS) was primary endpoint of this phase 2 

trial (β = 20%, α = 20%, n = 102). Secondary endpoints included adverse events (AEs), 

overall survival (OS), and response rate (RR). 

Results: Baseline characteristics in arm A (n = 61) v B (n = 58): median age 62 v 63 

years; male 36 v 38; PS of 1 22 v 22; squamous 17 v 16; nonsmokers 19 v 14; EGFR 

mutations 5 v 5. For the nonsquamous stratum, 295 cycles were given in A (mean 

6.9; range 1-18) and 192 in B (4.8; 1-6), while for the squamous stratum, 95 in A 

(6.3; 1-24) and 49 in B (3.5; 1-6). The rates of grade 3 to 4 AEs were comparable in 

arm A v B: neutropenia 14% v 17% and fatigue 7% v 11%. Neither grade 3 to 4 AEs 

related to NGR-hTNF nor bleeding in pts with squamous histology were noted. With 

a median follow-up of 16.4 months for all pts, median PFS was 5.8 v 5.6 months, 

1-year OS rate was 58% v 56%, and RR was 25% v 21% in arm A v B, respectively. 

For the nonsquamous stratum, trends toward higher 6-month PFS rates for arm A v 

B were noted in pts with PS 1 (65% v 33%), nonsmoking history (59% v 33%), 

younger age (64% v 30%), and EGFR mutations (75% v 25%). Similarly, in these pts 

the 1-year OS rates were: PS 1 (60% v 56%), nonsmoking history (77% v 65%), 

younger age (75% v 63%), and EGFR mutations (100% v 50%). For the squamous 

stratum, median PFS was 5.6 v 4.3 months (HR = 0.71) and median OS was 14.2 v 

10.2 months (HR = 0.54) for arm A v B, respectively. In these pts, RR was 36% for 

arm A and 23% for arm B, while median changes from baseline in target tumor size 

after 2, 4, and 6 cycles were -27%, -39%, and -33%, respectively for arm A, and -18%, 

-22%, and -14%, respectively for arm B. 

Conclusion: NGR-hTNF can be safely given with standard chemotherapy and may 

have therapeutic potential in squamous NSCLC 

Disclosure: A. Lambiase: Employment - MolMed. C. Bordignon: Employment - 


1252P ACTIVITY OF AFATINIB IN UNCOMMON EPIDERMAL 

GROWTH FACTOR RECEPTOR (EGFR) MUTATIONS IN 

LUX-LUNG 3, A PHASE III TRIAL OF AFATINIB OR 

CISPLATIN/PEMETREXED IN EGFR MUTATION-POSITIVE 

LUNG CANCER 

J.C. Yang 1 , M. Schuler 2 , N. Yamamoto 3 , K.J. O’Byrne 4 , V. Hirsh 5 , T.S.K. Mok 6 , 

D. Massey 7 , V. Zazulina 8 , M. Shahidi 8 , L.V. Sequist 9 

1 Oncology, National Taiwan University Hospital, Taipei, TAIWAN, 2 Medicine, West 

German Cancer Center, University Duisburg-Essen, Essen, GERMANY, 

3 Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, JAPAN, 4 Oncology, St 

James’s Hospital, Dublin, IRELAND, 5 Oncology, McGill University Health Centre, 

Montreal, QC, CANADA, 6 Clinical Oncology, The Chinese University of Hong 

Kong, Hong Kong, CHINA, 7 Statistics, Boehringer Ingelheim, Bracknell, UNITED 

KINGDOM, 8 Clinical Research / Management, Boehringer Ingelheim, Bracknell, 

UNITED KINGDOM, 9 Medicine, Massachusetts General Hospital, Boston, MA, 


Background: Afatinib (A) is an irreversible ErbB family blocker of EGFR (ErbB1), 

HER2 (ErbB2) and ErbB4 with in vitro activity against activating and resistant EGFR 

mutations. LUX-Lung 3 demonstrated superiority of A vs cisplatin/pemetrexed (CP) 



in 345 treatment-naive pts with EGFR mutation-positive NSCLC; median 

progression-free survival (PFS) 11.1 vs 6.9 mo, HR 0.58, p = 0.0004 (ITT cohort) and 

13.6 vs 6.9 mo, HR = 0.47, p < 0.0001 for pts with common (Del19/L858R) mutations 

(n = 308). Here we present data from pts with uncommon EGFR mutations, detected 

by central EGFR screening assay (Theracreen29). 

Methods: All pts (n = 345) were stratified according to mutation (Del19, L858R, 

other) and randomized 2:1 to oral A 40 mg daily or IV CP (75 mg/m 2 + 500 mg/m 2 

q21 days up to 6 cycles) until progression. Other mutations were categorized into 5 

groups: T790M, G719X, S768I, exon 20 insertions, L861Q; the first 3 groups 

included double mutant pts. PFS, best overall response and tumour shrinkage by 

independent review were described per pt within these 5 groups. 

Results: Uncommon mutations comprised 10.7% (n = 37, A: 26, CP: 11) of the trial 

population. Breakdown into the 5 groups was: de novo T790M (A:11, CP:2), exon 20 

insertions (A:6, CP:3), G719X (A:3, CP:3), L861Q (A:3, CP:3), S768I (A:3, CP:0). 

Baseline imbalances between the A and CP arms were noted for smoking status 

(never smoker 65% vs 82%, respectively) and presence of brain (27% vs 0%) and 

liver metastases (27% vs 18%). Of 32 pts with target lesions, 19/23 on A and 8/9 on 

CP had measurable shrinkage. The small size of the uncommon mutation cohort, its 

molecular heterogeneity and numeric imbalances within genetic subgroups limited 

formal statistical analyses. Tumour response and prolonged PFS were noted in 

A-treated pts with L858R + T790M (1PR, 11.0 mo; 3SD, 9.6+ mo, 8.5 mo and 6.7 

mo); L861Q (1SD, 8.3 mo); G719X (1PR, 10.8 mo); S768I + L858R (1PR, 13.8+ mo); 

S768I (1PR, 19.2+ mo). 

Conclusions: RECIST responses and prolonged disease control were observed in pts 

with most types of uncommon EGFR mutations. The efficacy of A in uncommon 

EGFR mutations should be explored in larger cohorts in future studies. 

Disclosure: J.C. Yang: James Chih-Hsin Yang has received honorarium for speech 

and advisory roles from Astrazeneca, Roche, Pfizer, OSI. He was the advisor for 

Boehringer Ingelheim and Eli Lilly without payment. M. Schuler: Paid consultancy/ 

advisory relationship with: Boehringer Ingelheim; Research funding from: Boehringer 

Ingelheim; Travel support from: Lilly. K.J. O’Byrne: Paid consultancy/advisory 

relationship with: Boehringer Ingelheim, Lilly Oncology; Honoraria from Boehringer 

Ingelheim, Lilly Oncology; Research funding from Boehringer Ingelheim; Other 

remuneration from Boehringer Ingelheim, Lilly Oncology. V. Hirsh: Honoraria from 

the Boehringer Ingelheim Advisory Board. T.S.K. Mok: Paid consultancy/advisory 

relationship with and honoraria from: AstraZeneca, Roche, Eli Lilly, Merck Serono, 

Eisai, BMS, BeiGene, AVEO, Pfizer, Taiko, Boehringer Ingelheim; Research funding 

from: AstraZeneca. D. Massey: Employee of Boehringer Ingelheim. V. Zazulina: 

Employee of Boehringer Ingelheim. M. Shahidi: Employee of Boehringer Ingelheim. 

L.V. Sequist: Paid consultancy/advisory relationship with: Boehringer Ingelheim, 

Daiichi-Sankyo, Merrimack, Clovis and Celgene; Research funding from: Boehringer 

Ingelheim. All other authors have declared no conflicts of interest. 

1253P DOES GEFITINIB RE-CHALLENGE OR TREATMENT BEYOND 

PROGRESSION (TBP) PROLONG SURVIVAL OF NSCLC 

PATIENTS? - REAL WORLD EVIDENCE FROM GEFITINIB 

TREATMENT RESPONDERS 

Y. Namba 1 , F. Imamura 2 , S. Morita 3 , M. Mori 1 , K. Komuta 4 , T. Kijima 5 , 

Y. Nakazawa 1 , S. Yokota 1 , S. Yamamoto 4 , A. Kumanogoh 5 

1 Department of Thoracic Oncology, National Hospital Organization Toneyama 

National Hospital, Toyonaka, JAPAN, 2 Department of Thoracic Oncology, Osaka 

Medical Center for Cancer and Cardiovascular Diseases, Osaka, JAPAN, 

3 Biostatistics and Epidemiology, Yokohama City University Medical Center, 

Yokohama, JAPAN, 4 Department of Thoracic Oncology, Osaka Police Hospital, 

Osaka-City, JAPAN, 5 Department of Thoracic Oncology, Osaka University 

Graduate School of Medicine, Suita, JAPAN 

Background: After gefitinib was approved in July 2002, several patients have 

experienced long-term survival in the clinical setting. However, it is not yet clear 

which factor of treatment strategy is contributing to the long-term survival. 

Methods: We extracted information from medical records of advanced NSCLC 

patients with the following inclusion criteria: 1) Japanese patients who were 

diagnosed by October 2010 and treated with gefitinib after July 2002. 2) Performance 

status (PS) 0-2. 3) PR, CR, or long SD (6 months or more) by gefitinib. 4) Patients 

who had not received curative surgical operation or radiation therapy. The primary 

objective was to evaluate the effects of treatment histories on Overall Survival (OS). 

We also conducted a “Dynamic Treatment Regimen Analysis (DTRA)” to identify 

the key treatment strategy contributing to long-term survival. DTRA included 

baseline clinical factors (sex, age, stage, histology, PS, smoking) and time-dependent 

clinical factors (PS, pretreatment). 

Results: A total of 335 NSCLC patient details were extracted. The mean age was 64.8 

years and 90.3% had adenocarcinoma histology. Sixty five patients experienced 

gefitinib re-challenge and 93 patients experienced gefitinib Treatment Beyond 

Progression (TBP). There was a statistical difference in OS between gefitinib 

re-challenge group and non re-challenge group (median OS was 1272 days vs 774 

days; p < 0.001), Comparison of gefitinib TBP group and non TBP group also 

showed statistical difference (median OS was 1016 days vs 797 days; p = 0.035). Next, 

a cox regression model to investigate potential factors showed that “gefitinib 

re-challenge” was a factor which significantly contributed to long-term OS (HR: 

0.515, 95%CI: 0.363-0.731; p = 0.0002) whereas “gefitinib TBP“ was not (HR: 0.787, 

95%CI: 0.571-1.084; p = 0.1427). We confirmed this result using DTRA, The DTRA 

strongly supported the significant contribution of the gefitinib re-challenge treatment 

strategy to longer OS time. 

Conclusion: This retrospective cohort that gefitinib re-administration may have a 

significant impact on OS in long surviving patients who experienced response to 

gefitinib. 


1254P POOLED ANALYSIS OF CLINICAL OUTCOMES FOR 

PATIENTS WITH EGFR MUTATIONS IN NON-SMALL-CELL 

LUNG CANCER: AN UPDATE 

L. Paz-Ares 1 , D. Soulières 2 , B. Klughammer 3 , I. Bara 4 , J. Moecks 5 , T.S.K. Mok 6 

1 Oncology Service, Hospital Universtario Virgen del Rocío, Seville, SPAIN, 

2 Haematology and Medical Oncology, Centre Hospitalier de l’Université de 

Montréal, Montréal, CANADA, 3 Pharmaceutical Division, F. Hoffmann-La Roche 

Ltd., Basel, SWITZERLAND, 4 Global Medical Affairs Oncology, F. Hoffmann-La 

Roche Ltd., Basel, SWITZERLAND, 5 Biomathematics, BIOMCON GmbH, 

Mannheim, GERMANY, 6 Department of Clinical Oncology, Chinese University of 

Hong Kong Prince of Wales Hospital, Shatin, Hong Kong, CHINA 

Background: In 2010, the results of a pooled analysis examining the correlation of 

EGFR mutations with clinical outcome were reported [1]; EGFR TKIs appeared to be 

the most effective treatment for EGFR mutation-positive NSCLC. Since this report, 

more trials (including large controlled phase III studies) have been published, doubling 

the number of eligible patients. An updated analysis was carried out to provide a 

comprehensive dataset assessing the treatment of EGFR mutation-positive NSCLC. 

Methods: Congress reports and papers reporting progression-free survival (PFS) 

for EGFR mutation-positive NSCLC treated with chemotherapy, erlotinib or 

gefitinib (phase II/III studies/retrospective analyses) were identified in a literature 

search and checked for duplication. Most papers report high level results e.g. 

median PFS. Calculations were based on simplifying assumptions to allow for 

pooling of results and to obtain an accuracy estimate (surrogate for confidence 

intervals). The pooled median PFS, MPFS(all), was estimated by a study-size N (i) 

weighted average: MPFS(all)= 1/N(all)∑N(i)MPFS(i). The potential for publication 

bias was assessed using funnel plots. Permutation testing will be carried out. For 

full methodology see [1]. 

Results: Data were included from 20 chemotherapy studies (n = 984; updated from n 

= 375 [1]), 27 erlotinib studies (n = 735; from n = 365 [1]), and 56 gefitinib studies 

(n = 1843; from n = 1069 [1]). Longer PFS was seen with both EGFR TKIs compared 

with chemotherapy across treatment lines (Table). 

Conclusion: In the past three years, several important studies have examined EGFR 

TKI therapy in patients with EGFR mutation-positive NSCLC. This updated dataset 

provides a comprehensive picture of treatment outcomes in this patient subset, 

confirming that this subgroup derives a greater benefit from EGFR TKIs than from 

conventional chemotherapy, especially when administered as first line. [1] Paz-Ares J 

Cell Mol Med 2010 

Pooled median PFS (95% accuracy interval) for patients with EGFR 

mutation-positive tumours 

Single-agent erlotinib 

All lines of therapy (n = 735) 12.4 months (11.6–13.4) 

*Predominantly first-line (n = 354) 12.0 months (10.8–13.3) 

Single-agent gefitinib 



Chemotherapy (may be single- or multiple-agent 

treatment) 



*Predominantly first-line is ≥90% of patients treated in first-line setting 

Disclosure: L. Paz-Ares: Advisory board: Roche. D. Soulières: Advisory board: 

Roche, Boehringer Ingelheim. B. Klughammer: Stock ownership: F. Hoffmann-La 

Roche Ltd Employed by F. Hoffmann-La Roche Ltd. I. Bara: Employed by 

F. Hoffmann-La Roche Ltd. J. Moecks: Corporate sponsored research in 

biomathematics for Roche in several fields Former employee of F. Hoffmann-La 

Roche Ltd. T.S.K. Mok: Advisory board:AstraZeneca, Roche, Eli Lilly, Merck Serono, 

Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, BI, GSK Biologicals On the Board of 

Directos for IASLC Corporate sponsored research for AstraZeneca Employed by The 

Chinese University of Hong Kong 


1255P POPULATION BASED EVALUATION OF CHEMOTHERAPY 

USE AFTER FIRST LINE GEFITINIB IN EPIDERMAL GROWTH 

FACTOR RECEPTOR (EGFR) MUTATION POSITIVE 


C. Mariano 1 , I. Bosdet 2 , D. Ionescu 3 , A. Karsan 3 , S. Sun 1 , N. Murray 1 , 

B. Melosky 1 , J. Laskin 1 ,C.Ho 1 

1 Medical Oncology, British Columbia Cancer Agency, vancouver, BC, CANADA, 

2 Cancer Genetics, British Columbia Cancer Agency, Vancouver, CANADA, 

3 Pathology, British Columbia Cancer Agency, vancouver, CANADA 

Introduction: The IPASS trial demonstrated superior progression free survival for 

Asian, light/never smoking, advanced, adenocarcinoma patients treated with first line 

Gefitinib compared to carboplatin/paclitaxel, of which 59% of those tested were 

EGFR mutation positive (MUT+). In IPASS 39% of Gefitinib treated patients went 

on to receive platin based therapy. We hypothesize that in a population-based setting 

fewer patients receive second line platin based chemotherapy. 

Methods: The Iressa Alliance Program provided standardized EGFR mutation testing 

and appropriate access to Gefitinib to all patients in British Columbia (population 

4.5 million) with advanced, non squamous NSCLC. EGFR mutation testing was 

limited to the most common mutations; exon 19 and 21. We retrospectively analyzed 

clinical, pathologic and outcomes for all patients tested in this program between 

March 2010 and June 2011. 

Results: A total of 548 patients were referred for testing and 107 (19%) patients were 

MUT+. Baseline characteristics of MUT- and MUT + ; median age 67/65, male 41%/ 

31%, Asian 15%/51%, never smoker 21%/58%, stage IV 80%/91%. Overall survival was 

10.9 versus 14.9 months (p < 0.0001). In MUT + patients treated with first line 

Gefitinib average duration of therapy was 312 days. 5% of patients had a CR, 43% PR, 

34% SD, 5% PD with 12% not evaluable. 23% of patients continued on Gefitinib after 

radiographic progression. 51 Gefitinib treated patients progressed at the time of 

analysis; 15% of patients received Gefitinib only, 33% platin based doublet, 10% other 

chemotherapy and 42% no further treatment. Five patients received 3rd line therapy. 

Conclusions: This North American population based study shows similar efficacy of 

Gefitinib in MUT+ patients compared to the IPASS trial. Clinicians often continued 

Gefitinib past progression, likely due to ongoing clinical benefit. Contrary to our 

hypothesis, delivery of second line chemotherapy was feasible in a significant 

proportion of Gefitinib treated patients, similar to results seen in clinical trials. MUT 

+ patients have a better prognosis and this may contribute to their ability to receive 

further therapy. 


1256P LONG-TERM SURVIVORS IN NON-SMALL CELL LUNG 

CANCER (NSCLC) PATIENTS WITH EPIDERMAL GROWTH 

FACTOR RECEPTOR (EGFR) MUTATIONS: DATA FROM A 

RANDOMIZED PHASE III STUDY COMPARING GEFITINIB 

WITH CARBOPLATIN PLUS PACLITAXEL (NEJ002) 

Y. Minegishi 1 , K. Kobayashi 2 , M. Maemondo 3 , A. Inoue 4 , S. Sugawara 5 , 

S. Oizumi 6 , K. Hagiwara 7 , T. Nukiwa 8 , S. Morita 9 , A. Gemma 10 

1 Internal Medicine, Division of Pulmonary Medicine, Infectious Diseases, and 

Oncology, Nippon Medical School, Tokyo, JAPAN, 2 Respiratory Medicine, 

Saitama International Medical Center, Saitama, JAPAN, 3 Department of 

Respiratory Medicine, Miyagi Cancer Center, Natori, JAPAN, 4 Department of 

Respiratory Medicine, Tohoku University, Sendai, JAPAN, 5 Department of 

Respiratory Medicine, Sendai Kousei Hospital, Sendai, JAPAN, 6 First 

Department of Medicine, Hokkaido University School of Medicine, Sapporo, 

JAPAN, 7 Department of Respiratory Medicine, Saitama Medical University, 

Saitama, JAPAN, 8 Medical Commisioner, South Miyagi Medical Center, Miyagi, 

JAPAN, 9 Biostatistics and Epidemiology, Yokohama City University Medical 

Center, Yokohama, JAPAN, 10 Internal Medicine, Nippon Medical School, Tokyo, 

JAPAN 

Background: In the NEJ002 study comparing first-line gefitinib to a 

standard-chemotherapy of carboplatin plus paclitaxel for advanced NSCLC patients 

with tumors harboring sensitive EGFR mutations, progression-free survival was 

significantly longer in the gefitinib group compared with the standard-chemotherapy 

group. However, as 98% of the patients in whom first-line carboplatin-paclitaxel 

failed crossed over to gefitinib therapy, the overall survival was similar between the 

two groups. The 2.5-year survival rate of both groups in NEJ002 were very good at 

about 50%. In order to clarify the factors which contribute to the long-term survival 

of NSCLC patients with mutated EGFR, we evaluated any correlation between 

demographic factors and overall survival outcome in 230 patients enrolled in 

NEJ002. 

Methods: The analysis was performed independently from our previous reports. A 

total of 226 patients who received EGFR-tyrosine kinase inhibitors (TKI) and had 

survival confirmation were analyzed. Fourteen factors were evaluated using the 

cause-specific survival, and uni- and multi-variate analyses were conducted by Cox’s 

proportional hazard model. 

Results: Four prognostic factors were identified by univariate analysis: base-line 

performance status (PS), existence of the distant metastasis, response to 


standard-chemotherapy and EGFR-TKI (P < 0.05). There were no significant 

differences among age, sex, smoking status, histologic type, clinical stage, EGFR 

mutation type and the assigned treatment groups. Three independent prognostic 

factors were identified by multivariate analysis: PS 1 [hazard ratio 1.64: 95% CI 

1.14-2.36] and stable disease or progressive disease as response to 

standard-chemotherapy [HR 2.29 : 95% CI 1.31-4.02] and to EGFR-TKI [HR 3.18 : 

95% CI 2.01-4.00]. 

Conclusion: Base-line PS, responses to standard chemotherapy and response to 

EGFR-TKI were significant factors on the prognosis of NSCLC with sensitive EGFR 

mutations. Using updated survival data, a logistic regression analysis for long 

survivors (more than 3 years) will be presented. 

Disclosure: A. Inoue: I was paid lecture fees from AstraZeneca. S. Oizumi: I was paid 

an honorarium (AstraZeneca). K. Hagiwara: I was paid honoraria from AstraZeneca. 

A. Gemma: I (my department) received grant for basic research by AstraZeneca as a 

chief of department. All other authors have declared no conflicts of interest. 

1257P INFLUENCE OF SMOKING STATUS ON RESPONSE TO EGFR 

TKI – A RETROSPECTIVE ANALYSIS OF REFLEX EGFR 

MUTATION TESTING IN ASIAN PATIENTS WITH ADVANCED 

LUNG ADENOCARCINOMAS 

A. Jain 1 , S.L. Koo 1 , K.S. Chan 2 , Q.S. Ng 1 , N.M. Chau 1 , M.K. Ang 1 , L. Oon 2 ,W. 

T. Lim 1 , E.H. Tan 1 , D.S.W. Tan 3 

1 Department of Medical Oncology, National Cancer Centre Singapore, 

Singapore, SINGAPORE, 2 Department of Pathology, Singapore General Hospital, 

Singapore, SINGAPORE, 3 Department of Medical Oncology, National Cancer 

Center, Singapore, SINGAPORE 

Introduction: Although the role of EGFR mutations (mt) is established in predicting 

response to EGFR TKI, there is little data on the impact of smoking on mt subtypes 

and treatment outcomes. We hypothesized that mt spectra differ between 

never-smokers (NS) and those with a smoking history (ex-smokers or current 

smokers) (SM), and that SM may have poorer outcomes to EGFR TKI. 

Methods: All cases that had undergone reflex EGFR mt testing between 6/10 – 3/12 

were reviewed for smoking status, performance status, patient demographics and type 

of EGFR mt. In patients who were treated with EGFR TKI, progression free survival 

(PFS) and 1-year overall survival (OS) was determined. 

Results: 742 patients (M:F 384:358) were identified of which 342 (46.1%) were EGFR 

mt+. Majority were females 64.6% (n = 221, S:NS 15:197) while males comprised 

35.4% (n = 121, S:NS 54:66). Mts in order of frequency: Exon (Ex) 19 deletions (del) 

(52.3%), L858R 33.9%, Ex 20 insertion (ins)/duplication (4.9%), G719X (4.1%), 

L861Q (1.8%), T790M (1.2%), and Exon 19 ins (0.3%). In patients with known 

smoking status and mt status, (n = 332), median age was 63 years in both NS (n = 

261) and SM (n = 71). There was no significant difference in location of mt (Ex 18, 

19, 20 and 21, p= 0.991), or the type of mt (Ex19 deletions vs. point mutations, p = 

0.723). When we reviewed the clinical outcomes of 127 TKI naïve patients (NS n = 

103, SM n = 24) receiving gefitinib or erlotinib monotherapy with at least 6 months 

of follow up, median PFS was 11.9 months (m)and OS at 1 year was 75.3%. In 

subgroup analysis, PFS for NS vs. SM was 11.9 m and 14.7 m (p = 0.855) and 1 year 

OS 75.3% vs. 65.7% (p = 0.683). 

Conclusion: EGFR mutations occur in 46% of patients in Singapore, of which 

one-fifth of patients had significant smoking history. Contrary to our hypothesis, the 

EGFR mt spectra and clinical outcomes is similar in NS vs. SM underscoring the 

importance of reflex testing in a population where mt prevalence is high. 


1258P GEFITINIB (G) AND PEMETREXED (PEM) AS A FIRST LINE 

TREATMENT IN PATIENTS WITH EGFR MUTANT ADVANCED 

NON-SMALL CELL LUNG CANCER (NSCLC): A PHASE II 

STUDY 

N. Yoshimura 1 , K. Matsuura 1 , S. Mitsuoka 1 , K. Asai 1 , Y. Tochino 1 , T. Kimura 1 , 

M. Nakai 1 , Y. Mitsukawa 2 , K. Hirata 1 , S. Kudoh 1 

1 Department of Respiratory Medicine, Osaka City University Medical School, 

Osaka, JAPAN, 2 Pharmaceutical Department, Osaka City University Hospital, 

Osaka, JAPAN 

Background: G is the key drug for patient (pts) with NSCLC harboring mutations of 

EGFR as a first line treatment. However, they have disease progression in most cases. 

PEM and G are reported to have a schedule-depended cytotoxic synergism. 

Objectives: We evaluated the efficacy and safety of G and PEM as a first line 

chemotherapy in pts with NSCLC harboring mutations of EGFR. 

Methods: Eligibilities were histologically or cytologically proven non-squamous 

NSCLC with EGFR active mutation, chemotherapy naïve, measurable lesion, ECOG 

PS0-1, adequate organ function, life expectancy longer than 12 weeks and written 

informed consent. G (250mg/body) was administered on days 2-16 and PEM 

(500mg/m2) was administered on day 1. This combination was repeated every 3 

weeks until progressive disease (PD). Primary endpoint was overall response rate 



(ORR) and secondary endpoints were toxicities, disease control rate (DCR), 

progression free survival (PFS), and overall survival (OS). The planed sample size 

was 26 pts. 

Results: From March 2010 to May 2012, 20 pts were enrolled and eligible: males/ 

females 10/10; median age 66 (range 59-75); PS 0/2 2/18; stage III/IV 1/19; adeno/ 

others 20/0. Nineteen pts were eligible for efficacy and toxicity; a total of 226 cycles 

(median 12 cycles, range 1-27) was given. Major grade 3/4 toxicities were 

neutropenia, leucopenia, liver dysfunction and infection, respectively. There was no 

treatment-related death. ORR was 68.8%, and DCR was 100%. Median PFS is 18.2 

months and median OS is not reached. 

Conclusions: This combination showed longer median PFS and acceptable toxicity. 

Randomized trial of PEM + G compare with G alone is warranted. 


1259P GEFITINIB FOR NON-SMALL CELL LUNG CANCER (NSCLC) 

WITH MINOR EGFR MUTATIONS: A RETROSPECTIVE STUDY 

FROM THE NORTH EAST JAPAN STUDY GROUP (NEJ) 

S. Watanabe 1 , H. Yoshizawa 1 , M. Maemondo 2 , A. Inoue 3 , S. Sugawara 4 , 

H. Isobe 5 , M. Harada 6 , Y. Ishii 7 , K. Hagiwara 8 , K. Kobayashi 9 

1 Bioscience Madecal Research Center, Niigata University Medical and Dental 

Hospital, Niigata-City, JAPAN, 2 Department of Respiratory Medicine, Miyagi 

Cancer Center, Natori, JAPAN, 3 Department of Respiratory Medicine, Tohoku 

University, Sendai, JAPAN, 4 Department of Respiratory Medicine, Sendai Kousei 

Hospital, Sendai, JAPAN, 5 Clinical Oncology, KKR Sapporo Medical Center, 

Sapporo, JAPAN, 6 Department of Pulmonary Disease, National Hospital 

Organization Hokkaido Cancer Center, Sapporo, JAPAN, 7 Department of 

Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School 

of Medicine, Mibu, JAPAN, 8 Department of Respiratory Medicine, Saitama 

Medical University, Saitama, JAPAN, 9 Respiratory Medicine, Saitama 

International Medical Center, Saitama, JAPAN 

Background: In NSCLC, the sensitive mutations of epidermal growth factor receptor 

(EGFR), such as exon 19 deletion and L858R point mutation, are predictors of 

response to EGFR tyrosine kinase inhibitors (TKIs). However, it is still uncertain 

whether minor EGFR mutations are associated with sensitivity to EGFR-TKIs. 

Materials and methods: Retrospective review of 221 EGFR mutated (exon 19 

deletion, L858R, G719X and L861Q) patients who were treated with gefitinib in a 

NEJ002 study was performed. We identified 7 patients with G719X and 3 patients 

with L861Q. 

Results: Among 10 patients harboring minor EGFR mutations (G719X or L861Q), 5 

patients were treated with gefitinib as the 1st line treatment, and 5 patients were 

treated with carboplatin/paclitaxel as the 1st line chemotherapy, and then received 

gefitinib as the 2nd line treatment. Only 2 patients showed PR, 4 achieved SD, and 4 

had PD with gefitinib treatment. The overall response rate was 20% and the disease 

control rate was 60%. The overall survival (OS) from enrollment was significantly 

shorter in patients with minor mutations (median OS, 12 months (95% CI, 5.8 - 

30.5)) compared to patients with 19 deletion or L858R (median OS, 28 months (95% 

CI, 24.1 – 33.2), P = 0.0057). Tendency of longer progression free survival and OS 

were observed in minor EGFR mutation patients who received carboplatin/paclitaxel 

as the 1st line treatment (median PFS, 5.3 months (95% CI, 3.7 – 8.9) and median 

OS, 22.8 months (95% CI, 9.9 – 41.8)) compared to those who were treated with 

gefitinib as the 1st line treatment (median PFS, 2.2 months (95% CI, 0.5 – 10.6), P = 

0.997 and median OS, 11.9 months (95% CI, 5.8 – 22.6), P = 0.1021). 

Conclusions: Our results indicate that NSCLC patients with G719X or L861Q minor 

EGFR mutations are less responsive to gefitinib than those with 19 deletion or 

L858R. 


1260P A PHASE II STUDY OF ERLOTINIB AS FIRST-LINE 

TREATMENT IN JAPANESE ADVANCED NSCLC PATIENTS 

HARBORING EGFR MUTATIONS 

A. Horiike 1 , M. Nishio 1 , K. Goto 2 , N. Yamamoto 3 , K. Chikamori 4 , 

M. Maemondo 5 , T. Hida 6 , N. Katakami 7 , T. Tamura 3 

1 Thoracic Oncology Center, The Cancer Institute Hospital of Japanese 

Foundation for Cancer Research, Koto-ku, Tokyo, JAPAN, 2 Division of Thoracic 

Oncology, National Cancer Center Hospital East, Kashiwa, JAPAN, 3 Division of 

Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, 

Chuo-ku, Tokyo, JAPAN, 4 Oncology Medicine, National Hospital Organization, 

Yamaguchi - Ube Medical Center, Ube, JAPAN, 5 Department of Respiratory 

Medicine, Miyagi Cancer Center, Natori, JAPAN, 6 Department of Thoracic 

Oncology, Aichi Cancer Center Hospital, Nagoya, JAPAN, 7 Integrated Oncology, 

Institute of Biomedical Research and Innovation Hospital, Kobe, JAPAN 

Background: Several studies of EGFR TKIs have shown a benefit in response and 

progression-free survival (PFS) for NSCLC patients harboring EGFR mutations in 

the first-line setting. This is the first prospective study to investigate erlotinib for the 

first-line treatment of NSCLC patients harboring EGFR mutations in Japanese 

patients. 

Methods: We undertook the single-arm phase II study at 25 centers. Eligible patients 

were adults (over 20 years) with advanced or recurrent NSCLC harboring EGFR 

mutations (Exon 19 deletions (19del) or Exon 21 L858R mutation) with no prior 

chemotherapy for NSCLC. The primary endpoint was progression-free survival (PFS) 

and safety. Secondary endpoints were overall response rate (ORR), disease control 

rate (DCR), overall survival (OS), and response duration. 

Results: Between April 8 and October 6 2010, 103 patients were enrolled. All 

patients were administered erlotinib and included in the safety analysis. One 

patient was excluded from efficacy analysis, because of the deviation of GCP. Thus 

102 patients were analyzed in the efficacy analysis. At Data cut-off (Sep 1, 2011), 

median PFS assessed by Independent Review Committee was 11.8 months [95 % 

CI 9.7- not reached]. The updated median PFS incorporated with follow up 

assessments will be obtained in August 2012. The most common adverse events 

were rash and diarrhea in 82.5 % and 80.6 % respectively, with Grade 3 was 13.6 

% and 1.0 % respectively, and there were no Grade 4/5 rash and diarrhea. Six 

treatment-related ILD like events were reported by investigators, and of which two 

were fatal. ORR was 78.4 %, DCR was 95.1 %, and response duration was 11.1 

months [95 %CI 9.4- not reached], OS data is immature at this time (only ten 

deaths events). Median PFS in 50 patients with 19del was 12.5 months, in 50 

patients with L858R was 11.0 months, and two patients with L858R/T790M was 

3.8months. 

Conclusion: This study showed a promising efficacy and safety profile of erlotinib in 

Japanese advanced NSCLC patients harboring EGFR mutations. 

Disclosure: A. Horiike: Corprate-sponsored research: Chugai, Pfizer, Merck, 

KyowaKirin, Taiho, Eisai, Novartis, AMGEN. M. Nishio: Corporate-sponsored 

research: Chugai, Eli Lillly, Pfizer, DiichiSankyo, KyowaKirin, Taiho, Eisai, Novartis. 

Lecture fees: Chugai. K. Goto: Corporate-sponsored research: Chugai, Pfizer, 

KyowaKirin, Taiho, Eisai, Merckserono, Boehringer Ingelheim Lecture fees: Chugai, 

Taiho, Ono. N. Yamamoto: Corporate-sponsored research: Chugai, Pfizer, 

KyowaKirin. K. Chikamori: Corporate-sponsored research: Chugai, Taiho, Nippon 

Kayaku Lecture fees: Eli Lilly. M. Maemondo: Corporate-sponsored research: Chugai, 

Taiho, Janssen Lecture fees: Chugai, Eli Lilly. T. Hida: Corporate-sponsored research: 

Chugai, Eli Lilly, Bayer, Pfizer, DaiichiSankyo, KyowaKirin, Taiho, Boehringer 

Ingelheim, Merck, Aventis. N. Katakami: Corporate-sponsored research: Chugai, 

Pfizer, Kyowakirin, Ono, Janssen, Merckserono, Boehringer Ingelheim, 

Dainipponsumitomo, Eisai, Shionogi. T. Tamura: Corporate-sponsored research: 

Chugai, DaiichiSankyo, Boehringer Ingelheim, Abbott, Eisai, Bristol-Myers Squib, 

KyowaKirin Lecture fees: Taiho, Eli Lilly, Chugai 

1261P ERLOTINIB AS NEOADJUVANT TREATMENT IN PATIENTS 

WITH IIIA-N2 NON-SMALL CELL LUNG CANCER(NSCLC) 

WITH ACTIVATING EPIDERMAL GROWTH FACTOR 

RECEPTOR (EGFR) MUTATION (NCT01217619, ESTERN) 

B. Han, L. Xiong, R. Li, J. Sun, Y. Lou, Y. Zhang 

Department of Pulmonary Medicine, Shanghai Chest Hospital affiliated to 

Shanghai Jiaotong University, Shanghai, CHINA 

Background: Patients with stage IIIA N2 NSCLC have poor outcomes with 5-year 

survival rate of approximately 15% after treatment with surgical resection or 

chemo-radiotherapy. Tyrosine kinase inhibitor monotherapy have been demonstrated 

a significant improvement in tumor response rate and progression free survival as the 

first line treatment for metastatic NSCLC patients with activating EGFR mutation. 

The objective of this trial is to explore the efficacy and safety profile of erlotinib as 

neoadjuvant treatment in patients of stage IIIA-N2 NSCLC with activating EGFR 

mutation. 

Material and methods: This is a single arm, one center, phase II study of erlotinib 

as neoadjuvant treatment in patients with Endobronchial Ultrasound (EBUS) 

confirmed stage IIIA-N2 NSCLC with activating EGFR mutation in exon 19 or 21. 

The primary endpoint is to evaluate radical resection rate. A total of 44 patients will 

be enrolled. Major inclusion criteria: IIIA-N2 NSCLC Patients with pathologically 

confirmed ipsilateral mediastinal metastasis by EBUS. The biopsy specimen shows 

activating EGFR mutation in exon 19 or 21. 

Treatment schedule: All the recruitment patients will be treated by erlotinib 150mg 

orally per day for 56 days for neoadjuvant period. Patients will be assessed by Chest 

CT for the efficacy evaluation in day 29 and right after day 56. All the post-operative 

patients will receive standard adjuvant treatment which will be decided by the 

investigator. 

Current enrollment: 48 patients have been screened, and 7 patients met the 

inclusion criteria and were enrolled. 2 patients are still on neoadjuvant treatment, 5 

patients have completed the neoadjuvant therapy, and RECIST evaluation showed 

partial response in 2 patients, disease progression in 2 patients, and disease stable in 

1 patient. Due to active hepatitis and technical infeasibility, 2 patients with PR didn’t 

receive surgery, only one SD patient received R0 surgery. 



1262P DISTINCT SPREAD OF EGFR MUTATED PULMONARY 

ADENOCARCINOMAS 

D. Shin 1 , S.Y. Kwon 2 , C.H. Kim 1 , S.H. Yang 1 , I.I. Na 1 

1 Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological 

and Medical Sciences, Seoul, KOREA, 2 Hospice and Palliative Care Team, Korea 

Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 

Seoul, KOREA 

Introduction: Our aim in this study was to explore the potential association of 

epidermal growth factor receptor (EGFR) with characteristics of tumor spread in 

patients with pulmonary adenocarcinoma. Clinical implication of EGFR mutational 

status on brain metastasis was also evaluated in surgically treated patients. 

Methods: We analyzed clinical data on 317 patients who were tested for EGFR 

mutation and who underwent brain MRI at diagnosis between October 2005 and 

December 2011. The relationship between EGFR mutation status and clinical factors 

were analyzed. Initial metastatic disease was stratified according to brain metastases 

and their association with EGFR mutations was evaluated using multinomial logistic 

regression. 

Results: Of the 317 patients, 139 patients (43.85%) harbored EGFR mutations. EGFR 

mutations was more commonly found in patients with early nodal stage (71.9 % 

versus 28.1%, adjusted odds ratio [OR] = 1.90, p = 0.030) and distant metastases 

(54.0% versus 46.0%, adjusted OR = 2.05, p = 0.011). Further analysis showed that 

EGFR mutations were more likely to be detected in brain metastases (64.7% versus 

35.3%, p = 0.005), whereas their association with noncranial metastases was not 

significant (55.4% versus 44.6%, p = 0.960). In addition, survival analysis of 133 

patients treated with surgical resection showed that EGFR mutation status was a poor 

prognostic factor for brain metastasis (HR = 5.94, 95% CI = 1.08-16.28, p = 0.039) 

after adjustment of pathologic N stage. 

Conclusions: In this study, EGFR mutation status was significantly associated with 

early nodal and distant metastasis, in the patients with pulmonary adenocarcinoma. 

The current study also suggests the preference of brain metastases in mutant EGFR 

tumors at initial presentation and after curative resection. 


1263P IMPACT OF EPIDERMAL GROWTH FACTOR 

RECEPTOR-TYROSINE KINASE INHIBITOR TREATMENT IN 

ADVANCED NON-SMALL CELL LUNG CANCER: A 

META-ANALYSIS 

C.K. Lee 1 , C. Brown 2 , R. Gralla 3 , V. Hirsh 4 , A. Inoue 5 , V. Gebski 6 , C.J. Yang 7 

1 NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, AUSTRALIA, 

2 Clinical Trials, NHMRC Clinical Trials Centre, University of Sydney, Sydney, 

AUSTRALIA, 3 Department of Medicine, Hofstra University School of Medicine, 

New York, UNITED STATES OF AMERICA, 4 Oncology, McGill University Health 

Centre, Montreal, QC, CANADA, 5 Department of Respiratory Medicine, Tohoku 

University, Sendai, JAPAN, 6 Biostatistics and Research Methodology, NHMRC 

Clinical Trials Centre, University of Sydney, Sydney, AUSTRALIA, 7 Department of 

Oncology, National Taiwan University Hospital, Taipei, TAIWAN 

Background: Previous meta-analyses have reported that epidermal growth factor 

receptor (EGFR)-tyrosine kinase inhibitor (TKI) improves progression-free 

survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) 

harbouring EGFR mutation. We examined the influence of EGFR-TKI on PFS 

and overall survival (OS) in those with (EGFR+) and without mutation 

(EGFR-). 

Methods: We included published and unpublished randomised trials of advanced 

NSCLC that compared EGFR-TKI monotherapy or combination EGFR-TKI 

chemotherapy with chemotherapy or placebo. We used published hazard ratios (HR) 

if available, or derived treatment estimates from other survival data. We investigated 

treatment effects in different treatment settings and trial regimens. 

Results: We identified 20 eligible trials investigating EGFR-TKI in front-line (n = 12), 

second or subsequent (n = 5), and maintenance (n = 3) treatment, with EGFR status 

known in 3198 (23%) patients. Overall, HR for EGFR-TKI over control for PFS were 

(EGFR+) 0.37 (95% CI, 0.32 to 0.42; p < 0.001) and (EGFR-) 1.02 (95% CI, 0.93 to 

1.12; p = 0.67). EGFR mutation is predictive of PFS benefit with EGFR-TKI in all 

settings: front-line HR (EGFR+) 0.39, p < 0.005, HR (EGFR-) 1.07, p = 0.27, 

interaction p < 0.001; second or subsequent lines HR (EGFR+) 0.38, p = 0.01, HR 

(EGFR-) 1.22, p = 0.07, interaction P = 0.003; maintenance HR (EGFR+) 0.15, p < 

0.001, HR (EGFR-) 0.81, p = 0.02, interaction p = 0.02. There was no difference in OS 

for patients treated with EGFR-TKI or control in these subgroups of patients: HR 

(EGFR+) 0.95, p = 0.21; HR (EGFR-) 0.95; p = 0.29. 

Conclusions: In this meta-analysis, treatment with EGFR-TKI was found to 

significantly delay disease progression in EGFR+ patients; however, no impact on 

OS was identified. EGFR mutation is a predictive biomarker of PFS benefit 

with EGFR-TKI treatment in all settings. These findings support assessment for 


EGFR mutation before initiation of EGFR-TKI treatment and that EGFR-TKI 

should be considered as front-line therapy in EGFR+ patients with advanced 

NSCLC. 

Disclosure: R. Gralla: Consultant or advisory role for Boehringer Ingelheim. V. 

Hirsh: Advisory role for Boehringer Ingelheim. A. Inoue: Received lecture fees and 

research grants from AstraZeneca. C.J. Yang: Advisory roles for Boehringer 

Ingelheim, AstraZeneca, Roche and OSI, and have received honoraria from 

AstraZeneca, Roche and OSI. All other authors have declared no conflicts of 

interest. 

1264P CLINICOPATHOLOGIC FEATURES OF NEVER-SMOKING 

WOMEN LUNG CANCER (WLC): A REVIEW FROM THE 

SPANISH WORLD07 DATABASE 

J. De Castro 1 , D. Isla Casado 2 , M. Provencio Pulla 3 , M. Majem Tarruella 4 , 

N. Vinolas Segarra 5 , E. Felip 6 , A. Artal-Cortes 7 , R. García-Campelo 8 , 

M. Domine 9 , P. Garrido Lopez 10 

1 Medical Oncology, Hospital Universitario La Paz, Madrid, SPAIN, 2 Oncology 

Service, Hospital Clínico Universitario Lozano Blesa, Zaragoza, SPAIN, 3 Medical 

Oncology, Hospital Universitario Puerta de Hierro Majadahond, Majadahonda, 

SPAIN, 4 Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, 

SPAIN, 5 Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona, 

SPAIN, 6 Oncologia Médica, Vall d’Hebron University Hospital Institut 

d’Oncologia, Barcelona, SPAIN, 7 Servicio de Oncologia Medica, Hospital Miguel 

Servet, Zaragoza, SPAIN, 8 Medical Oncology, Complexo Hospitalario 

Universitario de A Coruña, La Coruña, SPAIN, 9 Oncology, Fundación Jiménez 

Díaz, Madrid, SPAIN, 10 Medical Oncology, Hospital Ramon y Cajal, Madrid, 

SPAIN 

Background: Lung cancer in never-smoker appears to be a distinct entity from lung 

cancer in smoker, with specific molecular characteristics and potential different 

treatment. Several factors like hormonal, environmental, genetic, pre-existing lung 

diseases, and virus, may play etiologic roles, and an in-depth understanding of them 

is needed. So, new clinicopathologic aspects of never-smoking WLC should be very 

important to know the biology of this tumoral disease. 

Methods: Information has been extracted from WORLD07 database, a prospective, 

from 32 Spanish centers, epidemiologic female-specific lung cancer e-database 

performed by ICAPEM, an association to research WLC. 

Results: From October 2007 to October 2011, 539 newly diagnosed never-smoking 

WLC were included in World07 database (39.3% of 1371 patients(p). P 

characteristics are: median age 71.1 years(y) (range: 22-91). Previous history of 

cancer (%): 13(breast, lung, cervix: 41.4,5.7,2.9). Gynecological features: median age 

of menarche 13y, Postmenopausal 88.9%, median age of menopause 49y. Median age 

of first child 26.4y Children: 91.2% (median: 2.3). Oral contraceptive: 11.9%. HRT: 

5.2%. Tobacco exposure: Second-hand smokers: 40%, work-exposure 17.1%, 

home-exposure 88.8%. Obesity: 16.3%. Familiar history of cancer: 39.9% (lung cancer 

29.8%).Lung cancer histology (%): adenocarcinoma/BAC/squamous/large cell/SCLC/ 

others: 69.2/6.8/5.7/5.0/3.8/3.8. EGFR mutated p (268 p analized): 55.5%, exon 19/ 

20/21(%): 61.1/7.4/36.9. TNM NSCLC I/II/III/IV (%): 14/3.3/19.8/60.3. Treatment: 

EGFR-TKI in p harboring EGFR mutations stage IV (1 st -/2 nd -line)(%): 51.7/15.4; 

stage IV NSCLC(1 st -line)(%): platinum-based chemotherapy 42.5, combinations with 

bevacizumab 2.9. Overall survival: median 27 months (m), 1/2-y(%) 74.8/55.2; stage 

IV NSCLC: median 20.5m, 1/2-y(%) 67/46; EGFR mutated p: median 27.3m, 1/2-y 

(%) 75/54.3. 

Conclusions: Never-smoking WLC represents 39% of Spanish World07 database. 

The high incidence of adenocarcinoma histology (69.2%) and EGFR mutated tumors 

suggests a different clinical and genetic profiling and recommend a different 

treatment approach for this group of patients. 


1265P IS THERE A BENEFIT ON SURVIVAL OF TYROSINE-KINASE 

INHIBITORS VERSUS CHEMOTHERAPY IN FIRST LINE IN 

MUTATED EGFR PATIENTS WITH ADVANCED NON-SMALL 

CELL CANCER (NSCLC)? A META-ANALYSIS 

G. Des Guetz 1 , B. Uzzan 2 , K. Chouahnia 1 , P. Nicolas 2 , L. Zelek 1 , M. Pailler 1 , 

J. Morère 1 

1 Oncology, Hôpital Avicenne, Bobigny, FRANCE, 2 Pharmacology, Hôpital 

Avicenne, Bobigny, FRANCE 

Background: Tyrosine-Kinase Inhibitors (TKIs) markedly improve Progression 

Free Survival (PFS) of advanced NSCLC patients mutated for Epidermal Growth 

Factor Receptor (EGFR). Results on Overall Survival (OS) are more questionable. 

Therefore, we performed a publication-based meta-analysis to further assess this 

issue. 



Methods: We did a PubMed query using keywords simultaneously (lung neoplasm, 

TKI, EGFR mutation, survival). We also searched for relevant abstracts in 

proceedings of ASCO, ESMO, WCLC annual meetings. We cross-checked all 

references from all articles. Only phase III randomized controlled trials comparing 

TKI and chemotherapy were included. We used EasyMA software. 

Results: The 6 eligible studies included 2223 patients (516 males, 1688 females, 

mostly Asian, median age 60 years, 2155 adenocarcinomas (97 %), 996 mutated 

tumors, 389 stage IIIB, 1572 Stage IV (71 %), 1989 never smokers (89.5 %). Four 

studies assessed gefitinib, 2 erlotinib. Chemotherapies were doublets including a 

platinum salt. Four studies included only mutated patients. Compared to 

chemotherapy, EGFR TKIs significantly improved PFS (HR = 0.39, 95 % CI 

0.28-0.53, random effect model). Conversely, OS was similar among patients who 

first received TKI or chemotherapy (HR = 1.00, CI 0.83-1.22, fixed effect model). PFS 

was significantly worse among non mutated patients in the 2 studies including both 

mutated and wild-type EGFR patients, whereas OS was unchanged. Concerning 

side-effects, rash, diarrhoea and interstitial lung disease were significantly more 

frequent after TKI (RRs 5.00; 2.40 and 6.07). As expected, fatigue (RR 0.41), nausea/ 

vomiting (0.19) and haematological disorders were all significantly more frequent 

after chemotherapy (RRs for neutropenia, thrombocytopenia and anaemia 0.08; 0.18 

and 0.26). 

Conclusions: The major discrepancy between a markedly improved PFS and a 

similar OS after TKI compared with chemotherapy could be related to the high level 

of crossing-over between the 2 groups. We found no detrimental effect on OS of 

TKIs among wild-type patients. 


1266P RETROSPECTIVE STUDY OF CLINICOPATHOLOGIC 

FACTORS ASSOCIATED WITH ALK REARRANGEMENT AND 

SURVIVAL OUTCOME IN CHINESE PATIENTS (PTS) WITH 

NSCLC 

X. Zhang 1 , C. Blanckmeister 2 , Y. Cheng 3 ,D.Wu 4 , J. Yang 1 , H. Tian 1 , J. Chen 5 , 

Z. Xie 1 ,H.Yan 1 ,Y.Wu 6 

1 Guangdong General Hospital, Guangdong Academy of Medical Sciences, 

Guangdong Lung Cancer Institute,, Guangdong, CHINA, 2 Pfizer, New York, NY, 

UNITED STATES OF AMERICA, 3 Oncology, Jiling Province Tumor Hospital, Jilin, 

CHINA, 4 Jilin Provincial Cancer Hospital, Jilin Province, CHINA, 5 Pfizer China 

Medical Affairs, Shanghai, CHINA, 6 Guangdong Lung Cancer Institute, 

Guangdong General Hospital (GGH) & Guangdong Academy of Medical 

Sciences, Guangzhou, CHINA 

Background: We tested 400 NSCLC pts for ALK, EGFR and KRAS status and 

correlated clinical factors with ALK status and overall survival (OS). 

Methods: ALK status was assessed with RACE-PCR, IHC and FISH; EGFR and 

KRAS status were assessed by direct DNA sequencing. OS was estimated by the 

Kaplan-Meier method. 

Results: Consecutive, unselected cases from southern (n = 294) and northern (n = 

106) China were tested; 31 (7.7%), 105 (26.2%) and 33 (8.2%) pts were ALK + , 

EGFR+ and KRAS + , respectively. ALK and EGFR aberrations were largely exclusive 

(P = 0.009); 2 cases were ALK + /EGFR+. ALK+ status was associated with female sex 

(P = 0.023), non/light-smoking (P = 0.001) and adenocarcinoma (P = 0.017), and was 

more prevalent in southern (9.2%; 27/294) than northern (3.8%; 4/106) pts. The 

ALK fusion partner was EML4 in all 31 cases; predominantly variants V1–3 (90.3%, 

28/31). In 326 modeled pts, female sex (HR = 2.84; P = 0.022), wild type EGFR (HR 

= 15.87; P = 0.001), non/light-smoking (HR = 3.95; P = 0.021) and adenocarcinoma 

(HR = 4.12; P = 0.031) were associated with ALK+. In 187 cases evaluated by IHC 

and RACE-PCR, IHC sensitivity was 100% (19/19; [5 IHC + ; 10 IHC + +; 4 IHC + + 

+ ]) and specificity was 79.8% (134/168). All 19 ALK+ cases by RACE-PCR were also 

ALK+ by FISH. In the first 303 pts, there were no significant OS differences between 

ALK + , EGFR + , KRAS+ and triple-negative pts, between ALK+ and ALK– pts, or 

between ALK+ cases matched with non-TKI-treated controls balanced for disease 

stage, sex, histology and EGFR/KRAS status. In ALK+ pts, non/light-smoking status 

(P = 0.016) and prior surgery (P = 0.024) were associated with increased OS by 

log-rank test. In a Cox model, disease stage (P ≤ 0.001 for both stage I and II), and 

surgical treatment (P = 0.001) were prognostic for OS. 

Conclusion: ALK fusion prevalence was 7.7% overall, and was higher in southern 

pts. ALK+ was associated with non/light-smoking, adenocarcinoma and female sex. 

ALK fusion variants were mostly V1–3, which may inform RT-PCR screening. IHC 

for ALK protein and FISH for ALK rearrangement may be useful for patient 

selection. ALK+ was not a favorable prognostic factor, although disease stage and 

smoking history may influence OS in ALK+ NSCLC. 

Disclosure: C. Blanckmeister: Employment: Pfizer. Myself. Compensated. Stock 

ownership: Pfizer. Myself. J. Chen: Employment: Senior Medical Affairs Therapeutic 

Area Manager. Pfizer. Myself. Compensated. All other authors have declared no 


1267P A LARGE RETROSPECTIVE ANALYSIS OF PEMETREXED 

(PEM) ACTIVITY IN PATIENTS (PTS) WITH ALK-POSITIVE 

(ALK+) NON-SMALL CELL LUNG CANCER (NSCLC) PRIOR TO 

CRIZOTINIB (CRIZ) TREATMENT 

G. Scagliotti1 , D.W. Kim2 , A.T. Shaw3 , S.I. Ou4 , G.J. Riely5 , S. Gettinger6 , 

B. Besse7 , K. Wilner8 ,Y.Tang8 , C.H. Bartlett9 1 2 

S. Luigi Hospital, University of Turin, Turin, ITALY, Department of Internal 

Medicine, Seoul National University Hospital, Seoul, KOREA, 3 Cancer Center, 


4 

Cancer Centre, University of California at Irvine, Irvine, CA, UNITED STATES OF 

AMERICA, 5 Medical Oncology, Memorial Sloan-Kettering Cancer Center, 

New York, NY, UNITED STATES OF AMERICA, 6 Thoracic Oncology, Yale 

University School of Medicine, New Haven, CT, UNITED STATES OF AMERICA, 

7 8 

Department of Medicine, Institute Gustave Roussy, Villejuif, FRANCE, Reseach 

and Development, Pfizer Oncology, La Jolla, CA, UNITED STATES OF AMERICA, 

9 

Medical Oncology, Pfizer Oncology, New York, NY, UNITED STATES OF 

AMERICA 

Background: Retrospective small cohort studies evaluating multiple lines of therapy 

suggest ALK+ NSCLC may be particularly sensitive to PEM treatment. 

Methods: PROFILE 1005 (NCT00932451; Pfizer) is a large phase 2 multinational, 

single-arm study of CRIZ in previously treated ALK+ NSCLC. We retrospectively 

assessed best overall response rate (ORR) and time to progression (TTP; 1st dose to 

objective progression) in pts who received PEM-based regimens prior to CRIZ in the 

1st-line (1L) and 2nd-line (2L) settings. ORR to CRIZ post-PEM-based regimens was 

assessed. 

Results: Of the 901 ALK+ pts enrolled as of Jan 2012, 711 (79%) received prior PEM 

(single-agent or combination; any line advanced/metastatic) with an ORR to PEM of 

19%. Pts who received 1L PEM combinations (n = 308) were predominately of young 

age (median 53 y, 82%

1268P VISUAL DISTURBANCES IN PATIENTS (PTS) WITH 

ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE 


TREATED WITH CRIZOTINIB 

B. Besse 1 , R. Salgia 2 , B. Solomon 3 , A. Shaw 4 , D. Kim 5 , R. Schachar 6 , 

K. Wilner 7 , A. Reisman 8 , C.H. Bartlett 9 ,S.Iyer 10 

1 Dept. of Medicine, Institut de Cancérologie Gustave Roussy, Villejuif Cedex, 

FRANCE, 2 Department of Medicine, Section of Hematology/Oncology, University 

of Chicago, Chicago, IL, UNITED STATES OF AMERICA, 3 Oncology, Peter 

MacCallum Cancer Centre, Melbourne, VIC, AUSTRALIA, 4 Hematology/ 

Oncology, Department of Medicine, Massachusetts General Hospital, Boston, 

MA, UNITED STATES OF AMERICA, 5 Oncology, Seoul National University 

Hospital, Seoul, KOREA, 6 Specialty Care, Pfizer, La Jolla, CA, UNITED STATES 

OF AMERICA, 7 Reseach and Development, Pfizer Oncology, La Jolla, CA, 

UNITED STATES OF AMERICA, 8 Statistics, Pfizer Inc., New York, NY, UNITED 

STATES OF AMERICA, 9 Oncology, Pfizer, New York, NY, UNITED STATES OF 

AMERICA, 10 Global Outcomes Research, Pfizer Oncology, New York, NY, 


Background: Crizotinib is a potent, small-molecule ALK inhibitor with a high 

response rate in advanced ALK-positive NSCLC. In early phase studies, patients (pts) 

commonly reported mild visual disturbances. Here we characterize such visual effects 

with objective and subjective measures in an ongoing phase II study (PROFILE 1005). 

Methods: Previously treated pts with advanced ALK-positive NSCLC received 

crizotinib 250 mg BID. Ophthalmological examinations, comprising best corrected 

visual acuity (BCVA), biomicroscopy, and fundoscopy, were performed at screening 

and after a visual effect event was reported, except for a subset of pts in France, 

where examinations were done every 4 cycles. In addition, on day 1 of each cycle, pts 

completed the Visual Symptom Assessment Questionnaire (VSAQ) that assessed the 

presence, frequency, timing, duration, and severity of visual effects and their impact 

on activities of daily living (ADL). 

Results: As of Jan 2012, 901 pts had enrolled in PROFILE 1005; 21 − 27% were 

evaluable for ophthalmological examinations (visual acuity: 193/901; biomicroscopy: 

239/901; fundoscopy: 239/901). There were no changes in BCVA, conjunctiva, cornea, 

anterior chamber, iris, lens, or fundus attributable to crizotinib. The most frequently 

reported ophthalmological finding was worsening of cataracts (right eye: 9%; left eye: 

10%), which was not attributed to crizotinib. Visual effects as identified by the VSAQ 

were reported by 65% of pts (405/622) at cycle 2 (C2), 58% at C3 (323/558), 55% at C4 

(287/519), and 50% at C5 (247/495). The most common were appearance of flashing 

lights, streamers/strings/floaters, and overlapping shadows. Most pts reported each 

event as lasting ≤1 min (C2: 63%; C3: 68%; C4: 72%; C5: 75%), occurring mostly in 

the morning (46–59%) and/or evening (70–74%). The majority of pts reported that 

visual effects were not at all or a little bothersome, with no or minimal impact on 

ADL. Similar results were observed in the French pt subset. 

Conclusions: There were no objective ophthalmological changes associated with the 

visual effects on crizotinib. Pt-reported visual effects were frequent, but transient, 

with no or minimal impact on ADL. 

Disclosure: B. Besse: Research funding: Pfizer. B. Solomon: Compensated advisory 

relationship: Pfizer. Research funding: Pfizer. A. Shaw: Compensated advisory 

relationship: Pfizer, Ariad, Chugai, Novartis, and Daiichi-Sankyo. Research 

funding: AstraZeneca and Novartis. D. Kim: Compensated advisory relationship: 

Pfizer. Honoraria: Pfizer. R. Schachar: Compensated employment: Pfizer. Stock 

ownership: Pfizer. K. Wilner: Compensated employment: Pfizer. Stock ownership: 

Pfizer. A. Reisman: Compensated employment: Pfizer. Stock ownership: Pfizer. C. 

H. Bartlett: Compensated employment: Pfizer. Stock ownership: Pfizer. S. Iyer: 

Compensated employment: Pfizer. All other authors have declared no conflicts of 

interest. 

1269P FINAL OVERALL SURVIVAL AND UPDATED BIOMARKER 

ANALYSIS RESULTS FROM THE RANDOMIZED PHASE III 

ICOGEN TRIAL 

S. Yan 1 , S. Yuankai 1 ,Z.Li 2 , L. Xiaoqing 3 , C. Zhou 4 ,Z.Li 5 , W. Dong 6 , L. Qiang 7 , 

S. Qin 8 , Z. Shucai 9 

1 Oncology, Cancer Hospital,Chinese Academy of Medical Science, Beijing, 

CHINA, 2 Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, CHINA, 

3 Oncology, 307 Hospital, Academy of Military Medical Science, Beijing, CHINA, 

4 Lung Cancer Institute, Shanghai Pulmonary Hospital, Shanghai, CHINA, 

5 Respiratory, Peking Union Medical College Hospital, Beijng, CHINA, 6 Oncology, 

Daping Hospital & Research Institute of Surgeryof the Third Military Medical 

University, Chongqing, CHINA, 7 Respiratory, Changhai Hospital of the Second 

Military Medical University, Shanghai, CHINA, 8 Oncology, The 81 Hospital of the 

Chinese People’s Liberation Army, Nanjing, CHINA, 9 Oncology, Beijing Chest 

Hospital, Capital Medical University, Beijing, CHINA 

Purpose: A total of 399 pretreated patients with advanced NSCLC were randomly 

assigned to receive gefitinib or icotinib in the phase III ICOGEN trial, the results of 


primary endpoint-PFS has been reported previously. This report presents updated 

efficacy and biomarker analysis results to determine the relationship between EGFR 

mutation and clinical outcomes. 

Methods: EGFR mutation was evaluated by Scorpion ARMS (QIAGEN, n = 152). 

Overall survival was analyzed by survival analysis at 82% matutity. 

Results: Median OS was 13.3 months for icotinib and 13.9 months for gefitinib 

(hazard ratio [HR] = 0.90; 95% CI, 0.79 to 1.02; P = .109). EGFR mutation rate was 

43% for icotinib group and 59% for gefitinib group. Compared to wild type patients, 

patients with EGFR mutation had longer PFS (median, 6.2m vs. 2.3m; P = .0000) as 

well as OS (median, 20.5m vs. 7.7m; P = .0000). There was no significant difference 

of PFS or OS between two treatment groups in EGFR mutation-positive (median 

PFS, 7.8m vs. 5.3m for icotinib and gefitinib groups, respectively, P =.3162; median 

OS, 20.9m vs. 20.2m for icotinib and gefitinib groups, respectively, P =.7611.) or in 

EGFR mutation-negative (median PFS, 2.3m vs. 2.2m for icotinib and gefitinib 

groups, respectively, P =.1531; median OS, 7.8m vs. 6.9m for icotinib and gefitinib 

groups, respectively, P =.7885.) subgroups. 

Conclusion: There was no statistically significant difference between icotinib and 

gefitinib in all patients or EGFR mutated patients. This suggests icotinib can 

provide similar overall survival to gefitinib. The EGFR mutation status is the 

strongest predictor in identifying which patients will be likely to benifit from 

icotinib. 


1270P MUTACT: AN OBSERVATIONAL STUDY OF EGFR MUTATION 

STATUS AND MANAGEMENT OF PATIENTS WITH 


ADENOCARCINOMA 

P. Souquet 1 , P. Fournel 2 , C. Locher 3 , J.C. Sabourin 4 , E. Garcia 5 , M. Licour 5 , 

N. Karam 5 

1 Département d’Oncologie Thoracique, Hospices Civils de Lyon, Pierre Bénite, 

Lyon, FRANCE, 2 Département d’Oncologie Médicale, Institut de Cancérologie 

Lucien Neuwirth, Saint-Priest en Jarez, FRANCE, 3 Service Pneumologie, Centre 

Hospitalier de Meaux, Meaux, FRANCE, 4 Service de Pathologie, CHU Charles 

Nicolle, Rouen, FRANCE, 5 Medical Department, AstraZeneca, Rueil-Malmaison, 

FRANCE 

Background: Certain mutations in the EGFR gene predict sensitivity to EGFR 

tyrosine kinase inhibitors (TKIs) in advanced NSCLC, and are more common in 

adenocarcinoma than other histologies. When this study was planned, 

epidemiological data on EGFR mutations were mostly derived from Asian studies. 

MUTACT aims to determine the frequency of EGFR mutation positive (EGFR M+) 

cases in a cohort of French patients with NSCLC adenocarcinoma, and the clinical 

outcomes of patients with EGFR M+ disease. 

Methods: All patients ≥18 years old with NSCLC adenocarcinoma and a planned 

EGFR mutation test were eligible for this observational study (NCT01167972, 

AstraZeneca sponsored). Demographics, disease characteristics and EGFR mutation 

status were recorded for all patients. Follow-up for treatment decisions and clinical 

outcomes for patients with EGFR M+ disease is ongoing. 

Results: Between Sept 2010 and Aug 2011, 1382 patients were enrolled at 76 

sites in France. Baseline characteristics were: male (57%), Caucasian (95%) and 

stage IV disease (79%), including more smokers (38%) than never-smokers (30%) 

or ex-smokers (29%). EGFR M + /M-/non-evaluable (Mx) disease rates were 

respectively 20.6%, 76.1% and 3.3%. Most samples were analysed by direct 

sequencing (69%) using primary tumour tissue (77%), with a median turnover 

time of 12 days. Patients with EGFR M+ disease were mostly female (67%) and 

never-smokers (70%). As expected, the majority of mutations were detected at 

exons 19 (54%) and 21 (37%), but mutations were also found at exons 18 (3%) 

and 20 (7%). Overall, 1% patients had mutations conferring decreased sensitivity 

to EGFR TKIs (exon 20). At inclusion, 633 patients (46%) were in 1 st line 

treatment (others had surgery or were in 2 nd /3 rd line). Of the 283 patients with 

EGFR M+ disease, 186 (66%) were in 1 st line treatment at inclusion; 158 (84%) 

of these received EGFR TKI. 

Conclusions: MUTACT provides a large epidemiological database of predominantly 

Caucasian patients with NSCLC. More females and never-smokers than expected in 

an adenocarcinoma population were included, resulting in a high EGFR M+ rate. 

EGFR TKIs were the most common 1 st line treatment in patients with EGFR M+ 

disease. 

Disclosure: P. Souquet: P-J Souquet is currently conducting research sponsored 

by AstraZeneca. He has also participated in several boards with AstraZeneca 

and has received fundings from AstraZeneca. J.C. Sabourin: J-C Sabourin is a 

member of a scientific board for AstraZeneca and has received funding for 

research from AstraZeneca. E. Garcia: E Garcia is an employee of AstraZeneca. 

M. Licour: M Licour is an employee of AstraZeneca. N. Karam: N Karam is an 

employee of AstraZeneca. All other authors have declared no conflicts of 

interest. 



1271P ANALYSIS OF PFS AND OS FROM THE SATURN STUDY 

ACCORDING TO EGFR IHC STATUS USING THE H-SCORE 

READING METHOD 

J. Mazières 1 , W. Brugger 2 , F. Cappuzzo 3 , P. Middel 4 , A. Frosch 5 , I. Bara 6 , 

G. Klingelschmitt 7 , B. Klughammer 8 

1 Thoracic Oncology Unit, Larrey Hospital, Toulouse, FRANCE, 2 Haematology/ 

Oncology, Schwarzwald-Baar Klinikum, University of Freiburg, 

Villingen-Schwenningen, GERMANY, 3 Oncology, Istituto Toscano Tumori, 

Livorno, ITALY, 4 Department of Pathology, Targos Advance AG, Kassel, 

GERMANY, 5 Department of Pathology, Göttingen University Hospital, Gottingen, 

GERMANY, 6 Global Medical Affairs Oncology, F. Hoffmann-La Roche Ltd, Basel, 

SWITZERLAND, 7 MDBB Biometrics, F. Hoffmann-La Roche Ltd, Basel, 

SWITZERLAND, 8 Department of Biomarkers, F. Hoffmann-La Roche Ltd, Basel, 

SWITZERLAND 

Background: In the phase III SATURN study, maintenance erlotinib significantly 

prolonged progression-free survival (PFS) vs placebo in patients (pts) with advanced 

non-small-cell lung cancer (NSCLC) and non-progressive disease after first-line 

chemotherapy (Cappuzzo et al, Lancet Oncol 2010). Epidermal growth factor 

receptor (EGFR) expression analysis by immunohistochemistry (IHC) found no 

significant difference in PFS (p = 0.63) or overall survival (OS; p = 0.52) with 

erlotinib by EGFR IHC status (Brugger et al, J Clin Oncol 2011). Recently, Pirker at 

al. (Lancet Oncol 2012) presented data on EGFR expression as a predictor of OS for 

first-line chemotherapy plus cetuximab in the phase III FLEX study, using a novel 

method (H-score) to assign EGFR IHC status. We used this method to reassess 

samples from the SATURN study. 

Methods: The H-score method assigns an IHC score to each pt on a continuous 

scale of 0–300, based on the percentage of cells at different staining intensities 

(Pirker et al, Lancet Oncol 2012). As per this method, the outcome-based 

discriminatory threshold IHC H-score for our analysis was set at 200 and existing 

samples were re-read and classed as low (H-score

MERCK SERONO: Advisor, speaker in symposia, research grant PFIZER: Advisor 

ROCHE/GENENTECH: Advisor, speaker in symposia. R. Pirker: The author declares 

the following: Honoraria for Advisory Board and speaker’s fee from AstraZeneca, 

Boehringer Ingelheim, Merck Serono and Roche. K.J. O’Byrne: The author declares: 

Payment from Merck Serono in relation to a protocol writing committee and 

advisory boards and travel costs in related to attendance. Honoraria from Merck 

Serono associated with presentation of data at satellite/company symposia. K.M. 

Kerr: Keith Kerr has acted on Advisory Boards and has received speaker’s fees from 

Merck Serono. He has had similar roles with Astra Zeneca, Roche, Eli Lilly, Daichi 

Sankyo, Pfizer, Boeringher Ingelheim and Glaxo Smith Klein. S. Störkel: The author 

has been involved in sponsored research by Merck KGaA. I. Celik: The author is an 

employee of Merck KGaA. A. von Heydebreck: Teh author is an employee of Merck 

KGaA and declares stock ownership in this company. F.A. Shepherd: Honorarium 

from Merck KGaA for presentation at Scientific, Industry-sponsored Satellite 

Symposium. Provided compensated consultation services to Merck KGaA. 

1273P T790M RESISTANT MUTATION IN PLASMA OF ACQUIRED 

RESISTANT EGFR MUTATED NON SMALL CELL LUNG 

CANCER (NSCLC) PATIENTS - THE TARZO TRIAL 

(NCT00503971) 

N. Reguart 1 , E. Nadal 2 , M.A. Molina 3 , E. Carcereny 4 , C. Queralt 4 , A. Insa Molla 5 , 

I. Aguirre 6 , M. Taron 7 , D. Isla Casado 8 , R. Rosell 9 

1 Medical Oncology, Hospital Clinic Barcelona, BARCELONA, SPAIN, 2 Medical 

Oncology, Hospital Duran i Reynals (ICO), Barcelona, SPAIN, 3 Laboratoy of 

Biology Department, Pangaea Biotech, USP Dexeus University Institute, 

Barcelona, SPAIN, 4 Medical Oncology Service, Hospital Germans Trias i Pujol 

(ICO), Badalona, SPAIN, 5 Medical Hematology and Oncology, Hospital Clinico 

Universitario de Valencia, Valencia, SPAIN, 6 Medical Oncology, Hospital 

Germans Trias i Pujol, Barcelona, SPAIN, 7 Medical Oncology, Hospital Germans 

Trias i Pujol (ICO), Barcelona, SPAIN, 8 Oncology Service, Hospital Clínico 

Universitario Lozano Blesa, Zaragoza, SPAIN, 9 Medical Oncology, Hospital 

Germans Trias i Pujol (ICO)Oncology, Badalona, SPAIN 

Background: EGFR-mutant NSCLC patients (pts) ultimately overcome resistant to 

tyrosine kinase inhibitors (TKIs). Among resistant mechanisms secondary EGFR 

T790M is the most frequent and account 50% of tumors. Previous data suggest that 

tumors with acquired T790M at post-progression biopsy specimen may have a more 

favorable prognosis and indolent progression. However, tumor re-biopsies at 

progression sites are scare in NSCLC patients and blood samples are a non-invasive 

method that may help to identify resistant mechanisms. 

Material and methods: Pts with advanced NSCLC harboring EGFR mutations (Exon 

19 and 21) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) were 

eligible. All patients where included in a phase II trial (TARZO) and treated with 

erlotinib 150 mg PO daily plus oral vorinostat 400 mg QD on days 1–7 and 15–21 in 

a 28-day cycle. Blood samples were required at study entry. We aim to determine the 

feasibility and incidence of T790M resistant mutation from plasma DNA from 

patients by mutation from cell free circulating DNA from patients using a 5 0 nuclease 

PCR assay (TaqMan assay) with a FAM MGB-labeled probe for the wild-type and a 

VIC MGB-labeled probe for the mutant sequence in the presence of a protein 

nucleic acid (PNA) clamp, which was designed to inhibit the amplification of the 

wild-type allele (Pangaea Biotech SL patent). 

Results: Twenty-five pts were included in the trial. From those, nineteen plasma 

specimens were obtained and used for DNA extraction. Overall T790M resistant 

mutation was detected from plasma DNA in 36.8% of the samples (7/19). There were 

no differences according patient characteristics (gender/ECOG-PS, smoking habits, 

number of previous treatments) or type of sensitizing mutation in tissue (Exon 19, 

L858R) and the presence of T790M. Median time to progression (TTP) and survival 

(OS) for the entire cohort was 2.4 months (IC 95% 1.2-3.6) and 13.2 months (IC 

95% 2.23-26.9 months). Median TTP and OS were 2.4 vs 1.8 (p 0.076) and 13.7 vs 

3.7 (p 0.095) in patients without and with T790M respectively. 

Conclusions: T790M mutation is a common feature of resistant acquired EGFR 

mutated NSCLC patients and can be detected using plasma DNA. 


1274P ALK AND EGFR MUTATION ANALYSIS IN A PHASE II TRIAL 

OF CISPLATIN/PEMETREXED IN JAPANESE PATIENTS WITH 

ADVANCED NON-SQUAMOUS NON-SMALL CELL LUNG 

CANCER 

N. Yanagitani 1 , K. Kaburaki 1 , F. Ohyanagi 1 , K. Kudo 1 , A. Horiike 1 , N. Motoi 2 , 

K. Takeuchi 2 , Y. Ishikawa 2 , T. Horai 1 , M. Nishio 1 

1 Thoracic Oncology Center, Cancer Institute Hospital, Japanese Foundation for 

Cancer Research, Tokyo, JAPAN, 2 Pathology, Cancer Institute Hospital, 

Japanese Foundation for Cancer Research, Tokyo, JAPAN 

Background: Recently, ethnic differences and genotypes such as EGFR mutation or 

fusion gene (ALK translocation) are important factors in non-small cell lung cancer 

(NSCLC) treatment. Pemetrexed (P)/cisplatin (C) is one of the standard treatments 


for advanced non-squamous (Nsq) NSCLC. However, the efficacy of the CP regimen 

has not been well examined in Japanese Nsq NSCLC patients; furthermore, the 

difference in efficacy between genotypes was not thoroughly examined. Therefore, the 

present study was conducted to evaluate the efficacy of the CP regimen in Japanese 

Nsq NSCLC patients, and to determine whether EGFR mutation and ALK 

translocation impacted the treatment. 

Methods: This study was conducted from May 2009 to December 2010. Patients 

were eligible for this study if they had histologically or cytologically confirmed 

recurrent or metastatic Nsq NSCLC previously untreated with chemotherapy, an 

ECOG performance status of 0 or 1, life expectancy of more than 12 weeks, and 

adequate organ function. Patients received C (75 mg/m2) plus P (500 mg/m2) on day 

1 every 3 weeks. Of the 50 patients initially enrolled, 49 were evaluated, and 43 

tumor samples were available for analysis. Most patients were male (80%), and 80% 

of the patients had adenocarcinoma. The primary endpoint was the response rate 

that was evaluated. according to RECIST. EGFR mutation was examined using 

PCR-based methods, and the ALK fusion protein was examined using a highly 

sensitive IHC method in the available tumor specimens. 

Results: The objective response rate and disease control rate in all patients were 

44.9% and 79.6%, respectively. The median progression-free survival was 4.4 months, 

and the 1-year survival was 73.5%. Toxicities were mild; no new toxicity profile was 

identified. Among the 43 samples, the following mutations were identified: 9 EGFRm 

(21%), 5 ALK (12%), and 29 wild-type (67%). Objective response was observed in 6 

(66.7%) EGFRm, 2 (40%) ALK (+), and 13 (44.8%) wild-type mutations. 

Conclusion: Although the CP regimen demonstrates consistent efficacy in Japanese 

Nsq NSCLC patients, EGFR mutation and ALK translocation may have impacted 

this treatment. 


1275P UPDATED SAFETY AND QUALITY OF LIFE (QOL) RESULTS 

OF PARAMOUNT STUDY: MAINTENANCE PEMETREXED 

(PEM) PLUS BEST SUPPORTIVE CARE (BSC) VS PLACEBO 

(PBO) PLUS BSC IMMEDIATELY FOLLOWING INDUCTION 

TREATMENT WITH PEM PLUS CISPLATIN (CP) FOR 

ADVANCED NONSQUAMOUS NON-SMALL CELL LUNG 

CANCER (NS-NSCLC) 

J. Pujol 1 , L. Paz-Ares 2 , M. Dediu 3 , M. Thomas 4 , P. Bidoli 5 , J. Corral 2 , 

N. Chouaki 6 , C.M. Visseren-Grul 7 , A. Zimmermann 8 , C. Gridelli 9 

1 Thoracic Oncologic Unit, Montpellier Academic Hospital, Hospital Arnaud de 

Villeneuve, Montpellier, Montpellier, FRANCE, 2 Medical Oncology, Hospital 

Universitario Virgen del Rocío, Seville, SPAIN, 3 Medical Oncology, Institute of 

Oncology Bucharest, Fundeni Clinical Hospital Alexandru Treistoreanu, 

Bucharest, ROMANIA, 4 Department of Thoracic Oncology, University of 

Heidelberg, Thoraxklinik Heidelberg, GERMANY, 5 Medical Oncology, Azienda 

Ospedaliera S. Gerardo U.O. Oncologia Medica, Monza, ITALY, 6 Medical 

Department, Eli Lilly, Paris, FRANCE, 7 Oncology Europe, Eli Lilly, RA Houten, 

NETHERLANDS, 8 Oncology, Eli Lilly and Company, Indianapolis, IN, UNITED 

STATES OF AMERICA, 9 Medical Oncology, UO Oncologia Medica “S.G. Moscati 

Hospital”, Avellino, ITALY 

Objectives: The PARAMOUNT trial showed that continuation maintenance therapy 

with pem after induction therapy with pem plus CP significantly reduced the risk of 

disease progression (HR = 0.62) and death (HR = 0.78) in patients (pts) with 

advanced NS-NSCLC. The purpose of this abstract is to present the updated safety 

and patients’ QoL results from the continuation maintenance treatment of the 

PARAMOUNT trial. 

Methods: In this phase III, randomized, double-blind, PBO-controlled study, 939 pts 

were treated with pem (500 mg/m 2 ) plus CP (75 mg/m 2 ) on day 1 of four 21-day 

cycles. Patients (n = 539) who had not progressed and had an Eastern Cooperative 

Oncology Group performance status (PS) of 0/1, were randomized (2:1; stratified for 

PS, induction response, and disease stage) to maintenance pem (500 mg/m 2 ,day1) 

plus BSC (n = 359) or PBO plus BSC (n = 180) until disease progression. All pts 

received vitamin B 12, folic acid, and dexamethasone. All randomized pts were 

qualified for the maintenance phase safety analyses, which included summaries of 

the incidence of adverse events by maximum Common Terminology Criteria 

Adverse Events, version 3, grade. All enrolled patients that had provided baseline and 

at least 1 subsequent measurement for EuroQol 5-dimensional (EQ-5D) scale were 

included in the analysis of patient-reported outcomes. 

Results: Safety and the QoL analyses in the continuation maintenance therapy will 

be presented. 

Conclusions: The long-term and low-grade toxicities of continuation maintenance 

therapy with pem will be discussed. 

Disclosure: C.M. Visseren-Grul: Employed by and own stock in Eli Lilly and 

Company. L. Paz-Ares: I have advisory board relationship and honararia to disclose 

with Eli Lilly and Company, Bayer, Roche, Pfizer. I. M. Dediu: Advisory Board - Eli 

Lilly and Company. M. Thomas: Advisory Board - Eli Lilly and Company Corporate 

Sponsored Trial - Eli Lilly and Company. N. Chouaki: Employed by and own stock 

in Eli Lilly and Company. A. Zimmermann: Employed by and own stock in Eli Lilly 

and Company. J. Pujol: Advisory Board - Eli Lilly and Company. C. Gridelli: 



Advisory Board, corporate-sponsored research, and honoraria/speaker bureau with 

Eli Lilly and Company. All other authors have declared no conflicts of interest. 

1276P SECOND-LINE ERLOTINIB THERAPY IN ELDERLY PATIENTS 

WITH ADVANCED NON-SMALL-CELL LUNG CANCER: 

IFCT-0501 RANDOMISED, PHASE 3 TRIAL 

E. Quoix 1 , V. Westeel 2 , J. Oster 3 , E. Pichon 4 , J. Dauba 5 , D. Debieuvre 6 , 

L. Baudrin 7 , F. Morin 8 , B. Milleron 9 , G. Zalcman 10 

1 Pneumologie, HUS, Strasbourg, FRANCE, 2 Pneumologie, CHU, Besançon, 

FRANCE, 3 Pneumologie, CH, Colmar, FRANCE, 4 Pneumologie, CHU, Tours, 

FRANCE, 5 Pneumologie, CH, Mont-de-Marsan, FRANCE, 6 Pneumology, General 

Hospital, Mulhouse, FRANCE, 7 Biostatistics, IFCT, Paris, FRANCE, 8 IFCT, 

PARIS, FRANCE, 9 Pneumologie, AP-HP Hôpital Tenon, PARIS, FRANCE, 

10 Pneumologie, CHU, Caen, FRANCE 

Background: The IFCT-0501 randomised, phase 3 trial showed a significant survival 

benefit for the experimental arm using carboplatin-weekly paclitaxel doublet 

chemotherapy (Arm B) over vinorelbine or gemcitabine monotherapy (Arm A), in 

elderly patients with advanced NSCLC (Quoix et al, Lancet 2011; 378:1079-88). In 

case of progression or toxicity, second-line (2nd) treatment with erlotinib was 

administered in both arms. Here we report the results of this 2nd-line therapy. 

Methods: Patients aged 70 to 89 years, with locally advanced or metastatic NSCLC, 

received erlotinib 150 mg daily as 2nd-line treatment until disease progression or 

excessive toxicity. 

Results: Among 443 patients who completed first-line chemotherapy, 292 received 

2nd-line erlotinib, at the same proportion in both arms (A: 64%, B: 67%, p = 0.46). 

Median duration of erlotinib treatment was not different according to first-line 

treatment arm, 2.01 and 2.24 months for arm A and arm B, respectively. Ability to 

receive 2nd-line treatment was significantly associated with performance status (0-1 

vs. 2-3), weight loss (≤5% vs. >5%), MMS (≤23 vs. >23) and ADL ( 80), sex or histology (squamous vs. 

non squamous). Response evaluated after 2 months of erlotinib was: CR: 1 (0,35%), 

PR : 25 (8,77%) and SD : 63 (22,1%). From the Day 1 of erlotinib administration, 

median overall survival was 4 and 6.8 months in arm A and B, respectively, with a 

1-yr survival rate of 26.4% and 33.7%, respectively (p = 0.08). Progression-Free 

Survival was 2.2 and 2.6 months, respectively (p = 0.36). Grade 3/4/5 toxicity was 

19.9/1/0%. 

Conclusions: In elderly patients with advanced NSCLC, administration of 2nd-line 

erlotinib is feasible, well tolerated, with a response rate comparable to that observed 

in previous trials, and maintained the survival advantage obtained with first-line 

carboplatin-weekly paclitaxel (NCT002598415). 

Disclosure: E. Quoix: Travel grants for meetings : lilly roche Advisory board : Lilly, 

Roche Grants for the study given to IFCT: BMS, pierre Fabre, Roche. V. Westeel: 

stock ownership: No membership on an advisory board or board of directors: roche, 

Lilly corporate-sponsored research: Roche other substantive relationships: Roche, 

Lilly, AstraZeneca, Boehringer Ingelheim. B. Milleron: stock ownership: No 

membership on an advisory board or board of directors: Yes Lilly, Roche 

corporate-sponsored research: No other substantive relationships: travel grants from 

Lilly and Roche. All other authors have declared no conflicts of interest. 

1277P COMPARATIVE EFFICACY AND SAFETY OF ERLOTINIB IN 

NON-SMALL CELL LUNG CANCER (NSCLC) OF SQUAMOUS 

CELL AND ADENOCARCINOMA HISTOLOGY IN THE PHASE 

III NCIC CTG BR.21 AND SATURN (BO18192) TRIALS 

S. Wojtowicz-Praga 1 , L. Leon 2 

1 Biooncology, Medical Affairs, Genentech, Inc., South San Francisco, CA, 

UNITED STATES OF AMERICA, 2 Biostatistics, Genentech, Inc., South 

San Francisco, CA, UNITED STATES OF AMERICA 

Background: Tumors of squamous cell (SC) histology are present in 25–30% of lung 

cancer patients (pts), and are more frequent in pts with a history of smoking. 

Erlotinib is an oral EGFR TKI shown to prolong progression-free survival (PFS) 

compared with placebo in first-line (1L) maintenance (SATURN; Cappuzzo, Lancet 

Oncol 2010) and second- or third-line (2L/3L) NSCLC settings (BR-21; Shepherd, 

NEJM 2005). Data from these pivotal studies were retrospectively analyzed to 

compare outcomes for pts with tumors of SC histology with those of pts diagnosed 

with adenocarcinomas (AD). 

Methods: BR.21 randomized ECOG PS 0–3 pts with advanced NSCLC who 

progressed after 1L or 2L chemotherapy 2:1 to erlotinib (150 mg daily) or placebo. 

SATURN randomized ECOG PS 0–1 pts with advanced NSCLC who did not 

progress after 1L chemotherapy 1:1 to maintenance therapy with erlotinib (150 mg 

daily) or placebo. PFS and overall survival (OS) were estimated using Kaplan-Meier 

methods. Hazard ratios (HRs) were calculated using Cox regression analysis. 

Results: 587 and 763 pts were evaluable in BR.21 and SATURN, respectively. A 

higher percentage of SC pts were smokers (current or ex-) and males versus AD pts 

in both studies. Most other baseline characteristics were similar between histology 

groups within each study. Efficacy and safety outcomes are shown (Table). In an 

interaction model analyzing for differential treatment effects on survival by SC and 

AD histology, P-values were >0.65 and >0.45 for PFS and OS in BR.21, respectively, 

and >0.2 for PFS in SATURN, providing no evidence for a statistically significant 

differential effect. 

Conclusions: Analyses of data from two large pivotal trials associated erlotinib 

treatment with significant survival benefit in both SC and AD histology subgroups, 

supporting its efficacy in pts with SC NSCLC in the 1L maintenance, 2L, and 3L 

settings. 

Measure 

BR.21 (N = 587) 

Grade 3–5 adverse events, n (%) 

Placebo arm Erlotinib arm HR (95% CI) 

AD (n = 365) 75 (63) 148 (60) – 

SCC 

Median PFS, mo 

56 (72) 109 (76) – 

AD 1.84 2.37 0.62 (0.49–0.79) 

SCC 

Median OS, mo 

1.81 2.27 0.48 (0.35–0.67) 

AD 5.36 7.75 0.76 (0.58–0.98) 

SCC 

SATURN (N = 763) 

Grade 3–5 adverse events, n (%) 

3.58 5.57 0.60 (0.44–0.82) 

AD (n = 403) 27 (14) 59 (29) – 

SCC (n = 360) 

Median PFS, mo 

23 (12) 41 (25) – 

AD 2.60 2.83 0.63 (0.51–0.78) 

SCC 2.60 3.02 0.77 (0.61–0.96) 

Disclosure: S. Wojtowicz-Praga: Dr. Wojtowicz-Praga is an employee of and holds 

stock options in Roche/Genentech. L. Leon: Dr. Leon is an employee of and holds 

stock options in Roche/Genentech. 

1278P CUMULATIVE EXPOSURE (EXP) TO BEVACIZUMAB (BV) 

MAINTENANCE AFTER INDUCTION THERAPY AND 

SURVIVAL IN ADVANCED NON-SMALL CELL LUNG CANCER 

(NSCLC): A TIME-DEPENDENT ANALYSIS FROM THE SAIL 

(MO19390) STUDY 

N. Thatcher 1 , P. Garrido Lopez 2 , N. Pavlakis 3 , J. Laskin 4 , E. Dansin 5 , 

F. Griesinger 6 , L. Leon 7 , D. Dalal 8 , P. Perez-Moreno 9 , L. Crino 10 

1 Department of Medical Oncology, University of Manchester, Manchester, 

UNITED KINGDOM, 2 Medical Oncology, Hospital Ramon y Cajal, Madrid, 

SPAIN, 3 Medical Oncology, Royal North Shore Hospital, St Leonards, 

AUSTRALIA, 4 Medical Oncology, BC Cancer Agency, Vancouver, CANADA, 

5 Département De Cancérologie Générale, CLCC Oscar Lambret, Lille Cedex, 

FRANCE, 6 Klinik für Hämatologie und Onkologie, Pius-Hospital Oldenburg, 

Oldenburg, GERMANY, 7 Biostatistics, Genentech, Inc., South San Francisco, 

CA, UNITED STATES OF AMERICA, 8 US Medical Affairs, Genentech, Inc., South 

San Francisco, CA, UNITED STATES OF AMERICA, 9 Pharmaceuticals Division, 

Gpsmo, F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 10 Department of 

Oncology, Hospital Santa Maria della Misericordia, Perugia, ITALY 

Background: Exploratory analyses from randomized and observational studies have 

shown that continuation BV until progressive disease (PD) is associated with 

prolonged overall survival (OS) in advanced NSCLC. We evaluated the correlation 

between cumulative exp to post-induction phase (post-IP) BV and OS in patients 

(pts) with NSCLC. 

Methods: The multinational phase 4 SAiL study enrolled advanced NSCLC pts 

receiving BV with 1st-line chemotherapy (CT). Pts who began BV and CT 

simultaneously and did not have PD after completing 12–18 weeks (4–6 cycles) of 

CT were included for analysis. OS was measured from the end of each pt’s BV+CT 

IP. BV exp, over follow-up, was defined as the cumulative days of post-IP BV 

treatment (tx). A time-dependent Cox regression model was fitted to assess the effect 

of cumulative post-IP BV exp on OS, while controlling for potential time-dependent 

and -fixed confounders. A landmark sensitivity analysis compared OS in pts in the 

analysis population who did and did not continue BV after IP. 

Results: Of 2212 pts in SAiL, 1625 NSCLC pts were alive and without PD through 

IP tx. Baseline characteristics (n = 1625) were: 58% male, 13% ≥70 y, 32% never 

smokers, and 4% ECOG PS ≥2. 1047 (64%) pts received post-IP BV. Baseline and 

end-of-IP characteristics were generally similar between pts receiving post-IP BV or 

no post-IP BV within the landmark period. Across follow-up, the hazard ratios 

(HRs) for OS decreased by ∼7% (range, 5%–9%) with each additional 21-day interval 

of cumulative exp (Table). Landmark sensitivity analyses also support that post-IP 

BV was associated with longer OS (post-IP BV vs no post-IP BV; HR, 0.74; 95% CI, 

0.64–0.85). 


Conclusions: These data from SAiL along with previously presented data from 

ARIES suggest that cumulative exp to post-IP BV is associated with incremental 

increases in OS for NSCLC pts. 

Cumulative 

post-IP BV cycles a 

No. of pts who received cumulative 

cycles of post-IP BV continuously b 

HR (95% confidence 

interval) for OS 

1 1006 0.91 (0.89–0.93) 

2 884 0.82 (0.79–0.86) 

3 758 0.75 (0.70–0.80) 

4 643 0.68 (0.62–0.74) 

5 530 0.62 (0.55–0.69) 

6 447 0.56 (0.49–0.64) 

7 370 0.51 (0.44–0.59) 

8 315 0.46 (0.39–0.55) 

a A cycle is approximately 21 days of post-IP cumulative exp. b Eg, n = 530 pts were 

continuously dosed through day 105 (cycle 5) after IP. 

Disclosure: N. Thatcher: Dr. Thatcher is a member of the Roche advisory board and 

has received speaker fees from Roche. P. Garrido Lopez: Dr. Garrido Lopez is a 

member of the Roche advisory board. N. Pavlakis: Dr. Pavlakis has received speaker 

honoraria and travel grants from Roche, and has participated in Roche Advisory 

Boards. J. Laskin: Dr. Laskin is a member of the Canadian National Ad Board for 

lung cancer for Astra Zeneca, BI, and Eli Lilly and has received research funding 

from Roche, Boehringer-Ingelheim, and Eli Lilly. E. Dansin: Dr. Dansin is a member 

of the Roche advisory board. F. Griesinger: Dr. Griesinger is a member of national 

and international advisory boards of Roche and has received honoraria for 

presentations at meetings. L. Leon: Dr. Leon is an employee of and holds stock 

options in Roche/Genentech. D. Dalal: Dr. Dalal is an employee of and holds stock 

options in Roche/Genentech. P. Perez-Moreno: Dr. Perez-Moreno is an employee of 

and holds stock options in F. Hoffman LaRoche. L. Crino: Dr. Crino received 

honorarium from Roche as a speaker in a scientific symposium. 

1279P CUMULATIVE EXPOSURE TO BEVACIZUMAB (BV) AFTER 

DISEASE PROGRESSION (PD) CORRELATES WITH SURVIVAL 

IN NON-SMALL CELL LUNG CANCER (NSCLC): A 

TIME-DEPENDENT ANALYSIS OF THE ARIES 

OBSERVATIONAL COHORT STUDY 

T.J. Lynch 1 , M. Jahanzeb 2 , D.R. Spigel 3 , A. Wozniak 4 , L. Leon 5 , S. Fish 5 ,E. 

D. Flick 6 , D. Dalal 6 , M.P. Kosty 7 

1 Yale School of Medicine, Yale Comprehensive Cancer Center, New Haven, 

UNITED STATES OF AMERICA, 2 University of Miami, Miller School of Medicine, 

Sylvester Comprehensive Cancer Center, Deerfield Beach, FL, UNITED STATES 

OF AMERICA, 3 Lung Cancer Research Program, Sarah Cannon Research 

Institute, Nashville, TN, UNITED STATES OF AMERICA, 4 Department of 

Hematology-Oncology, Wayne State University, Detroit, MI, UNITED STATES OF 

AMERICA, 5 Biostatistics, Genentech, Inc., South San Francisco, CA, UNITED 

STATES OF AMERICA, 6 Us Medical Affairs, Genentech, Inc., South 

San Francisco, CA, UNITED STATES OF AMERICA, 7 Department of Oncology, 

Scripps Clinic, La Jolla, CA, UNITED STATES OF AMERICA 

Background: Duration of BV use appears to contribute to treatment (tx) efficacy in 

some cancers (eg, CRC, ovarian). A phase 3 mCRC trial met its 1° endpoint of 

improved postprogression overall survival (ppOS) when continuing BV with 

chemotherapy (CT) into 2nd-line (2L) tx. A phase 2 study showed a trend for OS 

benefit when adding BV to CT in BV-naive 2L NSCLC (HR 0.71; 95% CI 0.41–1.21) 

(Herbst JCO 2007). This analysis evaluated whether BV exposure (exp) after PD 

correlates with ppOS in NSCLC. 

Methods: ARIES 1st-line (1L) BV-treated NSCLC patients (pts) who survived 1st PD 

were included. ppOS equaled the time from 1st PD to any-cause death. BV exp, over 

follow-up, equaled the cumulative days of BV from 1st PD. A time-dependent Cox 

regression model was fitted to assess the effect of cumulative BV exp on ppOS, while 

controlling for potential time-dependent and -fixed confounders. A landmark 

sensitivity analysis, also adjusting for confounders, compared ppOS in pts treated 

with BV beyond PD (BBP) and pts treated otherwise (No BBP) ≤30 days after PD. 

Results: As of 09/2011, of 1967 enrolled 1L pts, 1461 (74%) had 1st PD. 

Characteristics (n = 1461) were: 48% had 1st PD within 6 mos, 52% male, 31% ≥70 

y, 13% never smokers, and 13% ECOG status ≥2. The median ppOS for all pts with 

1st PD was 6 mos (95% CI 5.6–6.7). Among pts with any BV tx, the mean 

cumulative BV exp was 116 days (range, 2–1140). Across follow-up, the HRs for 

ppOS decreased by ∼4% for each additional 21-day interval of cumulative exp 

(Table). Cumulative BV duration was associated with improved ppOS (P < .0001). 

The landmark analysis also showed that BBP was independently associated with 

higher ppOS (BBP vs No BBP; HR, 0.75; 95% CI, 0.65–0.86). 

Conclusions: This analysis suggests that cumulative exp to BV after 1st PD may 

correspond with incremental increases in ppOS for NSCLC pts, and supports the 

conduct of the phase 3 AvaALL trial. 

Cycle a 

No. of pts who received 

cumulative cycles of BV 

continuously b 

Hazard ratio 

(HR) for ppOS 


95% confidence 

interval (CI) 

1 229 0.959 0.941–0.978 

2 159 0.920 0.885–0.956 

3 118 0.883 0.833–0.935 

4 84 0.847 0.784–0.914 

5 72 0.812 0.738–0.894 

6 55 0.779 0.694–0.874 

7 41 0.747 0.653–0.855 

8 32 0.717 0.614–0.836 

a A cycle is calculated as 21 days of cumulative exposure after PD. b Eg, n = 55 patients 

were continuously dosed through approximately day 126 (cycle 6) after PD. 

Disclosure: T.J. Lynch: Dr. Lynch is on the Infinity Pharmaceuticals board of 

directors, consults for Merck, Boehringer-Ingleheim and Astex, and holds a patent 

on EGFR testing from Partners Healthcare. M. Jahanzeb: Dr. Jahanzeb is a 

consultant/advisor for Genentech. D.R. Spigel: Dr. Spigel is an unpaid advisor/ 

consultant to Genentech. A. Wozniak: Dr. Wozniak has received honoraria and 

research support from Genentech and research funding from Eli Lilly. L. Leon: Dr. 

Leon is an employee of and holds stock options in Roche/Genentech. S. Fish: Dr. 

Fish is an employee of and holds stock options in Roche/Genentech. E.D. Flick: Dr. 

Flick is an employee of and holds stock options in Roche/Genentech. D. Dalal: Dr. 

Dalal is an employee of and holds stock options in Roche/Genentech. M.P. Kosty: 

Dr. Kosty has participated in the Genentech Speakers’ Bureau. 

1280P A PHASE II STUDY OF ERLOTINIB MONOTHERPAY IN 

PREVIOUSLY TREATED ADVANCED NON-SMALL CELL LUNG 

CANCER (NSCLC) WITHOUT EGFR GENE MUTATION WHO 

HAVE NEVER/LIGHT SMOKING HISTORY: NEJ006/ 

TCOG0903 

M. Maemondo 1 , Y. Ishii 2 , Y. Demura 3 , K. Okudera 4 , K. Takamura 5 , 

N. Morikawa 6 , M. Harada 7 , O. Ishimoto 8 , K. Kobayashi 9 , Y. Saijo 10 

1 Respiratory Medicine, Miyagi Cancer Center, Natori, JAPAN, 2 Pulmonary 

Medicine and Clinical Immmunolog, Dokkyo Medical University School of 

medicine, Tochigi, JAPAN, 3 Respiratory Medicine, Ishikawa Prefectural Central 

Hospital, Kanazawa, JAPAN, 4 Respiratory Medicine, Hirosaki Central Hospital, 

Hirosaki, JAPAN, 5 Respiratory Medicine, Obihiro-Kousei General Hospital, 

Obihiro, JAPAN, 6 Medical Oncology, Tohoku Kousei-Nenkin Hospital, Sendai, 

JAPAN, 7 Respiratory Medicine, National Hospital Organization Hokkaido Cancer 

Center, Sapporo, JAPAN, 8 Respiratory Medicine, Sendai Kosei Hospital, Sendai, 

JAPAN, 9 Respiratory Medicine, Saitama International Medical Center, Saitama, 

JAPAN, 10 Medical Oncology, Niigata University Graduate School of Medical and 

Dental Sciences, Nigata, JAPAN 

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors 

(TKIs) have dramatically improved clinical outcome in NSCLC harboring EGFR 

gene mutation. On the other hand, survival benefit from erlotinib was revealed even 

in the NSCLC patients with wild type (wt) EGFR gene by subset analyses of several 

phase III trials. Additionally, smoking status was identified as one of predictive 

factors of erlotinib efficacy. This study aimed to evaluate the efficacy of erlotinib in 

Japanese NSCLC patients with wt-EGFR and to find a biomarker that predicts the 

efficacy of erlotinib except EGFR gene mutation. 

Methods: The primary endpoint was an objective response rate. Secondary endpoints 

included disease control rate, overall survival, safety, and a biomarker finding. 

Advanced NSCLC patients without EGFR gene mutation who had received one to 

three prior chemotherapy regimens and who had never or light smoked were eligible 

in this study. EGFR gene status was evaluated by the PNA-LNA PCR clamp method. 

Erlotinib was administered daily (150mg/day) until disease progression or 

unacceptable toxicities. 

Results: Forty seven patients were enrolled between March 2010 and November 

2011. One patient was excluded for evaluation because having activating EGFR 

mutation. Efficacy and safety were evaluated among 46 patients. Best responses were 

PR 7 (15.2%), SD 12 (26.1%), PD 26 (46.4%), and NE 1 (2.2%). Response rate and 

disease control rate were 15.2% (95%CI: 4.9-25.5%) and 41.3 % (95%CI 27.1-55.5%) 

respectively. Median PFS were 1.5 months and 5 (11%) cases received erlotinib for 

more than 6 months. Grade 3 or 4 adverse events were anorexia (4), skin rash (2), 

neutropenia (1), leukopenia (1), anemia (2), elevation of AST/ALT (1), rectal ulcer 

(1), and cerebral infarction (1).Two patients suffered grade 3 interstitial lung disease. 

Conclusion: This is the first report to evaluate erlotinib efficacy in NSCLC selected 

by EGFR mutation negative and smoking status. This study elucidated that erlotinib 

has appreciable effect on some EGFR-wild cases without severe toxicities. Finding of 

predictive marker became more important. Biomarker analysis is ongoing. 

Disclosure: M. Maemondo: M. Maemondo received honoraria for lecture fees from 

Chugai. All other authors have declared no conflicts of interest. 



1281P MAINTENANCE THERAPY FOR NONSQUAMOUS 

NON-SMALL CELL LUNG CANCER (NSQNSCLC): 

PATIENT-REPORTED SYMPTOMS, PERFORMANCE STATUS 

(PS) AND EFFICACY 

C. Obasaju 1 , L. Bowman 2 , P. Wang 1 , W. Shen 3 , K.B. Winfree 2 , E.N. Smyth 2 , 

M. Boye 2 , W. John 1 , C.P. Belani 4 

1 Oncology, Eli Lilly and Company, Indianapolis, IN, UNITED STATES OF 

AMERICA, 2 Global Health Outcomes, Eli Lilly and Company, Indianapolis, IN, 

UNITED STATES OF AMERICA, 3 Global Statistics, Eli Lilly and Company, 

Indianapolis, IN, UNITED STATES OF AMERICA, 4 Cancer Institute, Penn State 

Milton S. Hershey Medical Center, Hershey, PA, UNITED STATES OF AMERICA 

Purpose: Ciuleanu et al. (2009) showed that pemetrexed (Pem) maintenance therapy 

is well-tolerated and offers significantly superior overall survival (OS) and 

progression-free survival (PFS) versus (vs) placebo (pbo) in patients (pts) with 

advanced nsqNSCLC. This retrospective analysis assessed the effect of maintenance 

therapy on OS and PFS by baseline patient-reported symptom burden and PS. 

Methods: Data from 481 nonsquamous pts were analyzed. Symptom burden of 464 

pts was captured with baseline values of the Lung Cancer Symptom Scale (LCSS), 

which includes 6 disease-specific symptom items (anorexia, fatigue, cough, dyspnea, 

pain, hemoptysis), each ranging from 0 (no symptoms) to 100 (worst symptoms). 

Average symptom burden index (ASBI) is the mean of the 6 items. Symptom 

subgroups were defined by ASBI: low symptom burden (LSB; ASBI < 25) and high 

symptom burden (HSB; ASBI ≥ 25). Multivariate Cox models were used to evaluate 

the maintenance treatment effect within ASBI subgroups adjusting for 9 

demographic/clinical (DC) factors, including ECOG PS and stage of disease. 

Similarly, maintenance treatment effects within PS 0, 1 subgroups were evaluated. 

Results: Controlling for PS and other DC factors, pts with LSB (n = 333) and HSB 

(n = 131) who received maintenance therapy had improved PFS vs pbo: 5.1 vs 2.4 

months [mos] (hazard ratio [HR] 0.49, p < 0.001) for LSB and 3.7 vs 2.8 mos (HR 

0.50, p = 0.003) for HSB. LSB pts had improved OS vs pbo (median OS 17.5 vs 11.0 

mos, HR 0.63, p = 0.001), but HSB pts did not (median OS 11.8 vs 10.6 mos, HR 

1.02, p = 0.92). PS was associated with patient-reported symptoms. PS 0 pts had 

lower mean LCSS scores than PS 1 pts for fatigue, pain, and ASBI (each p < 0.05). PS 

subgroup results are similar to the symptom-burden analysis: improved PFS in PS 0, 

1 pts and improved OS in PS 0 pts. 

Conclusion: NsqNSCLC pts with LSB and HSB at the end of induction therapy 

experienced significant improvements in PFS with Pem maintenance therapy. This 

translated into improved OS for LSB pts. These data suggest that maintenance 

therapy, rather than a break in treatment or “chemo holiday,” is an appropriate 

treatment strategy for nsqNSCLC pts at successful completion of induction therapy. 

Disclosure: C. Obasaju: Employed by and own stock in Eli Lilly and Company. L. 

Bowman: Employed by and own stock in Eli Lilly and Company. P. Wang: Employed by 

and own stock in Eli Lilly and Comany. W. Shen: Employed by and own stock in Eli Lilly 

and Company. K.B. Winfree: Employed by and own stock in Eli Lilly and Company. E.N. 

Smyth: Employed by and own stock in Eli Lilly and Company. M. Boye: Employed by 

and own stock in Eli Lilly and Company. W. John: Employed by and own stock in Eli 

Lilly and Company. C.P. Belani: Served on advisory board for Eli Lilly and Company 

1282P TOPICAL: RANDOMIZED PHASE III TRIAL OF ERLOTINIB 

COMPARED WITH PLACEBO IN PATIENTS WITH ADVANCED 

NON–SMALL CELL LUNG CANCER (NSCLC) UNSUITABLE 

FOR FIRST-LINE CHEMOTHERAPY: UPDATED ANALYSIS 

S. Lee 1 , S. Upadhyay 2 , C. Lewanski 3 , S. Falk 4 , G. Skailes 5 , E. Marshall 6 , 

Y. Ngai 7 , R. Rudd 7 , A. Hackshaw 7 , C. Boshoff 1 

1 Oncology, University College London (UCL) Hospitals & UCL Cancer Institute, 

London, UNITED KINGDOM, 2 Oncology, Scunthorpe General Hospital, 

Scunthorpe, UNITED KINGDOM, 3 Oncology, Charing Cross Hospital, London, 

UNITED KINGDOM, 4 Oncology, Yeovil District Hospital, Yeovil, UNITED 

KINGDOM, 5 Oncology, Royal Lancaster Infirmary, Blackpool, UNITED 

KINGDOM, 6 Oncology, Clatterbridge Centre for Oncology, Liverpool, UNITED 

KINGDOM, 7 Cancer Research Uk & Ucl Cancer Trials Centre, UCL Cancer 

Institute, London, UNITED KINGDOM 

Background: Despite the recommendation to treat advanced NSCLC with 

platinum-based chemotherapy, the majority of these pts receive only active 

supportive care (ASC) because of poor performance or multiple co-morbidities. We 

previously showed that erlotinib significantly improved PFS in such patients, but 

with an enhanced OS and PFS effect in female pts. Here, we report mature OS data 

including the association of first-cycle rash (FCR). 

Methods: 670 pts with stage IIIB/IV NSCLC (ECOG PS 2/3 or PS 0/1 with multiple 

co-morbidities unsuitable for chemotherapy) were randomized to receive placebo (n = 

320) or erlotinib 150 mg/day (n = 350) and ASC until disease progression/toxicity. OS, 

PFS, adverse events, and QoL were examined. Pre-specified subgroup analyses included 

erlotinib-rash ≤28 days of starting treatment (FCR), and EGFR where available. 

Results: Baseline characteristics were well balanced in these predominantly elderly 

NSCLC pts (median = 77 yrs, range 42-91). Among all pts, the hazard ratios (HRs) 

were 0.94 (95% CI 0.81-1.10, P = 0.46) for OS. Pts receiving erlotinib had a better 

PFS, HR = 0.83 (95% CI 0.71-0.97, P = 0.02). 59% of pts on erlotinib developed FCR. 

FCR was the only independent factor predictive of OS (HR = 0.17; P = 0.02) in a 

multivariate analysis containing rash, age, gender, histology, ECOG score and stage. 

There was a benefit for both OS (HR = 0.76, 95% CI 0.63-0.92, P = 0.01) and PFS 

(HR = 0.66, CI 0.54-0.80, P < 0.01), compared to placebo. The benefits were seen in 

all the subgps including those with the worst PS score (ECOG 3); OS HR = 0.58 and 

PFS HR = 0.41 & stage IV; OS HR = 0.66 and PFS = 0.56. The OS medians (months) 

were 6.2 (erlotinib-rash), 2.9 (no rash) and 4.1 (placebo). Continuous erlotinib, 

without rash, appeared to be associated with worse OS in some subgroups (e.g. 

males, ECOG 3). Results for EGFR and KRAS mutations are available on 390 pts. 7% 

(27/390) of pts had activating EGFR mutation; the benefits of erlotinib were seen 

regardless of EGFR status. KRAS mutations (19%, 73/390) were neither prognostic 

nor predictive of erlotinib benefit. Grade 3/4 diarrhea was more common with 

erlotinib (8.4% vs. 1.3%, p < 0.001); other adverse events were similar between 

groups. 

Conclusions: Erlotinib prolongs PFS and OS in patients with advanced NSCLC 

considered unsuitable for chemotherapy, but only if they develop FCR. 


1283P A COMPARATIVE STUDY OF EPIDERMAL GROWTH FACTOR 

RECEPTOR TYROSINE KINASE INHIBITOR IN TREATMENT 

OF PATIENTS WITH BRAIN METASTASIS FROM NON-SMALL 


L. Zhang 1 , L. Cai 2 , J. Zhu 1 

1 Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, CHINA, 

2 Radio-Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, CHINA 

Purpose: Brain metastasis (BM) presents 20-25% of patients with non-small cell lung 

cancer (NSCLC). Whole brain radiation therapy (WBRT) was considered as a 

standard therapy along with stereotactic radiosurgery (SRS), or surgical resection 

(SR) or chemotherapy (CXT). Median survival time ranged from 6.5-10 months for 

conventional therapy. In this study, we purposed to compare the outcomes of 

conventional therapy (CVT) combined with or without epidermal growth factor 

receptor tyrosine kinase inhibitor (EGFR-TKI) in the treatment for patients with BM 

from NSCLC. 

Methods: A total of 275 NSCLC patients with BM were treated sequentially between 

Jan, 1999 and Nov, 2011 according to our institutional protocol. Of these 275 

patients, 97 (35%) underwent EGFR-TKI combined with CVT (TKI + CVT), and 178 

(65%) underwent CVT. All patients received WBRT. Both treatment groups were 

similar with regard to age, sex, smoking status, histological subtype, number and size 

of BM lesions, extracranial lesions and intracranial symptoms. 

Results: Median overall survivals (MOS), median progress free survivals (MPFS), 

median progress free survivals of intracranial lesions (MPFSI) and median progress 

free survivals of extracranial lesions (MPFSE) were 28.2 (95% CI:22.3-34.1) and 13.7 

(95% CI:11.4-15.9) months, 10.9 (95% CI:8.4-13.4) and 6.7 (95%CI:5.1-8.4) months, 

18.7 (95%CI: 12.6-24.8) and 10.3 (95%CI:8.4-12.3) months, 11.1(95%CI:9.1-13.1) and 

7.9 (95%CI:6.2-9.5) months for TKI + CTV and CTV groups, respectively. With TKI 

+ CVT group, improved outcome was found to be significantly associated with no 

lymph node metastasis (P = 0.001) and adverse drug reaction (ADR) (P = 0.001) for 

MOS, MPFS, MPFSI and MPFSE. With CVT group, improved MOS was found to be 

associated with age

NSCLC diagnosis and time of BM diagnosis were estimated using Kaplan-Meier 

method. Association between delayed WBRT, after at least 2 cycles of chemotherapy 

(CT) or not, and death was evaluated using multivariable Cox proportional hazards 

model adjusted for gender, histology, smoking status and RPA score. 

Results: We included 175 consecutive pts: 61% were male, median age was 57 years 

[range = 27-79]. 68% had adenocarcinoma, 15% were never smoked. At first diagnosis of 

NSCLC, the TNM 2009 stage was mainly IV (68%) and III (21%). 42 % of BM were 

synchronous and 36% pts had no extracranial metastasis. The number of BM was: one 

in 34%, and more than three lesions in 41%. Karnofsky index was >= 70% in 79% of 

pts. The RPA class was good-I in 13 pts and poor-III in 37 pts. Radical surgery was 

performed in 23 pts (16%) while 8 pts (4.6%) received SRS. 70% had CT with a median 

nbr of 1 line [0-6], 31% were treated with anti EGFR therapy. Median OS from NSCLC 

diagnosis was 18 (95%CI = [15;20]) months. Median OS from BM diagnosis was 9m 

(95%CI = [7.6;10.6]) for the whole population, 43 m for RPA class I, 10 m for class II 

and 2 m for class III. In 26% of the pts, WBRT was delayed and delayed WBRT was not 

associated with survival in multivariable analysis (HR = 1.24 95%CI.0.85-1.80). 

Conclusions: Our results suggest that in NSCLC with BM, RPA class II could be 

easily treated with systemic therapy, with then long survival, selected RPA class III 

may benefit WBRT and systemic treatment. ALK and EGFR status will be presented. 


1285P BIWEEKLY CARBOPLATIN AND PACLITAXEL AS FIRST-LINE 

THERAPY FOR ELDERLY ADVANCED NON-SMALL CELL 

LUNG CANCER PATIENTS (PHASE II STUDY) 

I. Kota, K. Soejima, K. Naoki, H. Yasuda, H. Terai, A. Daisuke, K. Ohgino, 

S. Yoda, S. Ikemura, T. Betsuyaku 

Respiratory Medicine, Keio University School of Medicine, Tokyo, JAPAN 

Background: Incidence of elderly patients with advanced non-small cell lung cancer 

(NSCLC) is increasing, however the treatment for elderly patients is still waiting for the 

best answer. Although several studies had suggested the advantage of chemotherapy with 

platinum doublet for elderly patients with advanced NSCLC (e.g. Quoix E, et al., The 

Lancet 378, 2011), the application of platinum doublet to the elderly is still controversial. 

To evaluate the efficacy and tolerability of combination chemotherapy with biweekly 

carboplatin (CBDCA) and paclitaxel (PTX) for elderly patients with advanced NSCLC, 

we conducted a multicenter non-randomized open label phase II trial. 

Methods: Eligibility criteria were as follows; histologically proven NSCLC, aged 70 

years and older, ECOG Performance Status (PS) of 0 to 2, clinical stage IIIB and IV, 

chemotherapy naïve, and adequate organ function. Patients received CBDCA (AUC 

= 2.5) and PTX (90 mg/m2) on day 1 and 15 every 4-week for up to 6 cycles, until 

disease progression or intolerable toxicity. The primary endpoint was ORR, and the 

secondary endpoints were PFS, OS and tolerability. 

Results: 60 patients (median age 78 years old, range 70-85) were enrolled. 45 patients 

were male and 45 were stage IV. PS 0/1/2 were 26/30/4, respectively. The median 

number of treatment cycle was 3 (1-6). CR/PR/SD/PD were 0/28.9/37.8/33.3% as the 

best response, giving an ORR of 28.9 % and DCR of 66.7%. Median PFS and OS 

were 5.3 month (95% CI: 3.1-7.5) and 26.7 month (95% CI: 18.2-35.1), respectively. 

Grade 3/4 hematological toxicities were neutropenia (27%), leucopenia (15%) and 

anemia (8%). Grade 3 non-hematological toxicities were infusion reaction (2%), 

anorexia (2%), infection (10%), thrombosis (2%), fatigue (3%), diarrhea (2%) and 

gastrointestinal bleeding (3%). Although no grade 4 non-hematological toxicity was 

observed, one patient died probably due to treatment-related interstitial pneumonitis. 

The adverse events were relatively mild and manageable. 

Conclusions: The combination of biweekly CBDCA (AUC = 2.5) and PTX 

(90 mg/m2) was effective and well tolerated for elderly patients with advanced 

NSCLC. (This study was registered at UMIN 000001328) 


1286P A PHASE II STUDY OF PEMETREXED IN 

CHEMOTHERAPY-NAïVE ELDERLY PATIENTS WITH 

ADVANCED NON-SQUAMOUS NON-SMALL-CELL LUNG 

CANCER: HANSHIN ONCOLOGY GROUP 003 

M. Iwasaku 1 , Y. Hattori 2 , S. Morita 3 , H. Yoshioka 1 , K. Otsuka 4 , N. Katakami 5 , 

S. Fujita 5 , S. Yokota 6 , F. Imamura 7 , S. Negoro 8 

1 Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, JAPAN, 

2 Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, JAPAN, 

3 Biostatistics and Epidemiology, Yokohama City University Medical Center, 

Yokohama, JAPAN, 4 Division of Respiratory Medicine, Kobe City Medical Center 

General Hospital, Kobe, JAPAN, 5 Integrated Oncology, Institute of Biomedical 

Research and Innovation Hospital, Kobe, JAPAN, 6 Department of Thoracic 

Oncology, National Hospital Organization Toneyama National Hospital, Toyonaka, 

JAPAN, 7 Department of Thoracic Oncology, Osaka Medical Center for Cancer 

and Cardiovascular Diseases, Osaka, JAPAN, 8 Thoracic Oncology, Hyogo 

Cancer Center, Akashi, JAPAN 

Background: Single-agent chemotherapy (ie, doxetaxel, gemcitabine or vinorelbine) 

is one of the standard treatments for elderly patients with advanced NSCLC. 


Pemetrexed has clinically equivalent efficacy, but with less toxicity compared to 

doxetaxel in the second line setting of patients with advanced NSCLC. We conducted 

a phase II trial to evaluate the efficacy and safety of frontline pemetrexed in elderly 

patients with advanced non-squamous (non-Sq) NSCLC. 

Methods: In this multicenter phase II trial, we recruited elderly patients with non-Sq 

NSCLC. Eligibility criteria were as follows: chemonaïve; locally advanced or 

metastatic non-Sq NSCLC; age 75 or older; ECOG performance status 0-1; adequate 

organ function. Patients received pemetrexed (500 mg/m2) intravenously on day 1 

every 3 weeks until disease progression had been confirmed. The primary endpoint 

was response rate (RR). The secondary endpoints included progression free survival 

(PFS), overall survival (OS), disease control rate (DCR) and safety. The planned 

sample size was 45 patients. 

Results: Between August 2009 and July 2011, 47 patients were enrolled. Median age 

was 79 years (range: 75-91), 57% (20/47) were male, 36% (17/47) had never smoked, 

85% (40/47) had adenocarcinoma, 72% (34/47) had stage IV and 41% (16/39) had 

EGFR tyrosine kinase activating mutation. Median number of cycles was 4 (1 to 15). 

RR was 13.3% (95%CI: 5.1, 26.8), DCR was 66.7% (95%CI: 51.0, 80.0), PFS was 4.9 

months (95%CI: 3.0, 6.2 months), median OS was not reached. The most frequent 

treatment-related AEs were anemia, fatigue, hypocalcemia, mostly grade1/2. 

Treatment-related Grade 3/4 AEs were reported in 17.8% of patients (mostly 

neutropenia and fatigue). No treatment-related death occurred. 

Conclusions: The efficacy and limited side effects of pemetrexed are promising in 

elderly patients with non-Sq NSCLC. 

Disclosure: S. Negoro: HONORARIA: Lily. All other authors have declared no 


1287P FINAL RESULTS OF A PHASE 2, OPEN-LABEL STUDY OF 

RAMUCIRUMAB (IMC-1121B; RAM), AN IGG1 MAB 

TARGETING VEGFR-2, WITH PACLITAXEL AND 

CARBOPLATIN AS FIRST-LINE THERAPY IN PATIENTS (PTS) 

WITH STAGE IIIB/IV NON-SMALL CELL LUNG CANCER 

(NSCLC) (NCT00735696) 

D.R. Camidge 1 , R.C. Doebele 1 , M. Ballas 2 , T. Jahan 3 , M. Haigentz 4 , 

D. Hoffman 5 , J. Spicer 6 , H. West 7 , S. Yurasov 8 , A.C. Mita 9 

1 Oncology, University of Colorado Cancer Center, Aurora, CO, UNITED STATES 

OF AMERICA, 2 Oncology, New York University Langone School of Medicine, 

New York, NY, UNITED STATES OF AMERICA, 3 Division of Hematology/ 

Oncology, University of California - San Francisco, San Francisco, CA, UNITED 

STATES OF AMERICA, 4 Department of Medicine (oncology), Albert Einstein 

College of Medicine/Montefiore Medical Center, Bronx, NY, UNITED STATES OF 

AMERICA, 5 Oncology/hematology, Tower Hematology Oncology Medical Group, 

Beverly Hills, CA, UNITED STATES OF AMERICA, 6 Department, King’s College 

School of Medicine and Guy’s Hospital, London, UNITED KINGDOM, 7 Oncology 

- Medical, Swedish Cancer Institute, Seattle, WA, UNITED STATES OF 

AMERICA, 8 Medical, ImClone Systems, Bridgewater, NJ, UNITED STATES OF 

AMERICA, 9 Oncology, University of Texas Health Sciences Center, San Antonio, 

TX, UNITED STATES OF AMERICA 

Background: VEGF-mediated angiogenesis contributes to NSCLC pathogenesis. 

RAM is a recombinant human mAb that binds the extracellular domain of the 

vascular endothelial growth factor receptor-2 (VEGFR-2) and inhibits cancer growth 

in diverse preclinical models. 

Methods: Pts with advanced NSCLC (Stage IIIb not suitable for locoregional therapy 

or Stage IV) were eligible. Squamous histology and treated brain metastases were 

allowed. Exclusion criteria included prior bevacizumab, blood vessel invasion, 

intratumor cavitation, and recent gross hemoptysis. Pts received RAM 10 mg/kg, 

paclitaxel 200 mg/m 2 , and carboplatin AUC = 6 on Day 1 of a 3-week cycle for up to 

6 cycles, followed by maintenance RAM. The primary endpoint was PFS at 6 months 

(m); secondary/exploratory endpoints were safety, ORR, OS rate at 1 year, PK/PD 

profiles, and immunogenicity. 

Results: 40 pts were treated (15M:25F; median age 60; 39 nonsquamous / 1 

squamous); all have discontinued. 39 pts were evaluable for response. 22 of 40 

treated pts had an objective response (1 CR, 21 PR; ORR = 55%). 14 pts had a best 

response of SD. Median PFS was 7.85 m (95% CI: 5.49 m-9.86 m), and the PFS rate 

at 6 m was 62.5% (90% CI: 48.3%-75.3%); the 1-year survival rate was 74.6% (95% 

CI: 57.9%-85.4%). 34 of 40 pts (85%) reported an AE at least possibly related to 

RAM; the most common related AEs were fatigue (53%), peripheral neuropathy 

(33%), nausea (28%), myalgia (23%), and epistaxis (23%). Related AEs of Gr ≥ 3 

were reported for 15 pts; the most common were neutropenia (5 pts), 

thrombocytopenia (4 pts), fatigue, febrile neutropenia (3 pts each), peripheral 

neuropathy and pulmonary embolism (2 pts each). There were 5 pts with a total of 6 

Gr 4 related events: febrile neutropenia, pulmonary embolism (2 pts each), 

neutropenia and thrombocytopenia (1 pt each). 

Conclusions: RAM in combination with paclitaxel and carboplatin shows promising 

efficacy based on the overall disease control rate (CR + PR + SD) reaching 90% and 

PFS rate at 6 m of 62.5%, and is well tolerated by patients with NSCLC. 

Disclosure: D.R. Camidge: I have received research funding from Eli Lilly and 

Company and honoraria from ImClone Systems. R.C. Doebele: Research Funding: 

ImClone Systems, Eli Lilly & Co., Pfizer Inc. Honoraria: Boehringer Ingelheim, 



Abbott Laboratories, Pfizer Inc Stock: Ariad (

1291P PHASE I/II DOSE-FINDING STUDY OF CRIZOTINIB (CRIZ) IN 

COMBINATION WITH ERLOTINIB (E) IN PATIENTS (PTS) 

WITH ADVANCED NON-SMALL CELL LUNG CANCER 

(NSCLC) 

S.I. Ou 1 , R. Govindan 2 , K. Eaton 3 , A. Argiris 4 , G. Otterson 5 , F. Robert 6 , 

N. Brega 7 , T. Usari 7 ,W.Tan 8 , M. Gutierrez 9 

1 Chao Family Comprehensive Cancer Center, University of California at Irvine, 

Orange, CA, UNITED STATES OF AMERICA, 2 Medical Oncology, Washington 

University School of Medicine, St. Louis, MO, UNITED STATES OF AMERICA, 

3 Thoracic/head and Neck Oncology, Ùniversity of Washington/Seattle Cancer 

care Alliance, Seattle, WA, UNITED STATES OF AMERICA, 4 Oncology, University 

of Texas Health Sciences Center, San Antonio, TX, UNITED STATES OF 

AMERICA, 5 Comprehensive Cancer Center, The Ohio State University, 

Columbus, OH, UNITED STATES OF AMERICA, 6 Comprehensive Cancer Center, 

University of Alabama at Birmingham, Birmingham, AL, UNITED STATES OF 

AMERICA, 7 Oncology, Pfizer Italia, Milan, ITALY, 8 Oncology, Pfizer, San Diego, 

CA, UNITED STATES OF AMERICA, 9 John Theurer Cancer Center, Hackensack 

University Medical Center, Hackensack, NJ, UNITED STATES OF AMERICA 

Background: c-Met expression is common in NSCLC tumors and has been 

implicated in the development of resistance to EGFR inhibitors. Criz is an ALK and 

MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical studies, 

combining criz with an EGFR inhibitor enhanced anti-tumor activity in NSCLC cell 

lines that were sensitive or resistant to EGFR inhibition. The phase I portion of a 

phase I/II study (A8081002; NCT00965731) investigated the combination of E 

(EGFR TKI) and criz in pts with advanced NSCLC. 

Methods: Pts had advanced NSCLC, 1 or 2 prior chemotherapy regimens, and no 

previous MET-directed therapy. Endpoints included maximum tolerated dose (MTD) 

determination, safety, and pharmacokinetics (PK). Pts received E 100 mg QD for ≥7 

days before adding criz 150 or 200 mg BID (150 + 100 and 200 + 100, respectively). 

Results: As of March 15th 2012, 27 pts had started therapy. Median (range) duration 

of combination therapy in 150 + 100 (n = 19) was 7 weeks (0.1–28.0); for 200 + 100 (n 

= 7) was 6.9 weeks (1.9–77.6). Five pts had dose-limiting toxicities (grade [G] 2 and 

unable to receive at least 80% of the planned dose or ≥G3), all of which resolved: 3 pts 

at 150 + 100, G2 vomiting, G2 esophagitis and dysphagia, G3 diarrhea and 

dehydration; and at 200 + 100, G3 dry eye (1 pt) and G3 esophagitis (1 pt). Most pts 

(96%) experienced treatment-related adverse events (TRAEs), mainly of G1 or 2 

severity. Common TRAEs were diarrhea (73%), rash (62%) and fatigue (46%). Six pts 

discontinued therapy due to TRAEs (150 + 100: G3 diarrhea, G3 dehydration, and G1 

hyponatremia in 1 pt, G2 asthenia, G2 vomiting, G2 esophagitis, n = 1 each; 200 + 100: 

G3 dry eyes, G1 esophagitis, n = 1 each). One partial response (200 + 100; duration 73 

weeks) and 9 stable diseases (n = 7 150 + 100, n = 2 200 + 100; duration 8–62 weeks) 

were observed overall. Co-administration of both doses of criz with E increased E AUC 

by 1.8 fold; criz PK parameters appeared to be unaffected. Plasma exposure to E 100 

mg QD with criz was comparable to 150 mg QD from historical data. 

Conclusions: E plus criz at the MTD was well tolerated, with no unexpected AEs, 

and showed signs of activity in a pre-treated population. E 100 mg QD plus criz 150 

mg BID was defined as MTD. 

Disclosure: S.I. Ou: Advisory relationship with Pfizer and Genentech (both 

compensated). Received honoraria from Pfizer, Genentech and Lilly. Research funding 

from Pfizer. K. Eaton: Research funding from Pfizer. A. Argiris: Advisory relationship 

with Pfizer. Received honoraria from Pfizer. Research funding from Pfizer. G. 

Otterson: Received honoraria from Genentech and Abraxis/Celgene. Research funding 

from Genentech, Abraxis/Celgene, Pfizer, Tragara, Amgen, Pharmacyclics, OSI and 

GSK. F. Robert: Research funding to the University of Alabama at Birmingham. N. 

Brega: Employed by Pfizer as a Director. Hold Pfizer stock. T. Usari: Employed by 

Pfizer as a statistician. Holds Pfizer stock. W. Tan: Èmployed by Pfizer. Holds Pfizer 

stock. All other authors have declared no conflicts of interest. 

1292P PHASE II TRIAL OF AFATINIB AS A THIRD-LINE TREATMENT 

FOR KOREAN PATIENTS (PTS) WITH WILD-TYPE 

EPIDERMAL GROWTH FACTOR RECEPTOR (WTEGFR) 

STAGE IIIB/IV LUNG ADENOCARCINOMA 

M.A. Ahn 1 , S. Kim 2 , B. Cho 3 , J.S. Ahn 1 , D.H. Lee 2 , J. Sun 4 , D. Massey 5 , 

M. Kim 6 ,Y.Shi 7 , K. Park 1 

1 Division of Hematology/Oncology, Department of Medicine, Sungkyunkwan 

University, School of Medicine, Seoul, KOREA, 2 Division of Oncology, 

Department of Internal Medicine, University of Ulsan, College of Medicine, Seoul, 

KOREA, 3 Division of Oncology, Department of Internal Medicine, Yonsei 

University, College of Medicine, Seoul, KOREA, 4 Division of Haematology/ 

Oncology, Department of Medicine, Sungkyunkwan University, School of 

Medicine, Seoul, KOREA, 5 Statistics, Boehringer Ingelheim, Bracknell, UNITED 

KINGDOM, 6 Medical Affairs, Boehringer Ingelheim, Seoul, KOREA, 7 Medical 

Affairs, Boehringer Ingelheim, Beijing, CHINA 

Background: EGFR inhibition benefits not only pts with mutated (mut) EGFR 

non-small cell lung cancer (NSCLC), but also pts with wtEGFR. Afatinib (BIBW 


2992), an irreversible ErbB Family Blocker, has shown activity in heavily pretreated 

pts with mutEGFR NSCLC. This Phase II trial evaluated the efficacy of afatinib in pts 

with advanced wtEGFR NSCLC as third-line therapy at 3 Korean institutions. 

Methods: Eligible pts had Stage IIIB/IV or recurrent wtEGFR (by local lab) lung 

adenocarcinoma with measurable disease, ECOG PS 0–2 and had failed 2 lines of 

chemotherapy (1–2 platinum-containing regimens). Prior treatment with anti-EGFR 

agents was not permitted. Pts received oral afatinib 40 mg/day until disease 

progression or occurrence of intolerable adverse events (AEs). The primary endpoint 

was confirmed objective tumour response rate (complete response [CR] + partial 

response [PR]) by RECIST 1.1; secondary endpoints included disease control rate 

(DCR = CR + PR + stable disease [SD]), progression-free survival (PFS), and safety 

profile. 

Results: Forty-two pts received afatinib, but 4 pts were excluded from efficacy analyses 

because mutEGFR NSCLC was confirmed by central lab. Baseline pt characteristics 

were median age of 58.0 years, 79% male, 67% current/ex-smokers. Median treatment 

time with afatinib was 4.1 weeks (wks) (range 1.4–54.4 wks); 2 pts (1 pt with 

mutEGFR and 1 pt with wtEGFR) were still receiving afatinib at the time of analysis. 

No CRs or PRs were reported. DCR was 24% (9/38 pts) and the median duration of 

disease control was 19.3 wks (range 11.6–28.0 wks). Median PFS was 4.1 wks (95% CI: 

3.9, 8.0). The most frequently reported AEs (mainly Grade 1 or 2) were rash (76%), 

diarrhoea (62%), and decreased appetite (43%). AEs led to dose reduction in 6 pts 

(14%) and discontinuation in 7 pts (17%). No treatment-related deaths were reported. 

Conclusions: A proportion of heavily pretreated patients with wtEGFR NSCLC 

derived benefit from afatinib; further investigation will be planned including 

potential other biomarkers. Afatinib was tolerable as third-line treatment, with AEs 

that were manageable and consistent with the known safety profile. 

Disclosure: B. Cho: Lecture fees from Merck and AstraZeneca; consulting fees from 

Merck. D. Massey: Employee of Boehringer-Ingelheim. M. Kim: Employee of 

Boehringer-Ingelheim. Y. Shi: Employee of Boehringer-Ingelheim. K. Park: Advisor/ 

Consultant for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sereno, Pfizer, 

Roche; Steering Committee for AMGEN, Kyowa Kirin. All other authors have 


1293P FINAL RESULTS OF A JAPANESE PHASE 1 TRIAL 

EVALUATING A C-MET INHIBITOR TIVANTINIB IN 

COMBINATION WITH AN EGFR INHIBITOR ERLOTINIB IN 

ADVANCED/METASTATIC NON-SMALL CELL LUNG CANCER 

(ARQ 197-003/005 STUDY) 

N. Yamamoto 1 , H. Murakami 1 , T. Takahashi 1 , H. Hayashi 2 , Y. Fujisaka 3 , 

T. Hirashima 4 , K. Takeda 5 , M. Satouchi 6 , K. Nakagawa 2 

1 Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, JAPAN, 2 Medical 

Oncology, Kinki University School of Medicine, Osaka, JAPAN, 3 Medical 

Oncology, Kinki University Fuculty of Medicine, Osaka, JAPAN, 4 Department of 

Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and 

Allergic diseases, Osaka, JAPAN, 5 Clinical Oncology, Osaka City General 

Hospital, Osaka, JAPAN, 6 Thoracic Oncology, Hyogo Cancer Center, Hyogo, 

JAPAN 

Background: Tivantinib (formerly ARQ 197) is a selective, oral, non-ATP-competitive, 

small-molecule inhibitor of c-MET, and is metabolized by CYP2C19 and moderately by 

CYP3A4. A Japanese phase 1 study testing tivantinib as a single agent demonstrated that 

the major dose-limiting toxicity was neutropenia, and that the recommended doses were 

360 mg bid for CYP2C19 extensive metabolizers (EMs) and 240 mg bid for poor 

metabolizers (PMs). A Western phase 2 study showed a prolonged progression free 

survival in metastatic NSCLC patients treated with tivantinib in combination with an 

EGFR inhibitor erlotinib, which is mainly metabolized by CYP3A4. Here we evaluate 

the safety and tolerability of tivantinib in combination with erlotinib, in Japanese EMs 

and PMs (ARQ 197-003 /005), respectively. 

Methods: Heavily pretreated patients with advanced or metastatic NSCLC received 

tivantinib as a single agent for single dose analysis on day 1, and thereafter, started a 

repeating dose of tivantinib and erlotinib combination until progression or 

unacceptable toxicity. Tivantinib was separately escalated in EMs and PMs, up to the 

dose respective doses recommended by the previous single agent phase 1. Erlotinib 

was administered at 150 mg/day for all patients. 

Results: A total of 25 patients (16 EMs, 9 PMs) were treated. Tivantinib, when 

combined with erlotinib, was well tolerated up to 360 mg bid for EMs and 240 mg 

bid for PMs. Rash, dry skin, diarrhea, and nausea were the treatment emergent 

adverse events (TEAEs) observed in >25% of all patients. Grade ≥3 neutropenia was 

observed in 2 PMs (8% in all patients) throughout the studies, and the rate was not 

largely different from the previous phase 1 study. Drug-drug interaction was not 

observed in tivantinib metabolism in combination with erlotinib. All patients were 

evaluable for response; 3 PRs and 10 SD. 

Conclusion: Tivantinib at the recommended dose in single agent phase 1 could be 

combined with erlotinib without accelerating tivantinib-related AE, or significantly 

changing the pharmacokinetics. A pivotal phase 3 trial is currently underway in 

Asian non-squamous NSCLC with wild-type EGFR, to evaluate the OS-prolongation 

by the combination over erlotinib alone. 




1294P DEFINITIVE THORACIC CHEMORADIOTHERAPY IN 

NON-SMALL CELL LUNG CANCER PATIENTS WITH 

SOLITARY BRAIN METASTASIS 

C. Parlak 1 , O.C. Guler 1 , O. Ozyilkan 2 




Background: The aim of the study was to evaluate the impact of definitive thoracic 

chemoradiotherapy on outcomes in non-small cell lung cancer (NSCLC) patients 

with solitary brain metastasis. 

Materials and methods: Fifty four medically fit NSCLC patients with isolated BM 

were retrospectively evaluated. Patients were staged with PET-CT besides 

conventional staging tools. TRT to a total dose of 66 Gy in 2 Gy fx was delivered 

with 2 cycles of concomitant cisplatin –based chemotherapy (CT) following surgery 

+ 30 Gy whole-brain RT (WBRT) (n:18), 30 Gy WBRT + 15 Gy boost (n:22), or 30 

Gy WBRT + stereotactic radiosurgery (SRS) (n:14) for their BM. Response evaluation 

was done according to EORTC RECIST criteria 

Results: Pretreatment patients characteristics were as given in Table 1. Overall the 

treatment was well-tolerated and all patients received planned TRT and 2 cycles of 

CT. At a median follow up of 15.2 months (4.4-42.3), median overall, locoregional 

progression free and progression free survivals were 12.2, 8.5 and 5.9 months. 

Univariate analyses revealed that patients receiving WBRT + SRS for BM (P < 0.001), 

performance status of ECOG 0-1 (P < 0.001), older than median age of 50 (p:0.031) 

no weight loss (p:0.001) had better survival. Multivariate analysis based on these 

factors demonstrated that all factors except age retained their independent prognostic 

values (p

Network utilization of WBCGF in the metastatic setting to determine current 

practice and associated costs in this palliative chemotherapy setting. 

Methods: We retrospectively identified metastatic NSCLC patients between 7/2006 

and 6/2011 using the US Oncology Network EHR database (iKnowMed). 

Secondary diagnoses and clinical trials were excluded. Chemotherapy and WBCGF 

utilization was determined by the number of patients assigned to a 1st or 2nd+ (and 

beyond) line of therapy (LOT) during the study period. 

Results: During this timeframe, 10,374 patients (female: 44%; median age 67) 

diagnosed with metastatic NSCLC were identified. Of these, 3284 patients received 

WBCGF with chemotherapy; where, 2825 patients (33%) were administered 1st LOT 

and 459 patients (27%) were administered 2nd+ LOT. When reviewing the 

chemotherapy regimens assigned (regardless of WBCGF administration), the most 

commonly utilized regimens were: Carboplatin + Paclitaxel +/- Bevacizumab, 

Pemetrexed containing regimens, Docetaxel containing regimens, Gemcitabine 

containing regimens, and Vinorelbine. The average estimated cost for these 

chemotherapy regimens (Medicare Allowable 1Q2012) is $2589/cycle; the average 

estimated cost of WBCGF usage in the metastatic setting was $1889/dose (Medicare 

Allowable 1Q2012). 

Conclusion: The American Society of Clinical Oncology has recently identified two 

opportunities to reduce the cost of care without adversely affecting outcomes (i.e., 

ineffective chemotherapy at the end of life; the use of WBCGF in palliative 

chemotherapy where dose reduction is an option). These intersect in this study of 

NSCLC. These data indicate there is an opportunity to address 40% of the drug costs 

of NSCLC by the judicious use of protocols using dose reduction as a strategy. 

Disclosure: J.R. Hoverman: I am a medical director for Innovent Oncology. R. 

Beveridge: I am EVP, Medical Director for McKesson Specialty Health. All other 


1298P ANALYSIS OF ERLOTINIB-RELATED SKIN TOXICITIES FROM 

JAPANESE POST-MARKETING SURVEILLANCE 

(POLARSTAR) IN 9,909 NON-SMALL-CELL LUNG CANCER 

(NSCLC) PATIENTS (PTS) 

Y. Kiyohara 1 , N. Yamazaki 2 , A. Seki 3 , M. Fukuoka 4 

1 Dermatology Division, Shizuoka Cancer Center, Nagaizumi, Shizuoka, JAPAN, 

2 Department of Dermatologic Oncology, National Cancer Center Hospital, Tsukiji, 

Chuo-ku, Tokyo, JAPAN, 3 Pharmacovigilance Department, CHUGAI 

PHARMACEUTICAL CO., LTD., Muromach, Chuo-ku, Tokyo, JAPAN, 4 Medical 

Oncology, Izumi Municipal HospitalCancer Center, Izumi City, JAPAN 

Background: Skin toxicities (rash) are the most common adverse reaction associated 

with erlotinib. Most cases of rash are mild or moderate using appropriate rash 

management (RM). RM is very important for keeping good QOL during erlotinib 

treatment. Though steroids are commonly used as RM, the precise efficacy and the 

appropriate way of administration have not yet been fully established. Establishment 

of appropriate management of rash is necessary to continue erlotinib treatment for 

obtaining maximum benefit. In this surveillance, we analyzed RM in clinical practice 

from 9,909 NSCLC pts. 

Methods: From Dec 2007 to Oct 2009, all recurrent/advanced NSCLC pts in Japan 

treated with erlotinib were enrolled into this surveillance. The observation period was 

12 months and all adverse events were collected. Erlotinib related rash, interventions 

for the symptoms and outcomes of the interventions were analyzed. 

Results: A total of 9,909 pts were evaluated. Rash was occurred in 67.4 % (6,674) pts. 

Grade 1 / 2 / 3 of rash was observed (26.8 %, 32.4 %, and 7.2 %). Frequency and the 

median time to onset from erlotinib administration to per each acneiform rash, dry 

skin, and paronychia were 60.9 %, 9.0 days, 7.4 %, 16.0 days, and 6.6 %, 34.0 days, 

respectively. The most common RM was steroids in 75.0 % of acneiform rash. In the 

patients who were treated with steroids for their acneiform rash, more than 75 % of 

them started steroids within 4 days from onset date. Median time from steroids start 

to recovery in pts whose steroids were started after 0-1 days / 2-6 days / 7-13 days / 

14-20 days/ 21 days or later from rash observed were 35.0 days / 39.0 days/ 40.0 

days/ 64.0 days/ 103.5 days, respectively. In the patients who are initiated from 

medium potency of steroids for their rash, 32.4 % pts are required to change stronger 

potency steroids, and median time to recovery of them was 71.5 days. On the 

otherhand, Median time to recovery from rash onset was 40.0 days in the pts who 

were initiated with steroids of strong or strongest potency. 

Conclusion: Earlier initiation of management for rash with more than strong topical 

steroids achieves faster improvement. 

Disclosure: Y. Kiyohara: Chugai, Takeda, Merck Serono,Bristol-Myers Squibb, 

GlaxoSmithKline:advisory board. N. Yamazaki: Chugai, Takeda, Merck Serono, 

Bristol-Myers Squibb, GlaxoSmithKline: advisory board, Chugai: corporate-sponsored 

research. All other authors have declared no conflicts of interest. 

1299P PHASE II STUDY OF BEVACIZUMAB IN COMBINATION WITH 

1ST-LINE CHEMOTHERAPY OR 2ND-LINE ERLOTINIB IN 

NON-SQUAMOUS NSCLC (NS-NSCLC) PATIENTS WITH 

ASYMPTOMATIC UNTREATED BRAIN METASTASES 

(ML21823) 

B. Besse 1 , S. Le Moulec 2 , H. Senellart 3 , J. Mazieres 4 , F. Barlesi 5 , E. Dansin 6 , 

G. Robinot 7 , M. Perol 8 , D. Moro-Sibilot 9 , J. Soria 10 

1 Department of Medicine, Institut Gustave Roussy, Villejuif, FRANCE, 

2 Department of Oncology, Hôpital d’Instruction des Armées du Val-de-Grâce, 

Paris, FRANCE, 3 Department of Medical Oncology, Institut de Cancérologie de 

l’Quest, Site René Gauducheau, Nantes, FRANCE, 4 Department of Thoracic 

Oncology, Hôpital de Larrey, Toulouse, FRANCE, 5 Service d’Oncologie 

Multidisciplinaire et Innovations Thérapeutique, Aix Marseille University, 

Assistance Publique Hôpitaux de Marseille, Marseille, FRANCE, 6 Department of 

Medical Oncology, CLCC OSCAR Lambret, Lille, FRANCE, 7 Institut De 

Cancerologie, Centre Hospitalier Universitaire, Brest, FRANCE, 8 Department of 

Medical Oncology, Hôpital de la Croix-Rousse, Lyon, FRANCE, 9 Thoracic 

Oncology Unit, Hôpital A. Michalon, Grenoble, FRANCE, 10 Department of 

Cancer Medicine, Institut Gustave Roussy, Villejuif, FRANCE 

Background: Brain metastases (BM) occur in up to 56% of pts with advanced cancer 

and are no longer a contraindication to bevacizumab treatment based on safety data. 

The non-comparative phase II BRAIN trial (NCT00800202) is the first study to 

assess the efficacy/safety of bevacizumab in combination with systemic treatments in 

ns-NSCLC pts with untreated BM. 

Methods: Eligible pts (stage IV ns-NSCLC; PS 0–1; untreated, asymptomatic BM; 

ineligible for surgery/radiosurgery) received: arm A (n = 67),1 st -line bevacizumab 

(15mg/kg q3w until progression/unacceptable toxicity) plus carboplatin (AUC 6 

q3w, ≤6 cycles) and paclitaxel (200mg/m 2 q3w, ≤6 cycles) (B + CP); or arm B (n 

= 24), bevacizumab (as above) plus erlotinib (150mg/day until progression/ 

unacceptable toxicity) (B + E) in 2 nd line. Primary endpoint: 6-month 

progression-free survival (PFS) by treatment arm. Secondary endpoints: response 

rate (RR; RECIST v1.1), overall survival (OS) and safety. The trial could be halted 

if the incidence of brain haemorrhage (ICH) was >3 in B + CP or >2 in B + E. All 

sites of disease were assessed every 6 weeks including mandatory MRI for BM 

assessment. 

Results: Pt baseline characteristics and outcomes are shown (Table). Efficacy: the 

observed 6-month PFS was 56.5% (B + CP) and 58.0% (B + E). Safety: ICH frequency 

comparable to previously published data in a similar pt population (B + CP, n = 1 

grade 1; B + E, n = 0). Grade 3–5 adverse events of special interest (AESI) were seen 

in 19.4% (B + CP) and 20.8% (B + E) of pts. No erlotinib-related grade 3–5 AESIs 

were seen. There were 3 AEs leading to death (1 epilepsy, B + CP; 1 hypertensive 

encephalopathy, 1 ischaemic stroke, B + E). 

Conclusion: Bevacizumab with 1 st -line chemotherapy or 2 nd -line erlotinib 

demonstrated efficacy and acceptable safety in pts with ns-NSCLC with 

asymptomatic untreated brain metastases when compared to historical controls. 

Baseline characteristics and clinical outcomes for patients in the BRAIN study. 

B+CP B+E 

n=67 n=24 

Baseline characteristics 

Gender, n (%) Male 46 (68.7) 11 (45.8) 

Female 21 (31.3) 13 (54.2) 

Median age, years (range) 61.0 (40–79) 54.0 (34–70) 

ECOG performance 

status, n (%) 

0 37 (55.2) 13 (54.2) 

1 30 (44.8) 11 (45.8) 

WHO histology, n (%) Adenocarcinoma 59 (88.1) 23 (95.8) 

Large-cell carcinoma 8 (11.9) 1 (4.2) 

Recurrence, n (%) No 61 (91.0) 13 (54.2 

Yes 6 (9.0) 11 (45.8) 

Clinical outcomes (95% CI) 

6-month PFS, % 56.5 (43.8–67.4) 58.0 (36.0–74.8) 

Median PFS, months 6.7 (5.7–7.1) 6.3 (2.5–8.4) 

Median OS, months 15.1 (11.8–NR) 13.6 (7.5–26.3) 

12-month OS, % 62.8 (49.7–73.4) 50.7 (28.7–69.0) 

18-month OS % 41.1 (27.4–54.3) 40.5 (20.2–60.0) 

Overall RR, % 62.7 (50.0, 74.2) 12.5 (2.7, 32.4) 

RR, % Intracranial metastases 61.2 (48.5–72.9) 20.8 (7.1–42.2) 

Extracranial metastases 64.2 (51.5–75.5) 12.5 (2.7–32.4) 

NR = not reached 




Disclosure: B. Besse: Received grants from Roche. H. Senellart: Attended advisory 

boards. F. Barlesi: Attended adivsory boards for Roche. Received research funding 

from Roche. E. Dansin: Attended advisory boards for Roche, Lilly and 

Boehringer-Ingelheim. M. Perol: Attended advisory boards for Roche, Pfizer, Lilly 

and Boehringer-Ingelheim. D. Moro-Sibilot: Attended adivsory boards for Roche, 

Pfizer and Lilly. Received reserarch funding from Roche, Pfizer, Lilly, Astra Zeneca 

and BIF. Substantive Relationships with Roche, Pfizer, Lilly, Astra Zeneca and BIF. J. 

Soria: Attended Roche Advisory board. All other authors have declared no conflicts 

of interest. 

1300P HIGH EXPRESSION OF BAP1 IS BIOMARKER OF BETTER 

PROGNOSTIC IN ADVANCED NON-SMALL CELL LUNG 


Y. Zuo 1 , Z. Shen 2 

1 Department of Respiration Medicine, Lianshui People’s Hospital, Lianshui, 

Jiangsu, CHINA, 2 Department of Oncology, Shanghai 6 th People’s Hospital, 

Shanghai Jiao Tong University, Shanghai, CHINA 

Background: Non small cell lung cancer (NSCLC) is the leading worldwide source of 

cancer-related deaths. Although some drugs targeting EGFR mutations were 

developed, most of advanced NSCLC is still incurable. New targets for anticancer 

drugs are demanded. BRCA1-associated protein-1 (BAP1) is a component of the 

ubiquitin proteasome system (UPS). The UPS has emerged as a potential target for 

anticancer drugs. The expression of BAP1 protein in patients with NSCLC has not 

been reported to date. 

Methods: Here, we assessed BAP1 expression by Western blot in 103 cases patients 

with advanced NSCLC to investigate the impact of BAP1 on survival. 

Results: Our data revealed 49 (47.5%) patients were classified as high expression of 

BAP1. Squamous cell carcinomas were more likely to be BAP1 high expressers 

compared to adenocarcinomas (55.8% vs. 32.3%, p= 0.001). High BAP1 expression 

was associated with lymph node metastasis (p= 0.008) as well as remote metastasis 

(p= 0.012) and was not associated with other clinical or pathological characteristics. 

In Kaplan-Meier survival analysis showed that patients with high BAP1 expression 

had a longer median survival compared to low expressers (23.2 vs. 14.7 months, p= 

0.021) especially in the subset of squamous tumors (27.3 vs. 13.1 months, p= 0.013). 

Multivariate analysisrevealed that high BAP1expression was an independent lower 

risk for all 103 patients (HR = 0.61, 95% CI 0.32-0.71, p = 0.003). 

Conclusions: BAP1 may be a useful prognostic factor of NSCLC patients and 

potential target for anticancer drugs. 


1301P FINAL ANALYSIS OF RANDOMIZED PHASE II TRIAL OF 

CARBOPLATIN COMBINED WITH WEEKLY PACLITAXEL (CP) 

AND DOCETAXEL ALONE (D) IN ELDERLY PATIENTS (PTS) 

WITH ADVANCED NON-SMALL CELL LUNG CANCER 

(NSCLC): NJLCG 0801 

T. Harada 1 , M. Maemondo 2 , S. Sugawara 3 , A. Inoue 4 , K. Usui 5 , M. Ando 6 , 

N. Morikawa 7 , Y. Mori 8 , A. Gemma 9 , T. Nukiwa 10 

1 Center for Respiratory Diseases, Hokkaido Social Insurance Hospital, Sapporo, 

JAPAN, 2 Department of Respiratory Medicine, Miyagi Cancer Center, Natori, 

JAPAN, 3 Department of Respiratory Medicine, Sendai Kousei Hospital, Sendai, 

JAPAN, 4 Department of Respiratory Medicine, Tohoku University, Sendai, 

JAPAN, 5 Division of Respirology, NTT Medical Center Tokyo, Tokyo, JAPAN, 

6 Division of Internal Medicine, Tsuboi Cancer Center Hospital, Kooriyama, 

JAPAN, 7 Department of Medical Oncology, Tohoku Kosei Nenkin Hospital, 

Sendai, JAPAN, 8 Division of Respiratory Medicine, Iwate Prefectural Central 

Hospital, Morioka, JAPAN, 9 Internal Medicine, Nippon Medical School, Tokyo, 

JAPAN, 10 President, South Miyagi Medical Center, Miyagi, JAPAN 

Background: Standard first-line chemotherapy for elderly NSCLC pts has been 

considered as a monotherapy with vinorelbine or gemcitabine. D has been 

considered as an alternative option for this population in Japan (WJTOG9904, JCO 

2006). Meanwhile, we have shown the high efficacy of CP for elderly pts 

(NJLCG0403, Ann Oncol 2010). Thus we compared the two regimens to select a 

proper candidate for future phase III trial. 

Methods: Eligible pts were aged 70 years or older with newly diagnosed stage IIIB/IV 

NSCLC; ECOG performance status 0-1; adequate organ function; written informed 

consent. Pts were randomized to receive carboplatin (AUC 6) on day 1 and paclitaxel 

(70mg/m2 on day 1, 8, and 15) every 4 weeks or D (60mg/m2 on day 1) every 3 

weeks. The primary endpoint was overall response rate (ORR), and secondary 

endpoints were progression-free survival (PFS), overall survival, and toxicity profile. 

Assuming that ORR of 40% would be potential usefulness while ORR of 20% would 

be the lower limit of interest, 40 pts in each arm were required if expect 10% loss to 

follow up. 

Results: Between July 2006 and September 2010, 84 pts were enrolled and 41 pts in 

CP arm and 42 pts in D arm were eligible (median age, 76 years; 75% male; 72% 

stage IV). Median treatment cycle was 4 in each arm (CP, range 1-6; D, range 1-8). 

ORRs were 54% (95%CI: 39-69%) and 24% (95%CI: 11-37%) in the CP and D arm, 

respectively. With a median follow-up of 27.6 months, median PFS were 6.6 and 3.5 

months in the CP and D arm, respectively (P = 0.0005) and median survival time 

were 14.3 and 13.8 months in the CP and D arm, respectively (P = 0.24). Grade 3 or 

severer toxicities were as follows: neutropenia (CP, 56% and D, 79%), anemia (CP, 

15% and D, 7%), thrombocytopenia (CP, 10% and D, 0%), infection (CP, 20% and 

D, 25%). One treatment-related death due to neutropenia, pneumonia, and lethal 

arrhythmia occurred in D arm. 

Conclusions: The platinum doublet CP achieved higher activity with less toxicity 

profile for elderly pts with advanced NSCLC compared to monotherapy with D. The 

superiority of CP to the monotherapy in this trial is consistent with results of recent 

IFCT-0501 trial (Lancet 2011). 

Disclosure: M. Maemondo: Makoto Maemondo receives honoraria from Sanofi. S. 

Sugawara: Shunichi Sugawara receives honoraria from Sanofi. A. Inoue: Akira Inoue 

receives honoraria from Sanofi. All other authors have declared no conflicts of 

interest. 

1302P CLINICAL IMPACT OF PRESENCE AND TYPE OF KRAS 

MUTATION IN A POPULATION OF EGFR WILD TYPE (WT) 


PATIENTS (PTS) TREATED WITH PLATINUM-BASED 

CHEMOTHERAPY: A RETROSPECTIVE ANALYSIS 

G. Metro 1 , S. Duranti 1 , V. De Angelis 1 , R. Chiari 1 , C. Bennati 1 , M.F. Currà 1 , 

D. Giannarelli 2 , V. Ludovini 1 , V. Minotti 1 , L. Crinò 1 

1 Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, ITALY, 

2 Medical Oncology, Regina Elena National Cancer Institute, Roma, ITALY 

Background: In this retrospective analysis we assessed whether KRAS mutation 

would affect the clinical outcome of EGFR WT advanced NSCLC pts treated with a 

first-line platinum-based chemotherapy. Moreover, the effect of specific mutant 

KRAS was evaluated. 

Methods: One hundred and ninety-five EGFR WT, advanced NSCLC pts were 

included in the analysis. Study pts were treated at the Medical Oncology of the 

Perugia Hospital from Jan 2005 to March 2012. EGFR (exons 18 to 21) and KRAS 

(codons 12, 13 and 61) genes were amplified by nested PCR and sequenced in both 

sense and antisense directions. 

Results: Median age was 60 years (29-81); 181 pts (92.8%) were PS 0 or 1; 155 pts 

(79.4%) belonged to the non-squamous subtype and 39 pts (20.0%) were 

never-smokers. Treatment was as follows: platinum + a third generation agent in 103 

pts (52.8%); platinum + pemetrexed in 81 pts (41.6%); platinum-based doublet + 

bevacizumab in 11 pts (5.6%). Seventy-five pts (38.4%) were KRAS mutant (MUT), 

of which 60 pts at codon 12 (COD 12 MUT), 12 pts at codon 13 (COD 13 MUT) 

and 3 pts at codon 61 (COD 61 MUT). The most common amino acid changes 

found were: Gly12Cys (29 pts), Gly12Val (11 pts) and Gly13Cys (10 pts). In the 

whole study population, 69 pts (35.3%) responded to treatment and 62 pts (31.7%) 

achieved stable disease, for a disease control rate of 67.0%. At a median follow-up of 

14 months (2-102), median progression-free survival (PFS) and overall survival (OS) 

were 6.2 and 21.6 months, respectively. When analyzed according to KRAS mutation 

status, a significantly shorter PFS was noted for the EGFR WT/KRAS MUT 

subgroup (n = 75) compared with the EGFR WT/KRAS WT population (n = 120) 

[5.1 vs 6.6 months, respectively, P = 0.02; HR = 1.43 (95% CI, 1.05 to 1.95)]. 

Similarly, a significant difference was observed between the two groups in terms of 

OS [13.7 vs 26.1 months, respectively, P = 0.02; HR = 1.56 (95% CI, 1.06 to 2.30)]. In 

the EGFR WT/KRAS MUT subrgoup, OS for COD 12 MUT, COD 13 MUT and 

COD 61 MUT was 17.2, 10.2 and 8.0 months, respectively, P = 0.17. Multivariate 

analysis for PFS and OS confirmed that KRAS mutation was an independent 

predictor of poorer oucome. 

Conclusions: EGFR WT/KRAS MUT pts appear to experience a less favorable 

prognosis compared with the EGFR WT/KRAS WT genotype, with a significant 

difference in clinical outcome according to the mutant codon of KRAS. 



1303P COST EFFECTIVENESS OF PEMETREXED/CISPLATIN (PEM/ 

CIS) IN THE TREATMENT OF ADVANCED, NON-SQUAMOUS, 

NON-SMALL CELL LUNG CANCER (NSQNSCLC) PATIENTS 

K.B. Winfree 1 , M. Shah 2 , P. Peterson 3 , S. Gruschkus 2 , M. Eaddy 2 , M. Green 2 

1 Global Health Outcomes Oncology, Eli Lilly and Company, Indianapolis, UNITED 

STATES OF AMERICA, 2 Oncology, Xcenda AmerisourceBergen Consulting 

Services, Palm Harbor, FL, UNITED STATES OF AMERICA, 3 Oncology Statistics, 

Eli Lilly and Company, Indianapolis, IN, UNITED STATES OF AMERICA 

Purpose: Pem/cis is indicated for 1 st line therapy in patients (pts) with advanced, 

nsqNSCLC. Data from community practices provide an opportunity to evaluate the 

cost effectiveness (CE) of Pem/cis relative to other 1 st line regimens. 

Methods: Advanced nsqNSCLC pts receiving 1 st line therapy with Pem/cis, 

carboplatin/paclitaxel + bevacizumab (C/P + B), or carboplatin/paclitaxel (C/P) from 

2006–2009 were identified through EMRs of 20 large US community oncology 

practices. Pts were matched by stage, ECOG performance status (PS), gender, age, 

and index year. Progression-free survival (PFS)/overall survival (OS) were calculated 

and treatment effect was assessed via Kaplan-Meier and Cox regression analyses. 

Costs included chemotherapy, supportive care, and medical services. To evaluate CE, 

differences in costs/survival were calculated. Bootstrapping was used to estimate 95% 

confidence intervals (CIs) for mean differences and probability of falling within 

quadrants of CE plane. 

Results: Each comparison had 78 matched pairs. Mean age was 64.1, 59.0% were 

male and 78.2% had PS = 0/1. Median PFS for pts treated with Pem/cis (128 days) 

was significantly longer than those treated with C/P + B (112 days; P = 0.007) or C/P 

(105 days; P = 0.004). Pts treated with Pem/cis had higher median OS, however not 

significant. Analyses of costs/PFS and costs/OS revealed greater effectiveness with less 

cost for Pem/cis compared to C/P + B (Tables). 

Conclusions: Pts treated with Pem/cis experienced a significant PFS benefit and a 

trending OS benefit compared to C/P + B and C/P pts. Compared to C/P + B, Pem/ 

cis yielded greater effectiveness with less cost. 

Pem/cis vs C/P + B Pem/cis vs C/P 

Mean D OS (95% CI) 30 days (-44.0, 98.6) 57 days (-8.4, 134.6) 

Mean D Cost (95% CI) 

Probability Pem/cis is 

-$18,216 (-$33,306, -$3,889) $25,111 ($9,987, $30,627) 

less costly, more effective 83.7% 0% 

more costly, more 

effective 

1.0% 95.8% 

Pem/cis vs C/P + B Pem/cis vs C/P 

Mean D PFS (95% CI) 15 days (-53.3, 82.3) 39 days (-23.5, 99.7) 

Mean D Cost (95% CI) 

Probability Pem/cis is 

-$17,603 (-$27,547, -$2,817 ) $25,583 ($15,601, $38,741) 

less costly, more effective 63.4% 0% 

more costly, more 

effective 

1.2% 89.4% 

Disclosure: K.B. Winfree: I am an employee of and have stock ownership in Eli 

Lilly and Company. M. Shah: Eli Lilly and Company sponsored this research 

study. P. Peterson: I am an employee of and have stock ownership in Eli Lilly and 

Company. S. Gruschkus: Eli Lilly and Company sposored this research study. M. 

Eaddy: Eli Lilly and Company sposored this research study. M. Green: On 3/16/12 

I served as moderator for a Lilly Global Adv Board per my employment with 

Xcenda. Consistent with Lilly rules, the payments made to Xcenda for services 

will appear on the Lilly website delineating payments to physicians for services to 

Lilly. 


1304P CHARACTERISTICS OF 982 LUNG CANCER PATIENTS IN 

SERBIA ACCORDING TO THE WHO/IASLC CLASSIFICATION 

OF LUNG CANCERS AND SUBSEQUENT TREATMENT – 

AVATAR EPIDEMIOLOGY STUDY 

D. Jovanovic 1 , N. Secen 2 , Z. Murtezani 3 , M. Rancic 4 , V. Kacar-Kukric 1 , 

M. Velinovic 1 , A. Tepavac 5 , E. Budisin 5 , Z.G. Andric 3 , N. Vukobradovic Djoric 6 

1 Institute of Lung Diseases, Clinical Center of Serbia, Belgrade, SERBIA, 2 Clinic 

for Pulmonary Oncology - Department for Chemotherapy, Institute for Pulmonary 

Diseases of Vojvodina, Sremska Kamenica, SERBIA, 3 Medical Oncology, KBC 

Bezanijska Kosa, Belgrade, SERBIA, 4 Clinic for Pulmonary Diseases - Knez Selo, 

Clinical Center Nis, Nis, SERBIA, 5 Clinic for Pulmonary Oncology, Institute for 

Pulmonary Diseases of Vojvodina, Sremska Kamenica, SERBIA, 6 Medical, 

Roche, Belgrade, SERBIA 

Introduction/background: The purpose of this prospective study, conducted over 3 

months period, was to analyse demographic and clinicopathological features of lung 

cancer patients in Serbia, and subsequent treatment approach as well. 

Material and methods: The data on lung cancer patients were collected based on 

specific questionnaire at 4 major centers in Serbia. An analysis of demographic and 

clinical/ histological features with subsequent treatment was performed in 982 

patients (aged over 19 years). 

Results: Male to female ratio 709 (72%): 273 (28%), 46% aged < 60 years. Majority 

were current smokers (68%) and ex-smokers (21%), 11% non-smokers. NSCLC was 

diagnosed in 80% (789), and SCLC in 19 %. Among NSCLC patients, 71.6 % had 

stage IIIb and IV. Most common histological subtype was adenocarcinoma (46%), 

squamous cell carcinoma - 44%, large cell - 4% and the rest NOS and rare subtypes. 

Neodjuvant therapy was applied in 8%, 19% were operated: 64% of them recieved 

adjuvant chemotherapy. Most common adjuvant regimens were PE (65%) and 

platinum/gemcitabine (20%). First line chemotherapy was applied in 91% of stage 

IIIb and IV NSCLC patients: platinum/etoposide-51% and platinum/ 

gemcitabine-45% were most frequently applied. ECOG PS 0 and 1, was noted in 

92%. Second line chemotherapy was given to 27% of patients who recieved 1st line 

therapy. Most common 2nd line regimens were platinum/gemcitabine (35%), 

platinum/taxanes (18%), platinum/vinorelbine (13%) and taxanes monotherapy 

(12.5%). Only 8% recieved pemetrexed or erlotinib. Almost all 2nd line treated 

patients (93%) had good ECOG PS: 0 and 1. Third line chemotherapy was applied in 

22% of those who recieved 2nd line. 

Conclusions: This is the largest series of lung cancer patients in Serbia, analized by 

both, patient characteristics and therapy regimens. Compared with previous similar 

analysis from 2009, it can be concluded the number of NSCLC patients is increasing, 

especially in stage IIIb and IV (1.5% per year). Adenocarcinoma rate is also 

increasing (41% in 2009 vs 45% in 2011). Regarding treatment, we can conclude 

there is no major progress in treatment options in Serbia. 


1305P FACTORS PREDICTING BRAIN METASTASES IN PATIENTS 

WITH NON-SMALL CELL LUNG CANCER 

S. Hsiao 1 , C. Chung 1 , H.E. Liu 2 

1 Division of Pulmonary Medicine, Department of Internal Medicine, Taipei 

Medical University Hospital, Taipei, Taipei, TAIWAN, 2 Division of Hematolgy and 

Oncology, Department of Internal Medicine, Department of Medicine, Wanfang 

Hospital, Taipei Medical University, Taipei, TAIWAN 

Purpose: Brain metastases (BM), a common complication of non-small cell lung cancer 

(NSCLC), usually lead to a poor prognosis. Recent advances in BM therapy modesly 

prolong the survival after BM diagnosis in a subset of patients. Selection of treatment 

modalities for BM is based largely on the number of BM, BM-related symptoms and 

patient’s functional performance status. Therfore, early dection of BM in high-risk 

patients is crucial. In this study, we sough to elucidate the factors predicting BM. 

Methods and patients: Medical records of patients with stage 1-4 NSCLC were 

retrospectively reviewed for the period between January 2006 and December 2011 

under the approval of the joint institutional review board. Clinical demographic data, 



histology, stage of disease, presence of BM, survial were collected and analyzed. A 

multivariate logistic regression model was used to identiy the predictors of BM. 

Results: Among 596 NSCLC patients with a mean follow-up time of 12.5± 12.5 

months and a mortality rate of 62% at the last follow up, 187 (31%) experienced BM 

during their disease course. The accumulative incidence of BM was higher in patients 

with adenocarcinoma (ADC) than those with squamous cell carcinoma (SCC) (36% vs 

13%, p < 0.001). On multivatiate analysis, female, age < 60 years, ADC and stage 3b/4 

were significantly associated with BM (OR = 1.67, 95% CI = 1.06-2.63, p = 0.025, and 

OR = 1.89, 95% CI = 1.28-2.78, p = 0.001, and OR = 2.67, 95% CI = 1.35-5.26, p = 

0.017, and OR = 3.94, 95% CI = 2.15-7.13, p < 0.001, respectively). The incidence of 

BM in stage 3b/4 NSCLC patients was 36% and varied from 14% to 59% in patients 

with or without identified risk facotrs. Specifically, ADC patients with age less than 60 

years were more likely to experience BM than the elder with SCC (OR = 5.46, 95% CI 

= 2.79-10.71, p < 0.001). Additionally, prolonged survial after diagnosis of lung cancer 

heightened the risk of BM; its incidence was 42%, 54% and 64% in patients who 

survived longer than 3, 12 and 24 moths, respectively. 

Conclusion: We find that gender, age and histological subtype are independent 

factors predicting BM in NSCLC patients and suggest identification of patients at 

high risks for BM might help detect BM earlier and facilitate the design of clinical 

trials aming at the prevention of BM. 


1306P INITIAL REPORT OF COHORT STUDY IN PATIENTS WITH 

NON-SMALL-CELL LUNG CANCER (NSCLC) WHO WERE 

TREATED WITH 1ST-LINE PLATINUM-BASED 

CHEMOTHERAPY (SAPPHIRE STUDY) 

Y. Naito 1 , K. Kishi 2 ,K.Yoh 3 , Y. Goto 4 , Y. Ohashi 5 , H. Kunitoh 6 

1 Dept. of Hematology and Medical Oncology, National Cancer Center Hospital 

East, Kashiwa, JAPAN, 2 Dept. of Respiratory Medicine, Toranomon Hospital, 

Tokyo, JAPAN, 3 Division of Thoracic Oncology, National Cancer Center Hospital 

East, Kashiwa, JAPAN, 4 Department of Respiratory Medicine, Graduate School 

of Medicine, University of Tokyo, Tokyo, JAPAN, 5 Department of Biostatistics, 

School of Public Health, University of Tokyo, Tokyo, JAPAN, 6 Department of 

Respiratory Medicine, Mitsui Memorial Hospital, Tokyo, JAPAN 

Background: Although 2nd-line chemotherapy comprises the standard of care for 

NSCLC, not every patient could receive one. How many and why did they miss the 

opportunity are not fully investigated. 

Methods: We prospectively registered consecutive patients with NSCLC treated with 

platinum-based 1st-line therapy from April 2010 to September 2011 from 30 

institutions in Japan. Baseline characteristics, regimens and responses for the 1st-line 

therapy, whether the patients received 2nd-line chemotherapy or not, and if not 

treated, the reason was recorded. This study was supported by the Public Health 

Research Center Foundation CSPOR. 

Results: A total of 866 patients were registered. Patient characteristics were: median 

age, 65 (24 - 80); female patients, 27.5%; ECOG PS 0 or 1, 91.6%; adenocarcinoma, 

69.6%; squamous cell carcinoma, 20.1%; never smoker, 20.1%; EGFR activating 

mutation positive, 10.2%. Maintenance chemotherapy was administered to 28.9% 

(131 / 454) of patients whose disease did not progress during the course of 1st-line 

chemotherapy. Among 592 patients with at least 6 months of follow-up, 193 were 

excluded (129 PD during the course of 1st-line chemotherapy, 20 ongoing 1st-line 

chemotherapy, and 44 others). The remaining 399 patients were analyzed with regard 

to administration of 2nd-line chemotherapy. A total of 135 patients (33.8%) did not 

receive 2nd-line chemotherapy, and the reasons were: without disease progression, 42 

(31.1%); declined PS, 55 (40.7%); patient refusal, 20 (14.8%); death of any cause, 5 

(3.7%). Therefore, approximately 20% of patients missed their opportunity to receive 

appropriate 2nd-line chemotherapy during follow-up period after completion of 

effective 1st-line therapy. 

Conclusion: This is the largest prospective observational study exploring the 

proportion and the reasons for NSCLC patients not receiving 2nd-line 

chemotherapies. Further investigations to identify predictive factors for ‘missing the 

opportunity for 2nd-line chemotherapy’ are underway. 


1307P EFFECTIVENESS OF ERLOTINIB TREATMENT IN K-RAS 

WILD TYPE LUNG ADENOCARCINOMAS –RESULTS OF A 

HUNGARIAN OBSERVATIONAL COHORT STUDY (MOTIVATE) 

G. Ostoros 1 , V. Sárosi 2 , G. Losonczy 3 , J. Strausz 4 , E. Tolnay 5 , L. Molnár 6 

1 Department VIII, National Korányi Institute of Pulmonology, Budapest, 

HUNGARY, 2 1st Department of Internal Medicine Pulmonology Department, 

University of Pécs, Pécs, HUNGARY, 3 Department of Pulmonology, Semmelweis 

University, Budapest, HUNGARY, 4 Department Vi., National Korányi Institute of 

Pulmonology, Budapest, HUNGARY, 5 2nd Department, Pest County Institution 

of Pulmonology, Törökbálint, HUNGARY, 6 Pulmonology Department, Borsod 

County Szent Ferenc Hospital, Miskolc, HUNGARY 

Background: Erlotinib as a targeted therapy is a highly potent inhibitor of epidermal 

growth factor receptor tyrosine-kinase activity. K-RAS mutations are found in 

25-35% of lung adenocarcinomas, and these mutations may be predictive of 

resistance to treatment with erlotinib. The aim of our analysis was to investigate 

prospectively the efficacy and safety of second and third line erlotinib treatment in 

advanced lung adenocarcinoma excluding the K-RAS mutation positive cases. 

Materials and methods: This observational study was conducted in 27 Hungarian 

sites. Enrolled patients were treated with erlotinib. Analyzed patients have 

histologically or cytologically verified, advanced (IIIB/IV), K-RAS (codon-12, 

codon-13) mutation negative lung adenocarcinoma, refractory to at least one prior 

chemotherapy. Primary endpoint was progression-free survival. Secondary endpoints 

were best tumor response rate according to RECIST, overall survival and safety. 

Results: 327 patients’ data were analyzed, who were enrolled between February 2008 

and December 2010. The study closure date was 31. December 2011. Baseline 

patients’ characteristics: median age: 60,3 years; male: 50,2%; stage: III/B: 31,1%, IV: 

68,9%; smoking status: former/current/never smoker: 39,1/28,8/31,9%. ECOG PS: 0/ 

1/2/3: 35,9/51,8/11/1,2%. Best tumor response: CR/PR/SD/PD were achieved: 0,9/ 

16,2/41,9/24,5 % of all patients. The disease control rate was 70,48% in patients for 

whom the best response data were available . The median progression-free survival 

(PFS) was 3.27 months. The median overall survival was 14,1 months. For ECOG PS 

0-1 patients, the median OS was 16,1 months and the median PFS was 3,47 months, 

while median OS of 2.5 and median PFS of 1,9 months were detected for ECOG PS 

2-3 patients. 

Conclusions: Our results confirm the favorable efficacy of erlotinib in K-RAS 

mutation negative lung adenocarcinoma with an OS of 14,1 months in this real-life 

setting. A remarkable, 16.1 months median OS was identified in patients with ECOG 

PS 0-1 receiving erlotinib. 

Disclosure: G. Ostoros: corporate-sponsored research: investigator in 

company-sponsored (Roche) trials. All other authors have declared no conflicts of 

interest. 

1308P PKM2 EXPRESSION MAY PREDICT CHEMOSENSITIVITY TO 

CISPLATIN-BASED CHEMOTHERAPY IN METASTATIC 


C. Papadaki 1 , M. Sfakianaki 1 , E. Lagoudaki 2 , G. Giagkas 1 , E. Tsakalaki 1 , 

M. Trypaki 1 , S. Pontikakis 1 , A. Koulouridi 1 , V. Georgoulias 3 , I. Souglakos 4 

1 Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, 

Heraklion, GREECE, 2 Laboratory of Pathology, School of Medicine, University of 

Crete, Heraklion, GREECE, 3 Medical Oncology, University Hospital of Heraklion, 

Heraklion, GREECE, 4 Medical Oncology, University General Hospital of Heraklion, 

Heraklion, GREECE 

Background: Tumor cells have been shown to express exclusively the embryonic M2 

isoform of pyruvate kinase (PKM2). Overexpression of PKM2 has been correlated 

with cisplatin resistance in cell lines and xenograft models. We evaluated the 

predictive significance of PKM2 in patients with stage IV NSCLC. 

Methods: PKM2 mRNA expression was analysed by RT-qPCR in microdissected 

FFPE primary tumors from 305 NSCLC patients (148 as training set and 157 as 

experimental set) treated with front-line cisplatin-based chemotherapy and 85 

patients treated with a non-platinum doublet (as validation set). 


Results: The patients’ characteristics were all typical for metastatic NSCLC (median 

age 61 years, 86% males, 64% adenocarcinomas and 28% squamous cell carcinomas, 

ECOG PS 0-1: 83%). PKM2 was successfully amplified in all specimens. Progression 

Free Survival (PFS) was significantly lower in patients with overexpression of PKM2 

(4.9 vs. 6.4 months for high and low expression, respectively, p = 0.028) in the 

training set and the results were confirmed in the experimental set (3.7 vs. 5.9 

months, p = 0.006). Similarly, median overall survival (mOS) was significantly 

decreased in patients with upregulation of PKM2 in both sets: 10.1 vs 17.0 months in 

the training set (p = 0.01) and 8.3 vs 16.8 months in the experimental sets (p = 

0.003), for high and low expression, respectively. In contrast, there was no statistical 

difference in terms of PFS (5.6 vs. 5.9 months, p = 0.431) and mOS (9.8 vs. 10.1 

months, p = 0.512) between low and high PKM2 expression in the validation group. 

Multivariate analysis revealed that PKM2 high mRNA expression could be emerged 

as an independent factor associated with decreased PFS (training set: HR = 1.6, p = 

0.02; experimental set: HR = 2.1, p = 0.013) and mOS (training set: HR = 1.9, p = 0.02; 

experimental set: HR = 2.6, p = 0.001), but not in the validation set (PFS: HR = 1.1, p 

= 0.627; mOS: HR = 0.96, p = 0.495). 

Conclusions: These results indicate that the PKM2 mRNA expression may be used 

as a predictive factor for sensitivity to cisplatin-based chemotherapy. 


1309P ROLE OF THE HEDGEHOG PATHWAY IN MEDIATING 

RESISTANCE TO ANTI-EGFR TYROSINE KINASE INHIBITORS 

IN NON SMALL CELL LUNG CANCER 

F. Morgillo, C.M. Della Corte, G. Martini, A. Manzo, V. Gambardella, 

D. Vitagliano, E. Martinelli, T. Troiani, F. Ciardiello 

Medical Oncology, Second University of Naples, Napoles, ITALY 

In recent years, the management of non small lung cancer (NSCLC) has been 

moving towards molecular-guided treatment, and the best example of this new 

approach is the use of EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. 

The clinical benefit observed with EGFR-TKIs in NSCLC is limited to a subset of 

patients, and the development of resistance, even in responders, is sooner or later 

observed. Several studies have provided new insights into the molecular basis of 

EGFR inhibitors resistance. Recently our group demonstrated the acquisition of a 

mesenchymal phenotype in an in vitro model of NSCLC cell lines with acquired 

resistance to anti-EGFR TKIs. Among the various molecular pathways, the Hedgehog 

(Hh) signaling pathway has emerged as an important mediator of carcinogenesis and 

cancer metastases. The objective of this research is to investigate the role of Hh 

signaling pathway in human NSCLC cell models of constitutive or acquired 

resistance to EGFR-TKIs. To investigate the expression profile of Hh signalling 

components in our panel of sensitive and resistant NSCLC cell lines, we performed 

analysis of mRNA and protein levels of Shh, Gli1 and Smo by using semiquantitative 

PCR and Western blot analysis. The experiment showed a strong expression of sonic 

Hh and Gli1 in NSCLC cell lines resistant to EGFR TKIs. In addition, PTCH mRNA 

levels resulted increased in TKI-resistant cell lines. This is of relevance, because 

PTCH gene itself is a target gene of Gli1 transcriptional activity and its levels 

indicates an activation of Hh signalling in such cells. Treatment with cyclopamine, a 

Smo inhibitor, strongly inhibited the proliferation of resistant NSCLC cell lines. 

Furthermore, treatment with cyclopamine blocked the invasive and migratory 

behavior of resistant cells. Of interest, the inhibition of Smo and Hh signaling 

pathway was accompanied by an inhibition of MET and MAPK phosphorylation. 

Our study should provide the opportunity to better understand the role of HH 

pathway in mediating resistance to anti-EGFR TKIs and to design new strategies to 

be easily transferred into clinical practice. 


1310P PROGNOSTIC IMPACT OF SERUM CYFRA 21-1 IN 

ADVANCED LUNG ADENOCARCINOMA 

A. Ono 1 , T. Takahashi 1 , H. Akamatsu 1 , T. Taira 1 , T. Shukuya 1 , H. Kenmotsu 1 , 

T. Naito 1 , H. Murakami 1 , M. Endo 2 , N. Yamamoto 1 

1 Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, JAPAN, 

2 Division of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, JAPAN 

Background: Serum CYFRA 21-1 is one of the most important serum markers 

in diagnosing non-small cell lung cancer (NSCLC), especially squamous-cell 

carcinoma. It is not known whether pretreatment serum CYFRA 21-1 values 

(PCV) have prognostic implications in advanced lung adenocarcinoma. The aim 

of this study was to evaluate the prognostic implications of PCV in advanced 

lung adenocarcinoma. 

Material and methods: Out of 424 newly diagnosed lung cancer patients (pts) at our 

institution during the period April 2008- June 2010, we retrospectively reviewed 284 

consecutive pts who were diagnosed with advanced lung adenocarcinoma and had 

been treated with systemic chemotherapy. Survival was estimated using the 

Kaplan-Meier method. A log-rank test was performed to test the significance of 

differences in the overall survival among the groups. A multivariate analysis using the 


Cox proportional hazards model was used to establish the association between 

various prognostic factors and survival. 

Results: One hundred twenty one pts (43%) had activating EGFR mutations (Mt+) 

and 163 pts (57%) had EGFR wild type (Mt-). The median follow-up time was 29.7 

months (range: 2.8- 75.7 months). In univariate analysis, gender (male/ female), 

ECOG performance status (PS) (0-2/ 3-4), PCV (< 2.2ng/ml, > 2.2ng/ml), EGFR 

mutation (Mt + / Mt-), and smoking history (yes/ no) were favorable prognostic 

factors (p= 0.01, p< 0.0001, p< 0.0001, p< 0.0001, p= 0.0008 respectively), but not 

age ([< 70, > 70], p = 0.67). A Cox’s multivariate analysis showed that PCV (< 2.2ng/ 

ml) was significantly associated with prolonged survival (p< 0.0001, hazard ratio: 

0.38, 95% CI 0.32-0.63), when adjusted by PS (p< 0.0001), EGFR mutation status 

(p< 0.0001), gender (p= 0.37), and smoking history (p= 0.11). Furthermore, patients 

with Mt+ and CYFRA < 2.2ng/ml (n= 70) had a better prognosis than those with Mt 

+ and CYFRA > 2.2ng/ml (n= 48) (median survival time [MST]: 52.4 vs. 21.0 

months, p< 0.0001), and those with Mt- and CYFRA < 2.2ng/ml (n= 78) had a better 

prognosis than Mt- and CYFRA > 2.2ng/ml (n = 86) (MST: 24.1 vs. 10.2 months, 

p


Methods: The presence and relative quantity of two ALK exon spanning transcript 

targets located before (ALK-5’) and after (ALK-3’) the translocation breakpoints of 

this gene were assessed with qRT-PCR in 198 NSCLC RNA samples from paraffin 

tissues upon stringent intra- and inter-run assay performance validation. ALK 

mRNA expression was compared with ALK gene status assessed with FISH. Patients 

had been treated in the adjuvant and/or 1 st line setting. None of them received 

crizotinib. 

Results: Four patterns of ALK mRNA expression emerged: tumors negative for both 

transcripts (85/198, 42.9%) or positive for both (56/198, 28.3%), which were 

considered as close to normal (ALK-N); and, ALK-5’ positive only (34/198, 17.2%) 

or ALK-3’ positive only (23/198, 11.6%), which were termed as aberrant (ALK-A). 

ALK translocation was observed in 9/124 cases (7.3%). ALK copies >2.2 were noticed 

in 40 cases (32.3%) with >6 copies in 26 cases (21%) and overall complex gene gain 

patterns. ALK mRNA was unrelated to ALK translocation, but ALK-3’ was associated 

with increased ALK gene copies (p = 0.017). ALK-A was more common in stage 

IIIB-IV tumors, while ALK mRNA and gene copy gains were not associated with 

gender, smoking and histology. ALK gene status was not associated with patient 

outcome. In comparison to patients with tumors expressing ALK-N, those with 

ALK-A had a significantly shorter overall survival (OS, median 29.3 vs. 13.1 months, 

CI95% 19.1-39.6 vs. 5.4-20.9, p = 0.0007). The same unfavorable impact of ALK-N 

vs. ALK-A was observed on stage IIIB-IV patient OS (median 17.5 vs. 11 months, 

CI95% 9.1-26.0 vs. 6.6-15.3, p = 0.0050). 

Conclusions: ALK gene status and mRNA expression seem to suffer a complex 

pathology in NSCLC. When expressed, ALK mRNA may be fragmented, possibly 

due to currently unknown genomic alterations. Aberrant ALK mRNA expression 

appears to have an unfavorable prognostic impact on NSCLC patient outcome; its 

role on NSCLC biology merits further evaluation. 


1313 PROGNOSTIC SIGNIFICANCE OF EGFR, HER-2, CEA ON 

CIRCULATINGTUMOUR CELLS (CTCS) IN PATIENTS WITH 

METASTATIC NON-SMALL-CELL LUNG CANCER (MNSCLC) 

C. Loretelli 1 , E. Galizia 2 , M. Scartozzi 1 , R. Giampieri 1 , D. Gagliardini 1 , 

C. Brugiati 1 , S. Cascinu 1 , R. Cellerino 1 


Politecnica delle Marche, Ancona, ITALY, 2 Oncologia Medica, Ospedale “E. 

Profili”, Fabriano, ITALY 

Purpose: We aimed to assess the role of CTCs in providing prognostic information 

of mNSCLC patients receiving chemotherapy. 

Patients and methods: In this single-center prospective study, blood samples for 

CTCs analysis were obtained from patients with previously untreated mNSCLC. 

CTCs were measured using an epithelial cell adhesion molecule-based 

immunomagnetic technique. Immunomagnetic bead enrichment for cells expressing 

epithelial cell adhesion molecule (EpCAM) was performed, followed by multi-marker 

quantitative real-time PCR of a panel of marker genes: EGFR, HER-2, CEA. 

Results: We analysed 45 patients with mNSCLC: 24 adenocarcinoma, 8 squamous 

cell carcinoma and 13 poorly differentiated. EGFR, HER-2 and CEA expression 

were found in CTCs of respectively 12, 5 and 11 patients. Globally, 31 patients 

(68.9%) progressed during treatment, whereas disease control (i.e. patients with 

partial/complete response or stable disease) was achieved in 14 patients (31.1%). 

EGFR expression was detected in 11/31 patients with disease progression (35.5%) 

and in only 1 out of 14 patients with disease controlled (7.1%) (p 0.07). HER-2 

expression was detected in 3/31 patients with disease progression (9.7%) and in 2/ 

14 patients with disease controlled (14.3%) (p 0.64). CEA expression was detected 

in 10/31 patients with disease progression (32.3%) and in 1/14 patients with 

disease controlled (7.1%) (p 0.13). Only EGFR expression in CTCs showed a 

correlation with clinical outcome, expressed by progression free survival (PFS). 

Patients with and without EGFR expression in CTCs were homogeneous for 

clinical characteristics. PFS was 2.8 v 2.3 months (p 0.03) respectively for patients 

without and with EGFR expression. 

Conclusion: CTCs are detectable in patients with mNSCLC and could show novel 

prognostic factor for this disease. Further validation is warranted before routine 

clinical application. 


1314 ASSESSMENT OF THE PREDICTIVE/ PROGNOSTIC VALUE OF 

THE MYELOID-DERIVED SUPPRESSOR CELLS (MDSC) AND 

REGULATORY T CELLS (TREGS) IN NON-SMALL CELL LUNG 

CANCER (NSCLC). PRELIMINARY RESULTS 

E.K. Vetsika 1 , E. Skalidaki 1 , A. Koutoulaki 1 , D. Mavroudis 2 , V. Georgoulias 2 , 

A. Kotsakis 2 

1 Laboratory of Tumor Cell Biology, University of Crete, School of Medicine, 

Heraklion, GREECE, 2 Medical Oncology, University Hospital of Heraklion, 

Heraklion, GREECE 

Background: The circulating MDSCs and Tregs in cancer patients suppress immune 

system. This study is investigating the expression of the MDSCs and Tregs in the 

peripheral blood of NSCLC patients and their correlation with the clinical outcome 

of the 1 st line chemotherapy. 

Methods: 62 chemotherapy naive patients (57 males) with stage IIIB/ IV NSCLC 

have been enrolled in this study, so far; median age 67. Peripheral blood was 

collected prior to treatment. 19 healthy, aged-matched donors (12 males) were used 

as controls. The distinct MDSC subpopulations [A (monocytic): 

CD11b + CD14 + CD15 − CD33 + CD13 + IL-4R + Lin low/- HLA-DR − ; B (monocytic): 

CD11b + CD14 + CD15 + CD33 + CD13 + IL-4R + Lin low/- HLA-DR − and C (granulocytic): 

CD11b + CD14 − CD15 + CD33 + CD13 + IL-4R + )], CD4 + Tregs (CD4 + CD25 +high 

CD127 low FoxP3 + CD39 + CD13 + ) and CD8 + Tregs (CD3 + CD8 + CD25 + 

CD45RO + CD13 + CCR7 + FoxP3 + CD39 + ) were determined by using flow cytometry. A 

comparison of the overall survival (OS) and the progression-free survival (PFS) 

according to the frequency of the MDSC and Tregs was performed (high expression 

defined as the percentage of cells above the 75% percentile of the controls). 

Results: The levels of Tregs prior to treatment did not differ from the controls’. 

Patients with progression (PD) during the 1 st line treatment had significantly 

elevated percentage of CD4 + (24.6 ± 8.5) and CD8 + (0.7± 0.2) Tregs at baseline 

compared to those with no PD (3.7± 1.8, p = 0.04; 0.1± 0.05, p= 0.03, respectively). 

In contrast, MDSCs were significantly increased (A: 3.8 ±0.7; Β: 2.5 ± 0.5 and C: 10.8 

± 2.3) in patients compared to controls (0.8 ± 0.4, p = 0.001; 0.5 ± 0.2, p= 0.01, and 

2.7 ± 1.3, p= 0.05, respectively) but that difference was not associated with response 

to treatment. Patients with normal CD8 + Tregs levels at baseline had higher OS and 

PFS compared to those with high levels (13.2 mo vs 7.9 mo, p= 0.02 and 13.1 mo vs 

3.7 mo, p= 0.003, respectively). 

Conclusion: The MDSCs are elevated in NSCLC. The increased expression of CD4 + 

και CD8 + Tregs negatively correlated with the treatment outcome, indicating that 

CD4 + and CD8 + Tregs could be a potential predictive/prognostic biomarker. The 

study is still opened to accrual and more mature data will be presented at the 

meeting. 


1315 CYTOLOGY SAMPLES (S) FOR EGFR AND KRAS MUTATION 

(MUT) TESTING IN NON-SMALL-CELL LUNG CANCER 

(NSCLC).EXPERIENCE FROM A SINGLE INSTITUTION 

T. Moran Bueno1 , E. Castella Fernandez2 , M. Tierno Garcia1 ,C. 

Buges Sanchez1 , C. Queralt Herrero1 , M. Perez Cano1 , D. Naranjo Hans2 ,F. 

Andreo Garcia3 , L. Capdevila Riera1 , R. Rosell1 1 

Medical Oncology Department, Catalan Institute of Oncology Badalona, 

Hospital Universitari Germans Trias i Pujol, Badalona, SPAIN, 2 Pathology 

Department, Hospital Universitari Germans Trias i Pujol, Badalona, SPAIN, 

3 

Pulmonology Department, Hospital Universitari Germans Trias i Pujol, Badalona, 

SPAIN 

Background: Targeted therapy has yielded impressive clinical outcomes in advanced 

NSCLC. For molecular testing, cytology samples are not commonly used since the 

tumor content is less likely to be adequate. At ICO-Badalona, Hospital Germans 

Trias i Pujol we have used cytology specimens when biopsies are not available. We 

describe the general results when using cytology specimens in NSCLC to detect 

EGFR and KRAS mut. 

Methods: From January 2007 to February 2012, 227 cytology samples from patients 

with NSCLC were collected at the Department of Pathology as cell blocks or fresh 

specimens extended over an appropriate slide (MembraneSlide 1.0 PEN, Zeiss®). 

Tumor cells (8-150) were captured by laser microdissection. DNA sequencing for 


EGFR mut at exons 18, 19, 21, and KRAS mut at codons 12 and 13 and allelic 

discrimination technique for EGFR mut at exon 20 were performed at Molecular 

Biology Laboratory (ICO-Badalona). 

Results: EGFR mut were tested in 227 s. The overall output was 86.3% (15 not 

evaluable, 8 insufficient tissue, 4 no tumor cells, 4 not done). EGFR mut were 

detected in 8.81% (20/227). KRAS mut were tested in 41 s with results in 33, 80.5% 

(2 not evaluable, 3 insufficient tumor cells 1 no tumor and 2 not done). KRAS mut 

were positive in 14.6% (6/41). The output for cell block was 83.3% (124/148) and 

testing was not possible in 24 s (11 not evaluable, 6 insufficient tumor cells, 4 not 

tumor and 3 not done). The output for fresh specimens was 91.1% (72/79) and was 

not possible in 7 s (4 not evaluable, 2 insufficient tumor cells and 1 not done). 

Conclusions: Our results support the use of cytology samples for EGFR and 

KRAS molecular testing in NSCLC when biopsy specimens are not available. 

Both fresh specimens and cytology blocks have been used and are suitable for 

molecular testing. 


1316 FEASIBILITY AND USEFULNESS OF DETERMINING EGFR AND 

KRAS MUTATIONS IN CYTOLOGICAL SAMPLES AND CNB OF 

NSCLC USING AN AUTOMATED REAL-TIME PCR SYSTEM 

M.D. Lozano 1 , T. Labiano 1 , M. Montañana 1 , J.I. Echeveste 1 , A. Gurpide 2 , J.L. 

Pérez - Gracia 2 , F. Shieh 3 , T. Ramos 4 , J. Zulueta 5 , S. Martin Algarra 2 

1 Pathology, University of Navarra, Pamplona, SPAIN, 2 Clinical Oncology, Clinica 

Universitaria de Navarra, Pamplona, SPAIN, 3 Roche Molecular System, Roche 

Molecular System, Pleasanton, UNITED STATES OF AMERICA, 4 Roche 

Diagnostics, Barcelona, SPAIN, 5 Pulmonary Medicine, Clinica Universidad de 

Navarra, Pamplona, SPAIN 

Background: EGFR and KRAS gene mutations guide treatment selection in 

non-small cell lung cancer (NSCLC) patients. About 70%-80% of these patients are 

diagnosed at advanced stage, and mutational analysis has to be performed in small 

samples: core needle biopsy (CNB) and fine needle aspiration (FNA) cytology. 

Cobas® EGFR Mutation Test has been CE-IVD marked for the detection of 41 

mutations in formalin-fixed-paraffin-embedded (FFPE) NSCLC specimens. No 

validation studies have been performed using cytological samples. Determining the 

feasibility of cobas® test on such samples is an important step to extend the benefits 

of molecular targeted therapy. 

Methods: EGFR and KRAS mutations were studied in 64 non-selected samples from 

NSCLC patients: 31 CNB and 33 FNA. DNA was extracted directly from stained 

smears in FNA samples and from 4-micron sections in CNB. All samples contained 

at least 50% of tumor cells. All cases were studied using the cobas® test, and FNA 

samples were also analyzed by direct sequencing. DNA was extracted using the 

cobas® DNA Sample Preparation Kit. DNA concentration and DNA ratio of sample 

absorbance at 260/280nm (A260/280) were registered. U Mann Whitney test was 

used. 

Results: CNB diagnosis was: 23 SqCC, 6 AC, 1 BAC, and 1 NSCLC-NOS. FNA 

diagnosis was: 26 AC, 3 SqCC, 1 BAC, 1 LCC, and 2 NSCLC-NOS. Mean DNA 

concentration from CNB was 23.07ng/ul ± 20.99, and from FNA samples 12.41ng/ul 

± 20.04 (p < 0.001). However A260/280 was 1.61 ± 0.26 and 1.71 ± 0.55 respectively 

(p = 0.666). Mutational analysis results from all 31 CNB and from 19 FNA cases are 

shown in Table 1. Sanger sequencing in all FNA cases rendered concordant results. 

Updated results will be presented. 

FNA CNB 

EGFR WT 6 28 

EXON 19 DEL 2 1 

EXON 20 INS 0 1 

INVALID 1 1 

KRAS WT 9 26 

12/13 

MUTATED 

9 4 

INVALID 1 1 

Conclusions: Assessment of EGFR and KRAS mutations in FNA and CNB samples 

using cobas® EGFR and KRAS test is feasible and reliable. Quality of DNA (A260/ 

280) using cobas® DNA Sample Preparation Kit in FNA samples is similar to those 

from CNB. Molecular results from FNA samples using cobas® test and direct 

sequencing are concordant, though cobas® tests are simpler, faster and easier to use. 



1318 FREQUENCY AND SPECTRUM OF EGFR MUTATIONS IN 

MOROCCAN LUNG ADENOCARCINOMA PATIENTS 

I. Elghissassi 1 , H. Inrhaoun 2 , A. Boukir 2 , Y. Bensouda 2 , H. Mrabti 1 , H. Errihani 1 

1 Medical Oncology, Institut National d’Oncologie Sidi Mohamed Ben Abdellah, 

Rabat, MOROCCO, 2 Medical Oncology, National Institute of Oncology, Rabat, 

MOROCCO 

Background: EGFR mutations reported in lung cancer are potential therapeutic 

targets leading to improved response with tyrosine kinase inhibitors (TKI). The 

frequency of EGFR mutations is ethnicity-dependent with a higher proportion in 

Asian populations (30%) than in Caucasians (10-15%). Furthermore, exon 19 

mutation is associated with better response to EGFR-TKI compared to exon 21 

mutation. The aim of this study was to report the frequency and spectrum of 

EGFR mutations in unselected group of Moroccan lung adenocarcinoma 

patients. 

Methods: We summarized the result of the EGFR mutation analysis in exons 18-21 

for 83 patients performed from November 2010 to march 2012 in three laboratories 

in Rabat. Mutation detection techniques were PCR amplification and sequencing. 

Only Moroccan lung adenocarcinoma patients were included. 

Results: The overall frequency of the EGFR mutation was 22%. It was more frequent 

in female patients (58%) than in male ones (5%). Mutations were mainly detected in 

the exon 19 (67%) followed by exon 21 (17%) and exon 20 (11%), while that in the 

exon 18 was rare (5%). 

Conclusion: Some one fifth of Moroccan lung adenocarcinoma tumors harbor EGFR 

mutations. This mutation frequency is higher than that found in Caucasians but 

lower than in Asian population. The high rate of exon 19 mutation in Moroccan 

population may result in a higher frequency of response to TKI 


1319 THE ROLE OF EPITHELIAL-MESENCHYMAL TRANSITION AND 

IGF-1R EXPRESSION IN PREDICTION OF GEFITINIB ACTIVITY 

AS THE SECOND-LINE TREATMENT FOR ADVANCED 


W. Zhang, B. Chen 

Oncology, Guangzhou General Hospital of Guangzhou Military Command, 

Guangzhou, Guangzhou, CHINA 

We retrospectively analyzed the relationship of EMT, IGF-1R and gefitinib efficacy in 

53 NSCLC patients who accepted gefitinib as the second-line treatment. Compared 

with EMT (+), EMT (-) showed a higher ORR in both EGFR mutation subgroup 

(50.0% vs. 28.6%) and EGFR wild-type subgroup (20.0% vs. 4.5%), and a longer 

MST in EGFR wild-type subgroup (6 months vs. 3 months, P = 0.014). IGF-1R (-) 

showed a higher ORR tendency than IGF-1R (+) in EGFR mutation patients (54.6% 

vs. 30.0%) and EGFR wild-type patients (18.2% vs. 4.8%). EMT and IGF-1R are 

correlated with the efficacy of gefitinib as the second-line therapy for NSCLC, 

especially in patients with wild- type EGFR. (This work is supported by grants from 

the National Foundation of Natural Science, China. No. 81172225, No. 81101821 and 

No. 81000819) 


1320 PERIODIC MEASUREMENT OF N-TELOPEPTIDES OF TYPE I 

COLLOGEN IN SERUM (SNTX) FOR EARLY DIAGNOSIS OF 

BONE METASTASIS IN PATIENTS WITH LUNG CANCER 

H. Daga 1 , M. Tamiya 2 , S. Tokunaga 3 , K. Taira 3 , H. Okada 3 , H. Suzuki 2 , 

N. Okamoto 2 , N. Morishita 2 , T. Hirashima 2 , K. Takeda 3 

1 Department of Clinical Oncology, Osaka City General Hospital, Osaka, JAPAN, 

2 Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka Prefectural 

Medical Center for Respiratory and Allergic Diseases, Habikino-City, JAPAN, 

3 Clinical Oncology, Osaka City General Hospital, Osaka, JAPAN 

Background: The bone resorption biomarker sNTx has been previously shown to 

add value as an aid in the diagnosis of bone metastasis in patients with lung cancer. 

The objective of this prospective study was to determine if periodic sNTx 

measurements could lead to early diagnosis of bone metastasis in patients with lung 

cancer. 

Methods: Patients with newly diagnosed organ-confined lung cancer were enrolled. 

sNTx values were determined once each month using the OSTEOMARK TM serum 

NTx assay (Alere Medical). The presence or absence of bone metastasis was 

determined by monthly physical examination and by bone scintigraphy every 3 



months for 12 months. All patients were required to provide written informed 

consent. 

Results: Forty patients were enrolled between June and December 2010. One patient 

withdrew early and was excluded from analysis. The mean +/- 1 SD baseline level of 

sNTx was 17.5 +/- 4.4 nM BCE/L. Five patients developed bone metastasis (as 

characterized by bone scintigraphy) during the study period. The level of sNTx in 

subjects with bone metastasis was slightly increased (21.6 +/- 3.2 nM BCE/L), 

however, in these patients, there was no statistically significant difference between 

sNTx values at baseline (18.2 +/- 4.2 nM BCE/L) and when metastasis was 

diagnosed. (p = 0.176). When a cut-off value of sNTx was set to 22.0 nM BCE/L, the 

sensitivity and the specificity of detection of bone metastasis were 80.0% and 41.2%, 

respectively. Using this cut-off, the elevation of sNTx could predict bone metastasis 

at least one month before diagnosis by bone scintigraphy in all 5 patients, however, 

the specificity was relatively low for clinical implementation. Additionally, the 

sensitivity and the specificity of early detection of systematic spread of disease 

(including bone metastasis) were 70.6% and 45.5%, respectively. 

Conclusions: Periodic determination of sNTx in patients with organ confined lung 

cancer did not provide sufficient specificity for it to be used for the early diagnosis of 

bone metastasis or disease progression. 


1321 USEFULNESS OF SERIAL MEASUREMENT OF SERUM 

N-TELOPEPTIDES OF TYPE I COLLOGEN (NTX) IN PATIENTS 

WITH LUNG CANCER WHO DEVELOPED BONE METASTASIS: 

A PROSPECTIVE STUDY 

M. Tamiya 1 , S. Tokunaga 2 , H. Okada 2 , K. Taira 2 , H. Daga 3 , N. Morishita 4 , 

H. Suzuki 4 , N. Okamoto 4 , K. Takeda 2 , T. Hirashima 1 

1 Department of Thoracic Malignancy, Osaka Prefectural Medical Center for 

Respiratory and Allergic Diseases, Osaka, JAPAN, 2 Clinical Oncology, Osaka City 

General Hospital, Osaka, JAPAN, 3 Department of Clinical Oncology, Osaka City 

General Hospital, Osaka, JAPAN, 4 Thoracic Malignancy, Osaka Prefectural 

Hospital Organization Osaka Prefectural Medical Center for Respiratory and 

Allergic Diseases, Habikino-City, JAPAN 

Background: The bone resorption biomarkers urinary NTx (uNTx) and serum NTx 

(sNTx) have been shown to aid in the diagnosis of bone metastasis in patients with 

lung cancer. Patients with metastatic bone disease from lung cancer (MBDLC) are 

often treated with zoledronic acid. Zoledronic acid reduces the levels of bone 

resorption biomarkers and also the risk of skeletal adverse events in patients with 

MBDLC. We studied the effects of treatments including zoledronic acid on levels of 

sNTx during disease progression. 

Methods: Patients with MBDLC at the initial diagnosis were entered to this study. 

sNTx was measured once a month using the sNTx assay OSTEOMARK TM serum 

NTx (Alere Medical). MBDLC was characterized by monthly physical examination 

and by bone scintigraphy every 3 months for 12 months. All patients were required 

to provide written informed consent. 

Results: Twenty patients were enrolled between June and December 2010. The mean 

+/- 1 SD of the sNTx concentrations was 19.8 +/- 5.8 nM BCE/L at baseline. In the 

16 patients receiving zoledronic acid, the levels of sNTx showed a significant decrease 

in the first month of treatment (baseline: 21.3 +/- 5.5 nM BCE/L; one month later: 

13.6 +/- 2.7 nM BCE/L; p < 0.01). During follow-up period, 12 of the patients treated 

with zoledronic acid experienced worsening MBDLC or had died from lung cancer, 

and there were statistically significant differences in the levels of sNTx at baseline 

(19.7 +/- 4.47 nM BCE/L), at the lowest levels after the administration of zoledronic 

acid (11.5 +/- 2.73 nM BCE/L) and at the point of measurable disease progression or 

death (13.0 +/- 2.07 nM BCE/L). 

Conclusions: Serial measurements of sNTx in patients with MBDLC treated with 

zoledronic acid might predict disease progression of bone metastasis. Administration 

of zoledronic acid significantly decreased the level of sNTx from baseline within one 

month and maintained the level of sNTx lower than baseline during study periods. 


1322 PREDICTIVE BIOMARKERS IN NSCLC PATIENTS TREATED 

WITH ERLOTINIB AFTER CHEMOTHERAPY: EGFR 

EXPRESSION OR MUTATIONS? 

A. Inno 1 , E. Maci 1 , M. Martini 2 , V. Arena 2 , V.P. Di Noia 1 , G. Schinzari 1 ,L. 

M. Larocca 2 , A. Cassano 1 , C. Pozzo 1 , C. Barone 1 

1 Oncologia Medica, Università Cattolica del Sacro Cuore, Roma, ITALY, 2 Istituto 

di Patologia, Università Cattolica del Sacro Cuore, Roma, ITALY 

Introduction: Retrospective subgroup analysis from randomized trials did not show 

a significant association between activating EGFR mutations and benefit from 

erlotinib in patients with NSCLC previously treated with chemotherapy, so whether 

EGFR mutational status should be used as a tool to select patients for erlotinib in the 

second-line setting is debatable. Novel predictive biomarkers would be helpful to 

choose the most appropriate therapeutic strategy. 

Methods: We correlated retrospectively the mutational status of EGFR and KRAS 

and also the IHC expression of EGFR, cMET, IGF1R and HER2, with the outcome 

of 51 patients with metastatic NSCLC treated with erlotinib as second or third-line at 

our institution from 2009 to 2012. 

Results: EGFR and KRAS activating mutations were mutually exclusive and were 

found in 5 and 7 patients. IHC score for EGFR, IGF1R, cMET and HER2 was 3+ in 

11, 8, 7 and 1 patients, respectively. RR was 20% and 13% and PFS was 9 and 2 

months for EGFR mutant and wt patients, respectively, but the difference was not 

statistically significant. Similarly, KRAS mutational status did not significantly affect 

the outcome, although none of KRAS mutant patients achieved an objective response. 

RR and PFS were not related to IGF1R and cMET expression. Nine out of 11 patients 

(81.8%) with EGFR overexpression responded to treatment, compared with 13 out of 

40 patients (32.5%) with a lower EGFR level. EGFR overexpression was also associated 

with a longer PFS (8 vs 2 months, p = 0.05). Interestingly, in our study the outcome of 

patients was not affected by gender, performance status, histology or smoking history. 

Conclusion: cMET and IGF1R were not related to the efficacy of erlotinib as second 

or third-line treatment for metastatic NSCLC patients. No conclusions can be drawn 

about HER2 since only one case of overexpression was found. EGFR mutations are 

associated with a longer PFS, even if not significantly. The IHC expression of EGFR 

seems to be predictive of a better outcome, whereas KRAS mutations may represent a 

mechanism of resistance. Given the retrospective nature of our study, however, those 

findings should be confirmed within prospective clinical trials. 

Disclosure: A. Inno: Speaker at educational meetings sponsored by Merk-Serono and 

Amgen. All other authors have declared no conflicts of interest. 

1323 STUDY OF THE SAFETY AND EFFICACY OF EPIDERMAL 

GROWTH FACTOR RECEPTOR TYROSINE KINASE 

INHIBITORS IN 97 PATIENTS WITH EPIDERMAL GROWTH 

FACTOR RECEPTOR MUTATION-POSITIVE NON-SMALL CELL 

LUNG CANCER 

M. Ishibashi 1 , K. Ogawa 1 , S. Motizuki 1 , S. Hanada 1 , H. Uruga 1 , H. Takaya 1 , 

A. Miyamoto 1 , N. Morokawa 1 , T. Fujii 2 , K. Kishi 1 

1 Dept. of Respiratory Medicine, Toranomon Hospital, Tokyo, JAPAN, 2 Pathology, 

Troranomon Hospital, Tokyo, JAPAN 

Background: Recent phase 3 trials have demonstrated that first-line epidermal 

growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) improved the 

progression-free survival (PFS) in good performance status (PS) patients with 

non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. We 

aimed to study the safety and efficacy of EGFR TKIs in patients with activating 

EGFR mutation-positive NSCLC in a normal clinical setting. 

Materials and methods: Between August 2006 and October 2011, 487 patients with 

NSCLC were examined for EGFR mutations by the peptide nucleic acid–locked 

nucleic acid polymerase chain reaction clamp method at Toranomon Hospital. One 

hundred and forty-two patients were tested positive for EGFR mutations: 82 patients 

had exon 19 deletions and 60 patients had L858R mutations in exon 21. Of these 142 

patients, EGFR TKIs were administered in 97 patients (51 men and 46 women, with 

a median age of 68 years). We retrospectively studied the clinical data to determine 

the efficacy and toxicity of EGFR TKIs that were administered to these patients. The 

overall survival and PFS from the start date of EGFR TKI therapy were calculated 

using the Kaplan–Meier method. 

Results: Thirty-one patients were aged 75 or more. Fourteen patients had a poor PS of 

3 or 4 and 57 patients had previously undergone chemotherapy. Gefitinib was 

administered to 76 patients, erlotinib to 56 patients, and both drugs to 35 patients. The 

response rate was 49%. The median PFS was 10.6 months and the median survival 

time was 26.4 months. The following grade 3 or 4 toxicities were observed: skin rash 

(n = 6), increased aminotransferase levels (n = 4), and interstitial lung disease (n = 6). 

Conclusion: Although patients who are elderly, those with poor PS, and those who had 

previously undergone chemotherapy were included in this study, EGFR TKIs for 97 

patients with EGFR mutation-positive NSCLC in clinical practice showed a median PFS 

of 10.6 months and a median survival time of 26.4 months without treatment-related 

death. The results of this study were consistent with those of the recent phase 3 trials. 


1324 ANALYSIS OF EML4-ALK POSITIVE NON-SMALL CELL LUNG 

CANCER WITH ADVANCED STAGE 

J. Park 1 , C. Kondo 1 , J. Shimizu 2 , Y. Horio 1 , K. Yoshida 1 , Y. Yatabe 3 , 

T. Mitsudomi 4 , T. Hida 1 

1 Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, 

JAPAN, 2 Thoracic Oncology, Aichi Cancer Center, Nagoya, JAPAN, 

3 Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, 

Nagoya, JAPAN, 4 Department of Thoracic Surgery, Kinki University Faculty of 

Medicine, Sayama, JAPAN 

Background: The purpose of this study is to investigate the clinical characteristics 

and the efficacy of the cytotoxic chemotherapy in the first and second line setting in 

EML4-ALK positive NSCLC with advanced stage. 


Methods: EML4-ALK fusion was screened with RT-PCR and 

immunohistochemistry. When positive results were obtained with either 

method, gene rearrangement of ALK was confirmed with fluorescent in-situ 

hybridization. Clinical features and the efficacy of chemotherapy were evaluated 

retrospectively. 

Results: We evaluated 20 EML4-ALK positive patients with advanced stage. 

Seventeen (85%) of 20 had stage IV disease. Nine cases were male, and 11 were 

female. The mean ages were 46.3 years (range26-79). Most of their CT findings 

demonstrated mass or nodule in primary sites, while 2 cases showed air-space 

consolidation. In patients with stage IV the most common sites of metastasis at the 

first onset were bone (47.0%), followed by pleura (35.2%), liver (29.4%), and lung 

(23.5%). In 13 cases of which were evaluable in the first line setting, 7 (53.8%) had a 

partial response (PR), 4 (30.8%) had stable disease (SD), and 2 (15.4%) had 

progressive disease (PD). Among 10 evaluable cases in the second line setting, 2 

(20%) had a PR, 5 (50%) had SD, and 3 had PD (30%). Two patients who had a PR 

were both treated by oral ALK inhibitor (crizotinib). One case had no response to 

crizotinib. Within the 7 patients who were treated by cytotoxic agents, none had 

marked clinical response. Five patients (71.4%) had SD, 2 patients had PD (28.6%) 

on single cytotoxic drug. 

Conclusions: Our study suggests that the EML4-ALK positive patients may show 

relatively favorable response to cytotoxic drug in the first line setting, but low 

response in the second line setting. These data could be helpful for further clinical 

trials including EML4-ALK patients. 

Disclosure: T. Mitsudomi: Dr. Mitsudomi has received lecture fees from 

AstraZeneca and Chugai, and he is a member of advisory boards of Pfizer 

and Boehringer-Ingelheim. All other authors have declared no conflicts of 

interest. 

1325 FIRST-LINE GEFITINIB TREATMENT FOR ELDERLY PATIENTS 

WITH NON-SMALL CELL LUNG CANCER HARBORING EGFR 

MUTATION: MULTICENTER PHASE II TRIAL CJLSG0901 

K. Takahashi 1 , H. Saito 1 , M. Yamamoto 2 , E. Kojima 3 , T. Yokoyama 4 , Y. Sugino 5 , 

T. Kimura 6 , T. Ogasawara 7 , R. Suzuki 8 , Y. Hasegawa 9 

1 Respiratory Medicine, Aichi Cancer Center Aichi Hospital, Okazaki, JAPAN, 

2 Respiratory Medicine, Nagoya Ekisaikai Hospital, Nagoya, JAPAN, 3 Respiratory 

Medicine, Komaki Municipal Hospital, Komaki, JAPAN, 4 Respiratory Medicine, 

Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, JAPAN, 5 Respiratory 

Medicine, Toyota Memorial Hospital, Toyota, JAPAN, 6 Respiratory Medicine and 

Allergy, Tosei General Hospital, Seto, JAPAN, 7 Respiratory Medicine, 

NagoyaDaini Red Cross Hospital, Nagoya, JAPAN, 8 Respiratory Medicine, 

Toyohashi Municipal Hospital, Toyohashi, JAPAN, 9 Respiratory Medicine, 

Nagoya University Graduate School of Medicine, Nagoya, JAPAN 

Background: Recently, the elderly population of lung cancer patients is increasing 

worldwide. Although first-line Gefitinib is one of the standard treatments for 

advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor 

receptor (EGFR) mutation, few data have been reported on elderly patients. Thus, we 

conducted a phase II trial to evaluate the efficacy and safety of first-line gefitinib 

therapy for this specific population. 

Methods: Chemotherapy-naïve patients aged 70 years or older and diagnosed with 

stage IIIB or IV (including recurrent non-small cell lung cancer) harboring either 

exon 19 deletion or L858R point mutation were enrolled and treated with oral 

gefitinib 250 mg daily until disease progression or unacceptable toxicity occurred. 

The primary endpoint was response rate. Quality of life was also assessed 

prospectively. 

Results: Twenty patients were enrolled between June 2009 and March 2011. The 

median age was 79.5 years (range: 72-90). All the patients had adenocarcinoma, 12 

patients had exon 19 deletion, and 8 had L858R mutation. Overall response rate was 

70% (95% CI, 46 - 88%), and the disease control rate was 90% (95% CI, 68 - 99%). 

The median progression-free survival was 10.8 months. The median overall survival 

time has not been reached. The most common adverse events were rash and liver 

dysfunction, and grade 1 interstitial lung disease developed in one patient. No 

treatment-related death was observed. The scores of the Functional Assessment of 

Cancer Therapy-Lung Cancer Subscale (FACT-LCS) improved significantly four 

weeks after the initiation of gefitinib and maintained a favorable tendency during the 

12 weeks of treatment. 

Conclusion: First-line gefitinib therapy for elderly patients with NSCLC harboring 

EGFR mutation demonstrated a good response rate, quality of life, and tolerance. 



1326 PHASE II TRIAL OF CARBOPLATIN AND PEMETREXED AS 

FIRST-LINE CHEMOTHERAPY FOR NON-SQUAMOUS 

NON-SMALL CELL LUNG CANCER AND CORRELATION 

BETWEEN THE EFFICACY/TOXICITY AND GENETIC 

POLYMORPHISMS ASSOCIATED WITH PEMETREXED 

METABOLISM: HOKKAIDO LUNG CANCER CLINICAL STUDY 

GROUP TRIAL (HOT) 0902 

Y. Fujita 1 , H. Yokouchi 2 , S. Fujiuchi 1 , T. Harada 3 , M. Harada 4 , K. Takamura 5 , 

S. Oizumi 6 , H. Isobe 7 , H. Akita 8 , M. Nishimura 6 

1 Department of Respiratory Medicine, National Hospital Organization Asahikawa 

Medical Center, Asahikawa, JAPAN, 2 Department of Pulmonary Medicine, 

Fukushima Medical University Hospital, Fukushima, JAPAN, 3 Center for 

Respiratory Diseases, Hokkaido Social Insurance Hospital, Sapporo, JAPAN, 

4 Department of Pulmonary Disease, National Hospital Organization Hokkaido 

Cancer Center, Sapporo, JAPAN, 5 First Department of Medicine, Hokkaido P.W. 

F.A.C Obihiro-Kosei General Hospital, Obihiro, JAPAN, 6 First Department of 

Medicine, Hokkaido University School of Medicine, Sapporo, JAPAN, 

7 Department of Medical Oncology and Respiratory Medicine, KKR Sapporo 

Medical Center, Sapporo, JAPAN, 8 Department of Medical Oncology, Hokkaido 

University Graduate School of Medicine, Sapporo, JAPAN 

Background: The importance of biomarkers is increasing in individualized treatment 

strategy for cancer patients (pts). We evaluated the efficacy and safety of carboplatin 

(CBDCA) and pemetrexed (PEM) in Japanese pts with non-squamous non-small cell lung 

cancer (NSCLC), and single nucleotide polymorphisms (SNPs) associated with PEM 

metabolism were also analyzed to investigate their relationship with efficacy or toxicity. 

Patients and methods: Eligible pts had a performance status 0 or 1, aged from 20 to 

74 years, chemotherapy-naïve stage IIIB/IV non-squamous NSCLC, and adequate 

organ function. Pts received CBDCA at a dose targeting an area under the 

concentration-time curve of 5 and 500 mg/m 2 PEM every 3 weeks. More than 3 

cycles was considered as completion of treatment. Peripheral blood was drawn for 

SNPs analyses of thymidylate synthase gene (TS) and methylenetetrahydrofolate 

reductase gene (MTHFR) in pts with consent for the biomarker study. 

Results: Forty-one pts (28 men, 13 women; median age 63 years, range 43 - 73), 

with 39 adenocarcinomas and 2 large cell carcinomas, were enrolled and SNPs were 

analyzed in 37 pts. The median follow-up time was 16.1 months and the median 

number of treatment cycle was 4 (range 1 - 6). The completion rate was 80.5% (33 

pts). All pts were assessable for response; the overall response rate (RR) was 36.6% 

and disease control rate (DCR) was 85.4%. Median progression-free survival (PFS) 

and overall survival (OS) were 4.6 months (138 days: 95%C.I.; 107-168) and 16.1 

months (483 days: 95%C.I.; 180-786), respectively. Grade 3 or 4 hematologic 

toxicities included anemia (34.1%), neutropenia (29.3%), leukopenia (19.5%) and 

thrombocytopenia (17.1%). Grade 3 or 4 non-hematologic toxicities included 

anorexia (7.3%) and nausea (4.9%). No treatment-related death was observed. 

Although the SNPs had no relation to PFS, OS, RR nor hematologic toxicity, the 

variable number of tandem repeat (VNTR) of the TS significantly correlated with 

anemia (p = 0.047) and thrombocytopenia (p = 0.038). 

Conclusion: The efficacy of this regimen seems even better than previously reported, 

and with acceptable toxicities. VNTR of the TS has the possibility of being a 

predictive factor of anemia and thrombocytopenia for this regimen. 


1327 A PHASE II TRIAL OF CISPLATIN-DOCETAXEL-BEVACIZMAB 

INDUCTION CHEMOTHERAPY FOLLOWED BY BEVACIZMAB 

AND PEMETREXED MAINTENANCE THERAPY IN PATIENTS 

WITH NONSQUAMOUS CELL LUNG CARCINOMA: OKAYAMA 

LUNG CANCER STUDY GROUP TRIAL 0903 

A. Nishiyama 1 , H. Yoshioka 1 , K. Kunimasa 1 , K. Hotta 2 , N. Nogami 3 , T. Kozuki 4 , 

S. Harita 5 , N. Takigawa 6 , M. Tanimoto 2 , K. Kiura 2 

1 Respiratory, Kurashiki Central Hospital, Kurashiki, JAPAN, 2 Department of 

Respiratory Medicine, Okayama University Hospital, Okayama, JAPAN, 

3 Respiratory, NHO Shikoku Cancer Center, Matsuyama, JAPAN, 4 Dept of 

Thoracic Oncology, NHO Shikoku Cancer Center, Matsuyama, JAPAN, 

5 Respiratory, Chugoku Central Hospital, Hukuyama, JAPAN, 6 Internal Medicine, 

Kawasaki-Hospital, Okayama, JAPAN 

Background: Addition of bevacizmab (BEV) to platinum-based doublet yields a 

significant but only modest survival advantage. Recently, in the PARAMOUNT trial 



pemetrexed (PEM) maintenance therapy produced a high magnitude of PFS 

improvement. The OLCSG 0903 phase 2 trial investigated efficacy and safety of cisplatin 

(CDDP)-docetaxel (DOC)-BEV induction therapy followed by BEV-PEM maintenance 

therapy in patients with advanced nonsquamous non-small cell lung carcinoma. 

Methods: In this trial, 40 patients with good PS (0 or 1) participated in the induction 

phase, specified as four cycles of induction CDDP (80 mg/m 2 ), DOC (60 mg/m 2 ) and 

BEV (15 mg/kg) on day 1 of a 21-day cycle. Patients who had not progressed during 

CDDP-DOC-BEV induction received maintenance BEV (15 mg/kg) and PEM (500 

mg/m 2 ) on day 1 of a 21-day cycle until disease progression. The primary endpoint 

was PFS, and the secondary endpoints included toxicity, OS and response rate. 

Results: Patient characteristics were as follows: median age: 62 years; 78% male; 

100% Japanese; 30% PS 0; 73% stage IV; and 70% adenocarcinoma. At the time of 

this analysis, 23pts (58%) discontinued the treatment, and the proportion of 

discontinuations to AEs was 35% (8/23). The principal toxicity was 

myelosuppression (grade 4 hematological: 20 patients [50%]), and grade 3/4 febrile 

neutropenia was observed in 10 (25%) despite no treatment-related deaths. The 

objective response rate and disease control rate (% patients with CR/PR/SD) was 

82.5% and 97.5%, respectively. The median PFS time was 10.2 months, and the 

6-month PFS rate was 63.2% (95% confidence interval: 44.9-76.9 %). 

Conclusions: CDDP-DOC-BEV followed by BEV-PEM maintenance seems an 

effective and moderately tolerated treatment for patients with advanced 

nonsquamous non-small cell lung carcinoma. 

Disclosure: K. Hotta: Eli Lilly Japan sanofi-aventis Chugai Pharmaceutical Co. Ltd 

Nippon Kayaku. N. Takigawa: Eli Lilly Japan sanofi-aventis Chugai Pharmaceutical 

Co. Ltd. K. Kiura: Eli Lilly Japan sanofi-aventis Chugai Pharmaceutical Co. Ltd 

Nippon Kayaku. All other authors have declared no conflicts of interest. 

1328 META-ANALYSIS OF RELATIONSHIP BETWEEN SKIN RASH 

AND OUTCOME IN NON-SMALL-CELL LUNG CANCER 

(NSCLC) PATIENTS TREATED WITH ERLOTINIB (E) AND 

GEFITINIB (G) 

K.F. Borgonovo, F. Petrelli, M. Cabiddu, M. Ghilardi, M. Cremonesi, F. Maspero, 

S. Barni 

Medical Oncology Division, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, 

ITALY 

Introduction: Dermatological toxicity in the form of acneiform rash is a common 

event in NSCLC patients being treated with anti-EGFR TKIs. An association between 

clinical benefit by EGFR-targeted therapy and development of this form of skin 

toxicity has been noted. The objective of this meta-analysis was to assess the predictive 

value of skin rash for outcome in patients with NSCLC treated with E or G. 

Materials and methods: Prospective clinical trials or retrospective case series with 

reported survival (OS), progression (PFS/TTP) and response rate (RR) as a function 

of skin rash were serched in PubMed until January 2012. The selected studies have to 

include adult patients with histologically confirmed NSCLC treated with G or E, 

alone or in combination with other approved agents. Hazard ratios with 95% 

confidence intervals (HRs) for PFS/TTP and OS and risk ratios (RRs) for response 

rate in patients with rash were pooled in a meta-analysis. 

Results: Twenty-four publications were included in this meta-analysis (17 

prospective trials and 7 retrospective case series) for a total of 3032 patients. For the 

primary endpoint (OS) the occurrence of skin rash was significantly associated with 

reduced risk of death in patients treated with E or G (HR 0.30, p 3 14/7; 

non-smoker/smoker: 13/8, with EGFR mutations/without EGFR mutations – 12/9. 

Results: Median PFS was 7 months overall, ORR was 75% (9/12, 8 partial responses, 

1 complete response) and the MoS was not reached in patients with EGFR 

mutations. Median PFS was 2 months overall, no objective responses and the MoS 

was 4 months in patients without EGFR mutations. Differences are statistically 

significent in ORR and PFS (p < 0.05). 

Conclusions: EGFR TKIs showed high effectiveness and good disease control in 

patients with brain metastases from NSCLC with EGFR mutations. 


1331 COMPARISON OF SURVIVAL IN PATIENTS WITH ADVANCED 

LUNG ADENOCARCINOMA TREATED BEFORE AND AFTER 

GEFITINIB APPROVAL IN CHINA 

Y. Shi 1 ,Y.Liu 1 , X. Hao 1 ,J.Li 1 ,X.Hu 1 , Y. Wang 1 , Z. Wang 2 , H. Wang 1 , X. Han 1 , 

X. Zhang 1 

1 Oncology, Cancer Hospital-China Academy of Medical Sciences, Beijing, 

CHINA, 2 Medical Oncology, Cancer Hospital-Chao Yang District BeijingCAMS 

and PUMC, Beijing, CHINA 

Objective: This study compared the overall survival (OS) between advanced lung 

adenocarcinoma patients of before and after gefitinib approval in China. 

Methods: The clinical data of 558 advanced lung adenocarcinoma patients who ever 

received palliative chemotherapy were reviewed retrospectively. According to a 

matched-pair case-control study design, 255 patients of before gefitinib approval who 

only received palliative chemotherapy and 255 patients of after gefitinib approval 

who received gefitinib treatment were matched by age, sex and smoking history. 


Results: The median survival time (MST) of 510 advanced lung adenocarcinoma 

patients from the date of first-line palliative therapy was 22.8 months. MST was 

significantly longer among the patients treated with gefitinib after gefitinib approval 

compared with the patients treated before gefitinib approval (33.5 vs. 14.1months, p < 

0.001). Multivariate analysis showed that the independent prognostic factors to 

significantly improve OS of 510 patients included gefitinib treatment (hazard ratio 

0.175, P


received docetaxel (75mg/m2 IV), cisplatin (80 mg/m2 IV) and bevacizumab (15 mg/ 

kg IV) in cycles of 21 days. Patients did not receive maintenance bevacizumab. 

Results: All patients were eligible for response. Complete and partial responses were 

achieved in two (4,2%) and 14 (29.2%) patients, respectively [overall response rate: 

33,3%; 95% CI = (20.0%-46.7%)] whereas stable disease was documented in 14 

patients. The median PFS was 4, 4 months (95% CI: 1,32-7,48) and the median OS 

13,27 (95% CI: 9,72-16,81). Treatment-related grade 3 or 4 hematologic adverse 

events were leucopenia, neutropenia, and anemia in 8,4%, 18,7% and 2,1% of the 

patients, respectively. Three (6,3%) patients developed grade 2-4 febrile neutropenia 

and one (2.1%) patient (2,1%) died because of sepsis due to bowel perforation. 

Conclusions: The DCV regimen is an active regimen with manageable toxicity when 

administered as front line treatment in patients with advanced non-squamous 

NSCLC and merits to be further investigated. 


1336 CLINICAL MODES OF EGFR TYROSINE KINASE INHIBITOR 

FAILURE AND SUBSEQUENT MANAGEMENT IN ADVANCED 


H. Chen, J. Yang, H. Yan, X. Zhang, Z. Wu, Y. Wu 

Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) & 

Guangdong Academy of Medical Sciences, Guangzhou, CHINA 

Context: The diversity of epidermal growth factor receptor (EGFR) tyrosine kinase 

inhibitor (TKI) failure in advanced non-small cell lung cancer (NSCLC) has been 

reported sporadically, but there is no published overview of EGFR-TKI failure 

modes, which could hinder the appropriate management for patients with distinct 

failure modes. 

Objectives: This study mainly aimed to classify the diversity of TKI failure, and to 

investigate the usefulness of clinical modes in subsequent management and 

prognosis. 

Patients and methods: The retrospective study accrued 227 Chinese advanced 

NSCLC patients with EGFR-TKI failure. One-hundred and twenty consecutive 

clinical trial patients were enrolled as the training set to establish a clinical model 

based on clinical factors. Another 107 routine patients were enrolled as the validating 

set according to a Bayes discriminant analysis. EGFR mutations and c-MET 

amplification were analyzed. Kaplan–Meier survival analysis was used to test the 

differences of prognosis and subsequent management in clinical modes. 

Results: The duration of disease control, symptom improvement, and evolution of 

tumor burden were verified as feasible grouping variables. A correct grouping rate 

achieved 84.1%. The cohort was classified into three groups, as follows: 130 patients 

with dramatic progression, 42 with gradual progression, and 55 with local 

progression. Progression-free survivals (PFSs) for the dramatic progression, gradual 

progression, and local progression groups were 9.3, 12.9, and 9.2 months, 

respectively (P =0.007). Overall survivals for the groups (OSs) were 17.1, 39.4, and 

23.1 months, respectively (P

enefit from sustained EGFR blockade during subsequent salvage therapy is unclear. 

LUX-Lung 5 is an international, multicenter phase III trial studying the efficacy of 

BIBW2992 (Afatinib®, A), an irreversible erbB family blocker, in NSCLC pts 

progressing after treatment with ctx and E or G irrespective of their EGFR mutation 

status. Here we report the outcome of NSCLC pts treated within LUX-Lung 5 at a 

single center in relation to EGFR and KRAS mutation status. 

Methods: Pts with stage IV (UICC 7) NSCLC progressing after ctx and E or G were 

enrolled into LUX-Lung 5. In part A of the study pts received A (starting dose 50 

mg/d) until progression. In part B pts with clinical benefit ≥12 wks were randomized 

between A plus weekly paclitaxel vs investigator’s choice mono ctx. Following 

microdissection, tumor DNA was extracted and analyzed by PCR and Sanger 

sequencing. 

Results: Between May 2010 and February 2011 39 pts (20 f, 19 m; median age 61 

y, 38-83 y) were enrolled at the West German Cancer Center. Median number of 

pretreatments was 3 (1-8) including E or G. So far, tumor biopsies were retrieved 

from 25 pts (64%). Somatic EGFR mutations were detected in 11 pts (44% of 

analyzed tumors, 28% of entire cohort), whereas 14 pts (56%/36%) exhibited 

EGFR wild type (wt) sequences. EGFR mutation status remains unknown in 14 

pts (36%). KRAS mutation analysis was performed in 20 pts (51% of entire 

cohort) and 4 mutations were observed (20%/10%), 3 in EGFR wt and one in an 

EGFR mutant tumor. Median survival time from initiation of A was 432 d in 

EGFR mutant pts, 189 d in EGFR wt pts, and 255 d in KRAS mutant pts. 

Median survival time of pts with unknown EGFR mutation status was 191 

d. Safety of A was manageable. 

Conclusions: A can achieve disease control in heavily pretreated NSCLC pts. Pts 

with EGFR mutant tumors experience prolonged survival as compared to EGFR wt 

tumors (HR 0.29; 95% CI 0.07–0.64; p = 0.0058). This argues for sustained tumor 

dependency on EGFR signaling despite progression after E or G. 

Disclosure: J. Köhler: J. Köhler received financial support from Boehringer 

Ingelheim for writing a review article. T.C. Gauler: T.C. Gauler is principle 

investigator of the BI1200.43 trial testing Afatinib in HNSCC. D. Theegarten: 

D. Theegarten is member of the Lilly Advisory Board. W. Eberhardt: W. Eberhardt 

received honoraries for advisory board functions from Boehringer Ingelheim, Astra 

Zeneca, Roche, OSi Pharmaceuticals, Pfizer and honoraries for lectures from 

Boehringer Ingelheim, Astra Zeneca, Roche and Pfizer. M. Schuler: M. Schuler 

received research funding from Boehringer Ingelheim and travel support from Lilly. 


1340 PHASE II STUDY OF ERLOTINIB IN JAPANESE PATIENTS 

WITH PRETREATED EGFR MUTATION POSITIVE NON-SMALL 

CELL LUNG CANCER:LUNG ONCOLOGY GROUP IN KYUSHU, 

JAPAN (LOGIK0803) 

K. Takayama1 , Y. Nakanishi1 , S. Kawakami2 , K. Saruwatari3 , K. Yamada4 , 

R. Morinaga5 , N. Aragane6 , S. Nagata7 , J. Kishimoto8 , Y. Ichinose9 1 

Research Institute for Diseases of The Chest, Kyushu University, Fukuoka, 

JAPAN, 2 Respirology, Kyushu Kosei-Nenkin Hospital, Kitakyusyu, JAPAN, 

3 4 

Respiratory Medicine, Kumamoto University, Kumamoto, JAPAN, Division of 

Respirology, Kurume University, Kurume, JAPAN, 5 Medical Oncology, Oita 

University Faculty of Medicine, Oita, JAPAN, 6 Blood and Lung and Tumor 

Instituite, Saga University, Saga, JAPAN, 7 Respiratory Medicine, University of 

Occupational and Environmental Health, Kitakyusyu, JAPAN, 8 Center for Clinical 

and Translational Research, Kyushu University Hospital, Fukuoka, JAPAN, 

9 

Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, 

JAPAN 

Background: Erlotinib has been reported to be useful for treating EGFR 

mutation-positive (EGFR-mt) non-small cell lung cancer (NSCLC) (OPTIMAL 

ESMO 2010, EURTAC Lancet Oncol. 2012). However, its usefulness had not been 

investigated in Japanese patients. Hence, we conducted a multicenter phase II study 

to investigate the efficacy and safety of erlotinib in Japanese patients with pretreated 

EGFR-mt NSCLC. 

Methods: Erlotinib, 150 mg/day, was orally administered daily to patients with 

pretreated EGFR-mt (exon 19/21) NSCLC who had not been treated with 

EGFR-TKIs. The primary endpoint was objective response rate (ORR), and the 

secondary endpoints were disease control rate (DCR), progression-free survival 

(PFS), and safety. 

Results: Between April 2009 and January 2011, 26 patients were enrolled from 15 

participating centers. The patient characteristics were as follows: median age, 68 years 

(51 to 79); men/women, 11/15; adenocarcinoma/others, 24/2; nonsmoking/smoking, 

20/6; ECOG PS 0/1/2, 16/8/2; exon 19/21, 19/7; and 2nd/3rd line therapy, 25/1. The 

antitumor effect was as follows: PR, 14 patients; SD, 7 patients; PD, 4 patients; NE, 1 

patient; ORR, 54%; and DCR, 81%. The ORR and DCR according to the EGFR 

status were 47.4%/71.4% (exon 19/21, p = 0.3913) and 73.7%/100% (p = 0.2782), 

respectively. The PFS was 9.3 months (range, 0.9 to 19.2 mo). Major adverse drug 

reactions were rash (96%) and hepatic function disorder (40%); most episodes were 

grade 2 or less, and all were tolerable. No patients developed interstitial lung disease, 

and there were no treatment-related deaths. 

Conclusion: In this study, the usefulness of erlotinib was investigated prospectively 

in Japanese patients with pretreated EGFR-mt NSCLC for the first time, and this 


drug was shown to be effective and tolerable. At this congress, we will report the 

study results including the ORR and PFS according to the patient characteristics. 

Disclosure: Y. Nakanishi: From Chugai Pharmaceutical, I received 7500 Euro as 

honoraria on 2011, and 22000 Euro on 2010 and 70000 Euro on 2011 as research 

grant. Y. Ichinose: I have research funding with Chugai Pharmaceutical company. All 


1341 DOCETAXEL REGIMEN AS SECOND-LINE TREATMENT FOR 

PRETREATED ADVANCED NSCLC PATIENTS - A 

LARGE-SCALE, MULTICENTER, UNCONTROLLED, REGISTRY 

STUDY IN CHINA 

S. Lu 1 , Y.L. Wu 2 , Y.Z. Wang 3 , X. Song 4 , L.Q. Jia 5 , G.Y. Chen 6 ,T.Sun 7 ,K. 

H. Lu 8 , M. Ouyang 9 , H. Zhao 10 

1 Shanghai Lung Tumor Clinical Center, Shanghai Chest Hospital, Shanghai, 

CHINA, 2 Department of Clinical Oncology, Guangdong General Hospital (GGH) 

& Guangdong Academy of Medical Sciences, guangzhou, CHINA, 3 Department 

of Medical Oncology, Peking Union Medical College Hospital, Beijing, CHINA, 

4 2nd Department of Respiratory Diseases, Shanxi Cancer Hospital, Taiyuan, 

CHINA, 5 Oncology Department of Integrative Medicine, China Janpan Friendship 

Hospital, Beijing, CHINA, 6 Department of Medical Oncology, Heilongjiang Cancer 

Hospital, Harbin, CHINA, 7 Department of Medical Oncology, Liaoning Cancer 

Hospital, Shenyang, CHINA, 8 Department of Medical Oncology, Jiangsu 

Province Hospital, Nanjing, CHINA, 9 Department of Thoracic Surgery, The First 

Affiliated Hospital of Guangzhou Medical University, Guangzhou, CHINA, 

10 Department of Medical Oncology, The 301 Military Hospital, Beijing, CHINA 

Background: Docetaxel has been approved as a second-line therapy for advanced 

non-small cell lung cancer (NSCLC) patients. The objective of this study is to 

provide real-world data of docetaxel regimen as second-line treatment in Chinese 

NSCLC patients through comparing the efficacy, toxicities and therapeutic schema. 

Methods: 1220 advanced NSCLC patients who had received docetaxel regimen as 

second-line treatment from nationwide 47 clinical centers in China from April 2009 to 

October 2010 were analyzed. The primary end point was overall survival (OS). 

Progression-free survival (PFS), response, toxicities and therapeutic models of docetaxel 

were assessed as secondary end points. Survival analysis was evaluated by Kaplan-Meier 

method. Single factor analysis and the COX regression model were performed to 

analyze the relationship between the influential factors and the prognosis of disease. 

Results: Docetaxel as second-line treatment for NSCLC associated with high 

response rate (RR) of 29.7%, median PFS of 8.2 months, median OS of 16.1 months. 

TNM staging (IV vs non-IV, P = 0.0270) and docetaxel regimen (docetaxel-based 

combinations vs docetaxel alone, P < 0.0001) were the prognostic factors for the 

studied group. The hematologic toxicity was the main adverse effect for docetaxel 

regimen. The most common grade III/IV adverse events were febrile neutropenia 

(4.3%), leucopenia (9.3%), neutropenia (11.6%), thrombocytopenia (0.6%), anemia 

(0.3%), nausea (1.6%), vomiting (1.6%), and alopecia (5.2%) in the total group. 608 

(608/1220, 49.8%) patients were treated with docetaxel alone, and 612 (612/1220, 

50.2%) with docetaxel-based combinations. Compared with docetaxel alone regimen, 

docetaxel-based combinations better prolonged the PFS (9.0m vs 7.1m, P < 0.0001) 

and OS (20.6m vs 14.3m, P < 0.0001) for advanced NSCLC. The toxicity of 

combination therapy was significantly higher in terms of hematologic (P = 0.0197) 

and non-hematologic adverse events (P = 0.0322) compared with docetaxel alone. 

Conclusions: Docetaxel as a second-line treatment provides better PFS and OS for 

Chinese NSCLC patients. The hematologic toxicity is the main adverse effect for 

docetaxel regimen. Owing to the limitation of registry study, further studies are 

warranted to confirm these findings. 


1342 ERLOTINIB (ERL) VERSUS PEMETREXED (MTA) AS 

SECOND-LINE TREATMENT FOR NON-SQUAMOUS 

NON-SMALL CELL LUNG CANCER (NSNSCLC): EFFICACY 

AND SAFETY DATA 

J. Zugazagoitia 1 , J. Puente 1 , S. Hernandez 2 , J.L. Gonzalez-Larriba 1 , J. Sanz 2 , 

A. Manzano 1 , E. Diaz-Rubio 1 

1 Medical Oncology, Hospital Clinico San Carlos, Madrid, SPAIN, 2 Anatomic 

Pathology, Hospital Clinico San Carlos, Madrid, SPAIN 

Background: A recently published study shows that ERL and chemotherapy (MTA/ 

docetaxel) offer similar efficacy outcomes in pretreated patients (p) with advanced 

NSCLC, and a direct comparison of ERL versus MTA in a prospective, randomized 

phase III trial also shows equivalent efficacy. However, both studies were conducted 

before the treatment-by-histology interaction effect was observed for MTA and p 

were not prospectively selected based on histology. Moreover, both studies included p 

considered optimal candidates for randomized trials, not always representative of the 

entire patient population. 

Material and methods: P with advanced nsNSCLC treated with ERL (150 mg/d p.o.) 

or MTA (500 mg/m2 on d1, every 3 weeks) as 2nd-line treatment were included in 

the study. This single-centre, retrospective, observational study was conducted to 



compare the efficacy and safety of ERL versus MTA in non-selected p with nsNSCLC 

who have progressed after 1st-line chemotherapy in a clinical practice scenario. 

Results: From 2006-2011, 67 p fulfill eligibility criteria, ERL (n = 32) and MTA (n = 

35). Baseline characteristics ERL/MTA: median age 67/65 yrs.; male 69/80%; smokers 

34/40%; PS ≥ 2 22/26%; adenocarcinoma 91/71%; stage IV 81 /77%; EGFR mutation 

positive 19/3%. No difference in terms of OS, 8.9 m (ERL) vs 7.1 months (MTA) (p 

= 0.551). Statistically significant differences were recorded for PFS, 3.5 (ERL) and 2.3 

months (MTA) (p = 0.02) and a relative reduction in risk of progression of 53.5 % 

for ERL vs MTA (p = 0.005). SLP differences remained statistically significant when 

adjusting for EGFR mutation status, histology, prior response to 1st-line treatment 

and location of metastatic sites. OS showed a non-statistically significant difference 

after adjusting for each variable. The DCR was 40.6% in the ERL and 31.4 % in the 

MTA arm (p = 0.46). There was more grade 3-4 hematologic toxicity, anemia (8.5%), 

thrombopenia (11.4 %) and neutropenia (5.71%), in the MTA arm, and skin rash 

(9.3%) and diarrhea (6.2%) in the ERL arm. 

Conclusions: These results in real-life setting suggest that ERL offers similar efficacy 

outcomes as MTA for p with nsNSCLC, with less and easier manageable toxicity. 


1343 MULTICENTER SURVEY FOR MANAGEMENT BEYOND 

PROGRESSION DISEASE WITH GEFITINIB IN NON-SMALL 


T. Sawa 1 , Y. Futamura 1 , J. Shindoh 2 , Y. Ohno 3 , S. Shigeki Satoh 4 ,O. 

Osamu Taguchi 5 , M. Morise 6 , Y. Hasegawa 7 

1 Cancer Center, Gifu Municipal Hospital, Gifu, JAPAN, 2 Respiratory Medicine, 

Ogaki Municipal Hospital, Ogaki, JAPAN, 3 Respiratory Medicine, Gifu University, 

Gifu, JAPAN, 4 Medical Oncology, Nagoya City University, Nagoya, JAPAN, 

5 Respiratory Medicine, Mie University, Tsu, JAPAN, 6 Respiratory Medicine, 

Nagoya University, Nagoya, JAPAN, 7 Respiratory Medicine, Nagoya University 

Graduate School of Medicine, Nagoya, JAPAN 

Purpose: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is 

effective in patients with activating EGFR mutations, and median time to progression 

in such patients is generally up to 12 months. Usually, treatment with EGFR-TKI is 

terminated when disease progression ( PD) is confirmed, while acute exacerbation 

after the withdrawal of EGFR-TKI has been reported. To investigate current clinical 

management beyond PD with gefitinib, multicenter survey was conducted in Japan. 

Objective: All patients with EGFR mutation-positive non-small cell lung lancer 

confirmed PD in the treatment of gefitinib in 2010, were included in this survey to 

evaluate patients characteristics, progression free survival and overall survival with 

gefitinib, selection of regimen beyond PD, and response rate. 

Result: From the six participating institute, 64 cases (median age 69 years old, exon19 

in 37 cases, exon18 in 25 cases, another type in 4 cases respectively) had been enrolled. 

Gefitinib has been used as first line in 35 cases, as second line in 25 cases, as 3rd line 

or more in 6 cases. Progression free survival was 13 months, and overall survival was 

33 months. In PFS and OS, there is no difference between first line and second line use 

with gefitinib. Response rate shows good efficacy in patients with good performance 

status. Beyond PD, gefitinib administration was continued in 9 cases (including 

additional combined therapy in 4 cases), and erlotinib was switched in 15 cases while 

platinum doublet in 2 cases, another monotherapy in 19 cases respectively. Response 

rate was shown 22.2% in gefitinib, 26.7% in erlotinib even beyond PD. 

Conclusion: In the patients with active EGFR mutation, it is confirmed that 

antitumor effectiveness is recognized in patients who continues to be treated under 

EGFR-TKI after progression of gefitinib. 


1344 IS CHANGE TO ANOTHER TREATMENT IMMEDIATELY AFTER 

FAILURE OF GEFITINIB RECOMMENDED IN PATIENTS 

HARBORING ACTIVATING EPIDERMAL GROWTH FACTOR 

RECEPTOR MUTATIONS? 

K. Asami1 , T. Okuma2 , T. Hirashima3 , M. Kawahara4 , T. Kawaguchi5 , K. Okishio5 , 

N. Omachi6 , N. Takeuchi1 1 2 

Clinical Oncology, Kinki-chuo Chest Medical Center, Sakai, JAPAN, Radiology, 

Kinki-chuo Chest Medical Center, Sakai, JAPAN, 3 Department of Thoracic 

Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic 

Diseases, Osaka, JAPAN, 4 Clinical Oncology, Federation of National Public 

Service Personnel Mutual Aid Associations, Otemae Hospital, Osaka, JAPAN, 

5 

Internal Medicine, Kinki-Chuo Chest Medical Center, Sakai-City, JAPAN, 

6 

Internal Medicine, National Hospital Organization Kinki-Chuo Chest Medical 

Center, Sakai, JAPAN 

Background: Gefitinib is an effective agent for use in treating patients suffering from 

non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor 

(EGFR) mutations. However, no optimal strategies have been established for treating 

these patients after gefitinib fails. Here, we conducted a retrospective study to assess 

the survival benefit of continued gefitinib treatment in these cases. 

Patients and methods: We analyzed gefitinib responders with activating EGFR 

mutations who developed progressive disease (PD) during the course of therapy. 

Prognostic variables were analyzed using a Cox proportional-hazards model. 

Results: Among the 146 patients retrospectively reviewed, exon-19 deletion 

mutations and L858R point mutations were detected in 78 and 68 patients, 

respectively. Median survival time after PD confirmation was 14.9 months (95% 

confidence interval [CI]: 7.9-21.9), and the median duration of continued gefitinib 

therapy beyond PD was 3.4 months. Statistical analysis showed that good 

performance status (0-1) (hazard ratio [HR]: 0.7), progression of previously evaluated 

lesion (HR: 0.6), and at least 3 months of continued treatment (HR: 0.4) were 

independent prognostic factors. 

Conclusion: Continuation of gefitinib beyond PD is an effective optional treatment 

in EGFR-mutated patients. 


1345 POST-PROGRESSION SURVIVAL AFTER ERLOTINIB 

TREATMENT IN PATIENTS WITH ADVANCED NSCLC 

M.P. Trojniak 1 , A.C. Palozzo 1 , S. Imbevaro 2 , P. Rescigno 2 , D. Pastorelli 3 , 

A. Jirillo 2 

1 Pharmacy Department, Istituto Oncologico Veneto, IRCCS, Padova, ITALY, 


Oncologico Veneto IRCCS, Padova, ITALY, 3 Medical Oncology II, Istituto 

Oncologico Veneto IOV-IRCCS, Padova, ITALY 

Erlotinib is a potent inhibitor of epidermal growth factor receptor tyrosin-kinase 

activity and its efficacy has been demonstrated for the treatment of advanced NSCLC 

in large randomized trials. A prospective observational study was run, using 

institutional data collected through web-based National Oncology registry, from 

December 2006 to May 2011. The patients with non-small cell lung cancer, 

unselected for EGFR mutation/amplification and after at least one line 

chemotherapy, were treated with erlotinib (150 mg/day orally) until disease 

progression. Every patient was checked prospectively for toxicity, clinical outcomes, 

previous line treatments, length of treatment and for treatments following erlotinb 

using hospital databases. In overall study population (130 patients), the median Time 

to Progression (TTP) and Overall Survival (OS) were 2.4 and 4.4 months, 

respectively and 1-year survival rate was 25%. 4 patients achieved partial response 

and 23 patients achieved stable disease, making the disease control rate 21%. Grade 

1-2 rash and diarrhoea were the most frequent adverse events. The subgroups 

analysis showed significantly improved OS for patients with chemotherapy 

post-erlotinib (pemetrexed, docetaxel) compared to those with no chemotherapy 

post-erlotinib, 12.7 months and 3.0 months (p < 0.0001), respectively. The main 

prognostic factors, such as age, sex, histology, ECOG performance status, smoking 

status, treatment line and the median time to relapse of previous line treatments were 

equally distributed between these two subgroups. The data of EGFR mutation and 

EGFR FISH positive status were available for 21% of the patients, however we did 

not find a significant association between EGRF expression and treatment response 

in both groups. This evaluation has revealed significantly better survival with 

chemotherapy post-erlotinib regardless of the EGFR expression, giving evidence of 

other existing mechanisms. The post-marketing studies in real life practice are 

needed in order to verify both effectiveness and safety in general population, testing 

for external validity of the randomized trials. The post-progression survival 

assessment may be crucial to determine real clinical impact of investigational drug in 

combination with other treatments as it usually lacks in the approval RCTs. 


1346 ERLOTINIB ROLE IN PRETREATED EGFR WILD TYPE 

CAUCASIAN PATIENTS: A RETROSPECTIVE OBSERVATIONAL 

STUDY 

B. Gori, E. Del Signore, A. Fulvi, S. Ricciardi, M.R. Migliorino, R. Belli, S. Condò, 

S. De Santis, A.M. Colacchi, F. De Marinis 

1st Oncological Pulmonary Unit, San Camillo High Specialization Hospital, Rome, 

ITALY 

Introduction: Erlotinib in UE was approved in unselected A-NSCLC patients (pts) 

(2nd/3rd line and switch maintenance) and in EGFR mutated pts. 

Methods: We conducted a retrospective mono-institutional observational study (Jan 

2007- May 2012) of Caucasian pts with A-NSCLC, all EGFR wild-type (WT), who 

received erlotinib in 2nd, 3rd, 4th, 5th line of therapy.191 pts with pretreated 

A-NSCLC were evaluated, including 108 (57%) treated with erlotinib as 2nd line and 

83 (43%) as 3rd/4th/5th line. All pts were considered for survival, analyzing some 

different clinical characteristics for pts in 2nd line. All pts received a CT scan 

evaluation every two months of treatment. 

Results: Of 108 pts who received erlotinib in 2nd line the median PFS was 8,4 weeks 

(wks) with an Overall Survival(OS) of 16,8 wks, of which 59 pts (55%) with ECOG 

PS 1 had mPFS of 12,6 wks and mOS of 21 wks, compared with 49 pts (45%) with 

PS 2-3 who had 4,2 wks of mPFS and 8,4 wks of mOS. Selecting pts according to 

clinical prognostic/predictive factors we obtained different groups: the best one was 


epresented by 19 pts (32%) female, adenocarcinoma, PS1, never/former smokers 

with a mPFS of 25,2 wks and mOS of 37,8 wks against the worst one defined by 7 

pts (12%) male, squamous, current smokers with mPFS of 8,4 wks and mOS of 16,8 

wks. In subsequent lines of therapy where the mPFS of 83 pts (43%) was 8.4 wks 

with a mOS of 21.0 wks, the PS played a decisive role: PS 1 63 pts (76%) showed 

respectively 12,6 wks and 25,2 wks of mPFS and mOS respect of 4,2 wks and 8,4 wks 

of 20 pts (24%) with PS 2-3. 

Conclusions: 90% of the Caucasian patients do not express the EGFR mutation, 

estimated to date in no more than 50-60% of patients diagnosed with A-NSCLC. 

Erlotinib is a standard treatment in 2nd / 3rd line, without adequate studies 

comparing with chemotherapy in wild-type population. This retrospective analysis, 

original for the assessment of EGFR mutational status and for the large number of 

cases, confirms the predictive/prognostic role of the PS 1 for the WT EGFR pts treated 

with erlotinib across all the lines ( p = .0001), limiting the advantage in the PS 2/3. 

Moreover, the results of the 2nd line shows that it is possible to identify a group of WT 

pts with positive predictive characteristics (PS 1, ADC, never / former smokers, 

female) to receive a greater benefit in survival (p= .03) with the use of erlotinib. 


1347 EGFR-TYROSINE KINASE INHIBITOR TREATMENT BEYOND 

PROGRESSION IN LONG-TERM RESPONDERS TO ERLOTINIB 

IN ADVANCED NON-SMALL CELL LUNG CANCER: 

RELEVANCE OF EGFR MUTATION STATUS 

M. Faehling 1 , R. Eckert 2 , T. Kamp 3 , J. Sträter 4 , G. Ott 5 , W. Spengler 6 

1 Klinik für Kardiologie und Pneumologie, Klinikum Esslingen, Esslingen, 

GERMANY, 2 Oncology Group Practice, Wendlingen, GERMANY, 3 Oncology, 

Oncology Group Practice, Wendlingen, GERMANY, 4 Pathologie, Institut für 

Pathologie, Esslingen, GERMANY, 5 Pathology, Robert Bosch Krankenhaus, 

Stuttgart, GERMANY, 6 Medizinische Klinik II, Universitätsklinik Tübingen, 

Tübingen, GERMANY 

Introduction: Some patients with advanced NSCLC show prolonged disease 

stabilization on treatment with an EGFR-tyrosine kinase inhibitor (TKI) such as 

erlotinib. It is not clear how to treat patients who progress after prolonged response 

to erlotinib. We hypothesized that TKI therapy beyond progression with added 

chemotherapy, radiotherapy or best supportive care may improve survival. 

Patients and methods: We retrospectively analyzed all NSCLC patients treated with 

erlotinib at our institutions since 2004 who progressed after at least stable disease on 

erlotinib for at least six months. The first 16 patients did not receive further TKI 

treatment after progression (controls). The following 25 patients were treated with 

TKI beyond progression (TKI patients). Overall survival (OS) was analyzed for the 

whole population, a case-control analysis of pairs matched for gender, smoking 

status, histology, best response to first TKI therapy, and therapy line. Furthermore, 

OS of patients with known EGFR-mutation status (n = 24) and those treated with 

pemetrexed (n = 21) is reported. 

Results: Treatment with TKI and chemotherapy was well tolerated. TKI-patients had 

a significantly longer OS from progression on TKI (case control: median 14.5 vs. 2.0 

months, HR 0.154) and longer OS from diagnosis of lung cancer (case control: 

median 54.5 vs. 28.3 months, HR 0.474). Patients with an activating EGFR mutation 

had prolonged survival compared with patients without an activating EGFR 

mutation. However, both in patients with and without an activating EGFR mutation, 

patients treated with erlotinib beyond progression had a longer survival. 

Conclusions: In our case-control analysis in long-term erlotinib responders, 

treatment with TKI beyond progression in addition to chemotherapy or radiotherapy 

was feasible and lead to prolonged overall survival. A prolonged survival with 

erlotinib beyond progression was observed in both EGFR-mutation positive and 

negative long-term responders to erlotinib. 


1348 EFFICACY OF CHEMOTHERAPY (CHT) BEYOND TYROSINE 

KINASES INHIBITORS (TKI) IN ADVANCED NON SMALL CELL 

LUNG CANCER (NSCLC) PATIENTS (PTS) UNSELECTED FOR 

EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) MUTATION 

P. Trenta 1 , R. Iacovelli 1 , A. Palazzo 1 , D. Pellegrino 2 , C. Mosillo 2 , F. Rubini 2 , 

A. Prete 2 , V. Magri 2 , A. De Benedetto 2 , E. Cortesi 2 


of Rome, Rome, ITALY, 2 Department of Radiology, Oncology and Human 

Pathology, Policlinico Umberto I, Rome, ITALY 

Background: After failure of a second or third line therapy with TKI, many 

clinicians offer to their advanced NSCLC pts a new line of cht, even if there are no 

perspective trials that support this choice. We report our experience about cytotoxic 

treatment administered after a target therapy with Erlotinb or Gefitinib in pts with 

unknown EGFR mutational status or EGFR wild type. 

Patients and methods: Since January 2003 to December 2011, 84 pts received TKI 

in second or third line and after progression 34 of them were treated with at least 

one subsequent line of cht. We collected response data, analyzed overall survival 


(OS) and progression free survival (PFS) of cht beyond TKI with Kaplan-Meier 

method and correlated them with Disease Control (DC) and PFS of first line cht and 

TKI using log-rank test. 

Results: 29 out of 34 pts received cht as third and 5 pts as forth line treatment. 67,6 

% of pts received a monotherapy, while 32,4% a combination treatment, platinum 

based in 7 cases. A response rate (RR) of 20,5% and a DC rate of 52,9% were 

registered. Median OS post-TKI and PFS were 13 (95% C.I. 6,36-19,63) and 3 

months (mos) (95% C.I 0,5-5,5) respectively. OS of pts who obtained DC during TKI 

was 18,2 mos compared to 5,7 mos of pts not responder to target treatment (p = 

0,019). At univariate analysis good PS(≤1) after TKI (p = 0,022), DC (p = 0,025) and 

PFS > 6 mos with first line cht(p = 0,002) were found to be the only predictive 

factors of a better PFS with post-TKI cht. At multivariate analysis only the PFS > 6 

mos with first line cht was confirmed as an independent predictive factor of better 

PFS in post-TKI setting (p = 0,05). Age more or less than 65 years (p = 0,7) use of 

combination (p = 0,84) and platinum-based therapy (p = 0,75) seems not to improve 

survival outcome and DC of cht beyond TKI. 

Conclusions: DC with TKI identify a good prognostic group of pts. Good and 

prolonged response (> 6 mos) to the first line cht and a PS ≤1 are useful predictive 

factors to select pts who could benefit from receiving a cytotoxic treatment after 

target agents failure. Aggressive cht strategies do not seem to produce a real 

advantage in this setting. 


1349 SORAFENIB IN ADVANCED NON-SMALL-CELL LUNG 

CANCER: A RETROSPECTIVE ANALYSIS OF PATIENTS IN 

PROGRESSION AFTER TWO OR MORE LINES OF THERAPY 

S. Vazquez-Estevez 1 , S. Varela 2 , B. Campos 2 , R. Garcia-Campelo 3 , E. Alvarez 2 , 

G. Quintero 2 , L. Anton-Aparicio 4 , J.R. Mel 2 

1 Oncology, Hospital Universitario Lucus Augusti, Lugo, SPAIN, 2 Oncoloxia 

Médica, Hospital Universitario Lucus Augusti de Lugo, Lugo, SPAIN, 3 Oncology, 

Complejo Hospitalario Universitario A Coruña, A Coruña, SPAIN, 4 Medical 

Oncology, Complejo Hospitalario A Coruña, A Coruña, SPAIN 

Background: Sorafenib (SOR) is a potent inhibitor of c-Raf, b-Raf VEGFR-1/2/3 and 

PDGFR-β. In NSCLC, proliferative signaling through the Ras/Raf/MEK/ERK pathway is 

often activated from K-ras mutations. Their efficacy as monotherapy for treating advanced 

NSCLC has been demonstrated in several trials. In them, SOR improved the rate of disease 

stabilization in patients who had previously been treated with chemotherapy. Our 

objective is to confirm the clinical and safety results in daily clinical activity. 

Methods: Between October 2008 and December 2011, 16 Caucasian patients with 

metastatic NSCLC and measurable disease were treated after having received two or 

more prior lines of therapy for metastatic disease.SOR was administered at a starting 

dose of 400 mg bid continuously in 28-day cycles.The primary end-point was 

Progression Free Survival (PFS). The secondary end-points were Overall Survival 

(OS) and Response Rate (RR). 

Results: Median age was 59 years (40-86). 100% patients were PS (ECOG) 0/1 (5/11, 

31/69%). Most were males (n = 10, 62%). The predominant histologic type was 

adenocarcinoma (n = 10, 62%). Thirteen (81%) patients were in stage IV at diagnosis. 

The predominant metastatic sites were lung (n = 9, 56%), lymph nodes, (n = 6, 38%), 

pleura (n =3, 19%) and bone (n = 3, 19%) Patients received a median of 3 (range: 2 

to 4) treatment lines prior to the SOR regimen; Eleven (68.8%) patients received at 

least 3 treatment lines before SOR. The median duration of the SOR regimen was 

114 days (9-247).Median PFS and median OS were 2.8 and 3.3 months, respectively. 

After administration of SOR, 2 patients (13%) had a partial response and 5 (33%) 

had stable disease. The toxicity profile was mild. Adverse events CTC G3/4 were 

dyspnea (n = 4, 25%), skin toxicity (n = 1, 6%) and vomiting (n = 1, 6%). In 1 case, 

treatment was interrupted by non-hematological toxicity. 

Conclusions: Patients with advanced NSCLC receiving SOR after two or more lines of 

therapy got a 2.8 and 3.3 months median PFS and OS, respectively, with a 46% Disease 

Control Rate and with an acceptable safety profile. While still waiting for the results of 

ongoing trials, SOR is active and safe in this widely treated patient population. 


1350 METASTATIC NSCLC OUTCOMES AT A SINGLE CANADIAN 

INSTITUTION OVER A DECADE 

S. Otsuka, W. Boland, D. Hao, D. Morris, D.G. Bebb 

Oncology, Tom Baker Cancer Centre/University of Calgary, Calgary, AB, 

CANADA 

Background: In the past 10 years, the standard of care in non small cell lung cancer 

has seen the adoption of several less toxic and better tolerated therapies, allowing a 

greater proportion of metastatic patients the opportunity to receive 2 nd and even 3 rd 

line treatment. We investigated whether this improvement in the number of available 

therapies for metastatic NSCLC had any bearing on overall patient survival, by 

retrospectively analyzing patients diagnosed in 1999, 2004 and 2009 at our centre. 

Methods: Demographic details, clinical variables and outcome data were gathered 

retrospectively via chart review, on NSCLC patients diagnosed at the Tom Baker 



Cancer Centre (TBCC) in 1999, 2004 and 2009 (Glans-Look Lung Cancer Database). 

All patients were restaged according to the new 7th Edition of the American Joint 

Committee on Cancer TNM system for NSCLC staging. Survival was analyzed using 

the Kaplan-Meier method and differences measured by a log rank test. 

Results: 807 patients were included in the analysis (649 who were stage IV at 

diagnosis, 158 who recurred with metastatic disease). Of these patients, 22.1% 

received palliative systemic therapy (18.9% in 1999, 23.0% in 2004 and 23.1% in 

2009). During this time, the proportion of patients who received 2 or more lines of 

treatment almost doubled (6.9% in 1999, 9.0% in 2004 and 12.7% in 2009). In 

addition, there was a trend towards increasing median overall survival (MOS) of 

systemically treated patients over 1999-2009, from 10.8 months (95% CI: 8.4-13.3) in 

1999 to 14.7 months (95%CI: 9.6-14.4) in 2009 (p = 0.2). 

Conclusions: Our analysis suggests that there is an increasing proportion of metastatic 

NSCLC patients being treated systemically at our centre, specifically, the proportion of 

patients being treated with two or more lines of systemic therapy has increased over 

the decade from 1999-2009. This study also suggests a trend toward an increased MOS 

for systemically treated patients diagnosed in 2009 compared to those diagnosed in 

1999. However, the vast majority of patients (>3/4) are still not being treated with 

systemic therapy, despite the increase in available therapies now compared to a decade 

ago. The reasons for this are not clear but may include poor ECOG performance 

status, rapid decline, sub-optimal referral pathways and rural residence. 


1351 DOES ELIGIBILITY FOR BEVACIZUMAB (BV) LEAD TO 

SELECTION BIAS? 

Y. Takagi 1 , A. Toriihara 2 , Y. Hosomi 1 , Y. Nakahara 1 , M. Akahane 1 , Y. Okuma 1 , 

M. Iguchi 1 , T. Okamura 1 , M. Shibuya 1 

1 Department of Thoracic Oncology and Respiratory Medicine, Tokyo 

Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 

Tokyo, JAPAN, 2 Department of Radiology, Tokyo Medical and Dental University, 

Tokyo, JAPAN 

Background: Eligibility is often narrowed in clinical trials of targeted drugs 

because of specific adverse effects. Modified eligibility criteria can affect endpoints 

such as overall survival independently of the actual effect of an investigational 

drug. 

Methods: Patients with stage IIIB/IV, non-squamous non-small cell lung cancer 

(NSCLC) who started chemotherapy from 2005 to 2009 were reviewed. 

Bevacizumab (BV) was first used to treat lung cancer at our institution in 2010. 

We divided patients into BV-eligible (A) and -ineligible (B) groups. To estimate 

survival, Kaplan-Meier curves were calculated and compared between the groups 

using the log-rank test. We also examined the prognostic impact of age, gender, 

M factor, performance status (PS), use of platinum in first-line chemotherapy, 

history of hemoptysis, major blood vessel invasion (MVI) by the tumor and 

clinically significant cardiovascular disease upon overall survival using the Cox 

proportional hazards model. A radiologist who was blinded to the clinical 

outcomes evaluated MVI. All tests were two sided with a significance level of 

0.05. 

Results: Among 576 patients with lung cancer who undergone chemotherapy at 

our department, 283 of them had stage IIIB/IV non-squamous NSCLC. After 

excluding 15 patients with indications for combined chemoradiotherapy and 22 

with PS 3/4, the eligibility of 246 patients for BV was finally evaluated. 

Eighty-nine patients were considered ineligible for BV (cohort B), based on one or 

more of a history of hemoptysis (N = 32), MVI (N = 64) and cardiovascular 

disease (N = 13). Eligibility could not be determined in ten patients and the 

remaining 147 patients were classified into cohort A. Overall survival was 

significantly better in cohort A (median, 14.9 months) than in cohort B (median, 

8.6 months; hazard ratio, 0.55; 95%CI, 0.42-0.74; P < .0001). Multivariate analysis 

indicated that gender, PS, a history of hemoptysis and MVI are significant 

prognostic factors. 

Conclusion: Eligibility for BV itself is a powerful prognostic factor for patients with 

non-squamous NSCLC. 


1352 CLINICAL PROFILE AND PATTERNS OF PROGRESSION (PD) 

OF PATIENTS (PTS) WITH ADVANCED NON-SQUAMOUS 

NON-SMALL CELL LUNG CANCER (NSNSCLC) TREATED 

WITH FIRST LINE BEVACIZUMAB (B): AVVA STUDY 

J. De Castro 1 , J.M. Garcia-Bueno 2 , M. Domine 3 , S. Saura 4 , R. Garcia-Gomez 5 , 

M. Sereno 6 , O. Juan 7 , E. Pujol 8 , B. Rubio 9 , M. Cobo 10 

1 Medical Oncology, Hospital Universitario La Paz, Madrid, SPAIN, 2 Oncology 

Deparment, Hospital General de Albacete, Albacete, SPAIN, 3 Oncology, 

Fundacion Jeminez DiazClin Nstra Senora de la Concepcion, Madrid, SPAIN, 

4 Medical Oncology, Hospital Universitario Dr. Negrin, Las Palmas de Gran 

Canaria, SPAIN, 5 Medical Oncology, Hospital General Universitario Gregorio 

Marañon, Madrid, SPAIN, 6 Medical Oncology, Hospital Infanta Sofia, Madrid, 

SPAIN, 7 Medical Oncology, Hospital Arnau de Vilanova, Valencia, SPAIN, 

8 Medical Oncology, Hospital Santa Barbara, Soria, SPAIN, 9 Medical Oncology, 

Centro Integral Oncológico Clara Campal, Madrid, SPAIN, 10 Medical Oncology, 

Hospital Regional Universitario Carlos Haya, Malaga, SPAIN 

Background: B in combination with platinum doublets prolongs survival and delays 

PD in chemo-naïve pts with advanced nsNSCLC and its safety profile has been 

widely described in clinical trials. In this study we aim to evaluate the behavior, 

clinical profile and patterns of PD of real-life nsNSCLC pts treated with B in 44 

Spanish institutions. 

Methods: AVVA is a multicenter, epidemiological study to define the clinical profile 

(gender, age, PS, histology, stage, comorbidities, tumor load, Tx, response and 

tolerability) and describe the patterns of PD. Pts diagnosed with advanced nsNSCLC 

and evidence of PD after treatment (Tx) with standard chemotherapy (CT) plus B 

up to 6 cycles followed by maintenance B were included. 

Results: Data of 158 pts are presented. Clinical profile was: median age 58 years 

(range 34-79); male 65%; stage IV 91%; adenocarcinoma 77%; ECOG PS 0/1/ ≥ 2 

(%): 35/56/9; never/current/former smokers (%): 23/40/37. 64% of pts presented 

relevant concomitant disease at baseline (27% cardiovascular disease, 24% pulmonary 

disease). Tx received: B plus carboplatin-doublet/cisplatin-doublet/other (%) 70/25/5. 

Median no. of cycles for CT/B: 6/9. Patterns of PD: 44% presented high tumor load 

(tumor diameter ≥55mm and ≥5 lesions); 97% of pts presented intra-thoracic 

disease, 53% presented extra-thoracic disease and 13% only pulmonary disease. High 

tumor load was associated with extra-thoracic disease (p < 0.05). ORR was 53% (95% 

CI: 45-61) and disease control rate was 85%. Best response was achieved after a 

median of 4 cycles (range 1-16). ECOG 0/1 at PD (%): 15/50. Median PFS was 7.7 

months (95% CI: 7.3-8.1). No differences were found in ORR or PFS according to 

tumor load and intra/extra-thoracic disease. Grade 3/4 toxicities were: venous 

thrombosis (3.2%/0), proteinuria (0.6%/0), hemoptysis (0.6%/0), pulmonary 

embolism (0/0.6%) and mucositis (0.6%/0). 

Conclusions: B was effective in this real-life patients’ population, irrespective of 

tumor load and location of the disease. These results confirm the well-established 

safety profile and the efficacy of B as frontline Tx in nsNSCLC. 


1353 PHASE II TRIAL OF BEVACIZUMAB PLUS DOCETAXEL IN 

PATIENTS WITH PREVIOUSLY TREATED NON-SQUAMOUS 


F. Ohyanagi, K. Kudo, N. Yanagitani, A. Horiike, T. Horai, M. Nishio 

Thoracic Oncology Center, Cancer Institute Hospital, Japanese Foundation for 

Cancer Research, Tokyo, JAPAN 

Background: The additional effects of bevacizumab (B) as a first line chemotherapy 

for non-squamous (Nsq) non-small cell lung cancer (NSCLC) have been established. 

However, its efficacy as a second line or higher chemotherapeutic agent is not 

sufficiently investigated. Docetaxel (D) is a standard second line therapy for NSCLC, 

and the synergistic effects of a combination of D and B (D + B) have been 

demonstrated in preclinical models. Therefore, this phase II study evaluated the 

efficacy and safety of D + B in patients with previously treated Nsq NSCLC. 

Methods: Patients with histologically or cytologically confirmed Nsq NSCLC (20–74 

years) with an Eastern Cooperative Oncology Group performance status (PS) of 0-2 


and at least one prior course of chemotherapy were eligible for the study. Patients 

were treated with D (60 mg/m 2 ) and B (15 mg/kg) on day 1, which was repeated 

every 3 weeks until progressive disease (PD) or unacceptable toxicity occurred. The 

primary endpoint was the response rate (RR). 

Results: Between May 2010 and July 2011, 28 patients were enrolled in the study (16 

males/12 females; median age, 65 years; PS, 0/1/2: 19/9/0; adeno/other: 22/6; number 

of prior chemotherapy regimens, 1/2/3/4/5: 16/5/2/1/4). Of these, 28 patients were 

included in the analysis of toxicities and 27 were evaluated for their response. An 

objective response was observed in 18 patients (partial response, 18; stable disease, 8; 

PD, 1). RR and disease control rate were 66.7% and 96%, respectively. After a 

median follow-up of 15.7 months, the median progression-free survival was 7.2 

months and median overall survival was 16.7 months. The main toxicity observed 

was myelosuppression (grade 3/4 neutropenia, 85.7%; febrile neutropenia, 21%). Mild 

nonhematological toxicity with minimal bleeding was also observed. 

Conclusions: A combination of D and B was highly active in patients with 

previously treated Nsq NSCLC; further study is warrented. 


1354 PHASE II TRIAL OF SINGLE-AGENT PEMETREXED IN 

CHEMONAIVE ELDERLY PATIENTS WITH ADVANCED 

NON-SMALL-CELL LUNG CANCER (NSCLC) AND ITS 

ACCRUAL RATE IN A COMMUNITY-BASED CLINICAL TRIAL 

GROUP: LCEN1001 

N. Seki 1 , T. Yokoyama 2 , K. Kishi 3 , T. Takao 4 , I. Tsujino 5 , N. Takahashi 5 , 

H. Yoshifumi 5 , S. Maho 6 , S. Morita 6 , K. Eguchi 1 

1 Division of Medical Oncology, Department of Internal Medicine, Teikyo University 

School of Medicine, Tokyo, JAPAN, 2 Department of Respiratory Medicine, Kyorin 

University Hospital, Tokyo, JAPAN, 3 Dept. of Respiratory Medicine, Toranomon 

Hospital, Tokyo, JAPAN, 4 Division of Respiratory Medicine, Itabachi Chuo 

Medical Center, Itabashi, JAPAN, 5 Respiratory Medicine, Nihon University School 

of Medicine, Tokyo, JAPAN, 6 Biostatistics and Epidemiology, Yokohama City 

University Medical Center, Yokohama, JAPAN 

Background: Optimal treatment for elderly patients with advanced NSCLC has been 

under investigation. This study evaluated the safety and efficacy of single-agent 

pemetrexed for elderly patients with advanced NSCLC. Moreover, the reasons that 

prevented accrual and the preferential regimen for such patients in a 

community-based group were investigated. 

Patients and methods: Chemonaive elderly (≥ 70 years) patients with stage IIIB/IV 

non-squamous NSCLC received 500 mg/m2 of pemetrexed (day 1, every 3 weeks) for 

4-6 cycles. As a QOL assessment, FACT-L lung cancer symptom subscale and 

Comprehensive Geriatric Assessment were also evaluated. Moreover, clinical trial 

enrollment decisions were noted. 

Results: From May 2010 to October 2011, 193 consecutive patients were diagnosed 

as chemonaive elderly (≥ 70 years) patients with stage IIIB/IV non-squamous 

NSCLC. Among them, 25 patients were enrolled in phase II trial. Characteristics 

were m/f, 19/6; median age, 78 years (range 70-89); PS 0/1/2, 6/18/1; stage IIIB/IV, 6/ 

19. After a median of 4 cycles of pemetrexed, the ORR and DCR were 16.0% and 

68.0%, respectively. Furthermore, the median PFS was 126.0 days and the median OS 

was not reached. Grade 3/4 hematologic toxicity consisted of leukopenia (20%), 

neutropenia (24%), thrombocytopenia (4%), and anemia (12%), whereas grade 3/4 

nonhematologic toxicity consisted of nausea (4%), anorexia (12%), fatigue (8%), 

pneumonitits (G3, 8%), febrile neutropenia (0%), and treatment-related death (0%). 

Among 168 patients who were not enrolled in the trial, 83 and 85 patients were 

eligible and ineligible, respectively. Therefore, the accrual rate was 25 (23.1%) of 108 

eligible patients and 25 (13.0%) of total 193 patients, whereas ineligible rate was 85 

(44.0%) of total 193 patients. The most common reason for not participating in the 

trial despite appropriate eligibility was the preference of platinum doublet 

chemotherapy (57.8%), whereas the most common treatment choice for ineligible 

patients was best supportive care (67.1%). 

Conclusions: Single-agent pemetrexed has shown moderate activity and is well 

tolerated as first-line treatment for advanced NSCLC in elderly patients. However, in 

our community-based clinical trial group, platinum doublet chemotherapy was the 

preferential regimen for such patients. 



1355 ERYTHROCYTE MEAN CORPUSCULAR VOLUME CHANGE 

DURING PEMETREXED TREATMENT IN ADVANCED NON 

SMALL CELL LUNG CANCER PATIENTS 

S. Buti 1 , P. Bordi 1 , M. Tiseo 2 , S. Panni 3 , S. Novello 4 , E. Bria 5 , S.G. Rapetti 6 , 

S. Pilotto 7 , R. Camisa 1 , A. Ardizzoni 1 

1 Oncologia Medica, Azienda Ospedaliero-Universitaria di Parma, Parma, ITALY, 

2 Oncologia Medica, Azienda Ospedaliera di Parma, Parma, ITALY, 3 Oncologia, 

Azienda Istituti Ospitalieri di Cremona, Cremona, ITALY, 4 Department of Clinical 

and Biological Sciences - Thoracic Oncology Unit, Azienda 

Ospedaliero-Universitaria ASOU San Luigi Gonzaga, Orbassano (TO), ITALY, 

5 Medical Oncology, Azienda Ospedaliera Universitaria Integrata Verona - “Borgo 

Roma”, Verona, ITALY, 6 Department of Clinical and Biological Sciences - 

Thoracic Oncology Unit, Azienda Ospedaliero-Universitaria ASOU San Luigi 

Gonzaga, Orbassano, ITALY, 7 Medical Oncology, Azienda Ospedaliera 

Universitaria Integrata Verona-”Borgo Roma”, Verona, ITALY 

Introduction: Pemetrexed (Pem) has been approved for the treatment of advanced 

non small cell lung cancer (NSCLC) non-squamous histology, both as 1° and 2° line 

therapy with or without platinum compounds, respectively. Pem is an antimetabolite 

drug, that inhibits enzymes involved in nucleotides bio-synthesis arresting cancer 

cells cycle. Literature data show the effect of antimetabolities on increment of 

erythrocyte mean corpuscolar volume (MCV) in cancer patients (pts) treated with 

capecitabine and, recently, a positive correlation between increased MCV and 

response to capecitabine-based therapy has emerged [Arslan et al, Tumori 2011; 

Dellapasqua et al, Breast 2012]. The aim of this study was the evaluation of the 

impact of Pem on MCV change and its possible correlation with disease control rate 

(overall response + stable disease rate) (DCR), progression free survival (PFS) and 

overall survival (OS) in NSCLC pts. 

Methods: A retrospective collection of clinical and laboratory data (including basal 

MCV and maximum MCV occurred during Pem therapy) in 165 advanced NSCLC 

pts treated with Pem from 4 Italian centres was performed. 

Results: Pts characteristics: 59% men, median age 64 years (range 36-83), 58% 

ECOG PS 0, 90% stage IV and 10% stage IIIB (according 6 th TNM), 87% 

adenocarcinoma histotype, 74% current or ex-smokers, 59% as 1° line, 41% as ≥ 2° 

line, 68% in combination with a platinum compound, median cycle 4 (range 1-29). 

All pts received vitamin B 12 and folic acid supplementation. Mean MCV significantly 

increased from basal (89.6 fl) to “during treatment” (94.8 fl), with mean ΔMCV = 5.2 

fl (t test for paired data, p < 0.0001). The median time from therapy start to 

maximum MCV was 2.3 months (mos). DCR was 84% and 62% [χ 2 test, p = 0.002], 

median PFS was 6.9 [CI95% 5.7-8.1] and 3.6 [CI95% 1.9-5.3] mos [p = 0.0019], and 

median OS was 16.0 [CI95% 7.9-24.1] and 10.8 [CI95% 9.0-12.6] mos [p = 0.0346], 

in ΔMCV > 5 fl (n = 68) and in ΔMCV ≤ 5 fl (n = 97) pts, respectively. 

Conclusion: Pem induces significant increase of erythrocyte MCV. ΔMCV > 5 fl on 

Pem therapy appears to be correlated with better DCR, PFS and OS. These data 

should be related to a decreased metabolism of Pem and subsequent increased drug 

exposure in pts who develop higher ΔMCV during treatment. A larger prospective 

evaluation could be useful to better clarify these findings. 


1356 PHASE II STUDY OF PEMETREXED IN ELDERLY (≥75) 

NON-SQUAMOUS NON-SMALL-CELL LUNG CANCER: KYOTO 

THORACIC ONCOLOGY RESEARCH GROUP TRIAL 0901 

Y.H. Kim 1 , M. Hirabayashi 2 , S. Kosaka 3 , J. Nikaidoh 2 , Y. Yamamoto 3 , 

M. Shimada 2 , T. Toyazaki 3 , H. Nagai 1 , M. Mishima 1 

1 Respiratory Medicine, Kyoto University-Graduate school of medicine, Kyoto, 

JAPAN, 2 Respiratory Medicine, Hyogo Prefectural Amagasaki Hospital, 

Amagasaki, JAPAN, 3 Thoracic Surgery, Shimane Prefectural Central Hospital, 

Izumo, JAPAN 

Background: Single-agent chemotherapy with non-platinum agents, such as 

vinorelbine, gemcitabine, and docetaxel (DOC), is considered to be a standard 

therapeutic option for elderly non-small-cell lung cancer (NSCLC). Previous 

randomized trials have reproducibly demonstrated that pemetrexed (PEM) is more 

effective for non-squamous NSCLC, in contrast to be less effective for squamous cell 

lung cancer. In addition, although in second-line setting, subgroup analysis of the 



phase III study comparing PEM with DOC suggested that PEM was superior to 

DOC in the elderly population (≥70) in terms of both efficacy and toxicity. 

Patients and methods: This was a single-arm phase II study of PEM in elderly 

(≥75) Japanese patients with chemo-naive advanced non-squamous NSCLC. 

Patients received four cycles of PEM (500 mg/m 2 ) every 3 weeks. The primary 

endpoint was the response rate, and secondary endpoints were safety and 

survival. 

Results: Twenty-eight patients were enrolled between January 2010 and April 2012. 

Patient characteristics were as follows: male/female: 14/14; median age: 77 yr (75-88); 

histology, Ad/La: 27/1; disease stage, IIIB/IV: 6/22; PS, 0/1: 7/21. Five patients were 

still under protocol treatment, and 23 patients were evaluable for both safety and 

efficacy. There were 0 CR, 7 PR, 10 SD, 5 PD, and 1 NE. Response rate and disease 

control rate were 30.4% and 73.9%, respectively. Median treatment cycles were four. 

Grade 3/4 toxicity rates were 21.7% for leukocytopenia, 26.1% for neutropenia, 4.3% 

for anemia, 8.7% for thrombocytopenia, and 8.7% for nausea/vomiting, respectively. 

Four patients required G-CSF treatment, but no patients required blood transfusion. 

There were no treatment-related deaths. 

Conclusions: PEM was safe and effective in elderly (≥75) Japanese patients with nonsquamous 

NSCLC. Final results, including survival data, will be presented at the meeting. 


1357 VERY ELDERLY INOPERABLE NSCLC PATIENTS ABOVE 75 

YEARS COMPARED TO YOUNGER PATIENTS: EQUAL 

ACTIVITY OF PLATINUM-BASED DOUBLET CHEMOTHERAPY 

BUT HIGHER TOXICITY 

J.N. Jakobsen, S. Wallerek, S.A. Jensen, J.B. Sorensen 

Department of Oncology, Rigshospitalet, Copenhagen University Hospital, 

Copenhagen, DENMARK 

Purpose: Tolerability and activity of platinum-based doublet chemotherapy was 

examined in very elderly inoperable NSCLC patients aged >75 years and compared 

to younger patients. 

Patients and methods: Chemotherapy naïve inoperable NSCLC patients aged > 18 

years with no upper age limit received Carboplatin AUC 5 and Vinorelbine (VNB) 

25 mg/m2 day 1 and VNB 80 mg/m2 orally day 8 q 3 weeks for maximum 6 courses 

without g-csf. They were divided in group A being 70 years, group B 70-75 years, 

and group C > 75 years. 

Results: A total of 135 patients received 530 treatment courses (group A 70 patients, 

group B 40 patients, and group C 25 patients). There were no differences in 

pre-treatment characteristics such as gender, histologic subtype, performance status, 

weight loss, or stage. The median age (with range), and frequencies of performance 

status 2, stage IV, and subsequent 2nd line chemotherapy were in group A 59.8 years 

(36-69), 23%, 69%, and 39%, in group B 72.3 years (70-75), 25%, 60%, and 23%, and 

in group C 78.0 years (76-84), 20%, 60%, and 12%, respectively. The frequencies of 

grade 4 and grade 3 and 4 leucopenia were 32% and 48% in group C and 6% and 

23% in group A, respectively (p = 0.001, p = 0.018) and the frequency of febrile 

neutropenia in C (20%) and in A (7%) (p = 0.072). There were no toxic deaths. 

Response rates for groups A, B, and C were 33%, 34%, and 44% and median 

survivals (with range) were 35 weeks (1-336), 42 weeks (0-104+), and 58+ weeks 

(7-296), respectively (not significant). Median times to progression were 19, 29, and 

16 weeks, respectively. 

Conclusions: Very elderly patients aged > 75 years could receive similar number 

of treatment courses as younger patients and with similar level of toxicity except 

for leucopenia and febrile neutropenia, which were more frequent in the very 

elderly compared to the younger groups. The activity of Carboplatin and 

Vinorelbine was statistically similar between age groups, though with a 

remarkable trend towards higher disease control rate (NC + PR + CR) among the 

elderly and very elderly. Platinum-based doublet chemotherapy is feasible and 

highly active in very elderly NSCLC patients but require close hematologic 

monitoring. The use of bone marrow stimulating treatment may be considered to 

diminish toxicity in this population. 


1358 OUTCOMES FOR ELDERLY, ADVANCED–STAGE NON-SMALL 

CELL LUNG CANCER (NSCLC) PATIENTS TREATED WITH 

AMRUBICIN (AMR) AS THIRD-LINE OR FOURTH-LINE 

CHEMOTHERAPY: ANALYSIS OF HOKKAIDO LUNG CANCER 

CLINICAL STUDY GROUP TRIAL (HOT) 0901 

S. Oizumi 1 , T. Harada 2 , K. Takamura 3 , S. Sugawara 4 , M. Maemondo 5 , Y. Fujita 6 , 

I. Kinoshita 7 , H. Dosaka-Akita 7 , H. Isobe 8 , M. Nishimura 9 

1 First Department of Medicine, Hokkaido University School of Medicine, 

Sapporo, JAPAN, 2 Center for Respiratory Disease, Hokkaido Social Insurance 

Hospital, Sapporo, JAPAN, 3 First Department of Medicine, Obihiro-Kosei 

General Hospital, Obihiro, JAPAN, 4 Department of Respiratory Medicine, Sendai 

Kousei Hospital, Sendai, JAPAN, 5 Department of Respiratory Medicine, Miyagi 

Cancer Center, Natori, JAPAN, 6 Department of Respiratory Medicine, National 

Hospital Organization Asahikawa Medical Center, Asahikawa, JAPAN, 

7 Department of Medical Oncology, Hokkaido University Graduate School of 

Medicine, Sapporo, JAPAN, 8 Department of Medical Oncology and Respiratory 

Medicine, KKR Sapporo Medical Center, Sapporo, JAPAN, 9 First Department of 

Medicine, Hokkaido university School of Medicine, Sapporo, JAPAN 

Background: HOT0901 trial evaluated the efficacy and safety of AMR, 

third-generation synthetic anthracycline agent, for NSCLC patients as third-line or 

fourth-line chemotherapy. We conducted a subset analysis of HOT0901 to determine 

the outcome for elderly patients. 

Methods: Eligible patients had a performance status 0 to 2, failure of second-line or 

third-line chemotherapy, and adequate organ function. Patients received AMR 35 mg/m 2 

intravenously on days 1-3 every 3 weeks. The primary endpoint was disease control rate 

(DCR: CR + PR + SD). Secondary endpoints were overall survival (OS), progression-free 

survival (PFS), response rate (CR + PR), and toxicity profile. Elderly patients were defined 

as those at least 70 years of age at the time of enrollment. The efficacy and safety data for 

AMR therapy was compared between the elderly and younger patients (< 70 years). 

Results: There were 14 elderly and 27 younger patients in this study. Elderly patients 

accounted for 34% of the study cohort. Clinical characteristics such as PS or histologic 

subtypes were similar between the groups. The median number of treatment cycles was 

3 in elderly and 2 in younger patients. The overall response rate and DCR were 14.3% 

and 71.4% in elderly patients and 7.4% and 55.5% in younger patients, respectively (p = 

0.42 and 0.26). Median PFS was 3.6 and 2.4 months (p = 0.70), whereas median survival 

time was 11.3 and 13.9 months (p = 0.67) in elderly and younger patients. The most 

common grade 3/4 toxicity was neutropenia (64.3 vs. 70.4%); overall, there was no major 

difference in the incidence of hematological and nonhematological toxicities between the 

groups. No treatment-related death was observed in this study. 

Conclusion: Third-line or fourth-line AMR yielded the similar efficacy and toxicity 

profiles between elderly and younger NSCLC patients. Data from this post-hoc analysis 

encourage prospective evaluation of potential benefit of AMR in elderly NSCLC patients. 


1359 MULTI-CENTER OBSERVATIONAL STUDY ON THE DIAGNOSIS 

OF NON-SMALL CELL LUNG CANCER BONE METASTASIS 

AND THE EFFICACY AND SAFETY OF BISPHOSPHATES 

TREATMENT (C-TONG 0801) 

Y. Wu 1 ,Z.Li 2 , C. Zhou 3 , L. Shun 4 , Y. Zhang 5 , M. Hou 6 , W. Liu 7 , J. Wang 8 , 

G. Chen 9 , Y. Zhou 10 

1 Department of Clinical Oncology, Guangdong General Hospital (GGH) & 

Guangdong Academy of Medical Sciences, Guangzhou, CHINA, 2 Oncology, Sun 

Yat-Sen University Cancer Center, Guangzhou, CHINA, 3 Lung Cancer Institute, 

Shanghai Pulmonary Hospital, Shanghai, CHINA, 4 Shanghai Lung Cancer 

Clinical Center, Shanghai Chest Hospital, Shanghai, CHINA, 5 Oncology, Zhejiang 

Cancer Hospital, Hangzhou, CHINA, 6 Oncology, West China Hospital, Chengdu, 

CHINA, 7 Oncology, Xijing Hospital, Xi’an, CHINA, 8 Oncology, Beijing Cancer 

Hospital, Beijing, CHINA, 9 Oncology, Heilongjiang Cancer Hospital, Harbin, 

CHINA, 10 Oncology, Henan Provincal Hospital, Zhengzhou, CHINA 

Objective: To study the current status of the NSCLC bone metastasis (BM) in China, 

including the diagnosis, NTX parameters, and the efficacy and safety of 

bisphosphates (BP) treatment. 


Methods: NSCLC patients with radiographic verification of BM were treated with 

at least one kind of BPs in this prospective observational study. NTX, SRE 

incidence and adverse event (AE) data were collected at baseline and every 3 

months after treatment. Treatment continued at least until death. NTX levels 

were characterized as normal (N; = 50 nmol/ 

mmol). 

Results: By the time of this analysis, 580 patients were enrolled into this study with 

the median follow-up of 6.1 months. There were 566 patients with baseline NTX 

results. Most patients (86.7%) had BM diagnosed using of CT containing method. 

The E baseline NTX patients were 374 (66.6%). Patients with multiple BM (459 pts, 

81.2%) had significantly higher NTX baseline level than those with single BM (108.9 

vs 67.3 nmol/mmol, p = 0.0003). The OS was 23.2 months. The overall SRE was 

22.2%, and the annual SRE was 3.4 times/person/year. Patients with E baseline NTX 

had trend of earlier onset of SRE (the median time to first SRE: 1.2 vs 1.6 months, p 

= 0.179) and shorter OS (20.6 vs not reached, months), especially after 15 months. 

The frequency of adverse events was 17.1%, study drug related AE was 7.1%, and 

serious AE was 2.6%. There were no significant changes in serum creatinine levels 

before and after bisphosphate therapy. No cases of osteonecrosis of the jaw (ONJ) 

were observed. Zoledronic Acid-related AE was observed in 37 cases (7.7%), and SAE 

was observed in 14 cases (2.9%). 

Conclusion: NSCLC bone metastasis is a relatively common and serious clinical 

problem in Chinese patients, which were most frequently identified by CT. Baseline 

NTX level has significant negative impact on SRE. Prolonged bisphosphate therapy 

could help reduce SRE with acceptable safety profiles. 


1360 RETROSPECTIVE STUDY OF RADIOLOGICAL FINDINGS OF 

PULMONARY EMBOLISMS (PE) IN PATIENTS (PTS) WITH 


E. Capelletto 1 , S. Novello 1 , F. Solitro 2 , L. Focaraccio 1 , M. Giaj Levra 1 ,S. 

G. Rapetti 1 , T. Vavala 1 , J. Menis 3 , A. Veltri 2 , G.V. Scagliotti 1 

1 Department of Clinical and Biological Sciences - Thoracic Oncology Unit, 

Azienda Ospedaliero-Universitaria ASOU San Luigi Gonzaga, Orbassano, ITALY, 

2 Department of Radiology, Azienda Ospedaliero-Universitaria ASOU San Luigi 

Gonzaga, Orbassano, ITALY, Orbassano, ITALY, 3 Department of Medical 

Oncology, University Hospital Santa Maria della Misericordia, Udine, ITALY 

Introduction: Venous thromboembolism (VTE) is one of the leading cause of death 

for cancer pts, with an incidence of 1 event per 110-120 patients, mainly within the 

first year from diagnosis. Cancer pts with VTE show a 2.2-fold increase in mortality 

and lung cancer is the second tumor type with the highest incidence of VTE. 

Considering that chemotherapy is associated with a 6 times increased risk of VTE 

and that biological agents, especially antiangiogenetic compounds, cause an 

additional risk, the aim of the study is to evaluate, with a radiological retrospective 

evaluation, the real incidence of PE in selected cohorts of advanced NSCLC patients 

and the impact of PE on survival. 

Materials and methods: This retrospective monocentric study enrolled 141 advanced 

NSCLC pts, diagnosed between June 2007 and June 2008 (cohort 1), and between 

January 2010 and December 2010 (cohort 2). Pts were mostly men, with a median 

age of 63 years, performance status of 0 and a prevalence of comorbidities 

predisposing to VTE of 42.0% and 70.0% in first and second cohort, respectively. 

74.1% and 43.3% of pts received biological agents in first and second cohort; 39.5% 

and 21.7% antiangiogenetic agents. 

Results: Retrospective review of 460 contrast-enhanced multidetector computed 

tomography studies showed a prevalence of PE of 13.6% in the first cohort and of 

15.0% in the second one. Survival analysis didn’t show any statistically significant 

differences in terms of OS and TTP in the first cohort. In the second cohort, Kaplan 

Meier curves showed a significantly difference in terms of TTP in favor of pts who 

never developed PE, p-value = 0.003. Similar results were observed considering as 

stratification factors the use of biological agents, p-value = 0.007, and of 

antiangiogenic agents, p-value = 0.010. 

Conclusion: The higher incidence of PE in the second cohort, despite a lower 

exposure to biological and antiangiogenic agents, could be related to a greater 

thrombogenic action of these drugs, but also a higher prevalence of comorbidities 

predisposing to VTE. Descriptive analysis was confirmed by survival data, underlining 

the need of further studies to clarify the role of predisposing factors for PE. 


1361 RISK OF KIDNEY FAILURE IN PATIENTS WITH NON-SMALL 

CELL LUNG CANCER (NSCLC) TREATED WITH PEMETREXED 

P. Kongsted, A. Mellemgaard 

Oncology, Herlev University Hospital, Herlev, DENMARK 


Background: Pemetrexed is effective as both first and later lines of chemotherapy for 

non-squamous NSCLC. In first-line pemetrexed is used in combination with cis- or 

carboplatin. In progressive or relapsing disease after platinum based combination 

chemotherapy it is used as a single-drug. Drug elimination is mainly renal. A few 

case-reports have described acute renal failure during treatment with pemetrexed. 

Aim: To determine the incidence rate of acute renal failure in patients treated with 

either single agent pemetrexed or combination therapy, evaluate reversibility of possible 

renal failure and to identify possible risk-factors for developing acute renal failure. 

Material and methods: A total of 54 consecutive patients receiving single agent 

pemetrexed and 55 consecutive patients receiving combination platin and 

pemetrexed were included. Patients were treated between 2008 and 2011. 9 patients 

did not receive treatment and were excluded. Pretreatment and all subsequent 

creatinine levels were registered. Acute renal failure was defined according to the 

RIFLE-criteria as a more than 50 % rise in pretreatment creatinine level within 30 

days of latest pemetrexed infusion. 

Results: Fourteen percent in the single agent group and 8 % in the combination 

chemotherapy group developed acute renal failure (non significant, 

Chi-Squared-Test). Of these 11 patients, 3 (27 %) regained pretreatment values of 

creatinine. In the remaining 8 cases, 5 (63 %) had persistent or progressive renal 

failure (2 in the combination group and 3 in the single agent group). Three patients 

died shortly after established renal failure (2 in the single agent group and 1 in the 

combination group). No patients were treated with dialysis. Age, sex, disease stage, 

performance status, pretreatment creatinine values, number of treatment cycles and 

co-morbidity were unrelated to development of kidney failure. 

Conclusion: Out of 100 patients treated with pemetrexed, 11 % developed acute 

renal failure. In the majority of cases, kidney failure was irreversible. We were unable 

to identify pretreatment factors predictive of kidney injury. Further studies are 

warranted to address causality between pemetrexed treatment and acute renal failure. 


1362TiP A PHASE II STUDY OF SORAFENIB MONOTHERAPY IN THE 

PATIENTS WITH ADVANCED OR RECURRENT 

NON-SMALL-CELL LUNG CANCER AFTER FAILURE OF 

EGFR-TKI (CTONG0805) 

Q. Zhou 1 , C. Zhou 2 , G. Chen 3 , Y. Cheng 4 , C. Huang 5 , L. Zhang 6 , Y-L Wu 1 

1 Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong 

Academy of Medical Sciences, Guangzhou, CHINA, 2 Lung Cancer Institute, 

Shanghai Pulmonary Hospital, Shanghai, CHINA, , 3 Haerbing Medical University 

Affiliated Tumor Hospital, Haerbing, CHINA, 4 Jiling Province Tumor Hospital, Jilin, 

CHINA, 5 Fujian Province Tumor Hospital, Fujian, CHINA, 6 Sun Yat-Sen University 

Cancer Center, Guangzhou, CHINA 

Background: Sorafenib is a multikinase inhibitor with antitumor and anti-angiogenic 

activity. This study was designed to evaluate the efficacy and tolerability of sorafenib 

monotherapy for patients with advanced lung adenocarcinoma previously treated 

with EGFR tyrosine-kinase inhibitors. 

Methods: A phase II, single arm clinical trial (NCT00922584) was conducted in 6 

centers in China. Patients with stage IIIB or IV adenocarcinoma, ECOG score of 0-2, 

no more than 1 previous chemotherapy regimen with 1 prior EGFR-TKI treatment 

failure, or, with K-ras mutation were enrolled. Patients received oral sorafenib 400mg 

bid continuously until disease progression or intolerable toxicity. 

Results: Between Dec 2008 and Jun 2010, 65 patients were enrolled and 64 could be 

analyzed. The median time of sorafenib administrated was 3.7 months (range, 0.23 - 

14months). The median follow-up time was 5.5 months (range, 0.3 – 30.6months). 

The primary endpoint disease control rate (DCR) was 32.8%, including 2 (3.2%) 

partial responses and 19 (29.7%) patients with stable disease (lasting more than 3 

months), which did not meet the predefined statistical hypothesis of 38.4%. However, 

the secondary endpoint including median PFS and OS were improved compared 

with history data (pemetrexed1, EGFR TKIs2-3), 3.7 months (95%CI:3.5 ∼ 3.9) and 

7.4months (95%CI:5.7 ∼ 9.2) respectively. Logistic and COX regression analysis 

showed no correlation between DCR or survival results with age, gender, smoking 

status, PS, and other clinical factors. The most common toxicity was hand foot skin 



reaction (HFSR) (71.9%), and the incidence at 4weeks, 8weeks,12weeks was 

64.1%,45.3% and 37.5% respectively, showing a decline of HFSR incidence along 

with the time of therapy . 21.9% of patients occurred ≥grade 2 other dermatologic 

reactions other than HFSR, followed by diarrhea (26.2%), hypertension (15.4%) . 

Dose interruptions due to toxicity happened in 19 patients (29.2%). 

Conclusion: Sorafenib monotherapy has encouraging efficacy improving PFS and OS 

with tolerable toxicity as second or third line treatment in patients with advanced 

lung adenocarcinoma, who have failed prior chemotherapy and EGFR-TKI 

treatment. Further randomized studies are needed to confirm the clinical benefit of 

sorafenib in such patients. 


1364TiP A RANDOMIZED, PHASE II, MULTICENTER, 

DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF 

ONARTUZUMAB (METMAB) WITH EITHER BEVACIZUMAB + 

PLATINUM + PACLITAXEL OR PEMETREXED + PLATINUM 

AS FIRST-LINE TREATMENT FOR PATIENTS (PTS) WITH 

STAGE IIIB OR IV NON-SQUAMOUS NON-SMALL CELL 

LUNG CANCER (NSCLC) 

H. Wakelee 1 ,W.Yu 2 , K. Rittweger 3 , V.E. Paton 2 

1 Thoracic Oncology, Stanford University Cancer Center, Stanford, CA, UNITED 

STATES OF AMERICA, 2 Oncology, Genentech Inc, South San Francisco, CA, 

UNITED STATES OF AMERICA, 3 Oncology, Hoffman-La Roche, Nutley, NJ, 


Background: Dysregulation of the HGF/Met pathway has been associated with 

tumorigenesis in many malignancies, including NSCLC. Onartuzumab (MetMAb) is 

a recombinant, humanized, monovalent monoclonal antibody directed against Met. 

In a phase Ia/Ib study, onartuzumab (+/- bevacizumab) was well tolerated in pts with 

advanced solid tumors (Moss et al. Ann Oncol 2010;21(Suppl. 8):Abstr. 504P). In a 

phase II study of pts with previously treated NSCLC, onartuzumab + erlotinib was 

associated with a significant benefit in PFS (HR 0.53; p = 0.04) and OS (HR 0.37; p = 

0.002) compared with erlotinib alone in pts with Met IHC diagnostic-positive 

(Met-positive) tumors (Spigel et al. J Clin Oncol 2011;29(Suppl.):Abstr. 7505). Pts 

with Met-negative tumors who received onartuzumab + erlotinib reported worse 

outcomes compared with erlotinib alone (PFS HR 1.82, p = 0.05; OS HR 1.78, p = 

0.16). An interaction between onartuzumab and erlotinib could explain this outcome 

and therefore may not be seen in this study with chemotherapy. The most 

commonly reported adverse events associated with onartuzumab are peripheral 

edema and fatigue. An early safety review is planned for this study. 

Methods: In this study the treating physician will assign appropriate chemotherapy 

for each pt (Cohort 1: bevacizumab + platinum + paclitaxel; Cohort 2: pemetrexed + 

platinum). Eligible pts within cohorts will be stratified by Met IHC status (positive vs 

negative) and randomized (1:1) to receive 4 cycles of chemotherapy + onartuzumab 

or placebo. Thereafter, pts without disease progression may continue to receive 

placebo or onartuzumab (+ cohort-assigned chemotherapy, without platinum or 

paclitaxel) until disease progression, unacceptable toxicity, or death. The co-primary 

endpoints are PFS in all pts and by Met status. Secondary endpoints include OS, 

ORR, safety, and PK. Approximately 260 pts will be randomized until 130 pts with 

Met-positive NSCLC are enrolled. This study is open for accrual; further details can 

be found on ClinicalTrials.gov (NCT01496742). 

Disclosure: H. Wakelee: Dr. Wakelee reports an uncompensated consultancy/ 

advisory relationship with Genentech-Roche. Dr Wakelee receives research funding 

(through Stanford University) from Genentech-Roche. W. Yu: Dr Yu is a full-time 

employee of Genentech, Inc. and minor stockholder of Hoffmann-La Roche, Inc. K. 

Rittweger: Mrs Rittweger is a full-time employee of Hoffmann-La Roche, Inc. V.E. 

Paton: Dr Paton is a full-time employee of Genentech, Inc. and minor stockholder of 

Hoffmann-La Roche, Inc. 

1365TiP A RANDOMIZED, PHASE II, MULTICENTER, 

DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF 

ONARTUZUMAB (METMAB) IN COMBINATION WITH 

PACLITAXEL + CISPLATIN (OR CARBOPLATIN) AS 

FIRST-LINE TREATMENT FOR PATIENTS (PTS) WITH 

STAGE IIIB OR IV SQUAMOUS NON-SMALL CELL LUNG 


F.R. Hirsch1 , D. Gandara2 , R. Govindan3 , V.E. Paton4 ,W.Yu4 1 

Department of Medicine, University of Colorado Denver, Denver, CO, UNITED 

STATES OF AMERICA, 2 Thoracic Oncolology Program, UC Davis Cancer Center, 

Sacramento, CA, UNITED STATES OF AMERICA, 3 Oncology, Washington 

University School of Medicine, St. Louis, MO, UNITED STATES OF AMERICA, 

4 

Oncology, Genentech Inc, South San Francisco, CA, UNITED STATES OF 

AMERICA 

Background: Dysregulation of the HGF/Met pathway has been associated with 

tumorigenesis in many malignancies, including NSCLC. Onartuzumab (MetMAb) is 

a recombinant, humanized, monovalent monoclonal antibody directed against Met. 

By binding to the extracellular domain of Met, onartuzumab selectively blocks 

ligand binding and subsequent activation by HGF. Current data support a strategy 

of combining onartuzumab with numerous chemotherapies and targeted agents 

(bevacizumab, erlotinib). In a phase Ia/Ib study, onartuzumab (monotherapy and in 

combination with bevacizumab) was shown to be well tolerated in pts with 

advanced solid tumors (Moss et al. Ann Oncol 2010;21(Suppl. 8):Abstr. 504P). A 

phase II study of onartuzumab in combination with erlotinib in pts with previously 

treated NSCLC reported a significant benefit in PFS (HR 0.53; p = 0.04) and OS 

(HR 0.37; p = 0.002) in pts with Met-positive (Met IHC diagnostic positive) tumors 

(Spigel et al. J Clin Oncol 2011;29 (Suppl.):Abstr. 7505). Pts with Met-negative 

tumors who received onartuzumab + erlotinib reported worse outcomes compared 

with erlotinib alone (PFS HR 1.82; p = 0.05; OS HR 1.78; p = 0.16). The most 

commonly reported adverse events associated with onartuzumab are peripheral 

edema and fatigue. 

Methods: In this phase II study, pts with squamous NSCLC are randomized (1:1) to 

receive 4 cycles of paclitaxel, cisplatin (or carboplatin) and either placebo or 

onartuzumab. Pts without disease progression may continue to receive placebo or 

onartuzumab as maintenance therapy until disease progression, unacceptable toxicity, 

or death. The primary study endpoint is PFS in all pts. PFS by Met IHC diagnostic 

status (Met positive vs Met negative) will also be analyzed. Secondary endpoints 

include OS, ORR, safety, and PK. A minimum of 110 pts will be randomized to 

achieve 55 pts with Met-positive squamous NSCLC. A maximum of 55 pts with 

Met-negative squamous NSCLC will be enrolled. This study is open for accrual; 

further details can be found on ClinicalTrials.gov (NCT01519804). 

Disclosure: F.R. Hirsch: Advisory relationship: Genentech-Roche, 

Boehringer-Ingelheim, Pfizer, Merck-Serono, Bristol-Myers Squibb. Research 

funding (through University of Colorado): Imclone-Lilly, Celgene, Morphotek. 

Board of Directors: IASLC. D. Gandara: Dr. Gandara reports a consultant/advisory 

relationship with Genentech, Inc. He also receives research funding from 

Genentech, Inc. R. Govindan: Dr. Govindan reports a consultant/advisory 

relationship with Bristol-Myers Squibb, Boehringer-Ingelheim, Astra Zeneca, Pfizer, 

Genentech, Inc. and GlaxoSmithKline. V.E. Paton: Dr Paton is a full-time employee 

of Genentech, Inc. and minor stockholder of Hoffmann-La Roche, Inc. W. Yu: Dr 

Yu is a full-time employee of Genentech, Inc. and minor stockholder of 

Hoffmann-La Roche, Inc. 

1366TiP PHASE II STUDY OF ERLOTINIB FOR PREVIOUSLY 

TREATED NON-SMALL CELL LUNG CANCER PATIENTS 

WITHOUT EPIDERMAL GROWTH FACTOR RECEPTOR 

MUTATION: CENTRAL JAPAN LUNG STUDY GROUP 

(CJLSG) 0903 TRIAL 

M. Morise 1 , H. Taniguchi 2 , H. Saka 3 , J. Shindoh 4 , R. Suzuki 5 , E. Kojima 6 , 

T. Hase 1 , M. Kondo 1 , H. Saito 7 , Y. Hasegawa 1 

1 Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, 

JAPAN, 2 Department of Respiratory Medicine and Allergy, Tosei General 

Hospital, Seto, JAPAN, 3 Medical Oncology & Respiratory Medicine, National 

Hospital Organization Nagoya Medical Center, Nagoya, JAPAN, 4 Respiratory 

Medicine, Ogaki Municipal Hospital, Ogaki, JAPAN, 5 Respiratory Medicine, 

Toyohashi Municipal Hospital, Toyohashi, JAPAN, 6 Respiratory Medicine, Komaki 

Municipal Hospital, Komaki, JAPAN, 7 Respiratory Medicine, Aichi Cancer Center 

Aichi Hospital, Okazaki, JAPAN 

Background: Erlotinib has been shown moderate activity for previously treated 

non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth 

factor receptor (EGFR). However, the sensitivity of methods for detection of EGFR 

mutations can influence the efficacy of erlotinib. Moreover, it is controversial about 

association between K-ras mutations and erlotinib resistance in EGFR wild-type 

NSCLC. Here, we conducted a phase II study of erlotinib for previously treated 

NSCLC patients without EGFR mutation screened by PNA-LNA PCR clamp 

methods, which is known to be highly sensitive method for the detection of EGFR 

mutations. Furthermore, we have planned exploratory reanalysis of EGFR mutation 

status and screening of K-ras mutation status by the Scorpion Arms method which 

is also highly sensitive method among patients whose samples are available for 

analysis. 

Patients and methods: Major eligibility criteria were advanced NSCLC with 

EGFR-wild type (gene analysis by PNA-LNA PCR clamp method), previously treated 

with one or two chemotherapy, and ECOG performance status (PS) of 0-2. Oral 

erlotinib 150mg was given daily until progression or unacceptable toxicity. The 

primary objective of the study was objective response rate. Secondary objectives were 

tolerability, progression-free survival, overall survival, verification of the concordance 

of EGFR mutation detection between the PNA-LNA PCR clamp method and 

Scorpion ARMS method, and screening K-ras mutation status by Scorpion ARMS 

methods. As of April 2012, enrollment of 55 patients has been completed. The study 

is in progress and we are planning data cut-off for efficacy and safety analysis in 

August 2012. (Unique trial Number; UMIN000002692) 

Disclosure: H. Taniguchi: Hiroyuki Taniguchi has served as a member of advisory 

boards for Boehringer-Ingelheim, Chugai-Pharma, Shionogi & Co. Ltd. H. Saito: 

Hiroshi Saito received research funding from Chugai Pharmaceuticals. Y. Hasegawa: 

Yoshinori Hasegawa received research funding from Chugai Pharmaceuticals. All 



1367TiP LONG-TERM ERLOTINIB THERAPY IN PATIENTS WITH 

ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC): 

INTERIM ANALYSIS OF BASELINE CHARACTERISTICS 

C. Chouaid 1 , R. Gervais 2 , C. Locher 3 , D. Moro-Sibilot 4 , B. Commenges 5 , 

S. Chenoufi 5 

1 APHP, Pneumologie, APHP, Paris, FRANCE, 2 Oncologie, CAC, Caen, FRANCE, 

3 Pneumologie, Meaux, Meaux, FRANCE, 4 Pneumologie, CHU Grenoble, 

Grenoble, FRANCE, 5 France, Roche, Neuilly, FRANCE 

Background: Erlotinib has been shown to improve outcomes in patients with 

recurrent or progressive NSCLC after platinum based chemotherapy. In this clinical 

setting, some patients derived long-term benefits from erlotinib treatment with at 

least 9 months of Progression Free Survival (PFS). The aim of this 

non-interventional prospective study was to analyze the clinical characteristics of 

these patients. A secondary objective was to evaluate erlotinib long-term safety. 

Patients and methods: Patients with advanced NSCLC with recurrent or progressive 

NSCLC after platinum based chemotherapy treated for at least 9 months by erlotinib 

and followed for at least 24 months have been included prospectively. Patients’ 

demographics, clinical and histological characteristics, treatments received before 

erlotinib initiation, data related to erlotinib therapy (line of treatment, dosage, 

duration of treatment, tolerability), median PFS, objective response rate, overall 

survival, safety and quality of life data were recorded. 

Results: Between June 2010 and June 2011, 205 patients have been included in 76 

French institutions. Patients’ characteristics were: mean age, 67.4 ± 10.1 years; 

Caucasian, 96.5%; ECOG performance status (PS) 0/1/2/3, 39.3/54.6/4.6/1.5 (%); 

male, 42.9%; current/former/never smokers, 5.9/45.6/39.2 (%); adenocarcinoma, 

82.2%; stage IV/IIIB, 83.3/16.7 (%). Among 42 patients tested, 50% presented 

activating epidermal growth factor receptor (EGFR) mutation. Erlotinib was 

administered as first/second/third line treatment in 20.5/50.7/22.4 (%) of patients. 

Since treatment initiation, most frequent reported grade 3/4 toxicities were folliculitis 

(8.8%) and diarrhea (4.4%). 

Conclusion: These are, to our knowledge, the first data reported prospectively of 

long-responders with advanced NSCLC treated with erlotinib. The long-term benefit 

of erlotinib according to the results of this interim analysis seems to be more marked 

in patients with adenocarcinoma, good PS and never or former smokers. Otherwise 

the benefit seems to be independent of gender. Erlotinib was well tolerated without 

life-threatening toxicities. 

Disclosure: C. Chouaid: In the past 5 years, I received fees for attending scientific 

meetings, speaking, organizing research from AstraZeneca, Boehringer Ingelheim, 

GlaxoSmithKline, Hoffman la Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis 

and Amgen. R. Gervais: In the past 5 years, Radj Gervais received fees for attending 

scientific meetings, speaking, organizing research or consulting from AstraZeneca, 

Hoffman la Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis and Amgen. 

C. Locher: In the past 5 years, Chrystel Locher received fees for attending scientific 

meetings, speaking, organizing research or consulting from AstraZeneca, Hoffman la 

Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis and Amgen. D. Moro-Sibilot: In 

the past 5 years, Denis Moro Sibilot received fees for attending scientific meetings, 

organizing research or consulting from AstraZeneca, Boehringer Ingelheim, Hoffman 

la Roche, Astra Zeneka, Sanofi Aventis, Lilly, Novartis and Amgen. B. Commenges: 

Commenges B is employed by Roche France. S. Chenoufi: Chennoufi S is employed 

by Roche France 

1368TiP RADIOTHERAPY WITH OR WITHOUT CONCOMITANT 

TEMOZOLOMIDE FOR BRAIN METASTASES OF 


M. Rajer, M. Vrankar, V. Kovac, M. Zwitter 

Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, SLOVENIA 


Introduction: Brain metastases from solid tumours are the most common CNS 

neoplasm, and non-small cell lung cancer is their single most common origin. The 

standard therapeutic option for multiple lesions is palliative radiotherapy, which 

while able to offer an efficient palliation of symptoms cannot prolong life. 

Chemotherapy has a limited role in the treatment of CNS neoplasms, almost 

exclusively in primary neoplasms. Standard chemotherapy for non-small cell lung 

cancer is not very useful in treatment of brain metastases. In some trials 

temozolomide, an alkylating agent used in treatment of gliomas, has shown some 

efficacy, while the combination of temozolomide and radiotherapy has not yet proven 

its value. 

Patients and methods: Patients with cytologically or histologically confirmed 

non-small cell lung cancer in performance status of 2 or better, brain metastases not 

amenable to local treatment (either surgery or SRS) and with adequate 

haematological and biochemistry function are randomized between either 

radiotherapy or concomitant chemo-radiotherapy with temozolomide. Radiotherapy 

is given in dose 35 Gy in 14 fractions and temozolomide in dose 75 mg per m2 from 

day 1 to 14 of radiotherapy including any eventual breaks. Standard haematologic 

and biochemistry tests are performed weekly. Response to treatment is assessed using 

CT/MRI, symptom relief and TTP/OS. 

Results: Currently, recruitment is still on-going, but an interim analysis was 

performed. Until now 20 patients were included. All patients had stage IV lung 

cancer with radiologically proven brain metastases. Median age was 55,8 (40-67 

years) and 7 were males. 12 patients received concomitant temozolomide. The main 

toxicity was haematologic. Although the number of patients is still small, the 

difference in survival seems to indicate there might be a connection between 

concomitant temozolomide use and longer survival. 

Conclusions: Chemo-radiotherapy with temozolomide for non-small cell lung cancer 

brain metastases seems to be a feasible treatment option, pending further evaluation. 

However, toxicity despite a lower cumulative dose is more pronounced than in 

primary CNS neoplasms and treatment should not be given outside clinical trials 

with cautious patient selection. 



oncology and public health 

1369P RISK OF MAJOR BLEEDING IN CANCER PATIENTS 

RECEIVING CHEMOTHERAPY 

J.H. Zong 1 , L. Eckert 2 , L. Zhang 1 , W.S. Dai 1 , A.T. Cohen 3 , G.H. Lyman 4 

1 Global Pharmacovigilance and Epidemiology, Sanofi R&D, Bridgewater, NJ, 

UNITED STATES OF AMERICA, 2 Global Evidence Value and Development, 

Sanofi, Chilly-Mazarin, FRANCE, 3 Vascular Medicine, Department of Vascular 

Surgery, King’s College Hospital, London, UNITED KINGDOM, 4 Medicine, Duke 

University, Durham, NC, UNITED STATES OF AMERICA 

Cancer patients receiving chemotherapy are at increased risk of venous 

thromboembolism (VTE). The presence of cancer and anticoagulant use are risk 

factors for bleeding, yet data on bleeding risk are limited in these patients. This 

analysis evaluated the risk of major bleeding in cancer patients receiving 

chemotherapy using a US claims database. This retrospective cohort study used the 

MarketScan® databases, a nationwide database containing data from about 100 payers 

and covering > 30 million patients annually. Adult cancer patients receiving 

chemotherapy within 6 months of cancer diagnosis between January 2004 and 

December 2010 were included. Cancers of interest were: lung, colon/rectum, 

pancreas, bladder, stomach, and ovary. The index date was the first date of 

chemotherapy. Patients were followed until the earliest of: 1) first diagnosis of major 

bleeding; 2) termination of enrolment in the health plan; 3) end of study. The 

primary outcome was the first occurrence of major bleeding, based on selected 

ICD-9-CM/CPT codes, following chemotherapy initiation. Of 74,575 patients 

identified, exclusion of those with prior history of bleeding at baseline (∼5%) 

resulted in 70,822 patients included in the analysis. Mean age was 62 years, 37% 

were ≥ 65 years, and 52% were male. Average time of follow up and chemotherapy 

were 14.3 and 8.6 months, respectively; 6% had a history of VTE within 6 months 

prior to the index date. Major bleeding occurred in 5.8% of patients and the 

incidence rate for all cancers combined was 4.9 per 100 person-year (PY) and 10.5, 

9.3, 6.2, 4.3, 3.6, and 3.3/100 PY for pancreatic, stomach, lung, bladder, colon/ 

rectum, and ovarian cancer, respectively. Approximately 14% of patients (N = 10,456) 

developed VTE after chemotherapy initiation (> half in the first 3 months of 

chemotherapy treatment). Of these, 7.8% experienced major bleeding with incidence 

rates ranging from 5.9-17.7/100 PY after VTE. Major bleeding incidence in cancer 

patients receiving chemotherapy varies by cancer type with the highest rates in 

patients with upper gastrointestinal cancer. Compared to the overall cohort, major 

bleeding risk was higher in cancer patients who developed VTE. 

Disclosure: J.H. Zong: Employee of Sanofi. L. Eckert: Employee of Sanofi. L. Zhang: 

Employee of Sanofi. W.S. Dai: Employee of Sanofi. A.T. Cohen: Consult: Astellas, 

Table: 1370P 

Drug Type Cancer Type 

PFS in RCT 

(months) 

PFS in Clinical Practice 

Oncology (months) 

AZ, Bayer, BI, BMS, Daiichi, GSK, J&J, Mitsubishi, Pfizer, Portola, Sanofi, S-P; 

ResFund: AZ, Bayer, BI, BMS, Daiichi, GSK, J&J, Pfizer, Sanofi, S-P; 

BoardSpeakerAdvis comm: Bayer, BI, BMS, Daiichi, GSK, J&J, Mitsubishi, Pfizer, 

Sanofi. All other authors have declared no conflicts of interest. 

1370P A NEW PROPOSAL OF DRUG PRICING BASED ON VALUE 

FOR EFFECTIVENESS IN REAL PRACTICE ONCOLOGY 

A. Jirillo 1 , M.P. Trojniak 2 , S. Imbevaro 1 , P. Rescigno 1 , D. Pastorelli 3 , 

A.C. Palozzo 2 


Oncologico Veneto, IRCCS, Padova, ITALY, 2 Pharmacy Department, Istituto 

Oncologico Veneto, IRCCS, Padova, ITALY, 3 Medical Oncology II, Istituto 

Oncologico Veneto IOV-IRCCS, Padova, ITALY 

In Europe pricing of new drugs is assessed directly by member countries 

contracting with pharmaceutical companies. Health technology evaluation is based 

on efficacy/safety results in approval RCTs and scarce resource allocation. Since 

clinical outcomes in wider population are more variable and conditions less 

selected, the clinical outcomes may result changed. The real cost benefit value 

should be revised once effectiveness data from clinical practice is available. The 

clinical data were collected from web-based national oncology registry Onco-AIFA, 

as part of mandatory surveillance. The observational study was performed on 724 

advanced cancer patients treated with high novel oncology drugs. The median 

follow up was 67 months form May 2006 to December 2011. Approval RCTs of 

seven selected drugs were reviewed. The comparison was performed between 

survival outcomes achieved from RCT and those from our setting (see table). 

Progression free survival is a valuable indicator for efficacy/effectiveness assessment . 

Based on the difference in benefit in PFS, a new price adjusted for effectiveness was 

proposed. The post-marketing evaluation showed that in all analysed drugs the PFS 

from clinical practice was shorter in comparison to RCTs outcomes. As a result the 

real price value should be revised taking into account the difference of clinical 

response. The calculated effectiveness adjusted price is ex-factory price, expressed in 

euro per 1 mg, proportional to the difference of PFS form RCTs and that from 

clinical practice. 

The post marketing study allows for assessment of response outcomes in 

real life practice in order to verify both effectiveness and safety in general 

population testing external validity of the randomized trials. This kind of 

assessment lacks in approval RCTs, further emphasizing the importance of 

observational investigations in clinical practice. The price should be based on net 

clinical benefits achieved in real life practice as more appropriate in evaluating 

cost-benefit balance. 


Ex-factory 

(euro /1mg) 

Effectiveness Ajusted 

Price (euro /1mg) 

Sorafenib Kidney 5,5 3,2 0,16 0,09 44% 

Sorafenib Liver 5,5 3,0 0,16 0,09 44% 

Erlotinib NSCLC 2,2 2,0 0,48 0,44 8% 

Sunitinib Kidney 11,0 7,0 3,87 2,46 36% 

Cetuximab Colorectal 4,1 3,0 2,08 1,52 27% 

Pemetrexed Lung adenoca 2,9 1,8 3,02 1,87 38% 

Bevacizumab Colorectal 10,6 6,3 3,36 2,00 40% 

Bevacizumab Breast 11,8 7,9 3,36 2,25 33% 

Panitumumab Colorectal 2,0 1,9 4,22 4,01 5% 

1372P HEALTH RESOURCE UTILISATION (HRU) IN EUROPE 

ASSOCIATED WITH SKELETAL-RELATED EVENTS (SRES): 

RESULTS FROM A RETROSPECTIVE STUDY 

J. Body 1 , J. Pereira 2 , H. Sleeboom 3 , N. Maniadakis 4 , E. Terpos 5 , J. Finek 6 , 

O. Gunther 7 , G. Hechmati 8 , T. Mossman 9 , R. von Moos 10 

1 Medicine, Centre Hospitalier Universitaire BrugmannUniversit, Brussels, 

BELGIUM, 2 National School of Public Health, Universidade NOVA de Lisboa, 

Lisbon, PORTUGAL, 3 Department of General Internal Medicine, HAGA Hospital, 

The Hague, NETHERLANDS, 4 Department of Health Services Management, 

National School of Public Health, Athens, GREECE, 5 Department of Clinical 

Therapeutics, University of Athens School of Medicine, Alexandra University 



Difference in 

priceDiscount proposal 

Hospital, Athens, GREECE, 6 Comprehensive Cancer Department, University 

Hospital, Plzen, CZECH REPUBLIC, 7 Centre for Observational Research, Amgen 

Ltd., Uxbridge, UNITED KINGDOM, 8 Health Economics, Amgen (Europe) GmbH, 

Zug, SWITZERLAND, 9 Biostatistics, Contractor Amgen Ltd., Cambridge, 

UNITED KINGDOM, 10 Medizinische Onkologie und H, Cantonal Hospital Graub, 

Chur, SWITZERLAND 

Objectives: To evaluate European HRU associated with SREs (radiation to bone 

[RB], surgery to bone [SB], pathologic fracture [PF], spinal cord compression 

[SCC]). 

Methods: Eligible patients (bone metastases from breast/lung/prostate cancer or 

multiple myeloma, with an index SRE [defined as an SRE preceded by an SRE-free 

period of at least 6.5 months] between July 2004 and July 2009) were enrolled from 



abstracts

Austria, Czech Republic, Finland, Greece, Poland, Portugal, Sweden and Switzerland 

(Study:20090146). HRU data were gathered from baseline (pre-index SRE period: 

3-month period, beginning 3.5 months pre-index SRE) and post-index SRE period 

(14-day diagnosis period pre-index SRE to 3 months post-SRE). We present mean 

(bootstrapped 95% confidence interval [CI]) change in HRU from baseline per index 

SRE for pooled country data. 

Results: The Table presents the mean change from baseline in HRU per index SRE for 

the pooled data from the 8 European countries included in this study. An increase was 

observed in all HRU types following the index SRE. Change in overall HRU was 

predominantly driven by increases in the duration of inpatient stays, with a mean 

increase of between 7.81 and 22.21 days depending on SRE type. Substantial increases 

were also seen in the number of procedures and the number of outpatient visits, with 

mean increases from 5.85 to 9.58 and from 2.58 to 4.24, respectively. Of the index 

SREs, SCC was associated with the greatest increase in HRU burden for the following 

HRU types: duration of inpatient stays, emergency room (ER) visits, and procedures. 

Conclusions: Overall, SREs are associated with substantial HRU burden. The largest 

increases in HRU burden were seen following SCC. 

Mean (95% CI) change from baseline in HRU according to index SRE type (full 

analysis set). 

SRE 

HRU type RB n = 482 SB n = 99 PF – long 

bone 

n = 118 

Inpatient 0.52 1.48 1.23 

PF – other 

n = 241 

SCC n = 82 

0.80 1.33 

stays (0.41, 0.62) (1.24, 1.72) (1.02, 1.44) (0.65, 0.95) (1.01, 1.65) 

Duration of 7.81 18.81 20.92 12.27 22.21 

inpatient (6.53, 9.09) (15.31, (16.90, (9.71, 14.84) (16.88, 

stays 

22.31) 24.94) 

27.54) 

Outpatient 4.24 2.65 2.58 3.96 4.06 

visits (3.67, 4.80) (1.52, 3.78) (1.70, 3.46) (3.22, 4.71) (2.65, 5.47) 

ER visits 0.10 0.18 0.30 0.22 0.45 

(0.03, 0.17) (0.03, 0.33) (0.17, 0.42) (0.12, 0.33) (0.27, 0.64) 

Procedures 8.51 6.36 6.10 5.85 9.58 

(7.84, 9.18) (4.83, 7.90) (4.80, 7.40) (5.03, 6.67) (7.82, 11.35) 

Disclosure: J. Body: Consultant for Amgen, Bayer, Novartis. Lectures for Amgen and 

Novartis. J. Pereira: Honorarium from Amgen. H. Sleeboom: Ad Board Novartis and 

Amgen, speaking honoraria Amgen. N. Maniadakis: Received honoraria and 

corporate sponsored research from Amgen Hellas. E. Terpos: Honorarium from 

Amgen. J. Finek: Consultant for GSK, Amgen, Bayer, Novartis and Roche. Lectures 

for Amgen, Novartis, Roche and Pfizer. O. Gunther: Employee of Amgen, holds 

Amgen stock. G. Hechmati: Employee of Amgen and holds Amgen stock. T. 

Mossman: Contractor of Amgen. R. von Moos: Receive research grants and speaker 

honoraria from Amgen and Roche. Participate in Ad Boards for Amgen, Roche and 

Novartis 

1373P ECONOMIC BURDEN OF COSTLY CANCER DRUGS IN A 

HEALTHCARE SERVICE 

M. Blanco Villalba, A. Pini, G. Streich, E. Molinas, J.R. Puyol, M.P. Bramajo, E. 

J. Batagelj 

Oncology, Centro Medico Austral OMI, Buenos Aires, ARGENTINA 

Background: The equitable access to medical treatment accordingly to individual 

needs is an important issue to discuss taking into account that resources are limited. 

In this study we describe the incidence of costly cancer drugs in a healthcare service 

with 200000 affiliates from Buenos Aires city, from January 2010 to December 2011 

and compare both years. We also calculate the total annual cost of expensive drug 

treatment and identify the highest cost drugs used. 

Material and methods: Retrospective study Source: clinical history and files from 

patients on anticancer treatment from January 2010 to December 2011 and drug 

costs information from the accounting department. 

Results: During the year 2010, 3% of the total cancer patients (906) received costly 

cancer treatment. The most used therapies were: Rituximab (39.2%), Trastuzumab 

(25%). Bevacizumab (10%).The total annual cost was $ 563188 of which 37.7% was 

for breast cancer, 30.3 % was for haematological cancer and 20.17% was for 

colorectal cancer. The mean annual cost per patient was $20113. During the year 

2011, 4, 5% of the total cancer patients (1135) received costly cancer treatment. The 

most used therapies were: Trastuzumab (54%).Rituximab (18%), Bevacizumab (8%). 

The total annual cost was $947873 of which 61.6% was for breast cancer, 13.3 % was 

for haematological cancer and 8.78% was for colorectal cancer. The mean annual 

cost per patient was $18957. 

Conclusion: The results of this analysis provide useful information to health care 

providers and decision makers in understanding the economic burden of cancer. 


Additionally, this cost information will greatly assist in determining the 

cost-effectiveness of new technologies and early detection systems. In order to 

warrant adequate access to these expensive treatments we need to generate a model 

of health coverage enhancing participation of all parts. 


1374P ADVANCING CLINICAL ONCOLOGY PRACTICE IN 

DEVELOPING COUNTRIES: INTEGRATING RESEARCH 

INFORMATICS FOR CONTINUOUS PROCESS IMPROVEMENT 

A.S. Alfaar, M. Kamal, O. Hassanain, M. Sabry, S. Ezzat, S. Abouelnaga 

Research Department, Children’s Cancer Hospital Egypt, Cairo, EGYPT 

In developing countries, Clinical Research is considered a luxurious interest with 

lower priority.Ongoing studies show considerable gap in responses between 

developed countries where most research is conducted and developing countries 

where most of needy population is located. We demonstrate a case where practice 

was improved in a multi-disciplinary cancer center through setting the institution 

vision and objectives to be patient centered, research focused and outcome oriented. 

Since the development of the Protocol Monitoring unit and the Research 

Department, a monitoring process has been established which identified violations 

and deviations from the developed clinical protocols with a continuous feedback to 

the attending treatment and research teams i.e treating each treatment regimen as a 

research protocol. 

This process proved effective and necessitated developing tools for providing 

more comprehensive treatment roadmaps and tracking patients’ treatment 

milestones. Another advantage of applying the system is the improvement of medical 

team conduct knowing that their performance is being reviewed in what’s known as 

Hawthorne Effect. With the establishment of first research informatics unit in the 

region Monitoring process became live web-based activity where performance 

and survival can be monitored instantaneously. The customized treatment protocols 

were developed through identifying key evidence-based practices, integrating it 

with research questions and local clinical expertise. Cooperation with international 

centers like St. Jude Children’s Research hospital and Dana Farber Cancer Institute 

as well as Children’s Hospital-Boston has supported our transition into an 

international center through benchmarking and training. 

Conclusion: Within five years we’ve developed a model example for 

developing countries to improve clinical practice through integrating research 

methods and informatics. Dealing with all treatment regimens as research 

protocol with the integration of audit and feedback approach in the treatment 

process definitely improves treatment outcome most specifically at poorly established 

settings. 


1375P CANCER AWARENESS PROGRAMMES IN URBAN AND 

SEMI-URBAN POPULATIONS OF WEST BENGAL, INDIA 

P. Das 1 , J. Basak 2 , C.K. Bose 3 , A. Mukhopadhyay 4 , S. Mukhopadhyay 1 

1 Dept of Molecular Biology, Netaji Subhash Chandra Bose Cancer Research 

Institute, Kolkata, INDIA, 2 Molecular Biology, Netaji Subhash Chandra Bose 

Cancer Research Institute, Kolkata, INDIA, 3 Clinical Reseach, Netaji Subhas 

Chandra Bose Cancer Research Institute, Kolkata, INDIA, 4 Dept. Medical 

Oncology, Netaji Subhas Chandra BoseCancer Research Institute, Kolkata, 

INDIA 

Background: Of the current world estimate of 9 million new cancer cases diagnosed 

each year, India contributes 7l akhs new cases every year with an overall count of 20 

lakhs. Of these, 2.3 lakhs cancer (33%) are obesity and life style related. 

Objectives: Our non-government cancer control program aims to educate the 

urban and semi-urban population in and around the outskirts of the city of Kolkata 

about the perils of cancer and its symptoms. Ultimately it aspires to create public 

awareness regarding the inter-relation between obesity, cancer and lifestyle 

modification, thus informing them about the benefits of minor lifestyle changes in 

preventing cancer. 

Methods: A 5 year (Jan‘06–Dec’11), bi-monthly awareness program was conducted 

by NCRI in Kolkata and its immediate outskirts targeting the urban and semi-urban 

population. Main concerns were oral, breast and cervical cancers detected by oral 

examination, self breast inspection, Pap Smear test followed by collecting patient 

history and lifestyle factors including dietary fat-caloric & tobacco intake, alcohol 

consumption, and weight of the subject which might act as a pre-determinant 

disease markers. Positive screening results stage-specific planning of treatment and/or 

palliative care at our institute. 

Results: Enthusiastic public participation (app.85%) including women was observed. 

Out of 46,000 screened individuals, cancer was detected in 3840 (8%) cases, of which 



58% were female and 42% were male. Incidence of breast cancer in female were 

predominant (29.99%), followed by cervical carcinoma (23.99%). Tobacco habits 

predominated among 80% of males and 20% of females. Hence oral cancer was the 

most common (35.98%) amongst men, followed by lung cancer (29.98 %). 

Conclusion: The results showed a strong association of overweight and obesity with 

cancer in this group primarily due to life style, dietary and smoking habits. Hence 

some minor lifestyle choices which encompasses dietary restriction of calorie/fat 

intake and avoiding animal protein especially red meat, cessation of tobacco and 

alcohol intake, exercising and maintaining an ideal body-mass index, healthy body 

weight and composition through a diet rich in fruits and green vegetables reduces the 

risk of cancer. 


1376P NEXT GENERATION CANCER REGISTRY; OPPORTUNITIES 

OF WEB 3.0 AND PHYSICIAN PERSPECTIVE 

A.S. Alfaar, M. Kamal, M. Sabry 

Research Department, Children’s Cancer Hospital Egypt, Cairo, EGYPT 

Background: Cancer registry is a systematic data collection about cancer incidents. 

They are either population based or hospital based (also known as center based) 

cancer registries. Population-based cancer registries can help in building hypotheses 

about cancer shared risk factors in contrast with hospital-based registries which focus 

more on improving quality of therapy. Standardizing documentation and 

communication methods fosters collaboration between different regional institutes for 

building a national cancer registry. In our study we aim at demonstrating how recent 

Web 3.0 technologies can help cancer registries. 

Material and methods: We started by studying the available information technology 

resources by qualified researchers who work on analyzing clinical research needs. 

We’ve developed a system analysis after studying paper and computer-based cancer 

registries. Starting from this set of recommendations we started to match needs and 

available technologies. Development took place in adherence to international 

standards of medical documentation and communication. Implementation and 

Evaluation phases were conducted with assistance of other clinical researchers, 

research nurses and cancer registrars. 

Results: The analysis phase stated that cancer registries can be improved using 

interoperability, semantic and visual data entry, client & server side-validation, 

real-time analysis, rich presentation, tagging, social integration, data mining and 

artificial intelligence technologies that are offered by current Internet era. 

. Delivery for mobile phones with intelligent validation and interpretation facilitated 

the portability of the system. Integration with knowledge bases added a decision 

support property to cancer registry with providing real-time reports and diagrams 

plotted over demographic maps. Usability was enhanced by providing user-friendly 

interfaces. 

Conclusions: Cancer registries have potential stunning future by gaining benefit 

from the recent web technologies. Research on improving cancer information systems 

should go hand in hand with continuous internet revolution. 


1377P BURDEN OF SKELETAL-RELATED EVENTS (SRES) IN 

PATIENTS (PTS) WITH SOLID TUMORS: RESULTS OF THE 

STARS OBSERVATIONAL STUDY IN THE US VS EU 

I. Duran 1 , A. Mahmood 2 , H. Hoefeler 3 , H. Ghazal 4 , D. Lueftner 5 , M. Fink 6 , 

A. Bahl 7 , G. Hechmati 8 ,R.Wei 9 , C. Atchison 10 

1 Departamento de Oncologia, Hospital Madrid Norte San ChinarroCentro 

Integral Oncologico Clara Campal, Madrid, SPAIN, 2 Cancer Specialists of South 

Texas, Corpus Christi Cancer Center, Corpus Christi, TX, UNITED STATES OF 

AMERICA, 3 Forschungszentrum Ruhr, Klifocenter, Witten, GERMANY, 

4 Oncology, Kentucky Cancer Clinic, Hazard, KY, UNITED STATES OF AMERICA, 

5 Oncology, Universitätsmedizin Berlin, Berlin, GERMANY, 6 Oncology, Orange 

Coast Memorial Medical Center, Fountain Valley, CA, UNITED STATES OF 

AMERICA, 7 Clinical Oncology, Bristol Haematology and Oncology Centre, Bristol, 

UNITED KINGDOM, 8 International Health Economics, Amgen (Europe) GmbH, 

Zug, SWITZERLAND, 9 Global Biostatistical Science, Amgen, Inc., Thousand 

Oaks, CA, UNITED STATES OF AMERICA, 10 Global Health Economics, Amgen, 

Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA 

Background: The STARS study was a prospective, multicenter, international, 

observational study designed to measure the burden of SREs (radiation or surgery to 

bone, pathologic fracture, or spinal cord compression) in pts with advanced cancer 

and bone metastases. Here we report results in pts with solid tumors by geographical 

region for US vs EU (Germany, United Kingdom, Spain, and Italy). 

Methods: This analysis included pts with bone metastases secondary to breast, 

prostate, or lung cancer and ≥1 SRE in the 97 days before enrollment (05/08 – 05/ 

10). Data on SREs and health resource utilization (HRU), including inpatient stays, 

outpatient visits, emergency room visits, nursing home/long-term care facility stays, 

home health visits, procedures, and certain medications, were collected 

retrospectively for the 97 days before enrollment and prospectively for up to 21 

months. Investigators were responsible for attributing HRU to each SRE. 

Results: US = 190 pts with 354 SREs; EU = 478 pts with 893 SREs. Baseline 

demographics and disease characteristics were similar for US and EU. Inpatient stays 

were more frequent in EU compared with US, and the length of stay was longer in 

EU (table). Outpatient visits were more frequent in US vs EU, while emergency room 

visits were similar between regions. Nearly every SRE was associated with a 

procedure in both regions; however, the number of procedures per SRE was higher in 

US, which was in part due to a much greater number of external beam radiation 

procedures per SRE in US likely reflecting standard use of multi-fraction radiation. 

Slightly more pts were receiving bisphosphonates at/before enrollment in US 

compared with EU, and pts in US received IV bisphosphonates sooner than in EU. 

Conclusion: The HRU burden of SREs was substantial in both US and EU. Some 

regional differences were observed, particularly with respect to hospitalization, length 

of stay, and time to receipt of IV bisphosphonates. 

HRU US (n = 354)* EU (n = 893)* 

Inpatient Stays (IS) Proportion of SREs with IS 

Number/SRE 

14.7% 29.5% 

Mean 0.18 0.32 

Median Length of Stay (days) 0.0 0.0 

Mean 10.6 19.9 

Median 7.0 17.0 

Outpatient Visits (OV) Proportion of SREs 

with OV Number/SRE 

88.1% 74.1% 

Mean 9.1 4.8 

Median 9.0 2.0 

Emergency Room Visits (ERV) Proportion of 

SREs with ERV Number/SRE 

4.0% 4.1% 

Mean 0.05 0.04 

Median 0.0 0.0 

Inpatient/Outpatient Procedures (P) 

Proportion of SREs with P Number/SRE 

95.5% 96.4% 

Mean 11.3 6.9 

Median 12.0 5.0 

Bisphosphate (BP) Use Proportion of pts 

receiving oral or IV BP 

70.0% 63.0% 

at or before enrollment Time from diagnosis of 

bone metastasis to first IV BP use (months), 

median** 

1.8 6.7 

*n = number of SREs; **Kaplan-Meier estimate 

Disclosure: I. Duran: Advisory Board Member, Amgen. A. Bahl: Advisory Board 

member Amgen, Novartis. G. Hechmati: Employee of Amgen and owns Amgen 

stock. R. Wei: Employee of Amgen and owns Amgen stock. C. Atchison: Employee 

of Amgen and owns Amgen stock. All other authors have declared no conflicts of 

interest. 

1378P STATISTICAL CONSIDERATION OF BIASES IN 

PROGRESSION-FREE SURVIVAL (PFS) RESULTING FROM 

DIFFERENCES IN IMAGING SCHEDULES 

T. Tanase 1 , C. Hamada 2 , H. Fujii 3 , N. Nakayama 4 , T. Denda 5 , T. Takayama 6 , 

T. Yoshino 7 , A. Ohtsu 7 

1 Data Science, Taiho Pharmaceutical Co., Ltd, Tokyo, JAPAN, 2 Faculty of 

Engineering, Tokyo University of Science, Tokyo, JAPAN, 3 Division of Clinical 

Oncology, Jichi Medical University, Tochigi, JAPAN, 4 Department of 

Gastroenterology, Kanagawa Cancer Center, Kanagawa, JAPAN, 5 Department 

of Gastroenterology, Chiba Cancer Center, Chiba, JAPAN, 6 Department of 

Gastroenterology and Oncology, University of Tokushima Graduate School, 

Tokushima, JAPAN, 7 Department of Gastroenterology & Gi Oncology, National 

Cancer Center Hospital East, Chiba, JAPAN 

Backgroud: In the three PIII trials for metastatic colorectal cancer (mCRC) patients 

who are refractory to standard chemotherapy: NCIC CTG CO.17 (NEJM 

2007;357:2040-8), 20020408 (JCO 2007;25:1658-65), and CORRECT (2012 

ASCO-GI, #LBA 385) trial, the median PFS (mPFS) were similar and the early part 

of PFS curves overlapped between treatment groups regardless of significance. 

Generally, experimental treatments can potentially have biomarkers in such cases. 

However, we consider that the scheduling of imaging tests affects PFS evaluations. 

Material and methods: We simulated PFS computationally under the assumptions 

for mCRC patients in first (L1), second (L2), and third line (L3) as “True 

Parameters” in the following table (show L3 only). In addition, we assumed that the 

probability of unscheduled progression was 0 and 20%, and the imaging schedules 


were every 6 weeks (wk) (S1), every 8 wk (S2), and 4, 8, 12 and every 8 wk thereafter 

(S3), sample size was 250 patients in each group. S3 is the same schedule plan as in 

the TAS-102 PII trial (2011 ECCO, #6005). 

Results: The following table shows the simulation results assumed that a probability 

of unscheduled progression is 0%. Simulated mPFSs were similar between the 

schedules in each treatment group of L1 and L2, but not in the control group of L3. 

Simulated hazard ratios (HRs) were almost the same regardless of the schedules in all 

lines. The difference of mPFSs between schedules in the control group of L3 

depended on the timing of first evaluation. The simulated mPFSs in L3S2 were 

similar to results of the above three PIII trials, and those in L3S3 were similar to 

results of TAS-102 PII trial. The simulation results assumed the proportion of 

unscheduled progression of 20% were similar to that of 0%. 

Setting True 

Paremeters Simulation Results 

mTTP, MST 

Mean of HR 

(mo) Mean of mPFS (mo) 

E C E C 

L3S1 2, 6 1, 4.5 1.9 [1.5, 2.6] 1.4 [1.4, 1.4] 0.58 [0.49, 0.67] 

L3S2 1.9 [1.9, 2.0] 1.8 [1.8, 1.9] 0.59 [0.50, 0.69] 

L3S3 1.9 [1.8, 1.9] 1.0 [1.0, 1.1] 0.57 [0.48, 0.65] 

TTP: Time To Progression, E: Experimental Group, C: Control Group, [ ]: 2.5 and 

97.5% percentiles. 

Conclusion: The HR in PFS is a more important indicator than mPFS regardless of 

the timing of the first evaluation of tumor response in patients with mCRC in the 

later line. These idea might be applicable for mCRC as well as other cancers. 

Disclosure: T. Tanase: Employed by, and own stock in, Taiho Pharmaceutical. C. 

Hamada: Taiho pharmaceutical. H. Fujii: Chugai Pharmaceutical, Bristol-Myers 

Squibb, Sanofi-Aventis, Novartis Pharma, GlaxoSmithKline, Eisai, Yakult Honsha, 

Takeda Pharmaceutical, Shionogi, Taiho Pharmaceutical, Ono Pharmaceutical, 

Takeda Bio Development Center. N. Nakayama: merck serono, Takeda 

pharmaceutical. T. Denda: Taiho Pharmaceutical, Pfizer, Yakult Honsha, Daiichi 

Sankyo. T. Yoshino: Consulting fee from Takeda; honoraria from Chugai, Takeda, 

Yakult, Bristol-Myers Squibb, and MerkSerono; research funding from Daiichi 

Sankyo, Taiho, Bayer, and ImClone. A. Ohtsu: Employment position in Bayer, and 

consulting fee from Takeda, Daiichi Sankyo, Novartis, Chugai,and Taiho; honoraria 

from Takeda, Daiichi Sankyo, Taiho, GlaxoSmithKline, Pfizer, Yakult, MerkSerono, 

and Bristol-Myers Squibb. All other authors have declared no conflicts of interest. 

1379P MOLECULAR THERAPEUTICS IN HEAD AND NECK 

SQUAMOUS CELL CARCINOMA: A SYSTEMATIC REVIEW OF 

COST-EFFECTIVENESS ANALYSES 

R. Zaim 1 , W.K. Redekop 2 , G.A.M.S. van Dongen 3 ,R.DeBree 3 , C.A. 

Uyl-De Groot 2 

1 Institute for Medical Technology Assessment Office J5-51, Erasmus University, 

Rotterdam, NETHERLANDS, 2 Institute for Medical Technology Assessment, 

Erasmus University, Rotterdam, NETHERLANDS, 3 Department of 

Otolaryngology/Head and Neck Surgery, VU University Medical Center, 


Background: The focus of locally advanced (LA) and recurrent and/or metastatic (R/ 

M) squamous cell carcinoma of the head and neck (SCCHN) therapy has recently 

shifted to the molecular level. Although the clinical effectiveness of novel therapeutics 

has been discussed extensively, the experience with cost-effectiveness analyses (CEAs) 

of targeted agents is limited. The objective of this study was to systematically review 

CEAs of molecular therapeutics in LA and R/M SCCHN. 

Methods: A systematic literature review was performed focusing on CEAs of 

molecularly targeted therapeutics in LA and R/M SCCHN using MEDLINE, 

EMBASE, NHS Economic Evaluation Database (NHS EED) and the Tufts CEA 

Registry. Studies were screened according to a priori eligibility criteria. Two 

independent reviewers appraised the studies using published criteria by Philips et al. 

to assess the quality and methodology of decision analytic models. 

Results: A total of four studies and eight CEAs met the inclusion criteria. All CEAs 

were conducted from the perspective of the health care sector. Country-specific costs 

were applied. Efficacy data for LA and R/M patients were obtained by the Bonner 

(Bonner et al.) and the EXTREME (Vermorken et al.) trials, respectively. Lifetime 

horizon and discounting were considered. The incremental cost-effectiveness ratios of 

combination therapy with cetuximab ranged from likely to be cost-effective in LA 

patients (€8,135-€30,691/quality-adjusted life year (QALY) gained) to unlikely to be 

cost-effective in R/M patients (€158,060/QALY gained). The most influential variable 

was the cost of cetuximab. Critical assessment of the CEAs revealed that decision 

analytic models varied in quality and methodology. Type of sensitivity analysis, 

justification of preferred methods, transparency and credibility were key areas in 

which differences were evident. 


Conclusions: Well-performed CEAs suggest that cetuximab may provide good value 

for money in LA SCCHN patients. Critical review of existing CEAs helps to improve 

the quality of forthcoming studies. Future research in LA and R/M SCCHN should 

explore the optimal role of molecularly targeted agents in daily practice. 


1380P THE QUALITY OF SAMPLE SIZE CALCULATION (SSC) 

REPORTING IN CANCER CLINICAL TRIALS 

G.M. Bariani 1 , A.C.R.C. Ferrari 1 , P.M. Hoff 1 ,R.Arai 1 , M. Precivale 2 , 

R.P. Riechelmann 1 

1 Medical Oncology, Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, 

BRAZIL, 2 Statistics, PGS Statistics, Sao Paulo, BRAZIL 

Background: SSC is a pivotal step in clinical trial concept and design. It determines 

the chance of detecting a significant result, ensures appropriate power, and helps 

sponsors to allocate adequate resources into trials. Here we describe the frequency 

with which randomized cancer clinical trials (RCT) report the data required for SSC. 

Methods: We systematically searched for phase III RCT published in top clinical 

oncology journals which were accompanied by editorials from Jan 2008 to Oct 2011. 

We assumed that RCT discussed by editorialists were clinically important. Two 

blinded investigators extracted data on SSC. Table 1 describes the information 

required for SSC according to variable type used for primary endpoint. 

Results: 140 out of 150 RCT were eligible. Median sample size was 596 subjects 

(50-40,000) per RCT. In 65.7% of RCT, the number of enrolled subjects was at least 

90% of the planned sample size. The primary endpoint was a categorical variable in 

10.0%, continuous in 27.9%, and time-to-event in 62.1%. In general, 80.7% reported 

a planned sample size, 57.9% described their null hypothesis (H0), with 20.7% giving 

a scientific rationale for H0. 57.9% informed their alternative hypothesis (H1). Alpha 

(α) and beta (β) errors were explicit in 92.9% and 90.7%, respectively. Expected 

difference between arms was reported in 88.6%. Only 2.9% of RCT provided all 

information for proper SSC (required and optional, Table). Excluding “optional 

information”, SSC could be reproducible in 18.6% of RCT. 

Conclusion: Regardless of the CONSORT 2010 statement, the quality of SSC 

reporting in phase III cancer RCT seems inadequate. This may compromise future 

study designs, pooling of data and interpretation of results. Lack of transparency in 

SSC reporting may also have ethical implications. 

Information necessary for SSC 

Variable Type Required information Optional information 

Categorical H1 

Dropout rate 

H0 

Statistical test used for SSC 

Expected difference between Scientific rationale for H0 

arms (delta) 

α and β errors 

and H1 

Continuous H1 

H0 

Delta 

Standard deviation for both 

arms 


Same as above 

Time-to-event H1 

H0 

Delta (hazard ratio) 

Length of recruitment 

Length of follow up for each 

patient 


Same as above 

Disclosure: G.M. Bariani: Travel expenses covered: Novartis, Roche. A.C.R.C. Ferrari: 

Travel expenses covered: Roche. R.P. Riechelmann: Honoraria (Roche, Merk Serono, 

Novartis and Bayer). Consultancy (Novartis and Merck Serono). Travel to scientific 

meetings (Roche, Merk Serono, Novartis e Bayer). All other authors have declared no 


1381P PERCEPTIONS OF CLINICAL TRIALS IN ASIAN CANCER 

PATIENTS: A COMPREHENSIVE SURVEY IN A KOREAN 

TERTIARY HOSPITAL 

S.J. Lee 1 , L.C. Park 2 , J. Lee 1 , S. Kim 3 , S. Kim 1 , W. Chang 1 , Y.S. Park 1 

1 Medicine, Samsung Medical Center, Seoul, KOREA, 2 Internal Medicine, Kosin 

University Gospel Hospital, Busan, KOREA, 3 Biostatistics Team, Samsung 

Medical Center, Seoul, KOREA 

Background: In the past few years, the number of clinical trials has increased rapidly 

in East Asia, especially for cancer types such as gastric and hepatobiliary cancer that 



are prevalent in Asian populations. However, the actual degree of understanding or 

perceptions of clinical trials by cancer patients in East Asian countries have seldom 

been studied. 

Methods: Between July 1st 2011 and November 30th 2011, we conducted a 

prospective study to survey cancer patients regarding their awareness of, and 

willingness to participate in, a clinical trial. The questionnaire consisted of 21 

questions based on an Index of Clinical Trial Understanding. Patients with 

gastrointestinal/hepatobiliary cancer who visited the Hematology-Oncology 

outpatient clinic at Samsung Medical Center (SMC) and who signed an informed 

consent form were enrolled. The survey was conducted by a well-trained research 

nurse and the data were statistically analyzed at the biostatistics core at SMC. 

Results: In this survey study, 1,000 patients were asked to participate and 675 

patients consented to participate (67.5%). The awareness of clinical trials was 

substantially higher in patients who had a higher level of education (p < 0.001), were 

married (p = 0.004), and had a higher economic status (p = 0.001). Willingness to 

participate in a clinical trial was not significantly increased by higher level of 

education (p = 0.286), marital status (p = 0.685), or economic status (p = 0.310). The 

most common source for acquisition of clinical trial knowledge was attending 

physicians (52.0%) followed by mass media (36.6%), other patients (6.39%), the 

internet (3.3%), and other sources (1.5%). The most influential factors for patient’s 

willingness to participate were physician’s opinion (N = 181, 26.8%), limited 

treatment options (N = 178, 26.4%), and expectations of effectiveness of new 

anti-cancer drugs (N = 142, 21.0%). Patients were likely to refuse to participate in a 

clinical trial due to unverified treatment modality (N = 320, 47.4%) and negativity 

toward clinical trials (N = 193, 28.6%). 

Conclusions: We surveyed a large patient cohort to specifically inquire about 

willingness to participate in, and awareness of, clinical trials in patients with 

Asian-prevalent cancer types. Further correlative analyses with diverse variables will 

be presented at the meeting. 


1382P AWARENESS AND UNDERSTANDING OF STRATIFIED/ 

PERSONALIZED MEDICINE IN PATIENTS TREATED FOR 

CANCER: A MULTINATIONAL SURVEY 

S. Tejpar 1 , T. Teague 2 , J. Lake 3 , J. Tabernero 4 , J.F. Vansteenkiste 5 , S. Vlassak 6 , 

F. Ciardiello 7 

1 Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, BELGIUM, 

2 Global Business Intelligence, Oncology, Merck KGaA, Darmstadt, GERMANY, 

3 Vivian Road, Mile End, London, UNITED KINGDOM, 4 Medical Oncology 

Department, Vall d’Hebron University Hospital, Barcelona, SPAIN, 5 Respiratory 

Oncology Unit (Pulmonology), University Hospital Gasthuisberg, Leuven, 

BELGIUM, 6 Global Clinical Development Unit-oncology, Merck KGaA, 

Darmstadt, GERMANY, 7 Division of Medical Oncology, Department of 

Experimental and Clinical Medicine and Surgery "F. Magrassi and A. Lanzara", 

Second University of Naples, Naples, ITALY 

Background: The identification of biomarkers predictive for the efficacy of targeted 

anticancer agents allows for the tailoring of treatment to maximize patient (pt) 

benefit and outcomes. It is important that information about the potential for the 

personalization of anticancer therapy is available to pts so that they are fully 

informed about treatment and biomarker screening options. The current survey 

assessed pt awareness and understanding of these issues. 

Methods: Pts with a diagnosis of late-stage breast cancer (BC), stage III/IV 

non-small cell lung cancer (NSCLC) or metastatic colorectal cancer (mCRC) within 

the previous 5 years were eligible. Participating physicians or pt organizations in 

seven countries (Argentina, China, France, Germany, Italy, Spain and the UK) 

identified potentially suitable pts and invited them to take part. Written informed 

consent was obtained from all pts, with those confirmed as eligible then completing 

a telephone-based questionnaire. 

Results: Questionnaires were completed by 811 pts: 164 previously diagnosed with 

BC; 157 with NSCLC and 490 with mCRC. Of those interviewed: 260/811 pts (32%) 

thought that there was no method of testing to determine which cancer treatments 

might work (or work better) in certain people, while 430/811 pts (53%) thought that 

such testing might be possible (62% of pts with BC, 48% with NSCLC and 52% with 

mCRC). Most pts (532/811, 66%) were willing to delay treatment if that helped select 

the most effective drug, 286/532 (54%) of those, by more than two weeks, and most 

(557/811, 69%) were willing to undergo a tumor re-biopsy as part of any such 

treatment selection process. Almost all pts (737/811, 91%) would allow a hospital to 

retain a tumor sample for future research. The internet was cited as a useful source 

of information regarding disease and treatment options by 192/811 pts (24%). 

Conclusions: Pts are generally willing to participate in biomarker test procedures to 

facilitate the personalization of their treatment. There is considerable scope for 

physicians and support groups to better inform pts that not all cancers are the same 

and that new tests may be able to identify which treatments will work most 

effectively for them. 

Disclosure: S. Tejpar: The author declares research and speakers’ bureau funding 

from Merck Serono. T. Teague: The author is an employee of Merck KGaA. J. 

Tabernero: The author declares: Consultant or Advisory Role (compensated) : 

Amgen, Bristol-Myers Squibb, Genentech, Merck KGaA, Millennium, Novartis, 

Onyx, Pfizer, Roche and Sanofi Honoraria: Amgen, Merck KGaA, Novartis, Roche 

and Sanofi. S. Vlassak: I am an employee for Merck Serono in the medical 

department. All other authors have declared no conflicts of interest. 

1383P WHEN DOES PERSONALIZED CANCER THERAPY 

RESEARCH PROVIDE POSITIVE RETURN ON INVESTMENT 

IN EUROPE? 

H.J. Conter 1 , D. Conter 2 , R.A. Wolff 3 

1 Cancer Medicine, UT M.D. Anderson Cancer Center, Houston, TX, UNITED 

STATES OF AMERICA, 2 Philisophy, Huron College, London, ON, CANADA, 

3 Gastrointestinal Medical Oncology, UT M.D. Anderson Cancer Center, Houston, 

TX, UNITED STATES OF AMERICA 

Background: Personalized cancer therapies targeting pre-specified genetic mutations 

currently benefits only subsets of patients. Developing the technologies and supporting 

the research to identify new targets and treatments requires a significant monetary 

outlay. How much money should the European public invest in such research? 

Methods: Since current investment should be less than or equal to the 

net-present-value (NPV) of the future health gains achieved, the marginal benefit 

gained from a new drug can be estimated by calculating the difference between the 

incremental cost-effectiveness ratio (ICER) and the willingness-to-pay (WTP) for the 

increase in health by society. We calculated the NPV of the future development for new 

drugs with similar characteristics to crizotinib, a prototypic personalized cancer therapy. 

Sensitivity analyses were performed to assess the influence of WTP thresholds, time 

horizon of return, and size of treatable population. Systematic reviews of PubMed and 

EMBASE were employed to determine the current range of ICERs for approved 

small-molecule inhibitors and monoclonal antibodies, and WTP thresholds. European 

cancer statistics were used to estimate the size of population who may benefit. 

Results: Of 1576 titles, 104 abstracts and manuscripts were included in the final 

analysis. The median ICER for targeted therapies was €45,000 (range, 

€10,000-€163,000), and median WTP was €50,000 (range, €12,000-€152,000). With a 

development time horizon of 8 years, €840 million in research funding provides 

positive societal returns for new pharmaceuticals bought at a marginal value of 

greater than €5,000. Doubling the time horizon reduces the NPV of current research 

by €230 million. If current-generation personalized therapies are dominated by newer 

technologies earlier than predicted, halving their market-life as an example, only 

€500 million in public investment would be worthwhile. The NPV of research was 

highly sensitive to changes in the estimated size of the treatable population. Focusing 

on drug development for breast, lung, and colon cancer only, may yield a NPV for 

research of €1.34 billion. 

Conclusion: Regional differences in cancer incidence and WTP for new therapeutics 

should be formally incorporated into research funding decisions to ensure optimal 

resource allocation. 


1384P ARE THERE DIFFERENCES IN PATIENT CHARACTERISTICS 

AND TREATMENT PATTERNS BY TREATMENT SETTING? 

C. Reyes 1 , S. Dacosta Byfield 2 , A. Small 3 

1 Health Outcomes & Payer Support US Medical Affairs, Genentech, 

San Francisco, CA, UNITED STATES OF AMERICA, 2 HEOR - Observational 

Reserach, OptumInsight, Eden Prairie, MN, UNITED STATES OF AMERICA, 

3 Oncology, Outcomes Research, Us Meidcal Affairs, Genentech, San Francisco, 

CA, UNITED STATES OF AMERICA 

Background: Few studies have examined whether differences in treatment and 

outcomes exist among cancer patients by the setting where care is delivered. This 

study investigates differences in demographics, treatment patterns and health care 

resource use among non-Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic 

Leukemia (CLL) patients receiving rituximab (R) or R+ chemotherapy based on site 

of care: office/clinic (OC) vs. hospital outpatient (HO). 

Methods: Patients ≥18 years with evidence of NHL or CLL diagnoses codes at least 

30 days apart and received ≥2 R claims from Jan 2007 to Mar 2011 were identified 

from a large US commercial insurance claims database. Patients were required to be 

enrolled in the health plan for at least 6 months before and after the index date (date 

of first R claim). The follow-up period was the date of the first infusion to 30 days 

after the last infusion prior to a gap of ≥7 months. Patients with evidence of 

multiple cancers or receipt of R at both sites of care were excluded. Cohorts were 

created based on site of care where R was administered. Multivariate analyses 

examined differences in number of infusions, ER visits and inpatient stays by cohort. 

Results: There were 2,594 OC and 286 HO patients with a mean follow-up of 242 

days and 209 days, respectively. Compared to the HO cohort, the OC patients were 

significantly younger (71yrs vs. 63 yrs), had a lower mean baseline Charlson 

comorbidity index (3.88 vs. 3.40) and a lower percentage were Medicare 


Advantage enrollees (83% vs. 25%) [each p < 0.01]. The mean R infusion count was 

7.4 (OC) vs. 5.4 (HO) with a monthly mean of 1.19 (OC) vs. 1.00 (HO) [each 

p < 0.01]. In adjusted analyses, R infusion counts were also lower for HO compared 

to the OC cohort (IRR 0.80, CI 0.75-0.86) and HO patients had higher number of 

inpatient stays (IRR 1.40, CI 1.07-1.84) though ER visits were not different between 

cohorts. 

Conclusions: Patients treated in the OC setting compared to the HO setting had 

different treatment patterns and fewer inpatient stays. These results warrant further 

investigation to assess whether clinical outcomes differ by site of care. 

Disclosure: C. Reyes: Has Roche stock and employment at Genentech/Roche. S. 

Dacosta Byfield: Employed at OptumInsight, the entity that was paid by 

Genentech to conduct the study. A. Small: Has Roche stock and employment at 

Genentech/Roche. 

1385P ABBREVIATED COMPREHENSIVE GERIATRIC ASSESSMENT 

(CGA) IN ELDERLY CANCER PATIENTS: PRELIMINARY 

RESULTS OF AN OBSERVATIONAL PILOT STUDY 

O. Mora 1 , L. Marelli 2 , P. Quadri 3 , M. Tettamanti 4 , C. Pedrazzani 2 , M. Ghielmini 5 

1 Oncology, IOSI Istituto Oncologico Svizzera Italiana, Bellinzona, SWITZERLAND, 

2 Medical Oncology, IOSI Istituto Oncologico Svizzera ItalianaOspedale Regionale 

Bellinzona e Valli, Bellinzona, SWITZERLAND, 3 Internal Medicine, Geriatric 

Department, Ospedale Beata Vergine, Mendrisio, SWITZERLAND, 

4 Neuroscience, Istituto Mario Negri, Milano, ITALY, 5 Medical Oncology, IOSI 

Ospedale San Giovanni, Bellinzona, SWITZERLAND 

Background: In Western countries elderly people constitute the fastest growing 

segment of the population and currently in our Institute patients aged ≥70 are about 

45% of all cancer patients. CGA is a key component of the treatment approach for 

this population, but it is time-consuming. 

Methods: This is an observational pilot study on consecutive therapy-naive elderly 

cancer patients (aged ≥ 70 years). The main aims were to verify the feasibility of an 

abbreviated CGA (aCGA) in an outpatient setting, the acceptability by patients, 

physicians, and nurses as well as the ability of this tool to discriminate the three 

prognostic classes of older cancer patients: fit, vulnerable, frail. Patients underwent 

aCGA (which consisted in filling in some short questionnaires, instead of the 

standard ones) with a medical oncologist (medical history, clinical examination, 

ECOG-performance status, Cumulative Illnesses Rating Scale-CIRS) and with a nurse 

(Activities Daily Living-ADL, Instrumental ADL, Mini Nutritional 

Assessment-MNA, cognitive Short Blessed Test, Geriatric Depression Scale-GDS, 

Quality of Life Health Survey-SF-12, motor status). 

Results: From January 2010 to November 2011, 151 patients were enrolled. Median 

age was 77 (70-91) years, and 47% were males. Patients, doctors and nurses evaluated 

the information obtained by aCGA as, respectively: very useful in 47, 66, 42% and 

quite useful in 47, 28, 52%. The time required for the compilation of the 

questionnaires with nurses was 60 min in 17%. Physicians considered to have had no difficulty (83%) or little 

difficulty (10%) in compiling the form,. For nurses these figures were 40% and 43%. 

aCGA allowed to differentiate patients into three prognostic classes: fit 34%, 

vulnerable 36%, and frail 30%. Each of these classes was proposed for treatment 

which was curative in 76, 55, 35% of cases, palliative in 20, 35, 27% and supportive 

in 4, 10, 38% of cases, respectively. 

Conclusions: aCGA is feasible in the outpatient setting. It is usually well accepted by 

patients, medical staff and nurses. It allows a distinction of prognosis of elderly 

cancer patients favouring an appropriate therapeutic choice. 


1386P WILL ‘FIT’ OLDER CANCER PATIENTS AS ASSESSED BY 

FRAILTY SCREENING TOOLS TOLERATE THE FIRST CYCLE 

OF (RADIO) CHEMOTHERAPY WITHOUT SERIOUS ADVERSE 

EVENTS? 

A. Baitar 1 , F. van Fraeyenhove 1 , A. Vandebroek 1 , E. De Droogh 2 , 

D. Galdermans 2 , J. Mebis 3 , D. Schrijvers 1 

1 Medical Oncology, ZNA Middelheim, Antwerp, BELGIUM, 2 Pulmonology, ZNA 

Middelheim, Antwerp, BELGIUM, 3 Medical Oncology, Virga Jessa Hospital, 

Hasselt, BELGIUM 

Background: There is a need for tools to effectively select elderly cancer patients for 

therapies with significant potential toxicity such as chemotherapy. The Comprehensive 

Geriatric Assessment (CGA) is recommended by several guidelines to guide the 

oncologist in treatment decision making. However, because CGA is time and 

man-power consuming a two-step approach with screening has been recommended. 

This pilot study was undertaken to evaluate the predictive value of 2 frailty screening 

tools in relation to the tolerability of chemotherapy in ‘fit’ older cancer patients. 

Methods: Patients over 65 years with various types and stages of cancer were 

screened for CGA before start of treatment with the Groningen Frailty Indicator 

(GFI) and the G8 screening tool. ‘Fit’ patients were defined as having a normal 


screening test. A G8 score of ≤14 corresponds with an abnormal screening test. For 

the GFI we evaluated 2 cut-off values. Serious adverse events (SAE) were recorded 

during the first cycle of treatment. 

Results: From October 2009 to December 2011, 85 patients (44 women) were 

included in the study. The median age was 76 years old (range: 66-88 years). The 

treatment intent was curative in 39 patients (46%) and palliative in 46 patients 

(54%). In total, 15 patients (18%) had a SAE of which 3 resulted in death. According 

to the GFI, 60% were ‘fit’ while the G8 identified 30% as ‘fit’ prior to treatment. The 

probability to complete the 1e cycle of chemotherapy without a SAE for ‘fit’ patients 

was according to the G8 and the GFI (cut-off ≥4) respectively 77% (95%CI: 63-89%) 

and 78% (95%CI: 73-86%). The alternative cut-off ≥3 for the GFI resulted in 

probability of 85% (95%CI: 73-94%) to tolerate treatment. 

Conclusion: Patients with a normal screening test for CGA are considered to be able 

to tolerate proposed treatments comparable to younger patients. However, no data 

exist concerning this assumption. In this study, we attempted to address this in a 

heterogenic sample of older cancer patients for 2 screening tools. Further research is 

needed to compare standard of care with this CGA-based approach with screening. 


1387P PREDICTORS OF NONCOMPLETION OF CANCER 

TREATMENTS IN ELDERLY PATIENTS: THE ELDERLY 

CANCER PATIENTS (ELCAPA) COHORT STUDY 

M. Laurent 1 , E. Paillaud 1 , M. Carvalho-Verlinde 2 , P. Caillet 1 , A. Le Thuaut 3 , 

E. Liuu 1 , S. Bastuji-Garin 3 , S. Culine 4 , F. Canouï-Poitrine 3 

1 Consultation d’Onco-Gériatrie (UCOG Créteil), AP-HP, Hôpital Henri-Mondor, 

Département de Médecine Interne et Gériatrie, Créteil, FRANCE, 2 Service de 

Pharmacie, AP-HP, Hôpital Henri-Mondor, Créteil, FRANCE, 3 Pôle Recherche 

Clinique et Santé Publique, AP-HP, Hôpital Henri-Mondor, Créteil, FRANCE, 

4 Oncology, Hôpital Saint-Louis, Paris, FRANCE 

Background: The objective was to assess 1) prevalence and the predictors of 

non-completion of cancer treatments in elderly and 2) prognosis value of 

noncompletion of cancer treatments. 

Methods: Between 2007-2010, 421 consecutive patients aged 70 years and older with 

solid tumors and indication of surgery, chemotherapy (CT), hormonal therapy (HT) 

or radiotherapy (RT) were included. Comprehensive Geriatric Assessment was 

performed at baseline. Patients were followed up for completion of surgery, first line 

CT (observed/expected number of cycles < 1), RT and HT (observed/expected dose < 

1) and one year overall survival. Multivariate logistic regression and Cox 

-Proportional Hazard Model were used to estimate predictors of noncompletion 

treatments and survival. 

Results: Mean age was 79.2 years (±5.4) years and 224 patients (53.2%) were 

women.190 (45. 1%) had gastro-intestinal, 109 (25.9%) gynaecologic and 97 (23%) 

genitor-urinary primary tumors.192 (45.6%) had metastatic disease. 76 (33.8%) 

received platinum-based therapy. • Rate of noncompletion was 39.1 % for CT versus 

6.5 %, 3.5 % and 2.4 % for HT, surgery and RT respectively. In multivariate analysis, 

predictors of noncompletion of CT were: poor performance status (PS ≥ 2) : OR = 

2.1, 95 %CI, [1.06-4.17], p = 0.03, (or Activity of Daily Living (ADL): OR 1 point 

decrease= 1.5, [1.1-2.0], p= 0.024), decreased renal function: OR 1 ml/min decrease Cockcroft 

clearance = 1.02, [1-1.03],p= 0.009 and living alone :OR = 1.9, [1-3.6], p = 0.05. One 

year rate of mortality was 26.2 %. Independant prognostic factors for survival were 

noncompletion of CT: HR = 3.6, [2.2-6], p < 0.0001, a poor functional status (ADL 

HR 1 point decrease =1.5, [1.3-1.9], p < 0.0001, metastatic disease:.HR = 3.3, [1.7-6.3], p 

< 0.0001 and malnutrition: HR = 2.6, [1.6-4.4], p < 0.0001. 

Conclusion: In the elderly with solid tumors, noncompletion of CT was common 

whereas HT, RT and surgery were not. Predictors of noncompletion of CT are poor 

functional status, decreased renal function and living alone. Noncompletion of CT is 

an independent prognostic factor for survival. 


1388P COMPLEMENTARY AND ALTERNATIVE MEDICINES (CAM) – 

A CURSE TO BREAST CANCERS OF THE INDIAN 

SUBCONTINENT 

K. Chatterjee1 , S.K. Sarkar2 , S.K. Mondal3 , J. Goswami4 , B. Chatterjee5 1 

Oncology, Institute of Post Graduate Medical Education and Research 

(IPGMER&SSKM Hospital) Kolkata, Kolkata, INDIA, 2 Oncology, Medical College 

Kolkata, Kolkata, INDIA, 3 Oncology, R.G Kar Medical College and Hospital, 

Kolkata, INDIA, 4 Radiation Oncology, West Bank Hospital, Howrah, INDIA, 

5 

Medicine, Mahesh Bhattacharyya Homeopathic P.G Medical College and 

Hospital, Howrah, INDIA 

Purpose: In India, CAM practitioners get a major share of the first visits by patients 

with breast lumps, leading to inadvertent delays in their management. This 

multi-institutional prospective study conducted in IPGMER, M.C.H & R.G Kar, 

Kolkata, aims to quantify the exact percentage prevalence of CAM usage, 



demographic factors, magnitude of delay & subsequent prognostic losses incurred by 

this population. 

Methodology: The study included all breast cancer cases reporting for treatment & 

permitting to be interviewed, in three medical colleges of Kolkata, India, between 1 st 

Jan’2011 and 31 st Dec’2011. Patients initially treated by CAM were subjected to 

detailed Questionnaires, focused on CAM professionals involved in the first medical 

attention; Initial size of the tumor (Based on Lumpometer designed by TMH, 

Mumbai); initial presence of nodal disease; history of Biopsy; demographic charters; 

the perceived benefits of CAM; & the time & costs involved. They were then staged 

and treated according to their present status. 

Results: Analysis included 736 patients. Prior to reporting at the study centers 

35.37% (260) patients opted for CAM. Analysis of this group revealed, 73.07 % 

came from Rural areas; 67.3% had poor socio-economic status; 46.16% were 

uneducated; none were screened or Biopsied. Homeopathy is the commonest 

form of CAM resorted to 70.76 %; Ayurveda 9.6%; Quack Allopathy 16.15%; 

Unani 1.92% & Spiritual Healing 1.53%.The median duration of symptoms at 

the first visit to the CAM professional was10 weeks [2-18]. 65.38% had 

non-tender breast lumps. The median initial T- Size was 2.5 cm [1-6.5]; median 

time lost 9.3 months [1.5 -28] & median expenditures 980 Rs [150-3500]. The 

median T-size at presentation to the study centers was 4.2 cm [2.8-12.5]. New 

onset nodal disease was seen in 38.0 %; Changes in disease staging seen in 56.15 

%. The reasons were overlapping, unaffordability 51.92 %; inaccessibility 34.61%; 

38.46% feared disfigurement; homeopathy can liquefy tumors was reasoned by 

30.76%. 

Conclusion: With more than 1/3 of breast cancer patients still opting for CAM for 

obvious reasons, none biopsied, valuable 9.3 months lost & 56% presenting upstaged, 

the anticipated prognostic losses are unacceptably large. 


1389P USE OF INTEGRATIVE THERAPIES IN BREAST CANCER 

PATIENTS. HEALTH SERVICE RESEARCH IN A NETWORK OF 

INTEGRATIVE ONCOLOGY 

F. Schad 1 , J. Axtner 1 , A. Happe 1 , A. Voigt 2 , J. Gutsch 3 , G. Spahn 4 , 

C. Herbstreit 5 , M. Debus 6 , M. Kroez 1 , H. Matthes 7 

1 Network Oncology, Research Institute Havelhoehe (FIH), Berlin, GERMANY, 

2 Gynaecology, Hospital Herdecke, Herdecke, GERMANY, 3 Outpatient 

oncologist, Gevelsberg, GERMANY, 4 Center for Integrative Medicine and Cancer 

Therapies, Hospital Oeschelbronn, Niefern-Oeschelbronn, GERMANY, 

5 Gynaecology, Hospital Havelhoehe, Berlin, GERMANY, 6 Medical Care Center 

Havelhoehe, Outpatient Oncologist, Berlin, GERMANY, 7 Internal Medicine, 

Hospital Havelhoehe, Berlin, GERMANY 

Background: Diagnosis of breast cancer induces high emotional distress. 

Integrative oncology (IO) responds to patients needs by offering a variety of nonpharmacotherapeutic 

interventions (NPI) and Viscum album extracts (VA). VA 

enhances health-related quality of life and reduces adverse effects caused by 

conventional strategies, whereas NPI activate patients’ resources. In the present 

study we evaluated the use of IO therapies in breast cancer patients from a clinical 

registry. 

Methods: We analyzed 3289 female patients collected by the Network Oncology, a 

conjoint clinical registry of German hospitals and out-patient practitioners. We used 

non-parametric Fisher exact test (F) to compare observed frequencies, Wilcoxon rank 

sum (W), Kruskal-Wallis test (KW) for differences between groups. We fitted a 

logistic regression model to explain use of VA and NMI. 

Results: Mean age was 54.5 ± 11.7 and frequencies of UICC stages were 0: 71%, I: 

31%, II: 41%, III: 15% and IV: 7%. 93% of the patients got VA and were in median 

three years younger than non-VA patients (medVA= 52, W, p= 0.002). Median length 

of VA was 4.11 years (1 st Q 0.13, 3 rd Q 7.42) and was neither influenced by UICC nor 

age. Median time until start of VA after diagnosis was 7 month (1 st Q 2.31, 3 rd Q 

17.43). Radiation, chemotherapy and surgery were significantly associated with 

getting VA (β rad =1.07, p rad< 0.001; β che= 0.49, p che= 0.006; β sur= -1.47, p sur= 0.042). 

68% of the patients got NPI (eurythmy 60%, massages 52%, embrocations 51%, 

wrappings 51%, drawing 41%, modeling 13%, music 8%, psychological 6%, lymph 

drainage 6% and hyperthermal therapy 2%) and choose in median 4 different NPI. 

Frequencies of NPI quantities were affected by UICC stage (F, p< 0.001). Chemo 

therapy, UICC IV, III and radiation were significantly associated with receiving NPI 

(βche= -0.83, pche< 0.001; βIV =0.83, pIV= 0.001; βIII =0.62, pIII= 0.003; βrad= -0.28, 

prad= 0.003). 

Conclusions: In an IO setting VA and NPI are part of standard care and frequently 

used by breast cancer patients. Conventional therapies are major predictors if 

patients receive VA or NMI. Results suggest that health service research data provide 

a solid data basis for warranted prospective studies on outcome related studies in IO. 

Disclosure: H. Matthes: PD Dr. med. Harald Matthes is member of the board of 

directors of the Weleda A.G. Arlesheim/ Switzerland. All other authors have declared 


1390P PATIENT CHARACTERISTICS IN RENAL CELL CARCINOMA 

AND DAILY PRACTICE TREATMENT WITH SORAFENIB 

(PREDICT) IN CHINA 

D-W. Ye 1 , J. Guo 2 , A. Zhou 3 , Y. Huang 4 ,H.Li 5 ,Z.Hu 6 ,C.Fu 7 , J. Liu 8 , M. Irwin 9 , 

J. Ma 10 

1 Urologic Oncology Surgery, Fudan University Shanghai Cancer Center, 

Shanghai, CHINA, 2 Oncology, Beijing Cancer Hospital, Beijing, CHINA, 3 Urologic 

Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences, 

Beijing, CHINA, 4 Urologic Surgery, Shang Hai Ren Ji Hospital, Shanghai, CHINA, 

5 Urologic Surgery, Union Medical College Hospital, Beijing, CHINA, 6 Urologic 

Surgery, Tongji Hospital, Huazhong University of Science and Technology, 

Wuhan, CHINA, 7 Urologic Surgery, 7Liaoning Provincial Tumor Hospital, 

Shenyang, CHINA, 8 Urologic Surgery, Huaxi Hospital of Sichuan University, 

Chengdu, CHINA, 9 Medical, Bayer Healthcare Company Ltd, Beijing, CHINA, 

10 Urologic Oncology Surgery, Cancer Institute & Hospital, Chinese Academy of 

Medical Sciences, Beijing, CHINA 

Background: Sorafenib is indicated for the treatment of the patients with advanced 

renal cell carcinoma (RCC). This post-marketing surveillance study was to evaluate 

patient characteristics in RCC patients as well as the efficacy and safety of Sorafenib 

under daily-life treatment conditions after its regulatory approval. 

Methods: This was a prospective, non-interventional, non-controlled multi-center 

observational study (NCT00895674). Patients with advanced RCC and the 

decision taken by the investigator to prescribe sorafenib were involved in the 

study. 

Results: A total of 1033 patients were enrolled. 963 patients were included in the 

safety and 853 patients in the efficacy statistical analysis. Baseline characteristics were: 

71% male; median age 53.0 years (17∼85 years); 91% ECOG 0-2; 88.3% clear-cell 

histology; 24% high MSKCC risk; 30% >1 location of metastasis; 77.6 % prior 

nephrectomy; 59.2% prior systemic anticancer treatment. 12.9% of patients had 

pre-existing hypertension and 5.6% had diabetes mellitus. The median follow-up 

time of this study was 10.0months (mos).A clinical benefit was observed for 72.8 % 

of patients (n = 612/841) and radiologically for 71.0 % of patients (n = 597/841) at 

the last follow-up visit. Median PFS was 10.0mos. The median duration of sorafenib 

therapy was 10.0 mos, clinically relevant subgroups was as follows : > = 70 years 

(7.6mos), without nephrectomy (7.9mos), not purely clear histologic subtypes 

(7.3mos), >1 metastases site (8.6mos). There was no other demographic or baseline 

characteristics revealing any considerable differences. Treatment was well tolerated. 

97.7 % received a daily dose of 800 mg sorafenib, only 5.7% with dose reduction at 

last visit. Drug-related adverse events (AEs) were 32.61%. The most commonly 

reported AEs in this study were HFSR or Palmar-plantar erythrodysesthesia (19.4%), 

rash (7.0%), diarrhea (6.9%), alopecia (4.7%), hypertension (3.0%) and fatigue 

(1.5%). Most of the AEs reported were mild to moderate (72.1%) according to 

CTCAE. 

Conclusions: This study has shown baseline characteristics and safety of advanced 

RCC patients treated with sorafenib in Chinese real world setting. The results suggest 

that sorafenib is broadly beneficial for advanced RCC patients, regardless of baseline 

clinical charateristics and prior cancer treatment. 


1391P INTERPRETING OVERALL SURVIVAL (OS) RESULTS WHEN 

PROGRESSION FREE SURVIVAL (PFS) BENEFITS EXISTS IN 

TODAY’S ONCOLOGY LANDSCAPE - METASTATIC RENAL 

CELL CARCINOMA (MRCC) CASE STUDY 

S. Negrier 1 , Y. Tang 2 , C. Chen 3 , P. Bycott 2 

1 Dept. of Oncology, Centre Léon Bérard, Lyon, FRANCE, 2 Statistics, Pfizer, Inc, 

San Diego, CA, UNITED STATES OF AMERICA, 3 Global Outcomes Research, 

Pfizer, Inc, New York, NY, UNITED STATES OF AMERICA 

Background: New cancer treatments (tx’s) have clinical and health policy challenges 

to demonstrate a survival benefit over active tx after showing a PFS benefit. 

Subsequent tx and long post progression survival periods can lead to significant 

variability posing hurdles in showing OS benefit. The objective of this analysis was to 

examine the likelihood of OS benefit when a PFS benefit exists. We analyzed Phase 

III (P3) AXIS 2nd line trial data of axitinib versus sorafenib in mRCC employing 

methods described by Broglio et al 2009. 

Methods: We conducted simulations investigating the OS and PFS relationship 

utilizing the AXIS trial. OS was partitioned into 2 parts, expressed as the sum of PFS 

and survival post progression (SPP). We assumed a median SPP ranging from 6 to 

18 months. The actual observed trial pooled SPP was 12.9 months. Median SPP was 

assumed equal in both arms. The impact on OS was directly reflective of PFS 

translated into a survival benefit. We further assumed a median improvement in PFS 

to 6.8 months in the axitinib arm from 4.7 months for sorafenib which translated 

into a HR = 0.69, based on P3 results. By bootstrapping the censoring times the 

simulations preserved and mimicked observed accrual, follow-up patterns, and 

censoring percentage of the P3 trial. 


Results: Based on 10,000 simulations per median SPP value and a PFS HR = 0.69, 

the likelihood of randomly observing an OS HR >0.9 ranged from 65% to 74% and 

increased with increasing median SPP up to 16 months and then appeared to 

plateau. 

Conclusion: Between 65% and 74% of the time, the HR for OS was >0.9 even when 

the HR was 0.69 for PFS. This gain was assumed to translate directly into a survival 

advantage (median SPP per tx arm was assumed identical). This may be due to 

variability during SPP follow-up (e.g. subsequent tx) which dilutes the OS 

comparison making it difficult to show statistical significance (Broglio et al 2009). 

The probability increased with increasing SPP up to 16 months. These results have 

important health policy implications. Powering a P3 trial and the long follow-up 

needed to show a statistically significant OS improvement may be costly, and prolong 

clinical trial read out in RCC. 

Disclosure: S. Negrier: Recieved honoraria from Pfizer and Novartis, and grants/ 

research support from GlaxoSmithKline and Roche. Y. Tang: Pfizer employee and 

stock shareholder. C. Chen: Pfizer employee and stock shareholder. P. Bycott: Pfizer 

employee and stock shareholder. 

1392P INCREASED INCIDENCE OF RENAL CELL CARCINOMA 

(RCC) AMONG MELANOMA PATIENTS 

K. Kim, J. Kim, H. Ryu, A. Bedikian, N. Papadopolous, P. Hwu, W. Hwu, 

S. Patel 

Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, 


Purpose: There is scant evidence for an increased risk for developing RCC among 

melanoma patients (pts), and evidence for possible risk factors for the association 

between melanoma and RCC is lacking. We examined the risk of developing both 

melanoma and RCC, and also the possible risk factors. 

Methods: We searched our institutional tumor registry for pts with a diagnosis of 

melanoma and RCC. We used summary statistics to describe the population of pts 

and calculate total person-years at risk for RCC. We computed standardized 

incidence ratios (SIRs), which is the ratio of the observed to the expected number of 

pts with RCC among pts with melanoma using the Cohort Analysis for Genetic 

Epidemiology program. The expected number of pts with RCC was determined from 

SEER data. The 95% confidence intervals (CI) for the SIRs were determined by 

assuming a Poisson distribution for the observed number of RCC. SIRs were also 

calculated for subsets of the data according to race and gender. 

Results: Between 1980 and 2005, we identified 15,482 pts with a diagnosis of 

melanoma: 59% were male and 94% were white. Among these pts, 114 (0.7%) pts 

had a diagnosis of RCC either before or after the diagnosis of melanoma. The mean 

age of RCC presentation was 59.4 years. The total person-years at risk for RCC were 

886,506. We observed a significant excess of RCC (SIR = 1.64, 95% CI = 1.37-1.95) 

among our cohort of melanoma pts. This excess of RCC was also significant among 

white pts (SIR = 1.64, 95% CI = 1.36-1.92) and among both genders. None of the 114 

pts with a diagnosis of both melanoma and RCC had a concomitant diagnosis of 

immunocompromised disease nor received chronic immunosuppressive drugs. Only 

17% of the pts received radiation or chemotherapy for melanoma. 

Conclusions: There is an increase risk of RCC among melanoma pts. Neither 

preexisting immunocompromised condition nor the chronic use of 

immunosuppressants were risk factors for developing both malignancies. 

Group Observed Expected 

SIR (95% CI) for 

development of RCC 

All (n = 15482) 114 69.53 1.64 (1.37-1.95) 

Gender M (n = 9072) 

81 33 54.85 14.67 1.48 (1.19-1.82) 

F (n = 6410) 

2.25 (1.61-3.08) 

Ethnicity White (n = 14580) 109 5 66.37 3.15 1.64 (1.36-1.96) 

Non-White (n = 902) 

1.59 (0.70-3.25) 


1393P INCIDENCE OF HEPATITIS B AND C INFECTIONS IN EARLY 

BREAST CANCER PATIENTS AND IMPACT ON SYSTEMIC 

TREATMENTS 

A. Levaggi 1 , G. Iacono 1 , F. Poggio 1 , C. Bighin 1 , S. Giraudi 1 ,A.D’Alonzo 1 , 

M. Lambertini 1 , A. De Maria 2 , P. Pronzato 1 , L. Del Mastro 3 

1 Oncologia Medica A, IRCCS AOU San Martino - IST-Istituto Nazionale per la 

Ricerca sul Cancro, Genova, ITALY, 2 Scienze Della Salute Unige, IRCCS AOU 

San Martino-IST, Genova, ITALY, 3 SS Sviluppo Terapie Innovative, IRCCS AOU 

San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genova, ITALY 

Background: few data are available about the prevalence of hepatitis B (HB) and C 

(HC) infections in early breast cancer patients and its impact on systemic treatments. 


Methods: we retrospectively reviewed hepatitis B or C serology in 746 consecutive 

early breast cancer patients treated at National Institute for Cancer Research between 

January 2009 and March 2011. All patients were screened for hepatitis Bs antigen 

(HBsAg), HBc antibodies (HBcAb), HBs antibodies (HBsAb) and HC (HCV) 

antibodies. Data collected included patients and tumour characteristics, treatment 

received, changes in aminotransferases and impact on systemic treatment (delay or 

discontinuation). A comparison between patients with positive serology (cases) and 

patients with negative serology or vaccinated for HBV (controls) was performed. 

Results: 371 patients were excluded because serology was not available. Among 375 

evaluable patients we indentified 312 controls (83.2%) and 63 patients (16.8%) with 

positive serology defined as cases: 16 patients (4.2%) with HCV infection, 8 (2.1%) 

with occult HBV (HBsAg negative, HBsAg Ab negative, HBcAg Ab positive), 36 

(9.6%) with cleared HBV (HBsAg negative, HBsAg Ab positive, HBcAg Ab positive) 

and 4 (1%) with chronic HBV (HBsAg positive, HBsAg Ab negative, HBcAg Ab 

positive). Because of the lack of serum HBV DNA and HCV RNA evaluation, we 

adopted only a clinical definition of hepatitis, i.e. at least threefold increase in serum 

ALT level. Hepatitis, according to this definition, during systemic treatments 

occurred in 9 (20.4%) of 44 evaluable cases and in 14 (5.9%) of the 234 evaluable 

controls. The increase in transaminases resulted in discontinuation of systemic 

treatment in 3 patients (6.8%) among cases and in 2 patients (0.85%) in the control 

group. 

Conclusion: Nearly 16% of newly diagnosed breast cancer patients have positive 

serology for viral hepatitis and about 20% of them may develop hepatitis during 

systemic treatment. Pretreatment serum detection of viral hepatitis B and C antigen 

and antibodies may be useful for adeguate monitoring of liver function during 

anti-cancer therapy. 


1394P THE RELATIONSHIP BETWEEN PREECLAMPSIA, 

PREGNANCY-INDUCED HYPERTENSION AND MATERNAL 

RISK OF BREAST CANCER: A META-ANALYSIS 

J.S. Kim 1 , Y.J. Choi 2 

1 Hemato-oncology, Korea University Medical Center, Seoul, KOREA, 2 Oncology, 

Asan Medical Center, Seoul, KOREA 

It has long been recognized that some human breast cancers are “hormone 

dependent”. Preeclampsia is a syndrome of pregnancy defined by the onset of 

hypertension and proteinuria and characterized by dysfunction of the maternal 

endothelium. Many hormonal changes occur with preeclampsia, and we hypothesize 

that these changes may influence the risk of maternal breast cancer. We also 

analyzed relation between PIH and maternal risk of breast cancer. Among 13 

relevant publications about preeclampsia and 6 relevant publications about PIH, 

some studies might be associated with a lower risk of breast cancer, but others did 

not. Therefore these results are inconclusive. According to pooled results, reduced 

breast cancer risk with preeclampsia was not shown in our meta-analysis (HR = 0.86; 

95% C.I = 0.73-1.01, p = 0.06); however, a trend toward reduced maternal risk of 

breast cancer was identified. The effect of PIH was similar to that of preeclampsia 

(HR = 0.83; 95% C.I = 0.66-1.06, p = 0.13). The results of this meta-analysis suggest 

that preeclampsia and PIH do not significantly decrease the maternal risk of breast 

cancer. 


1395P A PRELIMINARY STUDY OF THE EFFECT AND MECHANISM 

OF 1,25 (OH) 2D3 ON LUNG ADENOCARCINOMA CELL 

PROLIFERATION AND DIFFERENTIATION 

R. Li 1 ,Y.Lou 2 , L. Xiong 2 ,A.Gu 2 , B. Han 2 , Q. Dong 3 

1 Department of Pulmonary Medicine, 1 Shanghai Chest Hospital affiliated to 

Shanghai Jiaotong University, Shanghai, CHINA, 2 Department of Pulmonary 

Medicine, Shanghai Chest Hospital affiliated to Shanghai Jiaotong University, 

Shanghai, CHINA, 3 Cancer Stem Cells and Tumor Diagnosis, Shanghai Cancer 

Institute, Shanghai, CHINA 

Background: OCT4 + bronchioloalveolar stem cell (BASC) is a type of cancer stem 

cell (CSC)-like cell, and threat to the survival of lung cancer patients. Vitamin D has 

a certain role in tumor prevention and treatment, but the relationship between 

vitamin D and lung adenocarcinoma is still unclear. 

Objective: To make clear if lung cancer patients occur with vitamin D deficiency in 

China. Analyze the relationship between vitamin D levels and the pathology. To 

analyze the role of vitamin D on the differentiation of CSC-like, AT2-like and 

AT1-like lung adenocarcinoma cells. 

Methods: Chemiluminescence detection was used to detect serum 25(OH)D 

concentrations. The expression of CCSP, SP-C, OCT4, SP-B on CSC-like, AT2-like 

and AT1-like lung adenocarcinoma cells were detected by immunofluorescence 

detection. The CCK8 assay and the immunofluorescence detection were used 

separately to detect proliferation activity and the expression of OCT4 for the OCT4 

+BASC. 



Results: The mean serum 25(OH)D concentration of 197 cases with lung cancer in 

China was 10.63 ± 7.04ng/mL; the proportion of vitamin D deficiency was 173/197 in 

all patients, 103/112 in adenocarcinoma. and 31/39 in squamous cell carcinoma. The 

vitamin D deficiency ratio was higher in adenocarcinoma than in squamous cell 

carcinoma, p= 0.043. PGJ2\DFOM can induce OCT4 + BASC to be CCSP-\SP-C + 

\OCT4- cell, and then 1,25(OH)2D3 can prevent the expression re-recovery of 

OCT-4 and CCSP. DAPT significantly lowered CCSP expression in OCT4 + BASC, 

and then 1,25(OH)2D3 can make it become OCT4-\SP-C-\CCSP-\SP-B+ cell, which 

is a mature AT2-like cell. 1,25(OH)2D3 has no effect on OCT4 + BASC or AT1-like 

cell differentiation. 

Conclusion: Lung cancer patients are generally lacking vitamin D, and lung 

adenocarcinoma patients are more likely to be lacking vitamin D. 1,25(OH)2D3 can 

promote lung adenocarcinoma progenitor cell differentiation. 


1396P KBP-2010-CPHG: CHARACTERISTICS OF 6,083 NEW CASES 

OF NSCLC ACCORDING TO SEX 

D. Debieuvre 1 , C. Locher 2 , I. Bourlaud 3 , M. Zaegel 4 , M. Le Poulain-Doubliez 5 , 

J. Piquet 6 , T. Collon 6 , F. Martin 7 , F. Blanchon 2 , M. Grivaux 2 

1 Pneumology, General Hospital, Mulhouse, FRANCE, 2 Pneumology, General 

Hospital, Meaux, FRANCE, 3 Pneumology, General Hospital, Niort, FRANCE, 

4 Pneumology, General Hospital, Le-Coudray-Chartres, FRANCE, 5 Pneumology, 

General Hospital Manchester, Charleville-Mézières, FRANCE, 6 Pneumology, 

General Hospital, Montfermeil-Le-Raincy, FRANCE, 7 Pneumology, General 

Hospital, Compiègne, FRANCE 

Lung cancer is a major public health problem due to its continued increase. In 

2010, the French College of General Hospital Respiratory Physicians (CPHG) 

performed a prospective multicenter epidemiological study (KBP-2010-CPHG) to 

describe the baseline characteristics and management of all new cases of primary 

lung cancer; to evaluate 1, 4 and 5-year patient survival rates; and to compare 

results with those from a similar study performed 10 years ago (KBP-2000-CPHG). 

Data were collected on a standardized form for all patients ≥18 years with primary 

lung cancer, histologically or cytologically diagnosed between January 1 and 

December 31, 2010 and managed in a general hospital. 7,610 patients were enrolled 

in 119 centers. 6,083 patients (86.3%) had non-small-cell lung cancer (NSCLC); 

among them, 24.4% were female (vs. 16% in 2000; p < .0001). There was no 

difference between male and female NSCLC patients regarding age (65.7± 10.9 vs. 

64.9± 13.0, p = 0.03). Regarding smoking status, between 2000 and 2010, women 

remained more frequently non-smoker compared to men (34.2% vs. 4.7%), less 

frequently former smoker (21.3% vs. 46.8%) and showed lower consumption (37.2 

vs. 43.7 PY) (p < .0001). However, in 2010, the percentage of non-smokers nearly 

doubled in men (2.5% vs. 4.7%; p < .0001) whereas it remained stable in female (p 

< .32). Regarding tumor characteristics, between 2000 and 2010, the percentage of 

adenocarcinomas significantly increased in both women (53.4% in 2000 vs. 65.9% in 

2010; p < .0001) and men (32.4% vs. 49.4%; p < .0001). However, in 2010, tumors 

remained more frequently adenocarcinomas in women than in men (65.9% 

vs.49.4%; p < .0001). In addition, in 2010, when explored (48.5% in women vs. 

31.0% in men; p < .001), an EGFR mutation was more frequently found in women 

than men (20.6% vs. 5.2%; p < .0001), stage IV tumor was more frequent in women 

than men (62.4% vs. 56.9%; p = 0.0008), and regarding first-line treatment, 64.5% of 

women vs. 61.0% of men (p = .01) received chemotherapy and 13.4% of women vs. 

5.7% of men (p < .0001) targeted therapy. In 10 years, percentages of women, 

non-smokers among men, and adenocarcinomas in both men and women 

increased. However, differences between women and men in baseline and tumor 

characteristics persist. 


1397P CARDIAC SAFETY OF (NEO) ADJUVANT TRASTUZUMAB IN 

THE BRAZILIAN COMMUNITY SETTING: A SINGLE CENTER 

EXPERIENCE 

L.G. Fonseca 1 , T.K. Takahashi 2 , M.P. Mak 2 , R. Barroso-Sousa 1 , L. Testa 2 ,V. 

Petry Helena 1 , R. De Paula Costa 1 , P.M. Hoff 1 , M.S. Mano 1 

1 Medical Oncology, ICESP, Sao Paulo, BRAZIL, 2 Medical Oncology, Instituto do 

Cancer do Estado de Sao Paulo ICESP, Sao Paulo, BRAZIL 

Background: Trastuzumab-associated cardiotoxicity (TAC) has been established in 

the context of clinical trials. However, when newly registered agents are used in a 

broader patient population, their safety profile does not always mirror that of the 

pivotal trials. Trastuzumab (T) only became available in the Brazilian public sector in 

2008 and herein we report our off-trial experience so far. 

Methods: Retrospective, single center cohort of HER-2 positive breast cancer patients 

(pts) treated with (neo)adjuvant chemotherapy and T from July 2008 to March 2012. 

95.3% were treated according to local protocol (11.4% TCH; 83.9% AC-TH). Major 

cardiac event (MCE) was defined as a left ventricular ejection fraction (LVEF) drop 

of 10% and absolute drop to < 50 % by echocardiogram (ECHO) or as symptomatic 

heart failure (HF) regardless of the LVEF value or any cardiac event considered 

clinically meaningful. A multivariable Cox proportional hazards model was used to 

control for other cardiac risk factors. 

Results: 237 women were identified: median age 53 y (27-83), 99.6% ECOG-PS 0-1, 

median body mass index 27.4 kg/m 2 (17 – 46), 30.4% had hypertension (HTN), 8.8% 

had diabetes mellitus (DM), 5.9% had previous cardiopathy. 54.8% had ER-positive 

tumors; 40.7% received neoadjuvant T; most were stage II or III (22.3% and 37.1%). 

Median number of ECHO assessments was 2.7 (0-6); 136 pts (57.2%) completed T as 

planned. 20.2% had MCE (13.9% discontinued T). 3.8% discontinued T due to 

symptomatic HF and 5% for non-cardiac reasons. 41.6% of MCE pts recovered 

cardiac function. Median initial LVEF was 64.83 ± 1.5 % (no event) vs 64.81 ± 1.5 % 

(MCE) p = 0.26; median 3-month LFVE was 64.67 ± 4 % (no event) vs 56.12 ± 3 % 

(MCE) p = 0.0036. HTN, DM, obesity, age, radiotherapy, use of anthracycline and 

previous cardiopathy were not significantly associated with TAC. 

Conclusions: Our results suggest that TAC in our routine practice is slightly higher 

than reported in literature (6 to 17%), possibly reflecting selection bias in clinical 

trials. Symptomatic TAC was as expected for AC-TH (4%). We failed to identify risk 

factors for TAC, possibly due to the low number of events. Cardiac function must be 

closely monitored during T treatment and careful pt selection is crucial. 


1398P CLINICO-PATHOLOGICAL CHARACTERISTICS AND 

TREATMENT OUTCOME OF YOUNG BREAST CANCER 

PATIENTS: AN INSTITUTIONAL STUDY 

V. Raina 1 , A. Gogia 2 , S.V.S. Deo 3 , B.K. Mohanti 4 , N.K. Shukla 3 


Institute Rotary Cancer Hospital, New Delhi, INDIA, 2 Medical Oncology, All India 

Institute of Medical Sciences (AIIMS) Institute Rotary Cancer Hospital, New Delhi, 

INDIA, 3 Surgical Oncology, AIIMS, New Delhi, INDIA, 4 Radiation Oncology, All 

India Institute of Medical Sciences (AIIMS) Institute Rotary Cancer Hospital, New 

Delhi, INDIA 

Background: Breast cancer in young women (right side). Ninety percent of patients were married and median age at first child 

birth was 23 years. Positive family history was elicited in 10 patients. Five patients 

presented with synchronous malignancy. The TNM (7th edition) stage distribution was 

stage I - 2.5 %, stage II - 30%, stage III - 46.5%, and stage IV - 22%. The median clinical 

tumor size was 5.0 cm. Modified radical mastectomy was the commonest surgical 

procedure and this was done in 83 % of cases. The histopathological analysis showed 

94% had infiltrating ductal carcinoma. Thirty percent of tumors were high grade and 

70% had pathological node-positive disease. ER/PR and Her2neu positivity was 33% and 

29%, respectively. Triple-negative breast cancer (TNBC) constituted 31%. A combination 

of anthracyclines and taxanes were used in the majority of patients and trastuzumab was 

used only in 3 % of cases. With a median follow up of 28 months (non-metastatic 

group), 3-year disease-free survival (DFS) and overall survival (OS) was 50% and 60%. 

Higher Nodal stage, tumor size (>5 cm), negative hormonal status (triple negative) and 

visceral metastasis at baseline predicted poor outcome. 

Conclusion: Young women constituted 7.5 % of breast cancer cases. The proportion 

of triple negative (nearly one third) was also higher than the Western population. 

Higher stage and triple negative status results in poorer outcome. 


1399P MALNUTRITION AS A DETERMINANT OF OUTCOME OF 

PEDIATRIC CANCER PATIENTS 

S. Banerjee 1 , S. Mukhopadhyay 1 , S. Gangopadhyay 1 , A. Mukhopadhyay 2 

1 Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, 

Kolkata, INDIA, 2 Medical Oncology, Netaji Subhas Chandra Bose Cancer 


Childhood cancer is curable. Malnutrition poses a major problem amongst Indian 

children with around 40% of them suffering from undernourishment and starvation. 

It is one of the causes of poor outcome and toxicity of cancer patients. This study 

will help to highlight the close knitted relationship between the nutritional status and 

its influence on complete remission, disease free survival (DFS) and 

chemotherapeutic toxicity. In the present study, 500 cancer affected children were 

analyzed, who were being treated during a period from Jan, 2007 to Dec, 2011. The 

age range was 1-18 years (mean 12.5 years). There was male preponderance. 

Distribution of cases: Acute lymphoblastic leukemia 42%, Acute myeloid leukemia 

8%, Non Hodgkin’s and Hodgkin’s leukemia 14%, Rhabdomyosarcoma and other 


cancer tumors 12%, Germ cell tumor 8%, Brain tumor 4% and other 12%. During 

preliminary diagnosis of these patients prior to beginning of therapy, an initial 

anthropometry was done in all the cases that included measurements of Weight for 

age (WFA), Height for age (HFA), Mid arm circumference (MAC) and Biceps Skin 

Fold Thickness (BSFT). The values of these variables were compared with the ICMR 

recommended standards provided by percentile curve of the growth chart for that 

age and sex. BSFT lies between 3.8cm and 6.5cm but during malnutrition it falls 

below 3.8cm. We pursued initial diagnosis based on biochemical parameters, chiefly, 

serum total protein and serum albumin levels. The albumin level was considered 

normal if the value was equal to or more than 3g%. It was seen that 190 (38%) 

children were malnourished on diagnosis. The patients with malnutrition had poor 

outcome (45%) as compared to well-nourished children (80%). Malnourished 

children also showed significantly higher toxicity level (p < .0001). Hence we 

concluded that malnutrition was an important determinant factor for outcome of 

pediatric cancer patients. Next we would like to focus on assessment of nutritional 

status in children starting cancer chemotherapy, radiology and surgery. 


1400P IATRIGGER PROJECT: DEVELOPMENT AND VALIDATION OF 

A TOOL TO EVALUATE ADVERSE DRUGS EVENTS IN 

ONCOLOGY PATIENTS 

G. Hebert 1 , F. Netzer 1 , A. Fourcade 2 , M. Ducreux 3 , E. Minvielle 2 , F. Lemare 1 

1 Clinical Pharmacy, Institut Gustave Roussy, Villejuif, FRANCE, 2 Quality, Institut 

Gustave Roussy, Villejuif, FRANCE, 3 Oncologie Digestive, Institut de Cancérologie 

Gustave Roussy, Villejuif, FRANCE 

Objective: Adverse events related to drugs occur frequently and many of them are 

preventable. Despite cancer treatment are known to involve hazardous drugs, there 

are few practical methods to identify adverse drug events (ADEs) and measure harm 

to the patient. The purpose of this work was to develop a tool for adverse event 

detection in oncology patients. 

Methods: The Trigger Tool approach has been developed and tested in oncology. First, 

27 triggers were identified and flowcharts were constructed, based on international, 

national or local recommendations. Second, 11 clinical experts have validated the 

content of each trigger on three criteria: the criticality of the adverse event, the 

educational value of feedback, and the clinical relevance of the analysis. For each trigger, 

severity has been graded according to the NCI CTCAE 4.03. Third, the feasibility of the 

analysis based on a random sample of 130 patient records has been assessed through the 

time of analysis for each patient record, and the number of trigger and ADE observed. 

Results: Experts evaluated the criticality of the 27 triggers from 5.1 to 10.9/25 and 

their educational value from 4.5 to 7.7/10. Regarding the feasibility analysis, 1157 

hospital-bed days were reviewed from October 2010 to March 2011.It revealed 387 

positive triggers, 80 of which are adverse events and 46 were drug related (ADE). 

The study counted 0.6 ADE/patient, including 1 grade 3 or more ADE for 11.8 

patients. The most frequently observed ADE were constipation (7 ADE), fall (5 

ADE), hypo/hyperglycemia (4 ADE), hypo/hyperkaliemia (3 ADE). The average time 

of analysis was established at 26min35s by patient record. Based on these results, 22 

triggers have been preserved, composing the Iatrigger tool. 

Conclusion: ADE detection is an important priority in patient safety research. The 

use of a ADE detection method requires some resource commitments. However, a 

validated tool like the Iatrigger tool can be applied in different hospital settings, 

allowing a precise follow-up of this particularly frail population. 


1401P ESSOR STUDY: ORAL CHEMOTHERAPIES FOR ONCOLOGY 

PRACTICES: A RETROSPECTIVE ANALYSIS IN THE 

COMMUNITY SETTING FOR SELECTED DRUGS 

F. Grude 1 , J. Douillard 2 , C. El Kouri 3 , P. Donny 4 , M. Urbanski 5 , A. Chaslerie 4 , 

S. Piau 4 , H. Bourgeois 6 , J. Metges 7 , J. Pivette 4 

1 ICO Paul Papin, Observatoire dédié au Cancer, Angers, FRANCE, 2 Medical 

Oncology, Centre René Gauducheau (ICO) Institut de Cancerologie de l’Ouest, 

St Herblain Cedex, FRANCE, 3 Medical Oncology, Catherine de Sienne Institute, 

Nantes, FRANCE, 4 Pharmacy, DRSM Nantes Pays de la Loire, Nantes, FRANCE, 

5 Pharmacy, DRSM Rennes Bretagne, Rennes, FRANCE, 6 Medical Oncology, 

Centre Jean Bernard, Clinique Victor Hugo, Le Mans, FRANCE, 7 Medical 

Oncology, C.H.U. Morvan Institut de Cancerologie et d’Hematologie, Brest 

Cedex, FRANCE 

Background: Use of oral chemotherapies is still increasing: currently it represents 

about 10% of anti-cancer drugs. In 2015, it might be between 25-30%. Oral drugs 

take part in the increased survival and improvement of patient’s quality of life. The 

Observatory of Cancer Bretagne – Pays de la Loire and the French Regional Health 

Insurance System had made an observationnal study of oral cancer drug use in theses 

two area (10% of French Population). 

Methods: French Regional Health Insurance System has made an extract in its 

database for patients treated with oral cancer drugs (erlotinib, everolimus, gefitinib, 


sorafenib, sunitinib) between september 2009 and the end of 2010 (projected 

three-year follow-up) : prescriber (competence in oncology or not), patient care 

reimbursed by the health insurance system, gender, age, death, cancer location, type 

of drug have been collected. 

Results: 1313 patients (846 men and 437 women) were analysed: 630 patients from 

Brittany and 683 from Pays de la Loire. According to the National health system, 

13.5% of patients did not have optimal reimbursement for care. 30% of patients were 

under 59 years old, 35% between 60 and 69 and 35% over 70. The more significant 

cancer location was lung (53%), kidney (26%), digestive tract (19%) and breast (2%). 

Indeed oral cancer drugs have greatly improved the management of patients with 

non small cell lung cancer (erlotinib, gefitinib) or kidney cancer (sunitinib, sorafenib, 

everolimus). More than half of patients (52%) died between 2010 and the end of 

April 2011. 74% of patients have taken oral drugs for the first time in 2010. 82% of 

prescriptions have been done according to oral chemotherapy label (10 % for another 

cancer; 8 % insufficient data). 5% of patient have received more than a first line oral 

drug during the follow-up (mainly for kidney cancer). 

Conclusions: Few data have been published about successive oral chemotherapies and 

their impact on clinical response, overall survival, toxicities and quality of live. That’s 

why we wanted to complete these data via two dedicated studies about kidney cancer 

(IVOIRE) and lung cancer (EPINIB). Moreover, compliance of patients treated for a 

kidney cancer, toxicity of treatment and drugs interaction will be evaluated via a 

pharmaco economic approach through face to face interview (TOPTACOS). 


1402P DRUG INTERACTIONS IN CANCER PATIENTS TREATED 

WITH ORAL ANTI-CANCER DRUGS 

R.W. van Leeuwen 1 , D.H.S. Brundel 1 , C. Neef 2 , R.H.J. Mathijssen 3 , T. van 

Gelder 4 , D.M. Burger 5 , F.G.A. Jansman 6 

1 Department of Pharmacy, Erasmus University Medical Center, Rotterdam, 

NETHERLANDS, 2 Department of Clinical Pharmacy and Toxicology, Maastricht 

University Medical Center, Maastricht, NETHERLANDS, 3 Department of Medical 

Oncology, Erasmus University Medical Center, Rotterdam, NETHERLANDS, 

4 Departments of Internal Medicine and Hospital Pharmacy, Erasmus University 

Medical Center, Rotterdam, NETHERLANDS, 5 Department of Pharmacy & 

Radboud University Center for Oncology (RUCO), Radboud University Medical 

Center, Nijmegen, NETHERLANDS, 6 Department of Clinical Pharmacy, Deventer 

Hospital, Deventer, NETHERLANDS 

Background: Drug-drug interactions (DDIs) in patients with cancer are common, 

and most DDIs can cause considerable adverse reactions. At present, epidemiological 

data regarding DDIs in oral anti-cancer therapy is totally absent in the literature. 

Therefore, we assessed the prevalence of DDIs among ambulatory cancer patients on 

oral anti-cancer treatment. 

Methods: A search was conducted in a computer based medication prescription 

system for dispensing oral anti-cancer drugs to out-patients. DDIs were identified 

using electronic (Drug Interaction Fact software) and manual screening methods 

(peer-reviewed reports). DDIs were classified by the level of severity and the level of 

scientific evidence. Descriptive statistics and binary logistic regression analyses were 

performed to analyze the data. 

Findings: In the 898 patients included in the study, 1359 DDIs were identified in 

426 patients [46%, 95% confidence interval [CI] = 42% to 50%]. In 143 patients 

(16%) a major DDI was identified. The drug classes most frequently involved in a 

major DDI were coumarins and opioids. The majority of cases concerned central 

nervous system interactions (73%). DDIs that can cause gastrointestinal toxicity or 

prolongation of QT intervals were also seen frequently. In multivariate analysis, 

concomitant use of more drugs [odds ratio [OR] = 1.66, 95% [CI] = 1.54-1.78, P 


Aim: To develop a comprehensive database on the availability and accessibility of 

opioid medication for the management of cancer pain in: Africa, Asia, Latin America 

and the Caribbean and Middle East. The adequacy of formulary availability is 

evaluated relative to the International Association of Hospice and Palliative Care list 

of Essential Medicines for Palliative Care. Overregulation is evaluated according to 

descriptors identified by the World Health Organization and the International 

Narcotics Control Board. 

Results: Between 12/2010-7/2012, 156 reports were submitted from identified 

reporters in 76 countries and 19 Indian states (58% countries, 83% population). Very 

few countries provide all 7 opioids on the essential drug list of the IAHPC (codeine, 

immediate and slow release oral morphine, oral IR oxycodone and transdermal 

fentanyl) and in many countries less than 3/7 drugs are available. Furthermore, in 

most of the countries opioids are either not or are weakly subsidised by gov. and 

availability is often limited. Many countries have highly restrictive regulations that 

limit entitlement of cancer patients to receive prescriptions, limit prescriber 

privileges, impose restrictive limits on duration of prescription, restrict dispensing, 

and increase bureaucratic burden of the prescribing and dispensing process. 

Conclusions: In many places across Africa, Asia, ME and L + C America 

governments are failing cancer patients in delivery of adequate pain relief. There is a 

need for increased availability of affordable opioids for the management of cancer 

pain. A priority action is examination of drug control policies and repeal of excessive 

restrictions which impede this most fundamental aspect of cancer care. 

1403 FEASIBILITY ANALYSIS OF THE WINHO INDICATORS FOR 

OUTPATIENT CARE IN ONCOLOGY 

R.E. Buschmann-Maiworm 1 , W. Baumann 1 , A. Zimmermann 1 , S. Schmitz 2 ,U. 

R. Kleeberg 3 

1 WINHO, Cologne, GERMANY, 2 Hämatologie und Onkologie, 

Gemeinschaftspraxis, Cologne, GERMANY, 3 Hämatologie & Onkologie und 

Palliativmedizin, Hämatologisch-onkologische Praxis Altona HOPA, Hamburg, 

GERMANY 

Background: WINHO is an oncologist-led research department working on quality 

improvement and assurance and health care services research for out-patient care in 

Germany. A quality indicator project started in the middle of 2009. The project 

consists of 3 main parts: A) development of relevant measures, B) feasibility test, C) 

pilot study. QOPI is an important model for the scope of application and the 

methodological approach of the WINHO project. Taking into account the unique 

needs of the German health care system, a set of 46 relevant, evidence and consensus 

based quality measures has been developed. This was done with reference to 

internationally available indicator systems (QOPI, PQRSI and other sources). 13 

measures were newly developed by WINHO. This presentation is about the feasibility 

test (part B) of the WINHO quality indicator project. 

Methods: The feasibility analysis consists of 4 elements: 1. feasibility ratings of the 

expert panel (n = 15) in the RAND/UCLA procedure during part A of the project, 

2. distribution of a feasibility questionnaire among office-based oncologists, 

3. semi-structured depth interviews with 7 office-based oncologists, 4. randomized, 

retrospective chart abstraction from 59 charts for all 46 measures. 

Results: 2176 feasibility questionnaires went into statistical analysis (response rate 50 

%). Results from the questionnaire, interviews and trial chart abstraction show that 

the main problem lies within the retrieval of data from charts. Reasons for these 

findings may be the use of different electronic documentation systems, individual 

documentation habits and/or documentation of crucial information in running text. 

The estimated time to retrieve all data to calculate an indicator varies widely. A pilot 

study about the implementation of a routine data collection already started. 

(Supported by Deutsche Krebshilfe e. V.). 


1404 INTERNET USE BY CANCER PATIENTS AND THEIR 

RELATIVES: AN USEFUL INFORMATION TOOL IR OUR 

COUNTRY OR A CONFUSION ELEMENT? : FINAL RESULTS OF 

OUR STUDY 

C.O. Ruiperez 1 , M.L. Gomez 2 , M. Molina-Garido 3 , L.H. Martinez 4 ,A. 

Olaverri Hernandez 1 , M. Muñoz Sanchez 3 , J. Santiago Crespo 3 , F. Lobo 5 , 

A. Carrato 6 , J. Feliu 7 

1 Medical Oncology, Virgen de la Luz Hospital, Cuenca, SPAIN, 2 Medical 

Oncology Department, Infanta Sofia University Hospital, San Sebastian de los 

Reyes, SPAIN, 3 Medical Oncology, Hospital General Virgen de la Luz de Cuenca, 

Cuenca, SPAIN, 4 Medical Oncology, Spanish Association against Cancer 

(AECC), Cuenca, SPAIN, 5 Servicio de Oncologia, Fundacion Jeminez DiazClin 

Nstra Senora de la Concepcion, Madrid, SPAIN, 6 Medical Oncology, Hospital 

Ramon y Cajal, Madrid, SPAIN, 7 Medical Oncology, La Paz University Hospital, 

Madrid, SPAIN 

Introduction and objectives: To analyze Internet use in Cancer patients and their 

relatives, the type of information they obtained online, its usefulness and its impact 

on the patient-physician relationship and in treatment decisions. 

Materials and methods: Questionnaires were distributed to cancer patients (304) 

and their companions (231). The population sample came from a tertiary urban 

hospital in downtown Madrid, a secundary urban hospital in Cuenca, and two rural 

clinics in Ciudad Real. Student t-tests, chi-square tests and multivariate regression 

logistic analysis were carried out. The study was approved by the local ethics 

committee, and participants written informed consent. 

Results: Internet use was relatively low (35,2% patients, 55,8% relatives); Cancer specific 

information and treatment options were the main research topics between patients. In 

both subgrups, internet use was stadistical significative correlated with study levels 

(24,5% and 38,6% had Universitary studies ). No statistical differences between rural 

and urban population. Only 12% patients discussed the obtained information with their 

clinicians. The quality of the information was unreliable: 20% patients considered the 

information average or bad, and 16% felt more confused after Internet search. For 38% 

patients, the information had been useful; however, 9,6% patients did not think that 

Internet information was important to decide the type of treatment. 

Conclusions: Internet use to obtain medical information, is a tool which gets more 

and more useful in Oncology patients and their relatives in our country. Quality 

information is highly unrealible, althought it helps patients to cope better with 

cancer. A low percentaje of patients discusses the information with the physician. 


1405 QUALITY INDICATORS AND NON SMALL CELL LUNG CANCER 

INTEGRATED CARE PATHWAY: A SINGLE-CENTER 

EXPERIENCE 

J. Menis 1 , A. Follador 1 , F. Valent 2 , C. Rossetto 1 , M. Gaiardo 1 , L. Gurrieri 1 , 

E. Lugatti 3 , S. Pizzolitto 4 , V. Tozzi 5 , G. Fasola 1 

1 Department of Medical Oncology, University Hospital Santa Maria della 

Misericordia, Udine, ITALY, 2 Statistics, Friuli Venezia Giulia, Udine, ITALY, 3 Chest 

Medicine, University Hospital Santa Maria della Misericordia, Udine, ITALY, 

4 Pathology, University Hospital Santa Maria della Misericordia, Udine, ITALY, 

5 ICP Research Responsible, University Bocconi, Milan, ITALY 

Background: Non Small Cell Lung Cancer (NSCLC) diagnosis and treatment is a 

highly complex process, requiring managerial skills merged with clinical knowledge 

and experience. Integrated Care Pathways (ICP) might be a good strategy to overview 

and improve patient’s management. The aim of our study was to review our NSCLC 

patient’s ICP in order to provide evidence of clinical or organizational 

inappropriateness. 

Methods: We retrospectively reviewed the electronic medical records of 169 NSCLC 

patients who had had a first access at the Oncology Department of the University 

Hospital Santa Maria della Misericordia (Udine, Italy) during 2010. The ICP 

mapping and few quality indicators had already been settled by a previous study on 

the 2008 population and were integrated with new uptodate indicators selected from 

scientific literature and discussed at the weekly MDT. 

Results: 146 patients were considered eligible; median age was 67 years old. 

Patients were mainly males (65%), had adenocarcinoma histology and advanced 

disease at the time of diagnosis (52.7%). Distant from benchmark were the 

percentage of diagnostic bronchoscopic procedures (60.7 vs 80-85%), the number 

of surgical candidates who underwent mediastinoscopy for positive PET for 

mediastinal nodes (0 vs 100%), median time from diagnosis to surgery and to 

chemotherapy (58.5 vs 21 and 34 vs 21 days; p < 0.0001) and median time from 

PET to surgery (53.5 vs 14 days; p < 0.0001). No extemporary citology during 

bronchoscopy was performed and only 42.8% of the patients received concomitant 

chemo-radiotherapy for stage III disease. Stage was the only indipendent variable 

associated with shorter time from first chest physician examination to diagnosis 

(p = 0.028) and from diagnosis to the first chemotherapy administration (p < 

0.0001). 

Conclusion: Our analysis has highlighted a good adherence to current national and 

intenational guidelines and scientific literature as far as medical oncology treatment 

and pathological diagnosis are concerned. There is still room for improvement, most 

of all regarding the pre-surgical procedures and timing for surgery. The ICP study 

has proven to be a feasible ad efficacious methodology to point out the patient’s 

health management. 


1406 KNOWLEDGE ASSESSMENT OF MEDICAL AND 

ONCOLOGICAL TERMINOLOGY IN LUNG CANCER PATIENTS 

A. Kieszkowska-Grudny 1 , M. Rucinska 2 , E. Meszko 2 , S. Nawrocki 2 

1 Fryderic Chopin Memorial Hospital, The European Health Centre Otwock, 

Otwock, POLAND, 2 Department of Oncology, University of Warmia and Mazury, 

Olsztyn, POLAND 

Introduction: Lung cancer is one of the most common cancers. Clear information 

about diagnosis, prognosis, treatment and its side effects is important in cooperation 

between patients and medical staff. The aim of the study was to find out what lung 

cancer patients know about their disease and treatment. 


Material and methods: 50 lung cancer patients (41 - 70 years old) were included to 

the study. All patients were treated with radiotherapy, 39 patients (78%) have been 

previously treated by chemotherapy, 13 patients (26%) were after surgery. All 

patients have been informed by doctors about their cancer, treatment and side effects 

before radiotherapy started and got written information. Subjects filled out 

questionnaires that included closed questions with 5 responses, of which one was 

correct, 3 incorrect, and the last: “I do not know”. The wording used in the survey, 

such as: neoplasm, cancer, radiotherapy, chemotherapy, side effects, itching, peeling 

skin, etc., came from a consent form including side effects of treatment. Statistical 

analysis was done based on Chi2 test, descriptive statistics and logistic regression. 

The significance level was p < 0,05. 

Results: No one of lung cancer patients answered all asked questions correctly. 

Eleven patients (22%) were unable to properly answer any question. Only 15 pts 

(30%) were able to correctly answer at least half of questions. Only 8 people (16%) 

knew the right definition of cancer and there were no differences in this knowledge 

between patients age, sex, education, place of living and treatment obtained. Right 

awareness of radiotherapy and chemotherapy had 32% and 39% of patients, 

respectively. More than 50% of patients did not know what side effects or itching, 

skin’s exfoliation, sleep disorders mean. Interestingly, about 42% of patients knew the 

right definition of cardiac arrhythmias. We found out that only level of education is 

a predictor of better knowledge for many terms, like e.g.: neoplasm, radiotherapy, 

chemotherapy, sides effects (p < 0,05). 

Conclusions: Knowledge about cancer and treatment-related terms is very poor in 

lung cancer patients. Level of understanding varies depending on level of education 

and some on place of residence. Further studies are needed. 


1407 WHAT DO EUROPEAN COMMUNITY ONCOLOGISTS EXPECT 

FROM ESMO? A SURVEY IN GERMANY, GREECE, HUNGARY, 

ITALY, LUXEMBOURG, ROMANIA, AND SPAIN BY THE ESMO 

COMMUNITY ONCOLOGY WORKING GROUP 

R. Eckert1 , R. Curca2 ,G.D’Addario3 , M.V. Karamouzis4 , G. Lanzetta5 , 

P. Martin Martorell6 , D. Mauri7 , S. Rauh8 , S. Schmitz9 , K. Tamas10 1 2 

Oncology Group Practice, Wendlingen, GERMANY, Oncology, Alba County 

Hospital, Alba Iulia, ROMANIA, 3 Onkologie Schaffhausen, Schaffhausen, 

SWITZERLAND, 4 Dept. of Biological Chemistry, University of Athens Medical 

School, Kolonaki, GREECE, 5 Dept. Oncology, Instituto Neurotraumatologico 

Italiano(I.N.I) Grottaferrata, Grottaferrata, ITALY, 6 Oncology, Hospital Clinico 

Universitario de Valencia, Valencia, SPAIN, 7 Medical Oncology, General Hospital 

of Lamia, Roditsa Lamias, GREECE, 8 Oncologie / Med Interne, Centre 

Hospitalier Emile MayrischSite Niedercorn, Differdange, LUXEMBOURG, 

9 

Haematology and Oncology, Oncology Practice, Cologne, GERMANY, 

10 

Department of Oncology, Szent Laszlo Teaching Hospital, Budapest, 

HUNGARY 

Introduction: Community oncologists (COs) mainly work outside academic 

institutions and typically treat a wide range of tumours. It is estimated that COs care 

for over 50% of all cancer patients. Time-saving and efficient access to relevant and 

up to date information and tools could improve the quality of patient care and 

possibly disease outcomes. We asked COs from 7 European countries for their needs 

and wishes for support by a professional society like ESMO. 

Methods: In Germany, Greece, Romania, Hungary, Luxembourg, and Spain, 

questionnaires were distributed by email by WG members. In Italy and Spain, AIOM 

and SEOM member COs were asked to answer an online questionnaire. We asked 

about topics like ESMO membership, use of Clinical Practice Guidelines (CPG), use 

of electronic tools, and ESMO conferences. 

Results: 389 answers were received from COs in 7 European countries (DE 164, GR 

45, HU 21, IT 96, LU 12, RO 41, ES 10; average response rate where evaluable: 27%). 

52% of responding COs are ESMO members and 82% know ESMO’s home page. 

The use of ESMO CPGs varies greatly among countries (39-95%). 67% of COs have 

access to an intranet with electronic tools; yet 83% are interested in web based tools 

on the ESMO homepage, particularly guidelines, score calculators, and therapy 

protocols / planning aids. 87% of COs attend ESMO conferences at least 

occasionally; 62% of ESMO members attend regularly vs. 20% of non-members. 49% 

of COs are satisfied with the conferences’ scientific content, but miss practice 

relevance; 72% would like to have sessions particularly for COs. 

Conclusions: This is the largest survey among COs in Europe to date. In spite of 

Europe‘s political and cultural heterogeneity, we find a surprising homogeneity in 

most answers across countries. A high proportion of COs are ESMO members. There 

is a definite interest in ESMO also by non-ESMO-members. COs wish more practice 

relevant sessions at ESMO conferences. They are interested in online services 

provided by ESMO, particularly guidelines and tools. To support practising 

oncologists in delivering the best available care to their patients, ESMO and the 

Community Oncology WG have already implemented several measures, such as 

OncologyPro, a first CO Symposium at ESMO 2012, and additions to ESMO’s 

web page. 


1408 ONCOMOVIES: CANCER IN CINEMA 


G. Rosti 1 , A. Costantini 2 , M. Di Maio 3 , E. Bria 4 , D. Lorusso 5 , L. De Fiore 6 

1 Oncology, Ospedale Regionale Ca’ Foncello, Treviso, ITALY, 2 Psychology, 

Rome, ITALY, 3 Clinical Trials Unit, Istituto Nazionale Tumori di Napoli, Napoli, 

ITALY, 4 Oncology, Univesrity, Verona, ITALY, 5 Medical Oncology, Milan, ITALY, 

6 Phylosophy University Ll Sapienza, Phylosophy, Rome, ITALY 

Aim: To describe how movies portray cancer, and the experience of illness, through 

an analysis of movies throughout more than 70 years of cinema. 

Materials and methods: Cross-sectional descriptive study. In order to retrieve the 

relevant literature, we searched the Medline database using different keywords. A 

sample of convenience of films was analysed in which cancer had "prompt", 

"relevant", or "plot" character. Movies yearbook and databases (allmovie, IMDb, 

Movieplayer, Mymovies) were consulted. Each film was viewed by two observers 

who recorded patients variables (age, gender, marital status, etc), the cancer 

process (type, symptoms, therapy, and evolution), and the health care 

environment, among others. 

Results: 376 papers have been retrieved, but only a small percentage has been 

considered as relevant to the study. 75 films produced by 13 countries (years 

1939-2012) were analyzed. 40 patients were women, 35 men, and 64% belonged 

to the upper and upper/middle social class. The most common cancers were 

lymphoma, CNS tumours, and leukaemia. In 21 films the type of cancer was 

not mentioned. Symptoms were considered in 72% of the movies, while 

diagnostic tests were mentioned in 65%. The most frequent treatment 

mentioned in the movies was chemotherapy followed by antalgic therapy. Death 

occurred 46 times (63% of all moveis). Doctors and nurses turned up in 58 

films (77%). 

Conclusions: there is a trend of cancer narrative in movies, expecially in the last 

few years. Cancer experiences described in the films are quite different from the 

truth: movies prefer younger patients, higher social class; the prevalence of 

cancer site does not match the epidemiological data (e.g. breast cancer only in 5 

movies). However, symptoms, diagnostic tests, and treatments tend to be based 

on real life, particularly in the production of the last twenty years. Usually, 

cancer patients die at the end of the movie. Some of the films evaluated may be 

a first hand resource for training health professionals, while some others could 

be a valued example of malpractice. 


1409 NEOPLASIC DISEASE AND CHRONIC KIDNEY DISEASE: 

DOES THE ASSOCIATION WORSEN PROGNOSIS? 

D. Romeira 1 , C.T. Carvalho 1 , M. Proença 2 , M. Alface 2 , R. Cardiga 2 , R. Ferreira 2 , 

A. Leitão 2 , C. Fonseca 2 ,F.Ceia 2 , A.M. Martins 1 

1 Medical Oncology Unit, Hospital São Francisco Xavier, Lisboa, PORTUGAL, 

2 Internal Medicine, HSFX, Lisboa, PORTUGAL 

Neoplastic diseases (ND) and chronic kidney disease (CKD) are strongly 

related. Side effects of neoplastic treatments can cause CKD and the latter can 

be a risk factor for ND. Even in early stages of CKD, the risk of developing ND 

increases, the latter being drastically increased in patients (pts) treated with 

hemodialysis. 

Objectives: Compare, within a population of cancer pts with and without CKD, 

demographic characteristics, length of hospital stay, and prognosis. 

Methods: Observational prospective study with all consecutively admitted pts in an 

Internal Medicine department of a CentralHospital between November 2010 and 

October 2011. Collection of data using a previously normalized questionnaire, 

completed on admission and date of release, finalized with a posterior telephonic 

contact. The following characteristics of pts with ND and CKD (GFR CKD < 60 mL/ 

min/1,73m2) - GROUP A (GA) and with ND but without CKD - GROUP B (GB) 

were compared: demographics, in-hospital evolution, hospital stay and post-release 

mortalities 

Results: We evaluated 104 pts with ND with an average follow-up of 162 days. 

GA= 40 pts (38,5%) 78,9 ± 10,6 years, 52,5% women, GFR =39,6 ±12 mL/min/ 

1,73m2, stages III = 77,5%, IV = 22,5% GB= 64 pts (61,5%), 72,92 ± 12,6 years; 

46,9% women, GFR = 72,9 ± 14,5mL/min/1,73m2. Hospital stay length: GA 9,2 ± 

5 vs GB 9.9 ± 9,3 days. Hospital stay mortality: GA: 27,5% VS GB: 3,125%. CKD 

correlates with hospital-stay mortality: (χ2(2) = 13,371; p = 0,000 N = 104.); 

Significant differences were found between both groups pertaining to average 

survival during follow-up: (t(52) = -3,437; p = 0,01). The average length of 

hospital-stay and the number of readmissions are not related to the existence of 

CKD: (χ2(2) = 0,399; p = 0,53 N = 90) 

Conclusion: More than 1/3 of ND pts had CKD, the majority within stage III. ND 

pts with CKD were older. CKD contributed to hospital stay mortality and shorter 

survival rate on follow-up of pts with ND but did not contribute to an increase of 

hospital stay length. 




1410 CANCER AND LUNG TRANSPLANTATION 

D. Pérez Callejo 1 , R. Laporta 2 , E. Almagro Casado 1 , M. Palka 1 , 

A. Ruiz-Valdepeñas 1 , B. Cantos 1 , C. Maximiano 1 , M. Méndez García 1 , 

P. Ussetti 2 , M. Provencio Pulla 3 

1 Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, 

Madrid, SPAIN, 2 Pulmonology, Hospital Universitario Puerta de Hierro 

Majadahonda, Madrid, SPAIN, 3 Medical Oncology, Hospital Universitario Puerta 

de Hierro Majadahond, Majadahonda, SPAIN 

Introducation: Malignacies rank fourth on the leading causes of death in recipients 

of solid organ transplantation. High-dose immunosuppression, infections with 

oncogenic viruses and the pre-transplant risk, mainly due to tobacco, make these 

patients more susceptible for developing cancer. In the present study we reviewed a 

collective of 50 patients with lung transplantation (LT) and cancer. 

Patients and methods: Retrospective study of 503 lung transplant patients, 

performed at the Hospital Universitario Puerta de Hierro during 1993 and 2012. We 

included the following variables: date of birth, reason and date of transplantation, 

date of diagnosis of malignancy, histology and response to treatment, date and cause 

of exitus. The contrasts between proportions were performed using Chi-square test 

and survival curves using the product-limit method of Kaplan-Meier. 

Results: The 503 included transplant patients developed a total of 55 post-transplant 

malignancies in 50 patients. Four patients presented tumors already previous to the 

transplantation. The main underlying pathologies of the patient collective are 

idiopathic pulmonary fibrosis (50%), emphysema (30%) and cystic fibrosis (14%) 

The histology of the 55 post-transplant tumors were 18 skin cancer, 12 lung cancer, 

8 gastrointestinal cancer, 6 Non-Hodgkin’s Lymphoma, 2 bladder cancer, 2 

myelodysplastic syndrome, 2 sarcomas and 5 others. The mean age of diagnosis of 

malignancies is at 59 years (18-68). The mean time from transplantation to tumor 

diagnosis amounts 4 years (1-15). Of the 21 patients (42%) that have died until data 

collection, cancer was death cause in 15 (30%) 

Conclusion: Relying on our data, the majority of malignancies are skin and lung 

cancer and lymphoproliferative syndromes, attributing complications that should be 

considered in lung transplantation. 


1411 A REINFORCEMENT LEARNING APPROACH FOR 

OPTIMIZATION OF CHEMOTHERAPY AND ITS APPLICATION 

IN OPTIMAL CONTROL 

A. Fani Pakdel 1 , M. Rezazadeh 2 , M. Naghiby Sustany 2 

1 Radiation Oncology, Mashhad University of Medical Sciences Omid Hospital 

Cancer Research Center, Mashhad, IRAN, 2 School of Electrical Engineering, 

ferdowsi University, Mashhad, IRAN 

The diagnosis and treatment of the cancer has been the subject of discussion in 

different scientific fields in the recent years. In this paper, an optimal control strategy 

for the nonlinear systems is presented for application in chemotherapy of the cancer. 

The tumour growth model can be represented by a system of equations from 

population dynamics based on the competition between normal cells and tumour 

cells. The effect of the immune system on cancer is also included in the model. An 

optimal control method is applied to destroy the cancer cell with the minimum dose 

of chemotherapeutic agent. Reinforcement learning technique is proposed to 

construct an optimal control strategy for the nonlinear system and it was shown to 

be a suitable method to solve this problem. Simulation results show that cancer cells 

can be eradicated in a very short time with a small amount of drug using proposed 

optimal method of the therapy. They also show that the method is applicable to 

different models. It should be pointed out that the presented approach is a 

completely general procedure, and therefore, it can be applied to many problem of 

drug dosage optimization. 


1412 ALLOCATION OF PHYSIOLOGIC RESERVE FOLLOWING 

CHEMOTHERAPY AS A MARKER OF FRAILTY IN ELDERLY 


M. Molina-Garido 1 , C. Guillen-Ponce 2 , M. Muñoz Sanchez 1 , C. Ortega Ruiperez 1 , 

A. Olaverri Hernandez 1 , A. Carrato 2 , J. Santiago Crespo 1 

1 Medical Oncology, Hospital General Virgen de la Luz de Cuenca, Cuenca, 

SPAIN, 2 Medical Oncology, Hospital General Universitario Ramón y Cajal, 

Madrid, SPAIN 

Introduction: The aim of this study is to identify the presence of frailty in elderly 

patients with cancer by comparing their functional reserves before and after 

treatment with chemotherapy 

Materials and methods: This study is a prospective cohort study of cancer patients 

over 70 years of age who were consecutively evaluated between January 2010 and 

December 2011 in the Cancer Consultation in the Elderly program, Medical 

Oncology Section, Virgen de la Luz General Hospital in Cuenca. Group A comprised 

patients treated with chemotherapy, and group B comprised untreated patients. For 

each patient, we collected demographic data, data concerning the cancer and data 

describing the physiologic reserve relating to each individual (muscle mass evaluation 

[MME], walking speed, peak-flow, grip strength, creatinine clearance, and Pfeiffer 

score). The parameters of each patient’s functional reserve were determined at 

baseline (the day of the patient’s first visit) and 4 months later. Analyses of the data 

were conducted to identify whether there were significant differences between the 

groups for each of the variables under study pre- and post-chemotherapy (Student’s 

t-test and Fisher’s exact test for independent groups). 

Results: We analyzed data from 66 patients treated with chemotherapy (group A) 

and 68 patients who were not treated with cytostatic drugs (group B). The mean age 

of the patients was 78.68 +/- 4.90 years. There were 38 cases with metastatic tumors 

(28.8%). In our study there were no significant differences in walking speed (p = 

0.323), handgrip strength (p = 0.162), expiratory flow (peak-flow) (p = 0.954), 

cognitive status (Pfeiffer score) (p = 0.078), or creatinine clearance (p = 0.425). 

However, in patients treated with chemotherapy, there was an increase in the MME 

(0.618 kg/m2, 95% CI: 0.020 to 1.215, p= 0.043). 

Discussion: Physiologic reserve in the elderly, measured by walking speed, handgrip 

strength, creatinine clearance, the Pfeiffer questionnaire and peak-flow, does not 

change as a result of chemotherapy. Strikingly, the only parameter to undergo 

significant changes after the use of cytostatic medications is skeletal muscle mass. 

This work was funded by the "Young Investigator Grant SEOM 2008-2010". 


1413TiP QUALITY OF LIFE INCRIMINATING SYMPTOMS IN CANCER 

PATIENTS AND THEIR WEIGHT IN THE 

DOCTOR-PATIENT-TALK: A SURVEY OF THE “QUALITY OF 

LIFE” WORKING GROUP OF THE 

“ARBEITSGEMEINSCHAFT INTERNISTISCHE ONKOLOGIE” 

(AIO): A PRELIMINARY ANALYSIS 

F.K. Tauchert 1 , R. Hofheinz 2 , J. Quidde 3 , N. Marschner 4 , M. Hipp 5 , M. Weber 6 , 

H. Hoeffkes 7 , E. Jaeger 1 , S. Al-Batran 1 

1 Medizinische Klinik II für Hämatologie und Onkologie, Institut für klinische 

Forschung (IKF) am Krankenhaus Nordwest - UCT, Universitäres Centrum für 

Tumorerkrankungen Frankfurt, Frankfurt am Main, GERMANY, 2 , III. Medizinische 

Klinik für Hämatologie und Onkologie, Tagestherapiezentrum, 

2Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, GERMANY, 

3 Hubertus Wald Tumorzentrum, 3Universitäres Cancer Center Hamburg, 

Hamburg, GERMANY, 4 Praxis für interdisziplinäre Onkologie & Hämatologie, 

Freiburg i. Breisgau, GERMANY, 5 Klinik und Poliklinik für Strahlentherapie, 

Universitätsklinik Regensburg, Regensburg, GERMANY, 6 Medizinische Klinik III 

für Hämatologie, Internistische Onkologie und Pulmologie, Universitätsmedizin 

Mainz, Mainz, GERMANY, 7 Tumorklinik, Klinikum Fulda gAG, Fulda, GERMANY 

Introduction: Most cancer specific Quality of life (QoL) questioners (including the 

EORTC QLQ-C30) are based on the assumption that fatigue, pain, nausea & 

vomiting are the most important symptoms with impact on QoL of cancer patients. 

During the last 20 years, progress in supportive care has been made and the weight 

of symptoms may have changed. Using a standardized questioner, we investigated 

which symptoms incriminate cancer patients (pts) most. 

Methods: Pts were asked to provide confidential information on the following items: 

patient characteristics, underlying malignant disease and treatment, performance 

status (PS), incrimination of the QoL by various symptoms (19 items) and their 

weight in the patient-to-doctor talk. Data were collected and analyzed using standard 

statistical methods. 

Results: 1,300 pts participated so far. The median age was 63 years (18-93). 51.7% of 

pts were female and 72.7% had an ECOG PS of 0-2. Most frequent malignancies 

were breast cancer (211), colorectal cancer (153), lymphomas (98) and lung cancer 

(88). Most pts received chemo- or radiotherapy (67%). 16% were in follow-up or 

surveillance and 17% had other forms of therapy or did not state at all. The most 

incriminating problems were weakness, tiredness & poor concentration, the question 

“what is going to happen?” and alopecia. Sexual life, social trouble, depression, 

anxiety & sorrows and insomnia were reported as incriminating problems with 

inadequate attention in the doctor-patient-talk (adequate attention reported in 15.6% 

- 46.1% of pts respectively). Pts with metastatic disease reported significant more 

incrimination in QoL by weakness, dypsnea, pain, loss of appetite, “state of therapy 

and outlook”, “what is going to happen?” and anxiety & sorrows. Pts with colorectal 

cancer reported significantly more incrimination by diarrhea but less by weakness, 

dyspnea, alopecia, “what is going to happen?” and anxiety & sorrows than other pts. 

Conclusions: Overall pts reported fatigue, alopecia and insomnia as the QoL most 

incriminating symptoms. Pain and nausea & vomiting were less incriminating, 

possibly due to improved supportive care. Sexual life, social trouble, depression, 

anxiety & sorrows, and insomnia receive inadequate attention in the 

doctor-patient-talk. 



1414TiP IMPLEMENTATION OF CANCER REGISTRY IN GEORGIA 

N. Jokhadze 1 , M. Maglakelidze 1 , R. Gagua 2 

1 Cancer Control, National Cancer Center of Georgia, Tbilisi, GEORGIA, 2 General 

Director, National Cancer Center of Georgia, Tbilisi, GEORGIA 

Background: Georgian Population–based Cancer Registry was set up in 2000. In 

2009 most of medical facilities in Georgia became private. Currently private clinics 

are not instructed by law to submit data to central registry and nearly 30% of data 

are lost from the population registry. 

Objectives: The aim of the project was to:. 1. Implement Modern Cancer 

Registration System in Georgia. 2. Ensure compliance of reporting 

standards. 3. Create registry that will meet international data standards. 

Methods: In 2011 as a result of active work with Ministry of Health Care (MOH) • 

Cancer Registry program was included in NCCP • Government has funded a “State 

Program of Modern Cancer Registry Implementation”. By the end of the project 

Cancer Registry will be linked to EMR notification system that itself will be linked to 

public and death registry and data on every cancer patient will automatically appear 

in the cancer registry database 

Results: According to the schedule I stage of the program has been completed 

successfully. • New model of cancer registry has been developed • ICD-O third 

edition has been translated • Committee of Healthcare at Parliament of Georgia 

prepared legislation proposal for consideration. By the end of 2012 development of 

software, training of registrars and piloting of cancer reporting is planned. 

Conclusion: Developed model of Cancer Registry will serve as a basis for clinical, 

epidemiologic, and health care services research and for the assessment of their 

efficacy in Georgia. 


1416PD PROGRESS AND TRENDS FOR CANCER DRUG APPROVAL 

– AN ANALYSIS OF FDA ADVISORY COMMITTEE 

J.K. Chan 1 , I. Amanam 1 , T.K. Kiet 1 , N. Young-Lin 1 , D. Hoth 1 , D.S. Kapp 2 ,B. 

J. Monk 3 

1 Ob/Gyn & Reproductive Sciences, UCSF Helen Diller Family Comprehensive 

Cancer Center, San Francisco, CA, UNITED STATES OF AMERICA, 2 Radiation 

Oncology, Stanford University School of Medicine, Stanford, CA, UNITED 

STATES OF AMERICA, 3 Obstetrics and Gynecology, Creighton University School 

of Medicine at St. Joseph’s Hospital and Medical Center, a member of Dignity 

Health, Phoenix, AZ, UNITED STATES OF AMERICA 

Objectives: To evaluate the progress and trends for cancer drug approval over the 

last decade. 

Methods: From 2001 to 2011, applications from (Oncologic Drug Advisory 

committees) ODAC session were reviewed. 

Results: Of 46 applications, 34 (74%) involved solid and 12 (26%) hematologic 

tumors. These drugs were for leukemia (n = 8, 17%), lymphoma (n = 8, 17%), breast 

(n = 5, 11%), prostate (n = 5, 11%), and others (n = 20, 44%). 30 (65%) were phase III 

and 16 (35%) were phase II trials. 67% (n = 31) were full applications and 33% (n = 

15) were for accelerated approval. 22 (48%) drugs were not approved with most 

common concerns being: missing or inadequate data (65%), excessive toxicity (55%) 

and inappropriate study endpoints (45%). 19 applications used hazard ratios (HR), 

(median = 0.67) and 18 used response rates (RR) (median = 0.42%). In a predictive 

model combining efficacy and toxicity, drugs with lower HR or higher RR with lower 

toxicity were more likely to be approved vs. other drugs (89% vs. 46%; p = 0.025). We 

then divided applications into 3 periods with their corresponding approval rates: 

2001-2004 (n = 11; 55%), 2005-2008 (n = 12; 50%), and 2009-2011 (n = 23; 53%). 

Over time, there was a significant increase in the proportion of applications using 

progression-free survival as an endpoint (0% to 50% to 70%; p = 0.01). 

Conclusion: In this analysis of oncology drug applications, our model employing 

hazard ratio and toxicity correlates with a high rate of approval. The most common 

concerns of the rejected applications involved missing or inadequate data, excessive 

toxicity, and inadequate study endpoints. Clinical researchers need to consider these 

FDA recommendations in the future design of clinical trials. 


1417PD NICE TECHNOLOGY APPRAISALS AND THE UPTAKE OF 

BREAST CANCER DRUGS IN THE UK 

D. Bertwistle 1 , P. Anderson 2 , M. Jofre-Bonet 3 

1 HEOR, IMS Health, London, UNITED KINGDOM, 2 Swansea Centre for Health 

Economics, Swansea University, Swansea, UNITED KINGDOM, 3 Department of 

Economics, City University London, London, UNITED KINGDOM 

Background: Health technology appraisal (HTA) recommendations from the UK 

National Institute of Health and Clinical Excellence (NICE) are intended to 


standardise health care throughout the NHS, and to hasten the uptake of new, more 

effective medicines that are cost-effective. Although it is compulsory for the NHS to 

fund drugs recommended by NICE, it is not clear how well NICE guidance is 

implemented. A number of studies have investigated whether NICE guidance 

influences UK drug uptake as intended. Most have used sales data, however, this 

approach has significant limitations. Sales data do not reveal which indication, line of 

therapy, nor patient sub-group a drug has been used to treat. Many drugs are 

licensed for multiple indications, and many HTAs only recommend the use of drugs 

in defined sub-groups, often subsets of the licensed indication. To avoid the 

limitations of sales data-based analyses, this study used IMS Health’s Oncology 

Analyzer TM as the primary data source. Oncology Analyzer TM contains detailed 

records for a representative sample of patients, allowing analyses to be focussed on 

the particular indication and treatment criteria specified in NICE HTAs. 

Methods: HTAs for breast cancer drugs appraised by NICE from 2005 to 2008 were 

analysed. For each HTA, the proportion of the eligible patient sub-group that 

received the recommended (or not recommended) drugs from Q1 2005 to Q1 2009 

was determined. Changes in uptake of the drugs in the relevant patient populations 

were assessed for the UK, and were also compared to uptake in similar European 

countries. 

Results: NICE produced 6 HTAs for breast cancer, encompassing 8 drugs, during the 

period assessed. In 5 out of 6 cases, the publication of an HTA was followed by the 

recommended change in UK drug uptake. However, when UK uptake of drugs 

recommended by NICE was compared to uptake of the same drugs in four other 

European countries (France, Germany, Italy and Spain), the UK ranked at the 

bottom of the group. 

Conclusions: The NICE HTAs assessed were mostly followed by the intended 

changes in drug uptake, suggesting they were implemented, at least by some PCTs. 

Despite this, international comparisons of uptake for these drugs revealed that the 

UK performed poorly compared to similar European countries. 

Disclosure: D. Bertwistle: This research uses data from the IMS Health data asset, 

Oncology AnalyzerTM. I am an employee of IMS Health. P. Anderson: This research 

uses data from the IMS Health data asset, Oncology AnalyzerTM. I am a former 

employee of IMS Health. All other authors have declared no conflicts of interest. 

1419PD COLORECTAL CANCER SCREENING: FACTORS 

ASSOCIATED WITH NOT UNDERGOING AN EARLY 

COLONOSCOPY AFTER A POSITIVE FECAL OCCULT 

BLOOD TEST 

E. Ferrat 1 , J. Lebreton 1 , S. Bercier 2 , K. Veerabudun 1 , Z. Brixi 2 , E. Paillaud 3 , 

C. Attali 4 , S. Bastuji-Garin 1 

1 Laboratoire d’Investigation Clinique (LIC EA4393), University of Medicine, 

Créteil, FRANCE, 2 ADOC94, Association of Organized Cancer Screening, 

Joinville-le-Pont, FRANCE, 3 UCOG, Hôpital Henri-Mondor, Créteil, FRANCE, 

4 General Practice, Université Paris-Est(UPEC), Créteil, FRANCE 

Background: Current screening guidelines recommend a complete colon evaluation 

with colonoscopy after a positive fecal occult blood test (FOBT). However, no timing 

guidelines are provided. A recent study showed that delay from FOBT to 

colonoscopy was associated with an increased risk of neoplasia. Our aim was to 

identify individual and contextual predictors of not undergoing an early colonoscopy 

after a positive FOBT. 

Methods: All average-risk residents of a French county who have had a positive 

FOBT from June 2007 to December 2010 (n = 2369) during organized colorectal 

cancer (CRC) screening campaigns were included. Individual data were abstracted 

from the Organized Cancer Screening Association database and aggregated 

socioeconomic data (physician density, Townsend deprivation index) from the 

National Institute of Statistics and Economic Studies database. Multilevel and 

multinomial logistic regression analyses were performed to assess predictors of 

delayed colonoscopy (> median delay, 58 days), no colonoscopy and no response to 

cancer screening program after one year. Early colonoscopy was the reference 

category. 

Results: The rate of colonoscopy was 86.9%. 1 037 patients (45.3%) had an early, 

and 1 021 (44.6%) a delayed colonoscopy, 106 (4.7%) did not perform colonoscopy 

and 123 (5.4%) were nonrespondents. The multilevel analysis displayed a significant 

(p < 0.05) inter-area variation for not undergoing an early colonoscopy. In 

multivariate analysis, a delayed colonoscopy was associated with a first screening test 

(OR 1.61; 95% CI: 1.16-2.25). Not undergoing a colonoscopy and non response were 

associated with a FOBT received at home rather than given by the general 

practitioner (GP) (OR 1.94; 95%CI: 1.25-3.01 and OR = 2.74; 95%CI: 1.78-4.21, 

respectively) and living in the most deprived areas (OR 2.29; 95% CI: 1.20-4.37 and 

OR = 4.37; 95%CI: 2.23-8.55 respectively). There was no significant association 

between physician density, gender, age and follow-up after a positive FOBT. 

Conclusion: Actions to improve follow-up after a positive FOBT should focus on 

first CRC screening and population living in the most deprived areas. This study 

emphasizes the role of GPs in CRC screening. 




1420PD SCREENING TOOL FOR UNFITNESS IN GERIATRIC 

ONCOLOGY: WHAT DOES IT TELL US IN DAILY PRACTICE? 

C. Terret, S. Perrin 

Geriatric Oncology Program / Medical Oncology, Centre Léon Bérard, LYON, 

FRANCE 

Background: We are facing a growing number of cancer patients (pts) aged ≥ 70 

years. However, cancer treatment decision-making appears a difficult task in such 

heterogeneous population as solid recommendations are still lacking. The G8 scale 

was designed to help discriminate older cancer patients needing a geriatrician’s 

opinion before cancer treatment decision-making. This 8-item tool can be 

completed in

abstracts 

palliative care 

1422O EFFICACY AND SAFETY OF A TWO DRUG-COMBINATION 

REGIMEN FOR CANCER-RELATED CACHEXIA IN THE 

CLINICAL PRACTICE 

C. Madeddu 1 , A. Macciò 2 , M.C. Cau 1 , M. Dessi’ 1 , F. Panzone 1 , R. Serpe 1 , 

G. Antoni 1 , G. Mantovani 1 

1 Department of Medical Oncology, University of Cagliari, Cagliari, ITALY, 

2 Department of Obstetrics and Gynecology, Sirai Hospital, Carbonia, ITALY 

Background and aims: To test the safety and efficacy of a two-drug combination 

(including nutraceuticals, i.e. antioxidants) with carnitine + celecoxib for the 

treatment of cancer-related anorexia/cachexia syndrome (CACS) in the clinical 

practice. Primary endpoints: safety, increase of lean body mass (LBM) and 

improvement of quality of life. Secondary endpoints: increase of physical 

performance (tested by grip strength and 6-min walk test, 6MWT) and decrease of 

inflammation (assessed by serum levels of IL-6 and Glasgow prognostic score, GPS). 

Patients and methods: Outpatients with advanced cancer at different sites with 

CACS (i.e. loss of body weight >5% of the pre-illness or ideal weight in the last 

3 months) were eligible to receive: L-carnitine 4 g/day + Celecoxib 300 mg/day. All 

patients received as basic treatment polyphenols 300 mg/day, lipoic acid 300 mg/day, 

carbocysteine 2.7 g/day, Vitamin E, A, C, all orally. Treatment duration was 

4 months. 

Results: From June 2011 to April 2012, 50 patients with advanced cancer (all stage 

IV) at different sites were enrolled: 40 completed the treatment and were evaluable 

(mean age 63.8 ± 9.6, range 32-81 years). Results showed a significant increase of 

LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) from 

baseline as well as physical performance assessed by 6MWT. Quality of life (assessed 

by EORTC-QLQ-C30 and EQ-5D) also improved significantly. ECOG PS and GPS 

decreased significantly. The treatment was safe, no grade 3–4 toxicities occurred and 

no patient had to discontinue the treatment due to severe adverse events. 

Conclusions: The results of the present study confirm the efficacy and safety of the 

two-drug combination regimen previously shown in a randomized clinical trial 

(Madeddu et al, Clinical Nutrition 31:176-182, 2012). Therefore, this simple, feasible, 

effective, safe, with favorable cost-benefit profile, two-drug approach could be 

suggested in the clinical practice as a treatment for CACS. 


1423O REAL-TIME ELECTRONIC MONITORING OF 

PATIENT-REPORTED SYMPTOMS AND SYNDROMES (PRS): 

E-MOSAIC, A MULTICENTER PHASE III STUDY (SAKK 95/06) 

D. Blum 1 , D. Koeberle 2 , R. von Moos 3 , K. Ribi 4 , S. Aebi 5 , D.C. Betticher 6 , 

S. Hayoz 7 , J. Nadig 8 , S. Mauri 9 , F. Strasser 10 

1 Department of Cancer Research and Molecular Medicine, European Palliative 

Care Research Center Clinical, Trondheim, NORWAY, 2 Dept. Oncology/ 

Hematology, Kantonsspital St. Gallen, St. Gallen, SWITZERLAND, 3 Medizinische 

Onkologie und H, Cantonal Hospital Graub, Chur, SWITZERLAND, 4 IBCSG, 

IBCSG, Berne, SWITZERLAND, 5 Medizinische Onkologie, Luzerner 

Kantonsspital, Luzern, SWITZERLAND, 6 Oncology, Hospital Fribourg, Fribourg, 

SWITZERLAND, 7 Sakk, SAKK, Berne, SWITZERLAND, 8 Oncology, Oncology 

Buelach, Buelach, SWITZERLAND, 9 Oncologia, IOSI Oncology Institute of 

Southern SwitzerlandOspedale Regionale di Lugano, Sede Italiano, Viganello, 

SWITZERLAND, 10 Oncology and Palliative Medecine, Kantonsspital St. Gallen, 

St. Gallen, SWITZERLAND 

Background: In incurable cancer patients (pts) chemotherapy (CTx) may be used by 

oncologists (ONC) to alleviate PRSS. We assessed if E-MOSAIC influences global 

quality of life (G-QOL) and patient care. 

Methods: In this prospective, cluster (ONC) randomized trial pts with defined PRSS 

starting a new line of palliative CTx with expected response rate ≤ 20% completed a 

mobile computer-based (E-MOSAIC) assessment (Edmonton Symptom [SYM] 

Assessment Scale, ≤3 additional SYM, nutritional intake, body weight, Karnofsky 

Score, medications for main PRSS) before 6 consecutive weekly visits. Eligible ONC 



received (Intervention [IA]) or not (control [CA]) the cumulative computer printout 

of their pts results. Primary endpoint (PE) was the difference (Δ) between baseline 

(BL) and week 6 in G-QOL (EORTC-QLQ-C30, #29&30). Sample size per arm was 

84 pts from 20 ONC for 80% power to detect a 10 point Δ, significance level 5%. A 

planned interim analysis with 100 pts showed many for the PE non-evaluable pts: 

sample size was increased to 264 pts. Due to clustering, a mixed effects model 

adjusting for BL G-QOL and other preselected covariates was used. Secondary EP 

included SYM Distress (∑ 10 VAS, 0–10), pts-perceived ONC compassion 

(∑ 5 VAS, 0–100) and communication, coping, treatment burden and SYM 

management by nurse report. 

Results: In 8 centers, 84 ONC treated 264 pts (median 66y; overall survival IA 6.3, 

CA 5.4 mts) with various tumors. 102 pts (IA: 55; CA: 47) had uninterrupted (> 4/6 

visits, same ONC) pat-ONC sequences, required for PE. The between-arm Δ of PE 

was 6.8 (p = 0.11) in favor of the IA. In a sensitivity analysis with ONC treating ≥2 

pts (IA: 50; CA 39 pts) it was 9.0 (p = 0.07). BL G-QOL was the most influential 

factor (p < 0.01). Intention to treat analysis revealed improvement in SYM Distress 

(Δ BL-last study visit: IA -4.9 vs. CA 2.0, p= 0.003), compassion (Δ BL-week 6: IA: 

18.9 vs. CA: 4.3), communication, treatment burden and coping in favor of the IA. 

More pts with high SYM had ONC management. 

Conclusion: Our intervention of real-time monitoring of PRSS, delivered to 

oncologist, clearly improved SYM distress with a trend to better SYM management, 

communication and Qol.Further development is warranted. 


1424P COMPARISON OF 8GY SINGLE FRACTION RADIOTHERAPY 

VERSUS 20GY IN FIVE FRACTIONS OR 30GY IN 10 

FRACTIONS FOR THE TREATMENT OF METASTATIC 

BONE PAIN 

B. El Hawwari, A. Telfah 

Department of Hemato- Oncology, King Hussein medical Center, Amman, 

JORDAN 

Introduction: In 1974 the Radiation Therapy Oncology Group (RTOG) initiated a 

randomized clinical trial comparing various dose-fractionation schedules in the 

palliation of cancer metastatic to bone. The trial was closed in February of 1980 and 

results have been published in 1982, with the conclusion that: “low-dose short 

schedules are as effective as more aggressive protracted programs. Since that time, 

different radiotherapy schedules had been employed for palliation of bone metastasis: 

40 Gy in 20 fractions, 30 Gy in 10 fractions and single fractions of 8 Gy, 6 Gy or 4 

Gy. Several randomized prospective trials and meta-analyses have been reported 

showing the same results in pain relief when comparing single doses vs protracted 

treatments. 

Objectives: The aim of this study was to compare the most common fractionation 

used in oncology to treat bone metastases which are 8Gy single fraction, 20Gy in five 

fractions and 30Gy in 10 fractions. 

Method: A total dose of 120 patients who is known to have stage VI cancer with 

bone metastasis at King Hussein Medical Center between January 2007 and 

December 2009, were allocated to receive either 8Gy single fraction, 20Gy in five 

fractions or 30Gy in 10 fractions for the treatment of their pain. Patient recorded 

pain severity and analgesic requirements on questionnaire which was filled by the 

main investigator before treatment, at 2 weeks and at 1,2,3,4,5,6,8,10, and 12 months 

after radiotherapy. Pain relief was the primary endpoint of treatment benefit. 

Results: There was no difference in the time to first improvement in pain, time to 

complete pain relief or in time to first increase in pain at any time up to 12 months 

after randomization, nor in the class of analgesic used. Retreatment was twice as 

common after 8Gy than after multifraction radiotherapy, although retreatment for 

residual or recurrent pain did not reflect a difference between the three groups in the 

probability of pain relief. 

Conclusion: A single fraction of 8 Gy when used for the treatment of bone 

metastasis is as safe and effective as a multifraction regimen for the palliation of 

metastatic bone pain for at least 12 months. This may make it suitable alternative to 

the multifraction radiotherapy regimens. Keywords: Bone metastases; Radiotherapy; 

Pain relief; Palliation 





1425P PAIN MANAGEMENT IN EIGHT ITALIAN ONCOLOGICAL 

CARE CENTRES 

S. Barni 1 , K.F. Borgonovo 1 , F. Di Costanzo 2 , F. Cognetti 3 , G. Bernardo 4 , 

C. Boni 5 , B. Agostara 6 , P. Pronzato 7 , G. Colucci 8 , M. Mammucari 9 

1 Medical Oncology Division, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, 

ITALY, 2 Medical Oncology Unit, Azienda Ospedaliero Universitaria Careggi, 

Firenze, ITALY, 3 Division Medical Oncology A, Istituto Regina Elena, Roma, ITALY, 

4 Oncologia Medica 2, Fondazione S. Maugeri IRCCS, Pavia, ITALY, 5 Oncology 

Dept., Arcispedale S. Maria NuovaDivisione di Oncologia, Reggio Emilia, ITALY, 

6 Oncology Division, A.O. Civico Palermo, Palermo, ITALY, 7 Oncologia Medica A, 

IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, 

Genova, ITALY, 8 Oncology Division, Istituto Tumori Ospedale Oncologico, Bari, 

ITALY, 9 RMF, RMF, Roma, ITALY 

Introduction: Management of oncologic patients is different between treating 

centers, and in particular management of pain. We decided to perform a 

retrospective study to explore different approaches to oncological painful patients 

(pts) in different Italian Cancer Units. 

Materials and methods: We evaluated in 8 Italian cancer hospitals all consecutive 

pts during 5 days in order to investigate level of pain in the previous 7 days and in 

the following two weeks from the basal visit. Patients and oncologists filled up a 

questionnaire (type of pain, intensity, site of pain, and analgesic therapy). 

Results: 265 pts were enrolled, 59% female and 41% male; median age 61.5. 88% of 

pts had ECOG PS 0-1; 72.8% of pts reported metastatic disease and 86.4% were 

under chemotherapy treatment. Pain measured with VAS (Visual Analogic Scale) at 

baseline was 2.9. Pain was somatic in 32.4%, visceral in 12.5% visceral, 13.9% 

neuropathic, 41.2% mixed. The current analgesic therapy at baseline had been 

prescribed by oncologist in 38.2%, by other specialist in 42.1%, by family doctor in 

18.5% and by other doctor in 1.1%. The basal analgesic treatment was confirmed in 

57.3%, adjusted in 34%, and changed in 8.6%. At baseline we detected NSAIDS in 

69.4% pts, weak opioids in 34% of pts; strong opioids in 38.9%, and 27.7% of pts also 

had adjuvants (24.5% pregabalin, 57.1% steroids, 18.4% other drugs). At first weekly 

follow-up (216 pts) the intensity of pain was 2.6 (VAS). The analgesic therapy was 

confirmed in 72.2% and adjusted in 27.8%. New drugs prescribed at first follow-up 

were NSAIDS in 43.3%, weak opioids in 21.7%, strong opioids in 86.7%, adjuvants in 

55%. At second weekly follow-up (131 pts): 80.9% of therapies were confirmed and 

19.1% adjusted. 90.3% therapies of 72 pts coming to third follow-up were confirmed. 

In 85.7% of the adjusted therapies an adjuvant was prescribed. 

Conclusions: Our data suggest two important comments. First, we observed a poor 

utilization of adjuvants by physicians in oncologic patients, especially when therapies 

are not prescribed by oncologists. Second, our data confirmed the need for a close 

follow-up to improve analgesic therapy. 


1426P PAIN PALLIATION OF BONE METASTASES USING 

MAGNETIC RESONANCE GUIDED FOCUSED ULTRASOUND - 

MULTI-CENTER MULTI-TRIAL RESULTS 

R. Catane 1 , D. Gianfelice 2 , M. Kawasaki 3 , D. Iozeffi 4 , S. Kanyev 5 , A. Napoli 6 , 

P. Ghanouni 7 ,G.Lo 8 , Y. Inbar 9 , L. Shay Levi 10 

1 Division of Oncology, Chaim Sheba Medical Center, Ramat Gan, ISRAEL, 

2 Vascular/interventional Radiology, University Health Network, Toronto, CANADA, 

3 Orthopaedic Surgery, Kochi Medical School, Kochi, JAPAN, 4 Radiology, Rostov 

State Scientific Research Institute of Oncology, Rostov-on-Don, RUSSIAN 

FEDERATION, 5 Radiology, N.N. Petrov Institute of Oncology, Saint Petersburg, 

RUSSIAN FEDERATION, 6 Radiology, Sapienza University of Rome, Rome, ITALY, 

7 Radiology, Stanford University, Stanford, CA, UNITED STATES OF AMERICA, 

8 Radiology, Hong Kong Sanatorium & Hospital, Happy Valley, HONG KONG, 

9 Radiology, Chaim Sheba Medical Center, Ramat Gan, ISRAEL, 10 Application, 

InSightec, Tirat Carmel, ISRAEL 

Introduction: Magnetic Resonance guided Focused Ultrasound (MRgFUS) is a 

non-invasive, non-ionizing treatment for thermal ablation of tumors. The technology 

uses high intensity focused ultrasound ablation combined with continuous MR 

imaging to denervate pain. Precise targeting of the lesion and real time monitoring 

of tissue temperature rise are cornerstones of the technique. We present here results 

of multiple multi-center studies evaluating the safety and effectiveness of MRgFUS 

for painful bone metastases. 

Methods: 93 patients with painful bone metastases underwent MRgFUS in 14 

medical centers worldwide. Treated lesions had to be remote from nervous structures 

or joints. Effectiveness of pain palliation was evaluated with a standardized 11-point 

pain rating scale (0-no pain/10-worst pain) and by monitoring changes in 

pain-relieving medication. A reduction of 2 points or more was considered a 

significant response. Safety events were recorded and evaluated by severity. Results of 

31 patients treated in initial safety studies were previously reported by Liberman et al 

(Ann Surg Oncol. 2009 Jan; 16(1):140-6). 

Results: 107 procedures were performed, targeting 96 lesions in 93 patients. 3 

patients were treated twice targeting a different lesion; another 11 patients underwent 

a second treatment due to large lesions. Patients were followed-up for a period of 3 

months. Pain response was relatively rapid: within 3 days, on average, the clinical 

endpoint was met and maintained. Pain scores averaged 6.9 pre-treatment, decreased 

to 4.5 within 3 days post-treatment, to 3.3 at one month post-treatment, and further 

decreased to 2.6 at three month follow-up. There were no serious adverse events 

related to the treatment. 2 patients had mild skin erythema following the treatment 

and 5 patients (5%) had pain progression. Our updated results are similar to early 

reports. 

Conclusions: The presented results clearly show that MRgFUS can provide a quick, 

effective and safe palliative therapy for patients suffering from painful bone 

metastases. Current results are consistent with initial reported results. Randomized 

trials are being conducted in patients as a first line treatment of painful bone 

metastases vs. radiation therapy and in patients who failed radiation therapy vs. 

sham. 

Disclosure: L. Shay Levi: I work in InSightec as the global bone applications 

specialist. InSightec is the company sponsered these clinical trials.All other authors 


1427P CURCUMA LONGA EXTRACT IS EFFECTIVE IN IMPROVING 

INFLAMMATORY STATUS AND REDOX BALANCE IN 

PATIENTS WITH CANCER-RELATED CACHEXIA AND 

OXIDATIVE STRESS 

G. Mantovani 1 , C. Madeddu 1 , F. Panzone 1 , M.C. Cau 1 , G. Antoni 1 ,F.Leo 1 , 

A. Maccio’ 1 , R. Serpe 2 

1 Department of Medical Oncology, University of Cagliari, Cagliari, ITALY, 2 Parco 

Scientifico e Tecnologico della Sardegna, Nutrisearch SRL, Cagliari, ITALY 

Background: Curcumin (diferuloylmethane) is the biologically active compound of 

Turmeric (Curcuma Longa) and has long been used in traditional Asian medicine to 

treat diseases ranging from heartburn to arthritis: it is thought to have antioxidant 

and antinflammatory properties. 

Aim: To assess the antioxidant and antinflammatory properties of a curcumin extract 

in advanced cachectic cancer patients. 

Methods: From September 2011 to March 2012, 15 cachectic patients (M 7/F 8; age 

range 55–85 y) with cancer at different sites were enrolled, all stage IV. Twenty-one 

age/sex matched healthy controls were studied. All enrolled patients had 

inflammation and oxidative stress (high blood levels of proinflammatory cytokine 

Interleukin-6 (IL-6), high levels of blood C-reactive protein (CRP), high levels of 

ROS, low levels of blood antioxidant enzymes GPx and SOD and low levels of total 

blood antioxidant status, TAS, compared to controls. Patients were administered 4 

tablets (2 g/day, equivalent to 400 mg/day of active curcuminoids extract, Meriva, 

Indena, Milan, Italy). Treatment duration was 4 weeks. 

Results: A significant reduction of ROS levels ( 510 ± 120 vs 390 ± 186 Fort U) 

and a significant improvement of circulating levels of GPx (5630 ± 1189 vs 6590 ± 

2390 U/l) as well as a significant improvement of TAS (0.61 ± 0.23 vs 0.69 ± 0.4 

mmol Trolox eq.) was observed after treatment. The inflammatory marker CRP 

decreased significantly (38.12 ± 28.4 vs 20.24 ± 17.37 mg/dl), no significant decrease 

of serum IL-6 (25.58 ± 23.67 vs. 19.9 ± 16.8) was observed. No patient was withdrawn 

from the study and the treatment was safe and well tolerated. 

Conclusions: Curcumin extract added to the normal diet was able to significantly 

improve inflammatory status and counteract key parameters of oxidative stress, such 

as ROS, GPx and TAS. Curcumin antinflammatory-antioxidant activity could be 

useful in a multi-targeted combined pharmaco-nutritional approach to treat 

cancer-cachexia. Dr. Roberto Serpe was supported by grant CRP1_296 from the 

Regione Autonoma della Sardegna by PO Sardegna FSE 2007-2013 (L.R.7/2007) 

titled”Promotion of scientific and technological research in Sardinia”, Italy 


1428P APPLICATION OF KM-CART (ADVANCED CELL-FREE AND 

CONCENTRATED ASCITES REINFUSION THERAPY) 

TREATMENT TO PATIENTS WITH CANCEROUS ASCITES 

K. Matsusaki, K. Ohta, A. Yoshizawa, S. Goto 

Ascites Treatment Center, Japanese CART Study Group, Tokyo, JAPAN 

Purpose: The purpose of our study was to demonstrate the utility of KM-CART 

therapy in the care of patients with refractory ascites. We also report one colon 

cancer case treated with a dendritic cell vaccine that was prepared utilizing the high 

yield number of autologous carcinoma cells collected in KM-CART processing. 

Patients with refractory ascites can suffer severe bloating and/or respiratory 

discomfort disrupting both their activities of daily living (ADL) and terminating 

their anticancer therapy. We developed a novel KM-CART system for cancerous 

ascites using original CART system approved by the Ministry of Health, Labor and 

Welfare. KM-CART consists of ex vivo double filtration processing of autologous 

ascites fluid to prepare: (1) a protein (albumin and globulins) concentrate fraction 

suitable for intravenous fluid therapy back to the donor patient intravenously, and 

(2) a cell concentrate suitable for research for anticancer drug sensitivity and 

immunotherapy. 


Method and results: A total of 317 cancerous ascites cases with diverse tumor 

origins were treated with KM-CART during 2009 to 2012. The volume of ascites 

extracted ranged between 2 to 15 L with an average of 5.9 L. The average KM-CART 

processing time was 51 minutes to produce a protein concentrate volume of 80 to 

2,000 ml with a total protein concentration range of 8.0 - 21.0 g/dl. The protein 

concentrates were administered intravenously with an average infusion volume of 

630ml. In all the cases, patients had an immediate benefit of KM-CART treatment 

including relief of discomfort of abdomen distension, malaise, respiratory distress 

and improved resumption of ADL. A total of 3.5L protein concentrates including 

611g of albumin and globulin was re-infused into one 37 year old female patient 

with colon cancer over 3 periods of KM-CART treatment. Dendritic cell vaccine was 

prepared using total of 1.4x108 cancer cells which were collected from hollow fiber 

membrane filters. 

Conclusion: KM-CART treated patients were observed to reliably respond to 

treatment. It is concluded that processing a large quantity of ascites fluid using the 

KM-CART system offers a safe and effective means to enhance refractory ascites 

patient care. 


1429P ASSESSMENT OF QUALITY OF LIFE OF PATIENTS WITH 

CERVICAL CANCER DURING AND AFTER TREATMENT WITH 

RADIOTHERAPY IN INSTITUTO DE MEDICINA INTEGRAL 

PROFESSOR FERNANDO FIGUEIRA, RECIFE, BRAZIL 

A.A. Santos, C. Lima Santos, J.F.P. Moura, A.I. Souza 

Medical Oncology, IMIP, Recife, BRAZIL 

Introduction: Cervical cancer is the 2nd most frequent neoplasm among women in 

Brazil. Radiotherapy is one of the modalities used in the treatment of cervical cancer 

and may cause adverse events that compromise quality of life. The purpose of this 

study was assess quality of life in women with cervical cancer before, during the last 

week and six months after radiotherapy at a hospital in Northeast, Brazil. 

Method: We performed an exploratory, before and after longitudinal study, with 35 

women with cervical cancer treated with adjuvant radiotherapy, exclusively or 

concurrently with chemotherapy in Instituto de Medicina Integral Prof. Fernando 

Figueira (IMIP) between August 2012 and May 2012. The patients underwent three 

interviews (pre-treatment, last week and six months after treatment). To assess the 

quality of life it was used FACT-Cx score (Functional Assessment of Cancer 

Therapy-Cervix). The mean scores were compared using Student’s t and ANOVA 

test, with significance level of 5%. 

Results: The mean age was 50 (± 13.9) years. Most were single or widowed (58.8%) 

and only 2.9% were employed. About 75% attended just until elementary school. The 

FACT-Cx pre-treatment average scores was 110.9 and in the last week was 110.8, 

with no statistically significant difference (p = 0.966). The results corresponding to 

six months after therapy will be presented at the Meeting. 

Conclusion: The immediate results after radiotherapy showed no difference in 

quality of life. Analysis after six months may be different. These findings may modify 

therapeutic decision. 


1430P OPTIMAL CUT-POINTS FOR QLQ-C30 SCALES ASSOCIATED 

WITH OVERALL SURVIVAL IN PATIENTS WITH ADVANCED 

HEPATOCELLULAR CARCINOMA (AHCC): A COMPARISON 

OF TWO METHODS 

M. Diouf 1 , F. Bonnetain 2 , J. Barbare 1 , O. Bouché 3 , J. Meynier 1 , L. Dahan 4 , 

X. Paoletti 5 , T. Filleron 6 

1 Clinical Research, Amiens University Hospital, Amiens, FRANCE, 2 Biostatistic 

and Epidemiological Unit(EA 4184), Centre Georges François Leclerc, Dijon, 

FRANCE, 3 Hepatology-Gastroenterology, Hopital Robert Debré, Reims, 

FRANCE, 4 Service d’Hépato-Gastroentérologie et Oncologie Digestive, AP-HM, 

Marseille, FRANCE, 5 Service de Biostatistique, Institut Curie, Paris, FRANCE, 

6 Biostatistics, Institut Claudius Regaud, Toulouse, FRANCE 

Introduction: Health-related quality of life (QoL) has been validated as prognostic 

factor for patients with aHCC. However, to be used in routine practice, QoL should 

be dichotomized. Usually, cut-points were based on arbitrary percentile value. The 

main objective of this study was to identify optimal cut-offs for 5 scales: global health 

(GH), physical functioning (PF), role functioning (RF), fatigue (FA) and diarrhea 

(DIA). Two published methods were used to compare distributions of cut-offs and 

their risk-ratio. We finally evaluated the improvement of existing prognostic 

classifications (PC) by dichotomized QoL. 

Patients and methods: 271 patients with aHCC were included in CHOC trial. QoL 

was assessed in the 2 weeks prior to randomization with the EORTC QLQ-C30. 

Identification of optimal cut-points was based on two univariate methods proposed 

by Mazumdar and Farragi respectively. Mazumdar method was based on the 

« minimum p-value » approach. Adjustment of type I error were based on Altman 

formula. For Farragi method, the total sample was divided into two sub-samples: 


learning and validation. A cut-point was derived for each sub-sample using 

« minimal p-value » and each patient was classified according to the cut-point for 

the sub-sample to which it does not belong. The final cut-point was the one that 

minimize the p-value in the total sample. Stability of the results was evaluated using 

boostrap procedure (n = 500). Improvement of PC was studied with multivariate Cox 

model, QoL being dichotomized at its optimal cut-point. 

Results: QoL was available in 234 patients (86%). For RF, the most frequent 

cut-point was 30 with the two methods (Mazumdar: 496/500 – Farragi: 500/500). 

Univariate HR (95%CI) were 2.99 [1.62 – 5.52] and 2.80 [2.58 – 3.04] respectively 

for Mazumdar and Farragi. In Farragi method, the 2 sub-samples found the same 

cut-offs in 486/500B. The recommended cut-points were respectively 45, 50, 30, 30 

and 5 for GH, PF, FA, RF and DIA. Compared to CLIP + WHO PS, CLIP + QoL + 

clinical factors rose the C-index from 0.65 [0.62 – 0.69] to 0.70 [0.66 – 0.74]. 

Conclusion: The stability of the cut-points was good and precision of CI acceptable 

for both methods, but better for Farragi. Interestingly, this categorization of QoL 

increased the performance of all PC and should be considered as competing factor to 

WHO performance status. 


1431P REVIEW OF PATIENT DEATHS OCCURRING OFF THE END 

OF LIFE PATHWAY: A UK ONCOLOGY CENTRES’ 

EXPERIENCE 

C.L. Mitchell, T. Colby, R. Berman 

Medical Oncology, The Christie NHS Foundation Trust, Manchester, UNITED 

KINGDOM 

Background: Within the UK national audits have been performed to assess the care 

of the dying within the NHS and those receiving systemic cancer therapies. The 

National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report 

looked at aspects of end of life care in cancer patients in relation to the 

appropriateness of the decisions taken and the level of seniority at which clinical 

decisions were made. We performed an audit to assess patient deaths which did not 

occur on the end of life pathway (EoLP); specifically the input from senior clinicians 

in decision making and the appropriateness of ongoing interventions. 

Methods: All in-patient deaths within our centre for the 6 month period of April 

2010 until September 2010 were identified. Patients whose death occurred whilst on 

the EoLP were identified and excluded from the analysis. A retrospective case note 

review was then performed for the remaining patients. 

Results: In the six month period 82 patient deaths occurred, of these 27% (n = 21) 

were not on the EoLP at the time of death. 90% of these patients received at least one 

consultant review during their admission with 58% of the patients having a 

consultant review within 48hrs of death. At the time of death 84% of the patients 

were receiving ongoing medical intervention: 

Intervention Patients % 

Intravenous antibiotics 27 

Intravenous fluids 26 

Diuretics 15 

Steroids 12 

Blood Products 8 

Table 1: Medical interventions at time of death 95% of the patients had a 

documented management plan, with a do not resuscitate order present in 73%. 63% 

of patients had input from the hospital in-patient palliative care team. On review of 

the clinical notes 68% of the patients fulfilled the criteria for the EoLP. 

Conclusions: The audit highlighted that within our current clinical practice a 

proportion of patients continue to receive ongoing medical intervention despite 

entering the terminal phase of illness, with clinical decisions often being made at a 

junior level. Focus on education and training of clinical staff with increased 

consultant led input into patient care will be aimed at improving end of life care for 

our patient population. 


1432P THE IMPACT OF PALLIATIVE CARE ON THE 

AGGRESSIVENESS OF END-OF-LIFE CANCER CARE IN 

PATIENTS WITH ADVANCED PANCREATIC CANCER 

R.W. Jang 1 , M.K. Krzyzanowska 1 , C. Zimmermann 2 , S. Alibhai 3 

1 Department of Medical Oncology, Princess Margaret Hospital, Toronto, 

CANADA, 2 Department of Psychosocial Oncology and Palliative Care, Princess 

Margaret Hospital, Toronto, CANADA, 3 Medicine, University Health Network, 

Toronto, CANADA 

Background: To improve end-of-life care, quality indicators have been developed to 

avoid overly aggressive care in patients with advanced cancer. Advanced pancreatic 

cancer is a highly lethal disease with few life-prolonging options. Specialized palliative 



care (PC) consultation (defined as a physician consultation focusing on PC needs, 

lasting at least 40 minutes) could reduce overly aggressive care in this population. 

Purpose: To examine the impact of PC consultation on (i) subsequent use of 

chemotherapy within 14 days of death; (ii) more than one emergency department 

(ED) visit; (iii) more than one hospitalization; and (iv) at least one intensive care 

unit (ICU) admission, all within 30 days of death. 

Methods: A retrospective population-based cohort study using linked administrative 

databases was conducted with patients diagnosed with advanced pancreatic cancer 

from Jan 1 2005 to Dec 31 2010. Analysis was limited to those who had received 

palliative chemotherapy. Multivariable logistic analyses were performed with the 

above quality indicators as the outcomes of interest and PC as the main covariate, 

adjusting for other variables (age, sex, rurality, and health region). 

Results: Of the 6076 patients who had advanced pancreatic cancer, 5381 of these 

patients had died at last follow-up, and 1644 of those had received palliative 

chemotherapy. In this cohort, 986 (60%) received a palliative care consultation, 218 

(13%) received chemotherapy near death, 53 (3%) patients went to the ICU near 

death, 218 (13%) had multiple ED visits near death, and 213 (13%) had multiple 

hospitalizations near death. In multivariable analysis, PC consultation was associated 

with decreased use of chemotherapy near death (odds ratio (OR) 0.23; 95% 

confidence interval (CI) 0.17-0.32), and lower risk of ICU admission near death (OR 

0.19; 95% CI 0.10-0.36), multiple ED visits near death (OR 0.41; 95% CI 0.30-0.55), 

and multiple hospitalizations near death (OR 0.37; 95% CI 0.27-0.50). 

Conclusions: In patients with advanced pancreatic cancer who are receiving 

palliative chemotherapy, PC involvement is associated with less frequent overly 

aggressive care. Future analysis will explore the effect of timing of PC consultation 

(early vs late) on outcomes, and expand the cohort to all patients with advanced 

disease. 


1433P FACTORS ASSOCIATD WITH SURROGATE 

DECISION-MAKING IN ADVANCED CANCER PATIENTS: 

A LONGITUDINAL STUDY 

D. Heo, J.K. Lee, A. An, B. Keam, T. Kim, S. Lee, D. Kim 

Internal Medicine, Seoul National University Hospital, Seoul, KOREA 

Purpose: Although surrogate decision-making in cancer patients is well-known, few 

studies investigating the prevalence of surrogate decision-making over time have been 

reported. The objectives of this study were to investigate the level of surrogate 

decision-making in advanced cancer patients over time and the impact of 

demographic and clinical variables on surrogate decision-making. 

Methods: The level of surrogate decision-making was measured in 572 consecutive 

cancer patients who died between January 1 and December 31, 2009. We reviewed 

8,639 informed consent forms of these patients, calculated the proportion of 

decisions made by a surrogate (PDS) for each patient, and analyzed the association 

of PDS with demographic and clinical variables. 

Results: Surrogates completed 40.3% of all consent forms. The prevalence of 

surrogate decision-making was higher in the end-of-life period (death 365 days). Surrogates signed consent forms more frequently for 

do-not-resuscitate directives, intensive care unit admission, emergency hemodialysis, 

surgery and invasive interventions compared with chemotherapy, radiotherapy, and 

diagnostic tests (OR = 3.88, P < 0.001). Patients of older age (P = 0.036) and those 

with a shorter duration of management (P < 0.001) were independently associated 

with greater PDS. 

Conclusions: Surrogate decision-making was frequently observed among Korean 

cancer patients in this study, especially when the patient’s death was imminent, and 

for decisions related to end-of-life care. Surrogates were also frequently involved in 

decisions for elderly or rapidly deteriorating patients. Healthcare professionals should 

consider the significant role of familial surrogates in the end-of-life period; 

comprehensive approaches are needed to preserve the best interest of the patients. 


1434P THE UNDERSTANDING OF TERMINAL CANCER AND ITS 

RELATIONSHIP WITH ATTITUDES TOWARD END-OF-LIFE 

CARE ISSUES 

J.K. Lee 1 , D.S. Heo 1 , A.R. An 2 , Y.H. Yun 3 

1 Internal Medicine, Seoul National University Hospital, Seoul, KOREA, 2 Family 

Medicine, Seoul National University Hospital, Seoul, KOREA, 3 Department of 

Medicine, Seoul National University, Seoul, KOREA 

Objective: To investigate differences in the understanding of terminal cancer and 

determine the relationship between this understanding and attitudes toward 

end-of-life issues. 

Design: A questionnaire survey was performed between 2008 and 2009.Participants: 

A total of 1242 cancer patients, 1289 family caregivers, 303 physicians from 17 

university hospitals, and 1006 participants from the general population responded 

(response rates: 90.1%, 95.1%, 81.0%, and 75.9%, respectively). 

Main outcome measures: Individual understanding of terminal cancer and its 

relationship with preference for disclosure of terminal prognosis and critical 

end-of-life interventions. 

Results: A “six-month life expectancy” was the most common understanding of 

terminal cancer (45.6%), followed by “treatment refractoriness” (21.1%), 

“metastatic/recurred disease” (19.4%), “survival of a few days/weeks” (11.4%), 

and “locally advanced disease” (2.5%). The combined proportion of “treatment 

refractoriness” and “six-month life expectancy” differed significantly between 

physicians and the other groups combined (76.0% vs 65.9%, P = 0.0003). 

Multivariate analyses showed that patients and caregivers who understood 

terminal cancer as “survival of a few days/weeks” showed more negative 

attitudes toward disclosure of terminal status compared with participants who 

chose “treatment refractoriness” (adjusted odds ratio [aOR] 2.39, 95% CI 1.26 

to 4.54 for patients; aOR 2.94, 95% CI 1.58 to 5.47 for caregivers). Caregivers 

who understood terminal cancer as “metastatic/recurred” or “six-month 

survival” tended to disagree with withdrawing futile life-sustaining treatments 

(aOR 2.57, 95% CI 1.39 to 4.75 for “metastatic/recurred,” aOR 1.86, 95% CI 

1.06 to 3.28 for “six-month survival”) and active pain control (aOR 2.29, 95% 

CI 1.13 to 4.64 for “metastatic/recurred”, aOR 1.86, 95% CI 0.97 to 3.54 for 

“six-month survival”), compared with caregivers who selected “treatment 

refractoriness.” 

Conclusion: The understanding of terminal cancer varies among the four participant 

groups. It was associated with different preferences regarding end-of-life issues. 

Standardizing this terminology is needed to better understand end-of-life care. 


1435P THE CHARATERISTICS OF PALLIATIVE CARE IN A RURAL 

EUROPEAN REGION 

T. Sternfeld 1 , M. Flieser-Hartl 2 , U. Vehling-Kaiser 1 

1 Onkologische Schwerpunktpraxis, Onkologisches und Palliativmedizinisches 

Netzwerk Landshut, Landshut, GERMANY, 2 Krankenhaus Landshut-achdorf, 

Onkologisches und Palliativmedizinisches Netzwerk Landshut, Landshut, 

GERMANY 

The palliative care unit Landshut is one of the few centres accredited by the ESMO 

serving in a rural area (Lower Bavaria, Germany). It is part of the Network for 

Oncology and Palliative Care Medicine Landshut (Onkologisches und 

Palliativmedizinisches Netzwerk Landshut) which has been accredited 2010 by the 

ESMO as Designated Centre of Integrated Oncology and Palliative Care and the 

DGHO in 2011. The Network aims to improve the palliative care service with 

regard to the special needs of the rural cancer population. Data regarding palliative 

care of tumor patients in rural areas of Europe are lacking. In December 2010, a 

continuous data acquisition for patients on the palliative care unit located at the 

Hospital Landshut-Achdorf was started. We now present a cross sectional data 

analysis. Between December 2010 and March 2012, 499 patients were admitted for 

the first time to the palliative care unit. The majority of these patients were living 

outside the town boundaries, mainly in small villages. 84% of the patients were 

diagnosed with a solid tumour, 6% with a haematological malignancy, and 10% had 

a non-malignant disease. Before their first admission, 50% of the patients were 

treated with opioids, 44% of the patients had a central venous port system, 4% a 

gastric tube, and 10% had received parenteral nutrition. The most frequent 

symptoms leading to admission were reduced general health status (43%), 

uncontrolled pain (20%), dyspnoea (14%), nausea (8%), confusion (3%), and 

insufficient social support (3%). 48% of the patients died during the first admission. 

The mean time of hospitalization was 11 ± 7 days. After discharge from hospital, 

37% were cared for by themselves or family members, 23% were visited by a 

community nurse or other nursing services, 19% were cared for by the outpatient 

palliative care program, 14% were admitted to a nursing home, 4% were transferred 

to another ward, and 3% to the hospice which had opened as recently as January 

2012. Detailed data of the hospitalized palliative patients are presented and further 

discussed regarding the special needs of the growing rural palliative patient 

population. 



1436P SURVEY ON MODELS OF INTEGRATION OF ONCOLOGY AND 

PALLIATIVE CARE (PC) IN ITALIAN ONCOLOGY UNITS ESMO 

DESIGNATED CENTERS 

V. Zagonel 1 , C. Mastromauro 2 , M. Ciaparrone 3 , V. Franciosi 4 , L. Verna 5 , 

C. Moro 6 , Z.C. Di Rocco 3 , A.A. Martoni 7 , L. Cavanna 8 , G. Farina 9 

1 Italian Association of Medical Oncology, Task Force Continuity of Care, Padova, 

ITALY, 2 Italian Association of Medical Oncology, Task Force Continuity of Care, 

Venezia, ITALY, 3 Italian Association of Medical Oncology, Task Force Continuity 

of Care, Roma, ITALY, 4 Italian Association of Medical Oncology, Task Force 

Continuity of Care, Parma, ITALY, 5 Italian Association of Medical Oncology, Task 

Force Continuity of Care, L’Aquila, ITALY, 6 Italian Association of Medical 

Oncology, Task Force Continuity of Care, Bergamo, ITALY, 7 Italian Association of 

Medical Oncology, Task Force Continuity of Care, Bologna, ITALY, 8 Italian 

Association of Medical Oncology, Task Force Continuity of Care, Piacenza, 

ITALY, 9 Italian Association of Medical Oncology, Task Force Continuity of Care, 

Milano – on behalf of Task Force Continuity of Care in Oncology - Italian 

Association of Medical Oncology (AIOM), ITALY 

Background: The early integration of cancer treatment and palliative care (PC) is 

effective but the current state of integration in Italian Cancer Centers is unknown. 

Aims: To determine the models of integration of PC in Italian Oncology Units 

ESMO Designated Centers of Integrated Oncology and Palliative Care (ESMO-DCs). 

Methods: A questionnaire was sended by e-mail to the executives of the 20 Italian 

ESMO-DCs. 

Results: Twenty questionnaires were sent with a response rate of 100%. The 

geographical distribution of the ESMO-DCs is unbalanced: 12 (60%) in North-Italy, 

6 (30%) in the Center, 2 (10%) in the Islands and none in the South. The 

ESMO-DCs organization is oriented to integration of PC through at least one 

oncologist oriented to PC in 18 (90%) Centers; guidelines (LG) of symptomatic 

treatment in 18 (90%); PC beds in 14 (70%) and PC offices in 14 (70%). The name 

“PC office” is used only in 4/14 (29%) centers; in 10 (71%) Centers alternative names 

were chosen. ESMO-DCs showed a good integration with Home Care (HC): in 9 

(45%) Centers HC is managed by Palliative Care Physicians (PCPs); in 6 (30%) by 

General Practitioners (GPs); in 3 (15%) by oncologists and in 2 (10%) by PCPs with 

GPs. When HC is not directly managed by oncologists, the ESMO-DCs achieve the 

integration through home visits in 6/17 (35%), meetings and/or GL sharing with 

PCPs and GPs in 11/17 (65%) and 6/17 (35%), respectively. The ESMO-DCs showed 

a good integration with the Hospices (Hs): in 14 (79%) Centers Hs are managed by 

PCPs; in 2 (11%) by PCPs with GPs, in 1 (5%) by GPs and in 1(5%) by oncologists. 

When Hs are not directly managed by oncologists the ESMO-DCs achieve the integration 

through hospice visits in 7/17(41%), meetings and GL sharing with PCPs and GPs in 

11/17 (65%) and 7/17 (41%), respectively. The integration model of reference for 15/20 

(75%) ESMO-DCs is Integrated Care Model (see E.Bruera. JCO 2010). 

Conclusions: ESMO-DCs are not representative of Italian situation and lack in the 

South of Italy. The Integrated Care model of ESMO-DCs is Simultaneous 

Care-oriented but its achievement is different by Center. The “ESMO-DCs” 

experience is challenging for Oncology Units to improve early integration of 

palliative care, continuity and quality of assistance of cancer patients. 


1437P HEALTH SERVICE RESEARCH IN INTEGRATIVE ONCOLOGY: 

VISCUM ALBUM USE AND NON-PHARMACOTHERAPEUTIC 

INTERVENTIONS IN LUNG CANCER PATIENTS 

F. Schad 1 , J. Axtner 1 , A. Happe 1 , T. Breitkreuz 2 , J. Gutsch 3 , B. Matthes 4 , 

C. Grah 5 , G. Spahn 6 , H. Matthes 7 , M. Kroez 1 

1 Network Oncology, Research Institute Havelhoehe (FIH), Berlin, GERMANY, 

2 Internal Medicine / Oncology, Paracelsus-Hospital, Bad Liebenzell, GERMANY, 

3 Outpatient oncologist, Gevelsberg, GERMANY, 4 Medical Care Center 

Havelhoehe, Outpatient oncologist, Berlin, GERMANY, 5 Pneumology, Hospital 

Havelhoehe, Berlin, GERMANY, 6 Center For Integrative Medicine and Cancer 

Therapies, Hospital Oeschelbronn, Niefern-Oeschelbronn, GERMANY, 7 Internal 

Medicine, Hospital Havelhoehe, Berlin, GERMANY 

Background: Viscum album extracts (VA) and non-pharmacotherapeutic 

interventions (NPI) are frequently used in integrative oncology (IO). NPIs activate 

patients’ resources whereas VA enhances health-related quality of life and reduce 

adverse effects caused by conventional therapies. In the present study we evaluated 

the use of VA and NPIs in lung cancer patients from a clinical registry with a special 

emphasis on IO. 

Methods: We analyzed data of 1177 lung cancer patients collected by the Network 

Oncology, a conjoint clinical registry of German hospitals and out-patient 

oncologists. We used non-parametric χ 2 or Fisher exact test (F) to compare observed 

frequencies, Wilcoxon rank sum (W), Kruskal-Wallis test (KW) for differences 

between groups. We fitted a logistic regression model to explain use of VA. 

Results: 73% of the patients got VA and 54% NPI [embrocations, wrappings, 

eurythmic therapy, massages, music, drawing, modeling, psychological support or 

hyperthermal therapy]. No difference in UICC stage between VA patients and others 


were seen (pχ 2 = 0.213), but VA patients choose more NPI (medother= 0, medVA= 2, 

pW< 0.001). Women got VA more often (pF< 0.001) and chose in median more NPI 

(♂ =0,♀ = 2, pW< 0.001). Median length of VA application was 115.1 weeks. Median 

time between first diagnosis and start of VA was 3.94 months and was shorter for 

more advanced cancer (pKW< 0.001). Surgery was negatively (βsur= -1.93, psur< 

0.001), chemotherapy positively associated with getting VA (βche= 0.96, pche= 0.001; 

pNPI< 0.001). Median time between first diagnosis and admission did not differ 

between UICC stages (χ 2 = 2.61, df= 3, pKW= 0.455), but its variance decreased with 

diagnosis severity (χ 2 = 41.60, df= 3, pFK< 0.001). Conventional therapies showed 

lower frequencies after than prior admission to NO facilities (che/ sur/ rad; prior: 

49%/ 39%/ 39%, post: 38%/ 24%/ 22%; all p< 0.001). 

Conclusions: Results show that VA and NPI are part of standard care of lung cancer 

patients in IO settings. Female patients are more open-minded to IO therapies and 

use them more often. Our results suggest that health service research data provide a 

solid basis for generating hypothesis to conduct warranted prospective studies on 

effectiveness in IO. 

Disclosure: H. Matthes: PD Dr. med. Harald Matthes is member of the board of 

directors of the Weleda Weleda A.G. Arlesheim/ Switzerland.All other authors have 


1438P PROGNOSTIC ROLE OF LIPID PROFILE IN PATIENTS WITH 

ADVANCED CANCER 

F. Panzone 1 , C. Madeddu 1 , A. Macciò 2 , M.C. Cau 1 , G. Antoni 1 , R. Serpe 1 , 

G. Mantovani 3 

1 Oncologia Medica 1, Azienda Ospedaliero Universitaria Cagliari, Monserrato, 

ITALY, 2 Department of Obstetrics and Gynecology, Sirai Hospital Carbonia, 

Carbonia, ITALY, 3 Presidio Di Monserrato, Azienda Ospedaliero Universitaria 

Cagliari, Monserrato, ITALY 

Aims: Alterations of lipid metabolism and inflammatory parameters are frequently 

observed in cancer patients, especially at advanced stage, and are associated with poor 

prognosis; the pathogenetic mechanisms are not yet fully known and the identification 

of effective treatment is still far away. This study aimed to evaluate the lipid and 

inflammatory profile in cancer patients at diagnosis and to assess the correlation with 

clinical, nutritional, metabolic/functional and quality of life parameters. 

Methods: From June 2011 to March 2012, 116 patients with a new diagnosis of 

cancer (breast, lung, gynecological, gastrointestinal tract) were enrolled. Plasma lipids 

(i.e. total cholesterol, TC; high-density lipoprotein, HDL; low-density lipoprotein 

cholesterol, LDL; and triglyceride,TG), indices of inflammation (i.e. erythrocyte 

sedimentation rate, C reactive protein [CRP], ferritin and inflammatory cytokines) 

and oxidative stress (reactive oxygen species, ROS; and antioxidant enzymes, SOD 

and GPx) were analyzed. The laboratory data obtained were correlated with clinical 

variables such as sex, age, ECOG PS, Glasgow prognostic score (GPS), quality of life, 

site and stage of disease and survival. 

Results: Patients with advanced disease had a lower levels of fatty acids than patients 

at early stage. Cholesterol levels (TC, HDL and LDL) were positively correlated with 

survival and inversely with the GPS and stage. TG showed a direct correlation with 

stage only in patients with colon cancer. An inverse correlation between the levels of 

TC and the parameters of inflammation, in particular CRP ad IL-6, was observed. In 

the regression analysis IL-6 and CRP were predictors of TC and HDL, respectively. 

Albumin, a well known parameter of nutritional status, showed a direct correlation 

with HDL cholesterol levels, as in the general population. 

Conclusion: Our results confirm the pathogenic role of chronic inflammation in 

inducing changes of lipid metabolism that characterize cancer patients. Lipid profile at 

diagnosis was correlated with prognostic factors such as stage of disease, GPS and survival. 


1439 CHANGES IN SYMPTOM INTENSITIES AMONG CANCER 

PATIENTS RECEIVING OUTPATIENT PALLIATIVE CARE 

J.H. Kang 1 , D. Hui 2 , Y. Sriram 3 , J.H. Kwon 3 , E. Bruera 3 

1 Internal Medicine, Gyeongsang University Hospital, Jinju, KOREA, 2 Palliative 

Care and Rehabilitory Medicine, M.D. Anderson Cancer Center, Houston, TX, 

UNITED STATES OF AMERICA, 3 Palliative Care and Rehabilitation Medicine, 

M.D. Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA 

Purpose: Symptom changes are usually reported using summary statistics such as 

mean and/or median. The main objective of this retrospective study was to 

determine the magnitude of symptom changes as assessed by the Edmonton 

Symptom Assessment System (ESAS) after outpatient palliative care (OPC) at the 

first follow-up visit. 

Methods: We reviewed 1612 consecutive patients who were referred to the outpatient 

Supportive Care Center and who completed the ESAS at initial and first follow-up 

visits between January 2003 and December 2010. All patients received 

interdisciplinary care led by palliative care specialists following an institutional 

protocol. 



Results: The distribution of the magnitude of symptom changes was stratified by 

baseline intensities. Patterns were similar for different ESAS items. At the follow-up 

visit, 52% to 74% of patients achieved symptom improvement by >= 1 point. 

However, 48% to 80% of patients with moderate/severe intensity at baseline 

complained of symptoms with ESAS score >= 4 after OPC. Symptoms with absent/ 

mild intensity worsened ranging from mean of -3.04 to 0.12 at the first follow-up 

visit, whereas symptoms with moderate/severe intensity improved from -0.2 to 3.86 

(p < 0.001). 

Conclusion: Considerable patients with moderate or severe intensity at the baseline 

still had symptoms with ESAS score >= 4. Patients with absent/mild intensities at 

baseline complained of symptom exacerbation at the first follow-up visit. Various 

strategies are needed to optimize symptom control in advanced cancer. 


1440 HOW TO IMPROVE THE PAIN MEASUREMENT IN 

ONCOLOGICAL DAY HOSPITAL (DH) PATIENTS 

M. Cabiddu 1 , K.F. Borgonovo 2 , M. Ghilardi 3 , M. Cremonesi 1 , F. Petrelli 4 , 

F. Maspero 1 , S. Barni 1 


ITALY, 2 Medical Oncology Division, A.O. Treviglio-Caravaggio, Treviglio, ITALY, 

3 Medical Oncology Division, A.O. Trevilgio-Caravaggio, Treviglio, ITALY, 4 Uo 

Oncologia, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, ITALY 

Introduction: Quite all cancer patients experience pain. The Pain Visual Analogic 

Scale (VAS) is a useful tool for pain evaluation in every kind of patient, 

independently of his level of schooling and compliance. Patients are often reluctant 

to communicate the pain they feel to oncologist. In 2011 we conducted a survey in 

our Day Hospital about discrepancies between the pain score measured by an 

oncologist and a nurse using VAS. We explored the possible reasons and tried to 

overcame this problem. 

Materials and methods: From January 2010 to February 2011 we evaluated 1546 

DH admissions in 154 patients. Pain was measured by both an oncologist and a 

nurse, using VAS. The discrepancies were defined by at least 2 points of difference on 

the VAS score. On May 2011 we explored the possible reasons of discrepancy and we 

organized internal meetings with all oncological staff involved in the pain evaluation 

to examine this problem. From July to December 2011 we performed a new 

evaluation of discrepancies between VAS score measured by oncologist and nurse in 

194 patients for a total of 979 DH admission. 

Results: The characteristics of the two samples of patients were similar; the staff 

involved was the some too. In the first survey 43,2% of discrepancies were observed: 

in 9.4% of admissions the VAS score recorded by the oncologist was greater than that 

registered by the nurse; in 33.8% of admissions the opposite was noted. Overall the 

concordance between VAS score oncologist/nurse was of 56,8%. In the second survey 

the global discrepancies were only 18,6%, with 9% and 9,6% of discrepancies 

between the two measurements, with VAS score greater in nurse and oncologist 

evaluation, respectively. 

Conclusion: Our results appeared to confirm the reluctance of patients to reveal 

their pain, especially to the oncologist. Sometimes the oncologists are more focused 

on cancer treatment than on supportive care, and the pain measurement is 

performed so fast that the patient is brought to minimize the real entity of pain. 

Team training is useful to improve patient’s care and patient’s management in an 

oncological staff. 


1441 PAIN INTENSITY, PATIENT SATISFACTION AND PHYSICIAN’S 

PRESCRIPTION OF OUTPATIENTS WITH CANCER: A KOREA, 

REGIONAL CANCER CENTER SURVEY 

H. Shim, D.E. Kim, J.E. Hwang, W.K. Bae, I.J. Chung, S. Cho 

Department of Internal Medicine, Chonnam National University Medical School, 

Gwangju, KOREA 

Background: Pain is the one of most common and debiliating symptoms of patients 

(pts) with cancer. It is known that more than 50-70% of pts with cancer experience 

pain. The purpose of this study is to assess the prevalence of pain, analgesic use and 

satisfaction for cancer pain treatment of outpatients. 

Methods: Between July and August 2010, we enrolled pts who were taking analgesics 

with cancer in outpatients setting. The pts were asked to complete the 

self-administered questionnaire to assess their pain intensities and other symptoms 

in terms of their experience during the preceding 24 hours. 

Results: A total of 111 outpatients completed a questionnaire with characteristics, 

intensity of pain and other related symptoms. The median age of pts was 61 years, and 

69.9% were men. Only 8 pts (7%) reported no suffering from pain at the time of the 

interview. Approximately, 74 pts (67%) had mild pain, 25 (22%) had moderate pain and 

4 (4%) had severe pain. Fifty-five pts (49.5%) were being treated with strong opioids. 

Around 45% of pts (n = 50) were experiencing breakthrough pain one to three times a 

day and 6.4% (n = 7) were having breakthrough pain more than four times a day, but 

only 37 pts (33%) were prescribed short acting analgesics for breakthrough pain. There 

was no change of the dose of opioids analgesics for 61% of pts who had moderate or 

severe pain even if more analgesics were needed. Pts who were satisfied with their pain 

management was only 48%, 87% of them had mild pain. The remaining 52% were 

neither nor dissatisfied, 92% of which had moderate or severe pain. Around 84% (n = 93) 

pts thought they were asked about their pain, and 79% (n = 88) thought their physicians 

believed in reported pain intensities. About 50% (n = 56) pts reported that adverse effects 

of opioids should be anticipated and managed more aggressively. The prevalent 

symptoms associated with pain were reported; interference of physical activities (68.5%), 

loss of appetite (49%) and sleep disturbance (32%). 

Conclusions: Many number of outpatients with cancer still experienc pain and pain 

related symptoms. Improvement of cancer pain management is needed in outpatients 

setting. It is also important to provide adequate information on analgesics and 

adeverse effects as well as to assess the intensity of pain and change the dose of 

opioid according to pain intensities. 


1442 SURVIVAL PREDICTION IN AMBULATORY STAGE III/ IV NON 

SMALL CELL LUNG CANCER PATIENTS USING THE 

PALLIATIVE PERFORMANCE SCALE, ECOG AND LUNG 

CANCER SYMPTOM SCALE 

R. Mohajer 1 , S. Nathan 2 , K. Wells 2 , N. Kern 2 , M. Batus 3 , M. Fidler 3 , P. Bonomi 3 , 

S. O’Mahony 2 

1 Hematology and Oncology, Stroger Hospital of Cook County, Chicago, IL, 

UNITED STATES OF AMERICA, 2 Palliative Care, Rush University Medical Center, 

Chicago, IL, UNITED STATES OF AMERICA, 3 Hematology and Oncology, Rush 

University Medical Center, Chicago, IL, UNITED STATES OF AMERICA 

Objectives: Patients with advanced NSCLC have a life expectancy of less than one 

year, therefore, it is important to maximize their quality of life and to find a tool that 

gives the patients more accurate means of survival prediction. 

Materials: The Palliative Performance Scale has been designed and used for patients 

with far advanced disease for predicting survival probabilities. It has five functional 

dimensions: ambulation, activity level and evidence of disease, self-care, oral intake, 

and level of consciousness. It is scored in 11 levels from PPS 0 % to PPS 100% in 10 

percent increments- PPS 0% represents death and PPS 100% represents fully 

ambulatory and healthy status.PPS has been shown to be an effective tool in life 

expectancy prognostication in palliative and hospice patients. The value of PPS in 

ambulatory cancer patients has not been examined to date.The Lung Cancer 

Symptom Scale is a tool designed to measure the quality of life of lung cancer 

patients. It evaluates six major symptoms associated with lung malignancies and 

their affect on overall symptomatic distress and activity.We evaluated 62 adult 

patients with stage III or IV NSCLC in the thoracic oncology clinic. All of them had 

ECOG 1 or greater at the time of baseline evaluation. Symptoms and performance 

status were evaluated at baseline for 62 patients, of those 54 patients followed- up 

after 4 week using LCCS, PPS and ECOG. 

Results and conclusions: 54 patients completed baseline and follow-up measures. 

The mean age for patients was 63.7 years. 63% were receiving active chemotherapy at 

the time of evaluation. Seventeen patients died. Mean (range) baseline measures 

score were as follows: LCSS 6.18(1-14); PPS 66.6(40-90) and 1.82(1-4) for the ECOG. 

Censored survival times were calculated from the enrollment of the first subject for 

380 days. The last subject was recruited 357 days after the first subject. A 

proportional hazardous model was computed for survival status. Hazards ratios for 

death were 1.25(p= 0.013) for LCCS, 2.12(p= 0.027) for the ECOG and 1.02 for 

PPS (p= 0.49). The LCCS performed best as a predictor of prognosis in this 

study. Further analysis will include an assessment of association between symptom 

clusters and biomarkers. The PPS only functioned well as a predictor of survival time 

in patients receiving active treatment for advanced cancer. 


1443 A RETROSPECTIVE STUDY OF THE FACTORS TENDED TO 

TRANSFER TO PALLIATIVE HOME CARE FROM PALLIATIVE 

CARE UNIT AT A COMPREHENSIVE CANCER CENTER IN 

JAPAN 

T. Miura 1 , Y. Matsumoto 1 , A. Okizaki 2 , M. Oishi 3 , S. Motonaga 2 , Y. Higashi 1 , 

A. Sekimoto 4 , K. Abe 5 , M. Fukui 1 , H. Kinoshita 1 

1 Palliative Medicine and Psycho-oncology, National Cancer Center Hospital East, 

Kashiwa-shi, Chiba, JAPAN, 2 Pharmacy Division, National Cancer Center 

Hospital East, Kashiwa-shi, Chiba, JAPAN, 3 Nutrition Management Office, 

National Cancer Center Hospital East, Kashiwa-shi, Chiba, JAPAN, 

4 Nursing Department, National Cancer Center Hospital East, Kashiwa-shi, 

Chiba, JAPAN, 5 Palliative Care Center, Shimane University Hospital, Izumo-shi, 

Shimane, JAPAN 

Background: There are significant differences in the proportion of home death of 

cancer patients, 8.3% in Japan and 27.4% in the United Kingdom. However 63% of 

Japanese population hope home palliative care in their last 6 months. The palliative 


care unit (PCU) at the National Cancer Center Hospital East changed the 

administrative policy to amend patients unmet needs and strengthen the transition to 

palliative home care. Previous studies about the discharge from hospice indicated the 

factor of old age, female and poor performance status (PS). This study aimed to 

identify the factors tended to transfer to palliative home care in Japan. 

Methods: We reviewed the medical records of 333 consecutive cancer patients 

admitted to our PCU during period from October 2010 until September 2011. 

Patients transferred to other hospitals were excluded in this study.We identified 

variables associated with the discharged group and the deceased at PCU group, using 

the univariate and multivariate analyses. 

Results: There were 311 patients (Pts) during periods, 68 Pts (21.9%) discharged to 

palliative home care and 243 Pts (78.1%) deceased in our PCU. Characteristics of 

discharged group (68 Pts) were below: over 65 year-old (32%), female (53.0%), PS 4 

(7.4%), a relatively good amount of oral intake in first hospital day (76.1%), 

morphine use over 120mg/day at admission (23.5%), living alone (9.7%), married 

(74.6%), primary caregiver was partner (67.7%).Univariate and multivariate analysis 

identified: admission from their own home (OR 4.41; 95%CI 2.08-9.75), a good PS 

of > 4 (OR 6.21; 95%CI 2.11-23.18), a heart rate < 100 beats per minute (OR 3.72; 

95%CI 1.21-14.22), a good amount of oral intake (OR 1.71; 95%CI 1.26-2.43), 

dyspnea (OR 3.14; 95%CI 1.24-8.56), fatigue (OR 4.98; 95%CI 1.35-24.54) and 

abdominal distention (OR 11.00; 95%CI 1.94-209.60) as predictions of a transition to 

home from our PCU. 

Conclusion: Our study indicated the factors tended to transfer to palliative home 

care from PCU in Japan, however this study had some limitations. A prospective 

study is required to validate these factors. 


1444 INTEGRATED PALLIATIVE AND MEDICAL ONCOLOGY CARE 

FOR PATIENTS WITH SMALL CELL LUNG CANCER 

L. Selvarajah 1 , A.M. Sharkar 1 , S. Toner 2 , J. Clince 1 , M. Triggs 1 , N. Coleman 1 ,R. 

K. Morgan 2 , R. McQuillan 3 , L. Grogan 1 , O.S. Breathnach 1 

1 Medical Oncology, Beaumont Hospital Cancer Centre, Dublin, IRELAND, 

2 Pulmonary Medicine, Beaumont Hospital Cancer Centre, Dublin, IRELAND, 

3 Palliative Medicine, St. Francis Hospice, Dublin, IRELAND 

Introduction: Conventionally, palliative care services have been viewed as a terminal 

line of management when primary treatment is unsuccessful. Recent studies have 

shown that integration of palliative care medicine with medical oncology care 

substantially increases quality of life and survival duration in patients with non-small 

cell lung cancer 1 . This study was carried out in the Beaumont Hospital Cancer 

Centre highlighting the patterns of palliative care and medical oncology interventions 

in the management of patients with small cell lung cancer (SCLC). 

Methods: Information from patient records, intranetwork hospital databases, 

pathological reports, pharmaceutical entries and clinical notes of all patients 

diagnosed with SCLC through the Rapid Access Lung Cancer Clinic (RALCC) 

between 2008 to 2011 was compiled into a database. 

Results: Between 2008 to 2011, 58 patients presented to the RALCC and were 

diagnosed with small cell lung cancer. From this total amount, 50 patients were 

actively managed at our multidisciplinary centre. Of the 50 patients, 31 had extensive 

disease while 19 had limited disease. The median survival duration for actively 

treated patients with limited and extensive disease was 13 (range; 4 – 38) and 5.5 

(range; 0.5 – 17) months respectively. 46 (92%) patients received chemotherapy with 

the most common regimen being Etoposide and Carboplatin combination. The other 

4 (8%) patients did not receive chemotherapy due to various reasons mainly; 

patient’s preference, rapid deterioration and low performance status. 40 (80%) 

patients of the total cohort received palliative care services. The remaining 10 (20%) 

patients did not receive palliative treatment as the disease was well controlled by 

chemotherapeutic interventions. All patients who did not receive medical oncology 

services benefitted from palliative care treatments. 

Conclusion: This study revealed that almost all patients managed with medical 

oncology interventions had palliative care involvement, demonstrating significant 

integration between the disciplines. 1 Temel et al. Early Palliative Care for Patients 

with Metastatic Non–Small-Cell Lung Cancer. N Engl J Med. 2010;363:733-42. 


1445 LEVEL OF PALLIATIVE CARE EDUCATION AMONG 

ONCOLOGY NURSES IN THE STATE OF QATAR 


A.A. Hassan 1 , G.F. Abu Zeinah 2 , S.G. Al-Kindi 2 

1 Oncology/Haematology Departement, Al Amal HospitalHamad Medical 

Corporation, Doha, QATAR, 2 Medical College, Weill Cornell Medical College in 

Qatar, Doha, QATAR 

Objectives: Formal Palliative Care (PC) education is lacking in the Middle Eastern 

state of Qatar. This study was done to assess the need for PC education among 

oncology nurses in Qatar. 

Methods: A self-constructed questionnaire was distributed to 115 nurses at the Qatar 

National Center for Cancer Care and Research in March 2012. 

Results: One hundred fifteen nurses responded to the questionnaire. The majority 

(87.8%) were female. While 60% had more than ten years of work experience, only 

31% had received formal training in PC with only 6.1% having completed 

postgraduate training. The majority of responders (75%) attributed this issue to 

unavailability of PC courses rather than lack of time, interest or financial issues. 

Currently, only 16.7% did not express interest in the field, with 56% showing some 

kind of interest. In terms of knowledge, 54% of responders were familiar with the 

WHO ladder for pain relief. Only 43.6% know about Palliative Performance Scale 

and half of all nurses know the Edmonton Symptom Assesment System. Overall, 

56% of the nurses indicated a need for training in more than one aspect. These 

aspects included training in care of the dying patients (14.6 %), communication 

strategies (22%), caregiver support (10.6%), psycho-social care (15%), pain 

management (10.2%), other symptom management (13%) and other ethical/spiritual 

issues (14.2%). 

Conclusions: There is a clear deficiency in formal PC education among the nurses at 

the NCCCR in Qatar. This is reflected by their lack of experience and exposure to 

PC, and their mediocre knowledge in the field. This could be attributed to the fact 

that formal PC service was introduced only recently in Qatar (2008). Formal training 

courses in PC nursing are required. 


1446 VITAMIN D DEFICIENCY IN TERMINAL CANCER PATIENTS 

ADMITTED TO HOSPICE CARE CLINIC IN KOREA 

H.J. Shim, S. Cho, D.E. Kim, J.E. Hwang, W.K. Bae, I.J. Chung 

Department of Internal Medicine, Chonnam National University Medical School, 

Gwangju, KOREA 

Background: The prevalence of vitamin D deficiency in patients with terminal 

cancer is not well documented. The objective of this report was to describe and 

understand vitamin D status in terminal cancer patients. 

Methods: A total of 67 consecutive terminal cancer patients who were in the 

Hospice and Palliative Care Clinic at Jeonnam Regional Cancer Center during 

Aug 2011 to Mar 2012 were analyzed in this study. We investigated serum levels of 

25(OH) vitamin D, calcium, albumin and c-reactive protein. We also evaluated 

clinical characteristics, common symptoms including delirium, depression, fatigue 

and pain. 

Results: The median age of patients was 58 years, and 64.2% were men. 

Gastrointestinal (47.8%) cancer, hepatobiliary & pancreatic cancer (26.9%) 

and lung (13.4%) cancer were predominant. Sixty patients (89.6%) were vitamin D 

deficient (30 ng/mL). The level of vitamin D of 37 patients (55.2%) were less 

than 10ng/mL. Low serum vitamin D levels were independent of age, gender, 

primary disease site, body mass index, history of chemotherapy and disease duration. 

No significant association was found between vitamin D and symptoms such as 

delirium, depression, fatigue and pain. 

Conclusions: Vitamin D deficiencies were very common and severe in hopice 

population. There was no significant association between vitamin D levels and 

clinical factors. And also, we could not find a relation between vitamin D levels and 

symptoms including delirium, depression, fatigue and pain. 



prevention and screening 

1447PD POTENTIAL RISK OF ASBESTOS EXPOSURE AMONG 

JAPANESE GENERAL POPULATION: JAPANESE GENERAL 

SCREENING STUDY FOR ASBESTOS-RELATED DISEASES 

(JGSARD) 

N. Seki 1 , K. Eguchi 1 , M. Kusumoto 2 , M. Kaneko 3 , T. Yamaguchi 4 , 

J. Study Group 1 

1 Division of Medical Oncology, Department of Internal Medicine, Teikyo University 

School of Medicine, Tokyo, JAPAN, 2 Diagnostic Radiology, National Cancer 

Center Hospital, Tokyo, JAPAN, 3 Division of Endoscopy, National Cancer Center 

Chuo Hospital, Tokyo, JAPAN, 4 Medical Statistics, Tohoku University Hospital, 

Miyagi, JAPAN 

Background: Patients with pleural mesothelioma and lung cancer associated with 

asbestos exposure has been recently increasing in Japan. The aim of this study was to 

prospectively evaluate the actual situation of asbestos exposure and the prevalence of 

asbestos-related diseases among Japanese general population. 

Materials and methods: From 2006 to 2008, 9810 subjects (mean age, 57 years; 54% 

male and 50% smokers) underwent low-dose CT (LDCT) in 26 institutions in Japan. 

Then, 6286 (64.1%) subjects underwent subsequent screening after 2 years of 

interval. Clinical information such as history of asbestos exposure for all life was 

reviewed. Images were interpreted independently by 15 experts. 

Results: Self-reported history of occupational exposure was present in 2805 (28.5%) 

subjects, whereas self-reported history of residential exposure was present in 1193 

(12.2%) subjects although asbestos factory actually existed in 2870 (29.3%) subjects. 

Pleural plaque, pleural thickening, and pulmonary nodule were identified in 264 

(2.7%), 245 (2.5%), and 1003 (10.2%) subjects on LDCT. However, self-reported 

history of asbestos exposure was not confirmed in 77 (29.2%) of 264 subjects with 

pleural plaque although asbestos factory actually existed in 65 (84.4%) of such 77 

subjects. Pleural plaque on LDCT was significantly correlated with male (odds ratio 

OR, 2.32), age over 60 years (OR, 1.75), smoking (OR, 1.60), self-reported history of 

asbestos exposure (OR, 3.92), residential period in asbestos factory area (OR every 10 

years, 1.13), and asbestos-related work period (7 work identified, OR every 10 years, 

1.300-3–3.21). Moreover, lung cancer was identified in 29 (0.3%) subjects, resulting 

in significant correlation with age over 60 years (OR, 2.67) and pleural plaque (OR, 

4.17). After repeated LDCT screening, among 6286 subjects consisting of 165 and 

6121 subjects with and without pleural plaque on LDCT at baseline screening, 

respectively, 5 (3.0%) of 165 and 7 (0.1%) of 6121 subjects showed marked 

progression and new onset of pleural plaque, respectively. Again, lung cancer was 

identified in 8 (0.1%) subjects. 

Conclusion: Our results indicate the potential risk of asbestos exposure among 

Japanese general population and the importance of public relations and 

enlightenment for especially residential asbestos exposure. 


1448PD FIGHTING AGAINST CIGARETTE SMOKING AMONG 

MEDICAL STUDENTS- A SUCCESS STORY 

F. lcli 1 , D. Caliskan 2 , I. Gonullu 3 , H. Akbulut 1 , A. Ozkan 1 , S. Olmez 4 , U. Gonullu 5 , 

K. Sunguroglu 6 

1 Medical Oncology, Ankara University School of Medicine, Ankara, TURKEY, 

2 Public Health, Ankara University School of Medicine, Ankara, TURKEY, 3 Medical 

Education, Ankara University School of Medicine, Ankara, TURKEY, 4 Psychiatry, 

Ankara University School of Medicine, Ankara, TURKEY, 5 Pulmonology, Ankara 

University School of Medicine, Ankara, TURKEY, 6 Biochemistry, Ankara 

University School of Medicine, Ankara, TURKEY 

Physicians are important role models for the society regarding common health and 

disease prevention. Therefore, being aware of the health hazards of cigarette smoking, 



physicians should not smoke. In the year 1997 we surveyed 215 medical students 

at Ankara University in Ankara, Turkey to assess the smoking rates and factors 

they account for smoking. We found that 25.1% of the students were smoking 

(29.5% of males and 22.6% of females). Moreover, smoking rate was 35% for the 

6th year students (last year before graduation). We were sorry to find out that 

60% of the smokers started smoking following admittance to medical school. 

Our sense of responsibility led us to establish a “Cigarette Fighting Group” 

composed of voluntary academic staff, nurses, students, psychologists and a social 

worker aimed to lower the smoking rate and to eliminate it eventually among 

our medical students. Because of the difficulties of abandoning smoking, our 

main strategy was prevention of starting smoking. Several methods used 

including regular monthly meetings and they will be elaborated at the ESMO 

presentation. Consequently, our surveys in the years 2009 (641 students) and 

2012 (1737 students) showed that total smoking rates dropped to 15% and 11% 

respectively (p < 0.00001). Moreover, the smoking rate for 6th grade students 

dropped from 35% in 2007 to 21.8% and 8.8% in the years 2009 and 2012 

respectively (p = 0.005). In 2012, the smoking rates of 1st year and 6th year 

students were 7.8% and 8.8%, respectively. These close rates of smoking at the 

beginning and the end of medical school and the significant drop in smoking 

rates in 5 years confirms that, our group pursued a realistic and successful 

strategy against smoking. Details of the surveys will be presented at ESMO 

meeting. 


1449PD BREAST CANCER DETECTION AMONG IRISH BRCA1 & 

BRCA2 MUTATION CARRIERS 

E. Walsh 1 , M. Farrell 2 , R. Clarke 3 , C. Nolan 3 , M.J. Kennedy 4 , J.A. McCaffrey 5 , 

E. Connolly 6 , M. Kell 7 , T. Boyle 6 , D. Gallagher 8 

1 Oncology Dept, Mater Misericordiae University Hospital University College 

Dublin, Dublin, IRELAND, 2 Dept Cancer Genetics, Mater Misercordiae University 

Hospital & Mater Private, Dublin 7, IRELAND, 3 Dept Cancer Genetics, St James 

Hospital, Dublin 8, IRELAND, 4 Dept Medical Oncology, St James’s Hospital, 

Dublin, IRELAND, 5 Medical Oncology, Mater Misericordiae University Hospital, 

Dublin, IRELAND, 6 Dept Surgery, St James Hospital, Dublin 8, IRELAND, 7 Dept 

Surgery, Mater Misercordiae University Hospital, Dublin 7, IRELAND, 8 Dept 

Medical Oncology, Mater Misercordiae University Hospital & Mater Private, 

Dublin 7, IRELAND 

Background: High-risk breast cancer screening for BRCA1/2 mutations carriers with 

clinical breast exam, mammography and MRI have sensitivities approaching 100%. 

Even with intensive screening, BRCA mutation carriers can present with self-detected 

interval cancers. We investigate breast cancer screening practices and presentation 

among a cohort of Irish BRCA1/2 mutation carriers. 

Methods: Females with breast cancer belonging to kindreds now known to harbour 

BRCA1/2 mutations were retrospectively identified. Records were reviewed for BRCA 

mutation, demographics, breast cancer diagnosis, stage, histology and screening. We 

assessed screening modalities and whether breast cancers were diagnosed at screening 

or as interval cancers. 

Results: 53 cases of breast cancer were diagnosed from 1968 to 2010 among 53 Irish 

hereditary breast ovarian cancer kindreds. BRCA mutation status was unknown at 

time of diagnosis but subsequently confirmed. Detection method was identified in 

50% of patients: 84% by clinical breast exam (CBE), 4% by mammography, 4% by 

MRI and 8% by a combination of CBE and mammography. Fifteen women (28%) 

developed a second breast cancer; 9 (60%) were undergoing screening, 2 were not 

and 27% were unknown. Two cancers (22%) were detected by CBE alone; 34% by 

mammography; 22% by a combination of mammography and CBE and 22% by MRI. 

In 41%, histology changed between first and second diagnosis. Two women 

developed a third breast cancer. In one, the second was an interval cancer despite 

being in a screening programme. Her third was radiologically detected. 

Conclusions: In this cohort of Irish BRCA1/2 mutation carriers almost 25% of 

second breast cancers were not detected by screening. 4% of cases were phenocopies 

and in 41% histology changed between first and second diagnosis. 



abstracts

Characteristic No. % 

Total 63 

1 st Breast Cancer 53 84 

Median Age Range 42 24–73 

BRCA1 mutation 25 40 


Stage 

I 14 27 

II 25 48 

III 4 8 

Unknown 9 17 

Histology 

Ductal 30 57 

Other 10 19 

Unknown 13 24 

2 nd Breast Cancer 15 28 




Stage 

Stage I 8 53 

Stage II 3 20 

Stage III 3 20 

Histology 

Ductal 12 80 

Other 2 13 

3 rd Breast Cancer 2 4 



Stage 

I 1 50 

III 1 50 

Histology 

Ductal 2 100 


1450P EFFECT OF PRIOR METFORMIN INTAKE ON FIRST 

DIAGNOSIS OF BREAST CANCER 

S. Gupta 1 , D. Avila 2 , E.A. Mino 2 , P. Gosain 2 , K.K. Batra 2 , S. McDunn 3 

1 Div of Hematology-Oncology, John H Stroger Jr Hospital of Cook County, 

Chicago, IL, UNITED STATES OF AMERICA, 2 Internal Medicine, John H Stroger 

Jr Hospital of Cook County, Chicago, IL, UNITED STATES OF AMERICA, 

3 Hematology-Oncology, John H Stroger Jr Hospital of Cook County, Chicago, 

IL, UNITED STATES OF AMERICA 

Introduction: Metformin has been shown in pre clinical studies to have the ability to 

reduce tumor growth and exert anti cancer effects. It is being tested as a part of 

management of breast cancer (BC) in neoadjuvant and adjuvant settings and being 

entertained as a modality of chemoprevention in BC. We studied the effect of prior 

metformin intake on patients with first diagnosis of breast cancer. 

Methods: All patients with a diagnosis of BC were identified from the Tumor 

Registry of our hospital, which serves the underserved population of Chicago, USA. 

All charts were retrospectively screened for age, tumor grade, node status at 

diagnosis, onset of diabetes mellitus (DM) prior to cancer diagnosis and intake of 

metformin including duration. Patients with a diagnosis of DM after cancer, intake 

of metformin less than 6 months or incomplete medical record were excluded. 

Difference in means was calculated using the student t-test. 

Results: A total of 1569 patients were screened of which 133 patients were identified 

to have a diagnosis of DM before breast cancer and met the inclusion criteria. Of 

these, 95 patients were on metformin for an average 3.57 years (yrs) before BC 

diagnosis. Thirty-nine patients on metformin were younger than 60 yrs and 56 were 

older than 60 yrs age. Node positive disease was seen in 51.5% of metformin patients 

compared to 49% DM patients not on metformin (p = NS). However in patients 

younger than 60 yrs, node positive disease was seen in 66% of metformin patients 

compared to 86% non-metformin patients. The young patients on metformin had an 

average grade of 2.38 compared to non-metformin patients whose average grade was 

2.83 (p = 0.02). More patients in young non-metformin group were Her2-neu 

positive (43%) compared to 23% in young metformin group. In older patients more 

non-metformin patients had triple negative disease (20%) compared to 9% in 

metformin group. 


Conclusions: Prior metformin use may have a possible positive effect in patients 

with initial diagnosis of BC. This effect seems more pronounced in patients younger 

than 60 yrs of age where metformin intake was associated with a statistically 

significant reduction in tumor grade with a trend towards reduction in node positive 

disease and Her2 positivity. Further studies are needed to clarify the potential 

protective role of metformin in this younger group. 


1451P FIVE-YEAR RESULTS OF THE BREAST CANCER SCREENING 

PROGRAMME IN UGRA 

N.A. Zakharova 1 , S.W. Duffy 2 , J. Mackay 3 , E.V. Kotlyarov 4 , A.V. Filimonov 5 , 

K. Barinov 1 , I. Gromut 1 , E.V. Belan 1 

1 Oncological, State Oncology Center, Khanty-Mansiysk, RUSSIAN 

FEDERATION, 2 Wolfson Institute of Preventive Medicine, Queen Mary University 

of London, London, UNITED KINGDOM, 3 Consultant Clinical Genetic 

Oncologist, University College London, London, UNITED KINGDOM, 4 Oncology, 

State Medical Academy, Khanty-Mansiysk, RUSSIAN FEDERATION, 5 Chief, 

State Healthcare Department, Khanty-Mansiysk, RUSSIAN FEDERATION 

The main purpose of this study is to estimate the five-year result of the Breast 

Cancer Screening Program (BCSP) performed in the Khanty-Mansiysk Autonomous 

Okrug - Ugra. This Programme was initiated in 2007. The screening covers women 

over 40 years old. The screening interval is 2 years, with two-view mammography 

(MLO and CC) and single reading as the standard. During 2007–2011 within the 

BCSP, 201668 women were screened (177475 - prevalence screening). The screening 

coverage rate is approximately 56.4%. In 2011 we also evaluated the efficacy of usage 

for the mammography equipment in each district. According to the standard (RF) – 

there are 2840 examinations per day (2381 examinations per day - the average 

number in Ugra). Thus, the coverage rate only for the districts with the sufficient 

number of the examinations per day estimated as 68.4%. 10.3% of screened women 

were referred for further assessment. There were 460 breast cancer cases detected at 

the first round of screening and 22 cases in subsequent rounds. The cancer detection 

rate for prevalence was 2.6 and for subsequent rounds 0.9 per 1000 screened women. 

The test sensitivity for the first round was estimated as 77%. Also, we have tentatively 

evaluated the likely future effect on mortality from the breast cancer as a result of the 

BCSP in Ugra, on the basis of the changes in mortality seen at this early stage of the 

programme and of the changes in size and node status of the cancers diagnosed. In 

2009–11, a reduction in breast cancer mortality of the order of 15–20% was 

observed, compared to previous years. We anticipate a 20% reduction in deaths from 

breast cancer by 2015, on the basis of this and of reductions in the proportion of 

tumours of size >20 mm. The changes in the tumour size distribution do not appear 

to be due to length bias or overdiagnosis, since the overall incidence is consistent 

with pre-screening trends of increasing incidence. Analysis of node status is 

complicated by possible changes in practice with respect to axillary investigation. We 

are planning to increase the proportion of the digital mammography equipment in 

order to improve the quality of the examination and then - to implement the CAD 

(computer-aided detection) system. Thus, in the future in Ugra, it is planned to 

continue the BCSP, and to continue to improve the quality of screening. 


1452P CANCER SCREENING IN UNDERSERVED, VULNERABLE 

POPULATION. RESULTS FROM THE EDIFICE SURVEY 

F. Eisinger 1 , J. Viguier 2 , C. Touboul 3 , Y. Coscas 4 , X. Pivot 5 , J. Blay 6 , C. Lhomel 4 , 

J. Morère 7 

1 Oncology, IPC INSERM UMR 599, Marseille, FRANCE, 2 Centre De 

Coordination Des Dépistages Des Cancers, CHRU Trousseau, Tours, FRANCE, 

3 Oncology, Kantar Health, Montrouge, FRANCE, 4 Oncology, Clinique de la Porte 

de Saint Cloud, Boulogne Billancourt, FRANCE, 5 Service Oncologie Medicale, C. 

H.U. Jean Minjoz, Besancon, FRANCE, 6 Oncology, Centre Léon Bérard, Lyon, 

FRANCE, 7 Oncology, Hôpital Avicenne, Bobigny, FRANCE 

Background: Reducing cancer inequalities is one of the most critical goals of the 

current National Cancer Plan. The French health system allows fair access to care for 

all affected persons. In contrast, exposure to risk factors is far worse for underserved 

populations. The issue of cancer screening attendance distribution according to social 

factors, deserves to be assessed and regularly monitored. 

Methods: Accurate data on cancer screening in the population is available; however 

it is difficult to assess who belongs to an underserved/vulnerable subgroup. Many 

indicators could be used, such as the validated questionnaire “EPICES” with eleven 

yes/no questions.We analysed a sample of the general population (N = 1603) to 



assess if screening attendance is correlated with this validated synthetic score or by 

any of its components. 

Results: 

Breast 

40–74 

Breast 

50–74 

Official 

program CRC 40–74 

CRC 

50–74 

Official 

program Prostate 

Contact with social workers ns ns ns ns ns 

Additional health insurance ns ns ns ns ns 

Living alone ns ns p < 0.05 ns p < 0.05 

Home ownership p < 0.05 ns p < 0.01 p < 0.05 ns 

Financial difficulties p < 0.05 ns p < 0.01 ns ns 

Practicing sport p < 0.01 ns ns ns ns 

Performance attendance p < 0.01 ns ns ns ns 

Taking vacations ns ns p < 0.05 ns p < 0.05 

Family ties ns ns ns ns p < 0.05 

Housing support ns ns p < 0.01 ns ns 

Social support ns ns p < 0.01 ns ns 

EPICES Synthetic score ns ns ns ns ns 

Conclusions: It appears that social determinants of vulnerability are not key 

determinants for screening behaviour. However, there is still an impact on cancer 

screening attendance outside the official target age group. Under these circumstances, 

vulnerable populations use less health screening resources. Social support and home 

ownership are the most powerful predictors for screening attendance.Our data 

support the dramatic impact of organised programs which reduce or even remove 

inequities in access to cancer screening. 


1453P ATTITUDE, KNOWLEDGE AND FEARS CONCERNING 

CANCER AMONG LOW-INCOME RURAL WOMEN OF 

DIFFERENT RELIGION AND ETHNICITY 

S. Bhattacharjee 1 , C.K. Bose 2 , S. Koner 1 , A. Mukhopadhyay 3 

1 Community Medicine, Netaji Subhas Chandra Bose Cancer Research Institute, 

Kolkata, INDIA, 2 Dept. of Gynocological Oncology, Netaji Subhash Chandra 

Bose Cancer Research Institute, Kolkata, INDIA, 3 Medical Oncology, Netaji 

Subhas Chandra Bose Cancer Research Institute, Kolkata, INDIA 

The low participation level of rural women in cancer screening is a cause of concern 

especially in India. The role of predisposing knowledge and attitudes concerning 

cancer in many religious and ethnic groups is not studied well to find out cause of 

such reluctance in participation. We documented the knowledge and fears 

concerning such cancer in rural population of women of different ethnicity and 

religions in West Bengal province of India and how these factors relate to screening 

behaviour and socio-demographic characteristics. A baseline survey was conducted 

before the start of a community cancer awareness and screening programme. A total 

of 2000 rural women of different districts of West Bengal were interviewed in-person 

about their knowledge, attitudes and Pap smear and mammogram screening 

practices. Knowledge and attitude about cancer varied with age, education, 

socioeconomic status, ethnicity and religion. Women in the age range of 40–72 years 

(median 56 years) and least knowledgeable of cancer-detection methods and 

screening guidelines were considered for our study. Socio-economic markers were 

monthly income, literacy, nature of roof, and toilet. About 80% women, who 

participated, had no toilet facility. Women, who could not read and write, were more 

unaware of cancer signs and symptoms, risk factors and screening guidelines. 

However, biggest concern about was poor infrastructural facility for doing cervical 

examination and women are shy to have elaborate examination and treatment in 

their private parts in an open camp. Striking finding was full participation and 

cooperation in awareness and screening of cervical cancer among scheduled tribal 

women. They had near total participation which was far more than scheduled casts 

and Muslims. The low screening participation among rural Indian women may be 

due to their shyness to participate in a comparatively open camp and limited 

awareness and knowledge about screening examinations. Our study highlights the 

need for wide-scale cancer screening interventions consistent with prevailing rural 

belief. Tribal people are most cooperative among all ethnic and religious and 

socio-economic groups. 


1454P EVALUATION OF COLPOSCOPY AND LOOP 

ELECTROSURGICAL EXCISION PROCEDURE (LEEP) IN A 

RURAL MOBILE CERVICAL CANCER SCREENING UNIT IN 

WEST BENGAL, INDIA 

S. Koner 1 , C.K. Bose 2 , A.N. Sen 3 , A. Mukhopadhyay 4 


Kolkata, INDIA, 2 Dept. of Gynocological Oncology, Netaji Subhash Chandra 

Bose Cancer Research Institute, Kolkata, INDIA, 3 Surgical Oncology, Netaji 

Subhash Chandra Bose Cancer Research Institute, Kolkata, INDIA, 4 Medical 

Oncology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, 

INDIA 

Background: In recent years there are many attempts to see accuracy of colposcopy 

in poor resource setting where ‘see and treat’ approach is used. Sensitivity and 

specificity for colposcopy in India is not determined accurately so far because of 

poormethodology of experiments. 

Objectives: Hence, in a cervical cancer screening and management project for rural 

poor women in West Bengal province of India we tried to calculate specificity and 

sensitivity of colposcopy based on management by LEEP. 

Methods: VIA combined with colposcopy and LEEP using mobile van is planned in 

a biotechnology based programme for women under Department of Biotechnology, 

Govt. of India where efficacy of colposcopy was assessed by camp approach in rural 

area of a remote district. We used video colposcopy as triage and managed positive 

cases by LEEP. We randomly selected 50 cases that wereColposcopy negative & 50 

cases with CIN I and did biopsy cervix on all of them. We thus evaluated our early 

screeningand management to detect sensitivity & specificity of Colposcopy in this 

rural setting. 

Results: A total of 2836 women participated in our rural camp for screening during 

this period. We could detect 415 VIA positive cases. In this gold standard test we 

saw 12 cases of false positive. Only 14 cases of false negative that then underwent 

LEEP. Thus colposcopy in our series had 60% sensitivity and 63% positive predictive 

value while 87.7% specificity and 86% negative predictive value. Complication Rate 

was 3 percent (14 cases). 

Conclusion: In our series sensitivity of colposcopy was comparatively low. Main 

confounding variable producing false positive result was inflammation of cervix 

which seems to be a cause of concern in our country. However, obustness of VIA 

needs to be calculated in a bigger study to find out efficacy of such screening. 


1455P CERVICAL CANCER SCREENING USING VISUAL 

INSPECTION AFTER APPLICATION OF 5% ACETIC ACID 

(VIA) IN RURAL WEST BENGAL 

A.N. Sen 1 , C.K. Bose 2 , S. Koner 3 , A. Mukhopadhyay 4 

1 Surgical Oncology, Netaji Subhash Chandra Bose Cancer Research Institute, 

KOLKATA, INDIA, 2 Dept. of Gynocological Oncology, Netaji Subhash Chandra 

Bose Cancer Research Institute, Kolkata, INDIA, 3 Community Medicine, Netaji 

Subhas Chandra Bose Cancer Research Institute, Kolkata, INDIA, 4 Medical 

Oncology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, 

INDIA 

Background: Because of problem of manpower in developing countries, cytology 

screening for cervical cancer is gradually replaced by a Visual Inspection after 

application of 5% acetic acid (VIA) with triage of colposcopy. 

Objectives: Hence, government and other funding bodies in India are now eager to 

see its efficacy in the field to screen and manage cervical pre cancer (CIN) in a “see 

&treat” approach. 

Methods: This simple technology combined with colposcopy is planned in a 

biotechnology based programme for women under Department of Biotechnology, 

Govt. of India where efficacy of VIA was assessed by camp approach in rural area of 

a remote district (Burdwan) of West Bengal province in India from August 2010 to 

August 2011. We used video colposcopy as triage and managed positive cases by 

Loop Electrosurgical Excision Procedure (LEEP). We evaluated our early screening 

and management results by finding out detection rates of early lesions of cervix and 

in this uncontrolled observational study. 

Results: A total of 2836 women participated in our rural camp for screening during 

this period. Amongst them 2354women could be subjected to visual inspection by 

acetic acid (VIA) using 200 watt bulb and 5% acetic acid by the trainedcommunity 

nurse. We could not do VIA in 482 subjects because of no consent-22.80%, 

non-cooperation-23.40%, unmarried-18.60%, menstruating-12.80%, pregnant-10.50%, 


hysterectomised-9.10% and cervix cancer neglected or infollow up-2.50%. We could 

detect 415 cases of VIA positive cases showing white lesion in their cervix. 

Colposcopic prediction of cervical Intra-epithelial neoplasia grade I(CIN I) lesion 

could be detected in 174 cases. These cases are of no immediate risk and most of 

them actually showregression of their disease. Hence, they are advised to have 

follow-up colposcopy after six months. There were 25 cases of condyloma/ polyp. 

They were managed by electro- cautery. We could detect and treat 33 cases of CIN II 

andIII which are precursor of cervical cancer. They were treated by LEEP. 

Conclusion: Our results show that VIA with colposcopy triage is viable option in 

rural cervical cancer screening programme in our outreach program. 


1456P ENDOSCOPIC ULTRASONOGRAPHY IN HIGH-RISK 

POPULATION FOR PANCREATIC CANCER 

C. Guillen-Ponce 1 , E. Mocci 2 , A. Amendolara 2 , E. Vazquez-Sequeiros 3 , 

C. Gonzalez Gordaliza 4 , M. Muñoz Beltran 4 , A. Sanjuanbenito 5 , C. Gonzalez 

Garcia 6 , A. Custodio 7 , A. Carrato 1 

1 Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, 

SPAIN, 2 Medical Oncology, Ramon y Cajal University Hospital, Madrid, SPAIN, 

3 Digestive Department, Ramon y Cajal University Hospital, Madrid, SPAIN, 

4 Radiology Department, Ramon y Cajal University Hospital, Madrid, SPAIN, 

5 Surgery Department, Ramon y Cajal University Hospital, Madrid, SPAIN, 

6 Pathology Department, Ramon y Cajal University Hospital, Madrid, SPAIN, 

7 Medical Oncology, La Paz University Hospital, Madrid, SPAIN 

Introduction: Members of families with familial pancreatic cancer (FPC) have high risk 

of developing pancreatic cancer (PC). The risk increases with the number of PC in 

family members. In the last decade, several centers around the world are using screening 

programs for this high risk population, most of them based on endoscopic 

ultrasonography (EU) and computed tomography (CT) or magnetic resonance imaging 

(MRI). This work assesses the findings of screening in individuals at high risk of PC. 

Material and methods: It has recommended screening for PC in individuals at high 

risk of this cancer by EU and CT. In those cases in which it was suspected some 

alteration, we proceeded to MRI and/or puncture of the pancreatic suspicious lesions. 

Results: Since October 2011, we indicated the screening of 50 individuals belonging 

to 10 families. 9 families had FPC and one had a hereditary breast and ovarian 

cancer syndrome with a case of PC. They have been identified 4 lesions suspicious 

for EU, none of these correlated with suspected by CT or MRI. Suspicious lesions 

were found in 3 members of the same family and another from another family, all 

with FPC. It has been suggested puncture injuries in 2 cases and in both cases, the 

cytology results were negative. In the other two cases it was decided to follow up. 

Conclusions: Preliminary results confirm that the EU can detect small lesions 

undetectable by CT or conventional MRI. The phenotype found by EU has already 

been described in patients with strong family history of PC. It should explore the 

utility of other imaging tests such as MRI with diffusion, for monitoring individuals 

at high risk of PC. 


1457P CONTROL OF CANCER IN WEST BENGAL, INDIA BY 

SCREENING AND AWARENESS PROGRAM 

J. Basak 1 , A. Chakraborty 2 , S. Dasgupta 1 , D. Bhattacharya(majumder) 1 , 

S. Mukhopadhyay 1 , A. Mukhopadhyay 3 

1 Dept of Molecular Biology, Netaji Subhash Chandra Bose Cancer Research 

Institute, Kolkata, INDIA, 2 Molecular Biology and Human Genetics, Netaji Subhas 

Chandra Bose, Kolkata, INDIA, 3 Dept. Medical Oncology, Netaji Subhas 

Chandra BoseCancer Research Institute, Kolkata, INDIA 

Background: In India there are about 2.5 million cancer patients and it increases by 

1 million new cancer patients every year, which is 1/10 of total cancer burden in the 

world. The aim of our state based non-governmental Cancer Control Program is to 

reduce the cancer burden by proper awareness and screening. We also intended to 

teach about the early symptoms of cancer so that it can be detected early to provide 

appropriate treatment. Our motto is to serve people residing in remote villages of 

West Bengal where there are no modern medical facilities available for detection of 

cancer. 

Material and methods: During the period of January 2004–April 2012, a cancer 

screening & awareness program had been conducted in various districts of West 

Bengal, twice in every month by the members of NSCBCRI. We mainly dealt with 

oral, lung, breast and cervical cancer. We organized the awareness camps on a 

prefixed day with prior permission of the representatives. The cases which were 

detected positive were sent to our hospital for proper treatment and advanced cases 

were advised for pain and palliative treatment in our institution. 

Result: More than 80% of people participated spontaneously in awareness camps. 

Female cancer incidence was about 60%. We observed tobacco habits in 80% of 

males & 10% of females. The percentage of passive smokers among females is 

very high in West Bengal. Among 144256 screened population, we found 11541 

(8.0%) cancer patients in different stages of the disease. Ratio of male and female 

patients was 3:2. A total of 4986 (72%) male and 1200 (26%) female cancers 

were tobacco related. Among females the incidence of cervical and breast cancer 

were 34% and 23%, respectively. Among male oral and lung cancer incidence 

were 32% and 35%, respectively. About 67% of the cancer had been detected at 

an early stage. 

Conclusion: Through camps in remote rural areas of West Bengal we came to know 

that the majority of cancer cases are life style related. This can only be prevented by 

proper awareness camps. So, cancer detection and awareness camps are essential and 

important in rural areas to reduce the huge burden of cancer. 


1458P TOBACCO CESSATION IN THE COMMUNITY 


P. Hazra 1 , S. Mukhopadhyay 1 , A. Mukhopadhyay 2 


Kolkata, INDIA, 2 Medical Oncology, Netaji Subhas Chandra Bose Cancer 


Tobacco smoking is the most intensively investigated environmental cause of 

cancer. Smokes came out of cigarettes, bidis, hookahs etc. contains nicotine and 

other chemical compounds which are proved as dangerous carcinogens. Cancer 

causation by tobacco smoke is not attributable to any one chemical compounds 

but to an overall effect of the complex mixture of chemicals in smoke. Using 

tobacco, active smokers can get affected to lung and cancers in other organs such 

as larynx, oral cavity, pharynx, esophagus, pancreas, kidney and bladder. Non– 

smokers who are exposed to environmental tobacco either by family members or 

workplace are also equally at the risk of having lung, laryngeal cancers, other 

respiratory diseases and even breast cancer. This study aims to find out the 

tobacco use in the community and to stop usage. This was a population 

awareness study during period from September 2007 to 2012 in Mandarihaat 

village, Jalpaiguri district of North Bengal by the community medicine dept of 

NCRI. A population of 5000 people, in the age group between 6–45 years, was 

randomly interviewed following a structured questionnaire. We attended the 

village and did the awareness every three months. In our first visit, we have seen 

that 70% of the population was tobacco users, either by way of smoking (40%) or 

chewing (30%). We did a thorough awareness program and explained the 

different hazards of smoking for cancer and heart diseases. In the next visit, we 

advised them to quit smoking. Again after 3 months, we noticed that about 25% 

(875) of the tobacco users quit tobacco use. Thereafter, we screened the 

population every 6 months and continued our awareness program. At the end of 

4 years, only 5% people continued the habit of tobacco. We advised them to use 

nicotine tablets 4mg three times daily. At the end of 5 years, the entire smoking 

population except 0.05% (p value


a factor 2 to 10) the probability of having cancer after a positive test. In contrast, 

65% were aware of the possibility of a false negative test (neither gender, educational 

level, socio economic level impacted the knowledge). 

Conclusions: This study demonstrates a lack of detailed knowledge on the colorectal 

cancer screening process in the French national program. This raises the issue of the 

fairness of the process and may be a reason for the current poor uptake. This should 

be tackled by improving the transmission of information via general practitioners, 

institutional letters sent directly to subjects and mass media. 


1461 AWARENESS OF CANCER SCREENING DURING THE 

TREATMENT OF RENAL FAILURE PATIENTS: PHYSICIAN 

QUESTIONNAIRE 

O. Uysal Sonmez 1 , U. Uyeturk 2 , I.I. Budakoglu 3 , R. Kazancioglu 4 , I. Turker 5 , 

B. Budakoglu 6 , U. Yalcintas Arslan 6 , O.B. Oksuzoglu 6 

1 Department of Medical Oncology, S.B.Sakarya University Hospital, Sakarya, 

TURKEY, 2 Departmet of Medical Oncology, Abant Izzet Baysal University 

Hospital, BOLU, TURKEY, 3 Medicine Education, Gazi University Faculty of 

Medicine, ANKARA, TURKEY, 4 Nephrology Deoartment, Bezmialem Vakıf 

University, Istanbul, TURKEY, 5 Department of Medical Oncology, Trabzon 

Numune Research and Education Hospital, Trabzon, TURKEY, 6 Department of 

Medical Oncology, Ankara Dr.A.Y.Oncology Research and Education Hospital, 

ANKARA, TURKEY 

Background: Survival of patients with renal insufficiency has increased. With the 

prolonged survival, diagnosis of cancers is not infrequently seen. The aim of cancer 

screening is to increase the curability. 

Method: This study was done by face to face questionnaire in the 27th National 

Nephrology Congress to determine if the physicians dealing with chronic renal 

failure, hemodialysis or renal transplanted patients, recommend cancer screening or 

not and the methods of screening for cervix, prostate, breast and colon cancer. 

Results: One hundred and forty four physicians were included in the survey. 101 

participants were male. The most common age interval was between the ages of 40–49 

(55.6%). About 28.5% of the participants were specialist on nephrology, 27% on internal 

medicine, 47.9% of participants were hemodialysis certified general practitioners and 

4.9% were other areas of expertise. About 81.9% of the participants were working in the 

city and 59.7% of the participants in private dialysis centers. Patients were grouped as 

compensated chronic renal failure, hemodialysis or renal transplanted. Of the 144 123 

physicians recommended breast cancer screening and the most recommended subgroup 

was HD patients (15.5%). The most preferred methods of screening were combinations of 

mammography, self breast examination and physicians’ breast examination. One 

hundred and nine physicians recommended cervix cancer screening, and the most 

preferred method of screening was papsmear. Colon cancer screening was recommended 

by 105 physicians and prostate screening by 114 physicians. The most preferred methods 

of screening were fecal occult blood test and PSA plus rectal digital test, respectively. 

Conclusion: It is not obvious whether cancer screening in renal failure patients is 

different from the rest of society. There is a variety of screening methods. An answer 

can be found to these questions as a result of studies by a common follow-up 

protocol and cooperation of nephrologists and oncologists. 



abstracts 

psycho-oncology 

1462PD INTEGRATION OF PSYCHOSOCIAL CARE INTO ROUTINE 

CANCER CARE: FINAL RESULTS OF A LARGE 

COLLABORATIVE, HOSPITAL-BASED, QUALITY 

IMPROVEMENT STUDY (HUCARE PROJECT) 

R. Passalacqua 1 , C. Caminiti 2 , M.A. Annunziata 3 , C. Borreani 4 , J. Saleri 5 , 

F. Diodati 6 , L. Isa 7 , S. Filiberti 1 , D. Fagnani 8 and G. Donati 1 

1 Oncology Division, Istituti Ospitalieri di Cremona, Cremona, ITALY, 

2 Epidemiology, Azienda Ospedaliera Universitaria di Parma, Parma, ITALY, 

3 Psychology, CRO Aviano, Pordenone, ITALY, 4 Psychology, INT Milan, Milan, 

ITALY, 5 Oncology, Istituti Ospitalieri, Cremona, ITALY, 6 Epidemiology, Azienda 

Ospedaliera, Parma, ITALY, 7 Oncology, ASL Melegnano, Milan, ITALY, 

8 Oncology, AO Vimercate, Milan, ITALY 

Background: Incorporating psychosocial research into practice is challenging. Aim of 

this study is to assess the feasibility in real life of interventions which have been 

tested in RCTs and have demonstrated to improve pts psychosocial conditions. 

Methods: This is an implementation study of five EBM interventions, conducted in 

28 centers. We adopted the model of Pronovost [BMJ 2008], which includes: context 

analysis to identify local barriers, introduction of the interventions, and evaluation of 

how many pts receive the recommended interventions. Primary EPs: degree of 

implementation detected in a blinded fashion by external trained personnel. EBM 

interventions included: 1) communication courses for doctors and nurses [Ann 

Oncol 2011]; 2) use of a question prompt list (QPL) [Cancer 2008]; 3) creation of 

the Point of Information and Support (PIS) in the ward [J Clin Oncol 2009]; 4) 

identification of a referring nurse (RN) for informing and educating pts [J Clin Nurs 

2010]; 5) screening of distress and social needs [J Natl Compr Canc Netw 2010]. 

Results: 33 centers applied to partecipate, 29 were eligible and 28 are evaluable. Final 

blinded analisys was conducted on 305 consecutive patients. 156 oncologists and 401 

nurses attended the 3 days training course. An Australian QPL was subjected to 

cross-cultural adaptation, yielding the first validated Italian QPL [BMC Health Serv 

Res 2010]. 25 centers (89%) have successfully implemented the majority of 

interventions; 1 is too early and 3 centers failed for various reasons: internal conflicts 

of the staff, poor motivation, etc. Main results for each intervention are shown in the 

table: 

Conclusions: Using this methodology, a successful implementation of EBM 

measures is possible in the vast majority of centers and yields significant 

improvement in the delivery of psychosocial care. Funded by the Italian Ministry of 

Health and the Lombardia Region 


1463P EVALUATION OF SEXUALITY, QUALITY-OF-LIFE AND 

DEPRESSION IN ADVANCED CANCER PATIENTS TREATED 

IN A DRUG DEVELOPMENT UNIT 

M. Rouanne 1 , C. Massard 2 , A. Hollebecque 2 , V. Rousseau 3 , A. Varga 2 , 

A. Gazzah 2 , Y. Neuzillet 1 , T. Lebret 1 and J. Soria 2 

1 Urology, Hôpital Foch, Suresnes, FRANCE, 2 SITEP, Institut de Cancérologie, 

Villejuif, FRANCE, 3 Biostatistics, Institut Gustave Roussy, Villejuif, FRANCE 

Background: The advent of molecular targeted agents (MTA) opened a new era 

therapy in oncology. The objective of this study was to investigate quality of life, 

depression and sexual function in patients treated in a phase I drug unit evaluating 

MTA. 

Patients and methods: All patients included in a phase I clinical trial at the Gustave 

Roussy Institute were proposed a personal interview regarding their quality of life, 

depression, and sexual function. They completed 4 self-questionnaires containing the 

Medical Outcomes Study Short-Form General Health Survey (SF12), the Beck 

Table: 1462PD 

EBM TRAINING COURSES 

(No and % of attendee, 

oncologists plus nurses) 

REFERRING NURSE (RN) 

(No and % of 

pts with a RN) 

Depression Inventory (BDI-II), the International Index of Erectile Function (IIEF) 

and the Female Sexual Function Index (FSFI). 

Results: This is, to our knowledge, the first evaluation of quality of life, depression 

and sexual function in a phase I drug unit. Sixty-three patients were evaluated at 

baseline. Patients had a good mental and physical function despite their disease 

progression. The response rate was 75% for sexual questionnaires. For 57% of females 

and 68% of males, quality of sexual life was a subject of interest. After one month 

treatment, sexual dysfunction increased especially in lubrication and pain in females 

and erection in males with a statistical association of anti-angiogenic inhibitors in 

males (p = 0.04). 

Conclusions: Patients on MTA in phase I clinical trials had a preserved mental and 

physical activity whereas their sexual activity decline in both sexes. The impact of 

MTA on sexual function should be routinely assessed. 


1464P THE DIFFERENCE IN THE SERUM LEVELS OF BDNF, IL-6, 

IL-8, IL-10 AND EGF IN ONCOLOGY PATIENTS DIVIDED 

ACCORDING TO THE PRESENCE OF SYMPTOMS OF 

DEPRESSION 

L. Holubec 1 , O. Fiala 1 , V.M. Matejka 1 , J. Podlipny 2 , J. Dreslerova 1 , J. Vrzalova 3 , 

O. Topolcan 3 , J. Finek 1 and T. Svoboda 1 

1 Department of Oncology & Radiotherapy, University Hospital Pilsen, Pilsen, 

CZECH REPUBLIC, 2 Department of Psychiatry, University Hospital Pilsen, Czech 

Republic, Pilsen, CZECH REPUBLIC, 3 Department of Nuclear Medicine, 

University Hospital Pilsen, Pilsen, CZECH REPUBLIC 

Objective: To assess the differences in the serum levels of Brain-derived neurotrophic 

factor (BDNF), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10) and 

epidermal growth factor (EGF) in oncology patients with symptoms of depression 

and in oncology patients without symptoms of depression. 

Methods: We administered the following self – report questionnaires to the 

hospitalized oncology patients (n = 32): Zung´s Self-Rating Depression Scale (ZSDS) 

and Symptom Check List Psychiatric Rating Scale (SCL 90). We also collected blood 

samples from these patients for the detection of the following factors: BDNF, IL-6, 

IL-8, IL-10 and EGF. The procedures had been fully explained to all patients and 

written informed consent had been obtained. The patients were divided into two 

groups according to the scores in ZSDS: a group with the presence of symptoms of 

depression (n = 20) and a group without the symptoms of depression (n = 12). The 

differences in the levels of BDNF, interleukins and EGF between the groups were 

statistically assessed by Wilcoxon rank-sum test. 

Results: Oncology patients with the symptoms of depression showed significantly 

lower levels of BDNF (medians 1452.3 vs 3229.0 pg/ml, p = 0.014). There were no 

significant differences in the levels of IL-6, IL-8, IL-10 and EGF between the groups. 

Conclusion: This result supports the hypothesis of diminished neuroplasticity in 

oncology patients with the symptoms of depression as measured by the serum levels 

of BDNF. This study was supported by research project MSM 0021620819. 


1465P SLEEP DIFFICULTIES, PAIN AND STRESS IN COLORECTAL 

CANCER FEMALE PATIENTS 

P. Heras, V. Niarou, E. Andrikopoulos and M. Hera 

Internal Medicine, General Hospital of Naflio, Athens, GREECE 

Aim: This study examined sleep difficulties, pain and stress among women 

undergoing surgery for colorectal cancer(CC). 

Methods: Perceived distress was assessed with Perceived Stress Scale (PSS). Sleep 

quailty was assessed using the Pittsburgh Sleep Quality Index (PSQI). Pain severity 

and interference were assessed using the Brief Pain Inventory (BPI), while frequency 

PIS (No and % of 

Units with a PIS) 



USE OF THE QPL 

(No and % of pts who 

receive the QPL) 

PSYCHO-SOCIAL 

EVALUATION (No and % of 

screened patients) 

Pre-Implementation 0/598 (0%) 0% 4/29 (17%) 0% 0% 

Post-Implementation 557/598 (93%) 262/305 (86%) 24/29 (83%) 223/305 (73%) 253/305 (83%) 




of cancer-associated pain was assessed with a single item from the Functional 

Assessment of Cancer Therapy-Colorectal Cancer (FACT-CC) scale Participants were 

assessed immediately prior to surgery and then 4-6 weeks following surgery. 

Results: Participants were 68 women who completed at least the PSQI at presurgery, 

36 to 85 tears old ( M = 61.12, SD = 9.18). Clinically significant sleep disturbance was 

evident was evident in 48% of participants prior to surgery, 57% showed clinically 

significant sleep disturbance was associated with greater stress (p < 0.01), cancer pain 

frequency (p < 0.01) and pain interference (p < 0.01). Frequency of cancer pain 

decreased significantly following surgery (p < 0.05); however, there were no changes 

in sleep disturbance, pain severity/interference, all stress scores from pre to post 

surgery. Following surgery, greater total sleep disturbance remain associated with: 

greater stress(p < 0.01) and cancer pain frequency (p < 0.01) but was no longer 

associated with pain interference. 

Conclusions: Sleep disturbance is prevalent among women both prior to and 

following surgical resection for CC. In addition, associations among sleep 

disturbance, stress and pain are present shortly following CC diagnosis and persist 

throughout the perioperative period. 


1466P DIFFERENCES IN PERCEIVED AND OBTAINED SOCIAL 

SUPPORT IN CERVICAL CANCER PATIENTS AFTER 

RADICAL RADIO-CHEMOTHERAPY WITH COMPARISON 

WITH HEALTHY POPULATION 

A. Kieszkowska-Grudny 1 , M. Rucinska 2 , S. Biedrzycka 2 and S. Nawrocki 2 

1 Fryderic Chopin Memorial Hospital, The European Health Centre Otwock, 

Otwock, POLAND, 2 Department of Oncology, University of Warmia and Mazury, 

Olsztyn, POLAND 

Background: Cervical cancer is one of the most frequent neoplasms in women. 

Diagnosis and treatment engage a lot of patients’ emotion and therefore the social 

support becomes interesting subject of assessment for the clinical and psychological 

status of cervical cancer survivors. The aim of this study was to compare perceived 

and obtained social support in cervical cancer survivors after radical 

radio-chemotherapy and healthy women. 

Material and methods: 94 women were included to the study between November 

2009 and May 2010: 47 cervical cancer patients (27-69 years, median 55 years) 

minimum 3 months (median 37 months) after radical radio-chemotherapy and 47 

healthy women (24-64 years, median 52 years). Subjects filled out a questionnaire 

that included Berlin Social Support Scales (BSSS) which measures 10 different types 

of support, and additional demographic and medical questionnaires. In the statistical 

analysis chi2 test, t-Student test and linear regression were used. The significance 

level was p < 0.05. 

Results: Almost all types of social support were significantly higher assessed by 

women after cervical cancer treatment than healthy ones. While the need for support 

and seeking support was almost at the same level in both groups, women with cancer 

treatment currently receive more support than healthy women (p < 0.05). 

Significantly (p < 0.05) higher perceived emotional support, total currently received 

support and currently received instrumental support were found in cancer patients 

living in the village, city up to 50 thousand, and city between 50 and 200 thousand 

inhabitants, respectively. In addition, we uncovered predictors of better support, like: 

FIGO stage was predictor to perceived instrumental support and currently received 

emotional support, but age was a predictor of most intensive need of seeking for 

support (p < 0.05). 

Conclusions: Although the need for social support was the same in both groups, 

women after cancer treatment received it more, and evaluate it higher. FIGO stage 

and age were the most important predictors of perceived instrumental support, 

current emotional support and seeking form support. 


1467P QUALITY OF LIFE AMONG OLDER PATIENTS (AGE 65+) 

WITH CANCER IN A UNIVERSITY HOSPITAL IN INDIA 

A. Chandra and J.P. Martin 

Medical Oncology Unit, Department of General Medicine, SRI Ramachandra 

University, Chennai, INDIA 

Background: Cancer in older cancer patients, additional endpoints such as quality of 

survival and daily functioning might be considered equally relevant as overall or 

disease free survival. However, these factors have been understudied. Therefore, this 

study will focus on the impact of cancer, ageing, and their interaction on the 

long-term wellbeing of older cancer patients. 

Methods: This is an prospective study. We recruited 45 cancer patients above 65 

years with a new diagnosis of breast, prostate, lung or gastrointestinal cancer between 

November 2011 and January 2012. Data collected through personal interviews and 

self-administered questionnaire (consisting of socio-demographic information, 

general health information, a comprehensive geriatric assessment, quality of life, Mini 

Mental Status Examination, Barthel Index, geriatric depressive scale ECOG 

Performance status and Mini Nutritional scale), and assessment of medical records. 

Results: The four most prevalent symptoms/problems identified were fatigue, 

financial difficulties, reduced role function and reduced social function. The geriatric 

depressive scale showed 33.3 % normal and 53.3 % had mild depression. The Barthel 

index 28.8 % had score range 60-80 and 80-100 in 51.1 % patients. Mini Mental 

status majority had score range from 10-30. ECOG Performance status was 0-2 in 

70.9 %. Mini Nutritional status revealed risk of malnutrition in 71.1%. 

Discussion: This prospective data provides light on psychological adjustment of 

patients affected by cancer (diagnosis and treatment) and their interaction with aging 

in a developing country. Results may provide new insights, which might contribute 

to the improvement of care for older cancer patients. 


1468P THE INFLUENCE OF QUALITY OF LIFE ON PATIENT 

SATISFACTION IN AMBULATORY ONCOLOGY 

T.V.F. Nguyen 1 , A. Brédart 2 , J. Bosset 3 , A. Monnier 4 and M. Mercier 1 

1 Clinical Research Unit in Quality of Life, CHU Jean Minjoz, BESANCON, 

FRANCE, 2 Psycho-Oncology Unit, Institut Curie, Paris, FRANCE, 3 Radiotherapy, 

CHU Jean Minjoz, Besançon, FRANCE, 4 Radiotherapy, CH Belfort-Montbéliard, 

Montbéliard, FRANCE 

In the oncology setting, there has been an emphasis in evaluating outcomes of 

treatments in terms of quality of life and patient satisfaction. Our study aimed to 

investigate determinants of patient satisfaction and to assess the relationship between 

quality of life and satisfaction with care and their changes over time in curative 

treatment of cancer out-patients. Patients undergoing ambulatory chemotherapy or 

radiotherapy in 2 centers in France were invited, at the beginning of the treatment, at 

the end and 3 months after, to complete the OUT-PATSAT35, composed of 35 items 

and 13 scales, evaluating perception of doctors, nurses, as well as aspects of care 

organization and services. All measures range from 0 to 100, a higher score reflecting 

a higher level of satisfaction. Additionally, for each patient, data were collected on 

socio-demographic, clinical characteristics and quality of life (EORTC QLQ-C30). Of 

691 patients included, 561 answered to the 3 assessment timings. In multivariate 

analysis, at the end of the treatment, patients, whose global health was deteriorated, 

were less satisfied in most scales, and 3 months after, the same patients had lower 

satisfaction scores only in doctors’ evaluation. The longitudinal analysis evidenced a 

significant relationship between a deterioration of global health and a decrease of 

satisfaction in doctors’ domains and, conversely, between an improvement of global 

health and an increase of satisfaction in the overall satisfaction scale. Furthermore, 

perceived global health at the beginning of the treatment remained significantly 

associated with all satisfaction scores in the following timings. Radiotherapy (versus 

chemotherapy) was linked to less satisfaction with doctors’ and nurses’ provision of 

information and waiting-time, and head and neck cancer patients were less satisfied 

with the hospital environment. Pre-treatment self evaluated global health was the 

major determinant of patient satisfaction in ambulatory oncology. The subsequent 

deterioration of global health emphasized the decrease of satisfaction, mainly in 

doctors’ evaluation. Initiatives targeting these patients with poorer health status, 

before starting the treatment, should improve their pattern of care. 


1469P INFORMATION DESIRE OF PATIENTS WITH ADVANCED 

CANCER 

L. Oostendorp 1 , P.B. Ottevanger 2 , W.T.A. van der Graaf 2 and P.F.M. Stalmeier 1 

1 Epidemiology, Biostatistics, and Hta, Radboud University Nijmegen Medical 

Center, Nijmegen, NETHERLANDS, 2 Medical Oncology, Radboud University 

Nijmegen Medical Center, Nijmegen, NETHERLANDS 

Background: Studies on information desire of patients with cancer are typically 

performed in the curative setting or involve hypothetical decisions. In this study, we 

investigate the information desire of patients with advanced cancer at the point of 

decision making. 

Methods: 77 patients with advanced colorectal or breast cancer were included in this 

prospective study and filled in a questionnaire on sociodemographic data, well-being 

measures, and psychological measures, believed to be associated with information 

desire. Patients were faced with the decision whether or not to pursue second-line 

palliative chemotherapy. The oncologist provided the usual treatment-related 

information and made a substitute judgment of the patient’s information desire. A 

nurse administered a decision aid with additional information on adverse events, 

tumour response, and survival. For each item, the nurse asked the patient whether 

the information was desired and whether it had been disclosed by the oncologist. 

Logistic regression analysis was performed to explore factors associated with 

information desire. 

Results: Median age was 62 years (range 32-80), 38% of patients were male, and 28% 

had college education or higher. Oncologists judged that information on adverse 


events, tumour response, and survival would be desired by 100%, 97%, and 80% of 

patients. The information on these items in the decision aid was desired by 95%, 

91%, and 74% of patients. The question of whether the doctor had disclosed the 

information was answered positively by 72%, 53%, and 28% of patients. Results of 

the association between patient’s information desire and demographic, clinical, and 

psychological measures will be presented. 

Conclusions: Even in this advanced setting, most patients accepted all information 

in the decision aid. Patients perceived that the oncologists had not disclosed all 

desired information. While oncologists accurately judged that patients in this study 

had a high information desire, their judgment of information desire on tumour 

response and survival for an individual patient was no better than could be expected 

by chance. These results demonstrate the importance of ascertaining a patient’s 

information desire, and communicating more candid, especially on survival. 


1470P FAMILY CAREGIVER BURDEN: RESULTS OF A MOROCCAN 

PROSPECTIVE STUDY OF CANCER IN THE ELDERLY AND 

THEIR CAREGIVERS 

S. Lkhoyaali 1 , M. Ait El Haj 2 , S. Raissouni 3 , G. Rais 1 , H. Mrabti 3 and H. Errihani 3 

1 Medical Oncology, National Institut of Oncology, Rabat, MOROCCO, 2 National 

Institute of Oncology, INO, Rabat, MOROCCO, 3 Medical Oncology, Institut 

National d’Oncologie Sidi Mohamed Ben Abdellah, Rabat, MOROCCO 

Introduction: The support of older patients affected with cancer by their natural 

caregivers is not a simple task. It could be a painful experience with a major 

emotional, physical and economic impact on relatives. Usually family members do 

that task and they may not be prepared for the challenges. The needs of older 

patients are diverse and may include assistance with medication, transportation for 

treatment, and emotional support. 

Methods: This is a prospective descriptive study, conducted in the National Institute 

of Oncology in Rabat during a ten month period from December 2010 to September 

2011.We included relatives of patients aged 70 or older with histologically proven 

cancer and also their relatives. A questionnaire was given to participants. For all 

participants, demographics, disease characteristics, social, economical and 

psychological features were recorded. Psychological impact was assessed using 

DSM-IV. 

Findings: A total of 150 patients’ relative caregivers responded to the questionnaire. 

Mean age was 44.7 years old. More than two thirds live in urban areas and educated in 

62.7%. They were 56.7% sons or daughters, living with their relatives in 54% of cases. 

Most of participants were married and have familial responsibilities. In relatives, 

anxiety was found in 79.3%. It was related to fear of losing the patient in 57% and led 

to the use of anxiolytics in 10%. Guilty feelings toward patients regarding neglecting 

early symptoms was reported in 38% of the relatives. Depression and anxiety were 

more frequent among female relatives and in those of urban origin. Obsession with 

dying from cancer was present in about 30% and fear of contagion was more common 

among those from rural backgrounds and the illiterate. Economic resources were 

exceeded in 78.7%, and 56% have used credit, sale of properties and work lay-off was 

recorded in 54%. Relatives participated in treatment making decisions in 86%. 

Conclusion: Even where there was a great impact on older cancer patients’ relatives, 

the benefits of caregiving was observed in 80% in our study, these included greater 

self-esteem, personal growth, meaning and purpose in one’s life, and gratitude for 

being able to reciprocate care. Assistance and information from healthcare 

professionals remains the key to improving the ability of caregivers to cope with 

caring for older patients with cancer. 


1471P ANNOUNCING CANCER IN A DEVELOPING COUNTRY: HOW 

IS IT DIFFERENT? 

R. Belbaraka 1 , A. Mahfoudi 1 , M. Khouchani 2 and A. Tahri 2 

1 Centre Oncologie Hematologie, Cadi Ayad University, Marrakech, MOROCCO, 

2 CHU, Mohamed Vi, University Cadi Ayyad, Marrakech, MOROCCO 

Background: Announcing a cancer diagnosis, but also a relapse, a progression of the 

disease, or transition towards palliative care constitute particularly difficult 

communication issues for the patient as well as for the clinician, during the 

trajectory of care. The study aimed to describe the difficulties in establishing a 

“good” announcing consultation, to provide indications or even recommendations on 

the ways to facilitate communication in order to ensure a optimal quality of care, 

responding to patients needs and ensuring the continuity of the care. 

Patients and methods: A semi-directive questionnaire with 21 items in Arabic were 

conducted in patients with cancer to evaluate their perception of the announcement 

of cancer. 

Results: 189 patients aged 18-78 years participated in the questionnaire. Participation 

was on a voluntary basis and patients were informed they could be accompanied by 

an outside person if they wished. The analysis revealed that several factors 

determined the quality of the relation as perceived by the patient receiving the 


announcement of cancer: the relationship between the patient and the physician 

prior to the announcement, the practitioner’s consideration of the role of others 

(family, friends) close to the patient, the practitioner’s respect of the patient’s desire 

for information, and the modalities of the announcement. Modalities considered to 

be favorable were: the physician’s empathy and availability, a progressive 

announcement using clear terms, presence of family or friends at the time of the 

announcement if desired by the patient, absence of half-truths or lies. 

Conclusion: Announcing a diagnosis of cancer is a major challenge to the 

physician’s technical competence and human qualities. This is probably one of the 

greatest challenges that we have to face in oncology. This work confirmed that better 

knowledge of the patient’s experience is useful for examining our practices for 

announcing the diagnosis of cancer. 


1472P WHAT MOROCCAN CANCER ELDERLY PATIENTS WANT 

TO KNOW 

S. Raissouni 1 , S. Lkoyaali 1 , G. Rais 1 , M. Aitelhaj 2 , H. Mouzount 2 , H. Mrabti 1 and 

H. Errihani 1 

1 Medical Oncology, National Institute of Oncology, Rabat, MOROCCO, 2 Medical 

Oncology, INO, Rabat, MOROCCO 

Introduction: Announcing cancer to a patient is not a simple task. Usually doctors 

fail to inform patients about this diagnosis and this is still more likely in older 

people. The need of information in elderly cancer patients is not well established. In 

developed countries the majority of old patients demand exhaustive information 

about their disease. However in developing countries where social and cultural issues 

are different, perception of cancer in the elderly is not well studied. Therefore we 

conducted a prospective study on the needs of elderly Moroccan cancer patients for 

information about their disease. 

Methods: This was a prospective descriptive study, conducted in the National 

Institute of Oncology of Morocco (December 2010-September 2011). Cancer patients 

older than 70 were included. A questionnaire was given to participants. 

Demographics, disease characteristics, social and economic features were recorded. 

Informed consent was required. 

Results: 150 patients responded to the questionnaire. Mean age was 73. Men to 

woman sex-ratio 0.85. 72.7% of patients were diagnosed in advanced stages. Illiteracy 

was found in 76%. 87.3% of patients did not have health insurance. All patients were 

Muslim, practicing in 97%. 57% ignored diagnosis. 80% didn’t want to know further 

information about prognosis and treatment side effects. Family protection from 

information was found in 70%. 

Conclusion: Elderly Moroccans affected with cancer are less demanding of details 

about their illness. Illiteracy and cultural background may play major roles in this. 

Protection by relatives is also an influence. Comparative studies with young patients 

are needed. 


1473P PATIENT PREFERENCE, ADHERENCE AND OUTCOMES 

IN ONCOLOGY: DEVELOPMENT OF A THEORETICAL MODEL 

S.L. Shingler 1 , B. Bennett 1 , J. Cramer 2 , C. Twelves 3 , A. Towse 4 and A.J. Lloyd 1 

1 Patient Reported Outcomes, Oxford Outcomes, An ICON PLC Company, 

Oxford, UNITED KINGDOM, 2 School of Medicine, Yale University, New Haven, 

CT, UNITED STATES OF AMERICA, 3 Leeds Institute of Molecular Medicine & St 

James’s Institute of Oncology, St James’s University Hospital, Leeds, UNITED 

KINGDOM, 4 Health Economics, Office of Health Economics, London, UNITED 

KINGDOM 

Introduction: A patient’s preference may guide their behaviour and influence their 

treatment outcomes. However, the importance of understanding patient preferences 

within oncology is unclear. The present study was designed to review the literature 

regarding preferences, adherence and their link to outcomes specifically in the 

oncology setting and to propose a theoretical model. 

Methodology: Published data examining patient preference, adherence and 

outcomes, specific to oncology, from 1982 to 2012, was searched for in Embase, 

Medline and Cochrane Library databases. Articles were then reviewed independently 

by two researchers and rated on their relevance and quality. Information from the 

retrieved literature and discussion with experts in the fields of oncology and patient 

preference, informed the development of the theoretical model. 

Results: The search yielded 2359 abstracts, of which 93 were reviewed in detail after 

de-duplication and abstract review. Evidence from the highest quality and most 

relevant articles (n = 19) were included in the development of the theoretical model. 

Relationships between patient preference, adherence and clinical outcomes/HRQoL 

were found to exist. Adverse effects (AEs) were found to have a strong relationship 

with adherence. Patient beliefs and values were also identified as having a moderating 

effect on adherence. 

Discussion: This review identified external and cognitive variables related to patient 

preference, adherence behaviour and outcome, which are included in the theoretical 



model. Specifically, external variables have an impact on adherence behaviour. 

However, this relationship is moderated by cognitive variables. Central to the 

theoretical model is the dynamic influence of AEs. AEs are proposed as having an 

impact on clinical outcomes and HRQoL, directly and indirectly through adherence 

behaviour, as well as impacting on external factors and may influence cognitive 

variables. Improving patient preference may improve clinical outcomes/HRQoL in 

oncology patients. The proposed theoretical model provides the opportunity to 

identify such hypotheses for further research with a view to improving adherence 

and clinical outcomes in oncology. 

Disclosure: S.L. Shingler: Oxford Outcomes were paid a fixed fee for conducting this 

research project. B. Bennett: Oxford Outcomes were paid a fixed fee to conduct this 

research project. J. Cramer: Prof Cramer was paid a fixed honorary payment for her 

expert input on this study. C. Twelves: Prof Twelves was paid a fixed honorary fee 

for his expert input into this study. A. Towse: Prof towse was paid a fixed honorary 

fee forhis expert input into the study. A.J. Lloyd: Oxford Outcomes were paid a fixed 

fee for conducting this research project. 

1474 MORBIDITY IN ADVANCED BASAL CELL CARCINOMA (BCC) 

AND BCC NEVUS SYNDROME (BCCNS) FROM THE PATIENT 

(PT) AND PHYSICIAN PERSPECTIVE: DEVELOPMENT OF A 

PATIENT-REPORTED OUTCOME (PRO) QUESTIONNAIRE 

S.D. Mathias 1 , M. Chren 2 , Y.M. Yim 3 , H. Colwell 1 ,C.Reyes 3 , D.M. Chen 4 and S. 

W. Fosko 5 

1 Health Outcomes, Health Outcomes Solutions, Winter Park, FL, UNITED 

STATES OF AMERICA, 2 Dermatology, University of California, San Francisco, 

San Francisco, CA, UNITED STATES OF AMERICA, 3 Biometrics, Health 

Outcomes and Payer Support, Genentech/Roche, South San Francisco, CA, 

UNITED STATES OF AMERICA, 4 U.S. Medical Affairs, Genentech, South 

San Francisco, CA, UNITED STATES OF AMERICA, 5 Dermatology, St. Louis 

University, School of Medicine, St. Louis, MO, UNITED STATES OF AMERICA 

Purpose: Although BCC is the most common skin cancer, the pt experience is not 

well understood. In a small subset of BCC pts, extensive invasion to subcutaneous 

structures can lead to locally advanced disease or metastases (advanced BCC 

(aBCC)). BCCNS is a rare genetic condition associated with life long, multiple BCCs. 

BCCNS pts may also develop aBCC. Lesions are common in sun-exposed areas such 

as the face and upper trunk and may result in disfiguring scars. To inform the 

development of a PRO questionnaire, qualitative concept elicitation interviews were 

conducted with aBCC and BCCNS pts and physicians. 

Methods: In an IRB approved study, interviews were conducted in pts > 18 yr 

diagnosed with aBCC or BCCNS and physicians using an interview guide containing 

open-ended questions about impact of symptoms on functioning and well-being. 

Transcripts from each 1 hr interview were analyzed. 

Results: A total of 30 pts were interviewed, comprised of 14 aBCC (locally advanced, 

n = 8 and metastatic, n = 6; 73% male) and 16 BCCNS (50% male) pts. Mean (SD) 

age for aBCC pts was 64 (11) and 51 (10) for BCCNS pts. A variety of patient 

experiences were reported (eg, bleeding, oozing wounds, vision problems). Physical 

appearance, including scarring and disfigurement affected 73% of pts. 80% of pts 

made lifestyle changes such as avoidance of outdoor activities, meeting new people, 

and intimate relationships. Assistance in tasks was often needed. Emotional effects, 

including worry about when and where the next lesion would appear, were evident 

in BCCNS pts (81%). Physicians (n = 4) noted that aBCC pts worry about cancer in 

general and the possibility of more tumors, while BCCNS pts face tumor recurrence, 

multiple surgeries and disfigurement. Based on the interview results and lack of 

existing PRO questionnaires capturing these concepts, 2 questionnaires were 

developed for aBCC and BCCNS. 

Conclusion: aBCC and BCCNS can have significant and unique impacts on 

well-being, appearance, daily and emotional functioning, and overall quality of life. 

Results from an ongoing validation study will be used to finalize these PRO 

questionnaires. 

Disclosure: S.D. Mathias: Susan D Mathias is an employee of Health Outcomes 

Solutions, which was paid by Genentech Inc to undertake this study. M. Chren: 

Consultant for Genentech Y.M. Yim: Roche employment and stock ownership 

H. Colwell: Consultant for Genentech and Health Outcomes Solutions C. Reyes: 

Roche employment and stock ownership D.M. Chen: Roche employment and stock 

ownership S.W. Fosko: Consultant for Genentech 

1475 SOMATIC VULNERABILITY IN ONCOLOGICAL PATIENTS 

L. Onganía 1 , P. Climentzos 2 , M.P. Bramajo 2 , O. Osores 1 and M. Blanco Villalba 3 

1 Psychooncology, Lucha Contra el Cáncer Ushuaia, Ushuaia, ARGENTINA, 

2 Psychooncology, Centro Médico Austral Omi, Buenos Aires, ARGENTINA, 

3 Oncology, Centro Médico Austral Omi, Buenos Aires, ARGENTINA 

Introduction: Making a complete psychosocial diagnosis in oncological patients, at 

the beginning of medical treatment enriches the approach of interdisciplinary teams. 

It gives important information that may be used to decide future interventions. 

Somatic vulnerability is a psychoanalytic concept that shows some dimensions of the 

personality and environment that may put the patient in risk. Some of them are 

alexitimia (difficulty to express emotions), operatory thinking, over-adaptation, 

depression, anxiety, stress and supportive environment. Doctors are fairly used to 

detect some depressive symptoms, but no so familiarized with the detection of the 

other kind of dimensions that are also risky for the patient evolution or quality of 

life. 

Objectives: Observe the presence of somatic vulnerability in cancer patients. 

Material and methods: Descriptive, transversal and randomized study. Sample: 103 

cancer patients that attend to a private cancer center between April and June of 

2011. Instruments: Somatic Vulnerability Scale (EVS-25) and specifically designed 

questionnaire. 

Results: 50 of 103 patients show somatic vulnerability. The 54% of the vulnerable 

ones, doesn’t evidence any depressive disorder. Only 15% of the vulnerable patients 

are in psychological treatment. Most of them give high results for the other 

dimensions that involve somatic vulnerability (alexitimia, operatory thinking, 

over-adaptation, anxiety, stress or unsupportive environment in different 

percentages). 

Conclusion: This study shows that a high percentage of the patients have somatic 

vulnerability. The somatic vulnerability seems to be hard to be detected by doctors 

because it involves many specific mental dimensions. In fact, only 15% of the 

patients in risk are in psychological treatment. The intervention of a trained 

professional seems to be relevant to make an earlier diagnosis of the patients in risk, 

affecting directly in the evolution and quality of life of them and their families. 


1476 SEXUALITY OF BREAST CANCER PATIENTS TREATED WITH 

MASTECTOMY 

M. Yassine 1 , L. Védrine 2 , C. Chargari 2 , B. Ceccaldi 2 , S. Le Moulec 3 , M. Ichou 4 

and H. Errihani 1 

1 Department of Oncology, National Institute of Oncology, Rabat, MOROCCO, 

2 Oncology and Radiation Oncology, Hôpital d’instruction des armées du 

Val-de-Grâce, Paris, FRANCE, 3 Department of Oncology, Val de Grace Hospital, 

Paris, FRANCE, 4 Department of Oncology, Hôpital d’instruction des armées 

Mohamed V, Rabat, MOROCCO 

Background: Approximately 20% of breast cancer diagnoses are made in women 

younger than 45 years of age. Anticancer treatments are associated with serious 

problems in the sexual functioning of breast cancer patients. We assessed the sexual 

functioning of breast cancer patients treated with mastectomy. 

Patients and methods: We performed a prospective study in 110 women who had 

been treated with mastectomy for a breast cancer using a self-administered 

questionnaire on how the mastectomy had changed their sexual life since the 

primary diagnosis of breast cancer. 

Results: All patients expressed not having received sufficient information about how 

the disease and treatment including surgery might affect their sexual life. Sixty eight 

percent reported being still sexually active, but 62% revealed that the cancer 

treatment had affected their sexual desire or possibility to reach orgasm; 25% 

observed that their partner was afraid of sexual intercourse and 18% felt an 

emotional separation in the couple during the course of the disease. 

Conclusion: Problems related to body image and sexuality were identified in all 

women post mastectomy. It is time to better take into account quality of life, and 

more particularly the sexual function in breast cancer survivors. 



abstracts 

sarcoma 

1477O ADHESION TO CLINICAL PRACTICES GUIDELINES (CPG’S) 

AND ROLE ON SURVIVAL FOR SOFT TISSUE SARCOMA 

PATIENTS. ANALYSIS OF A POPULATION BASED COHORT 

FROM RHONE-ALPES REGION 

O. Derbel 1 , C. Cropet 2 , P. Meeus 3 , F-N. Gilly 4 ,G.Vaz 5 , P. Thiesse 6 , D. Cellier 7 , 

D. Vince-Ranchere 8 , J-Y. Blay 9 , I. Ray-Coquard 9 

1 Department of Medical Oncology, Centre Léon Bérard, Lyon, FRANCE, 

2 Biostatistic Department, Centre Léon Bérard, Lyon, FRANCE, 3 Department of 

Surgery, Centre Léon Bérard, Lyon, FRANCE, 4 Department of Digestive Surgery, 

University Hospital Lyon Sud, Lyon, FRANCE, 5 Department of Surgery, Hopital 

Edouard Herriot, Lyon, FRANCE, 6 Department of Imaging, Centre Léon Bérard, 

Lyon, FRANCE, 7 Merck Serono, Lyon, FRANCE, 8 Department of Pathology, 

Centre Léon Bérard, Lyon, FRANCE, 9 University of Lyon, Department of Medical 

Oncology, Centre Léon Bérard, Lyon, FRANCE 

Sarcoma treatment has been suggested to be improved by the management in a 

multidisplinary expert team and adhesion to CPG’s (ann oncol 04). To confirm the 

strong relation between medical practices and survival, an exhaustive analysis of the 

outcome of the sarcoma patients population was performed in the Rhône–Alpes 

region. 

Patients and methods: From March 2005 to February 2007, 634 patients > 18 

years old, diagnosed with localized sarcoma in Rhone-Alpes were included (Soft 

tissue sarcoma (STS): n = 472; GIST: n = 129; bone primary site: n = 33). 

Adhesion to national CPG’s was analysed for all patients. Prognostic impact of 

conformity to CPG’s on overall survival (OS) and progression free survival (PFS) 

was analyzed for STS patients, in in a univariate analysis and a Cox model 

regression. 

Results: Institutional records of 472 patients with localized STS sarcoma were 

reviewed., The sex ratio (male/female) was 1.1 and varied with the type of sarcoma. 

The median age was 60 years (range from 18 to 92).The most frequent histological 

subtypes were liposarcoma (N= 133, 28%), unclassified sarcoma (N= 98, 20.7%), and 

leiomyosarcoma (N= 70, 14.8%). Conformity to CPGs for patients with localized 

sarcoma was 40, 62, 87, 94 and 82% for global conformity, initial surgery, radiation 

therapy, chemotherapy and follow-up, respectively. In multivariate analysis, 

conformity of surgery to CPG’s was an independent prognostic factor of PFS in 

patients with STS, along with age at diagnosis, grade and histological subtype (HR: 

0.5, 95%CI: 0.36-0.67) (p < 0.0001). Conformity of surgery (HR: 2.6), Age (HR: 1.07) 

and grade (HR: 0.06) are independents factors for overall survival in multivariate 

analysis for patients with liposarcomas. 

Conclusion: Conformity to CPG’s improves progression free survival for sarcoma 

patients. Conformity of surgical procedure to CPG’s is a major independent factor 

predicting PFS for STS patients and OS for patients with liposarcomas. 




1478O CLINICAL BENEFIT WITH REGORAFENIB ACROSS 

SUBGROUPS AND POST-PROGRESSION IN PATIENTS WITH 

ADVANCED GASTROINTESTINAL STROMAL TUMOR (GIST) 

AFTER PROGRESSION ON IMATINIB (IM) AND SUNITINIB 

(SU): PHASE 3 GRID TRIAL UPDATE 

P.G. Casali 1 , P. Reichardt 2 , Y. Kang 3 , J. Blay 4 , P. Rutkowski 5 , H. Gelderblom 6 , 

P. Hohenberger 7 , M. Leahy 8 , M. von Mehren 9 , H. Joensuu 10 , G. Badalamenti 11 , 

M. Blackstein 12 , A. Le Cesne 13 , P. Schöffski 14 , R. Maki 15 ,J.Xu 16 , T. Nishida 17 , 

I. Kuss 18 , D. Laurent 18 , G.D. Demetri 19 

1 Struttura Semplice Trattamento Medico dei Sarcomi dell’Adulto, Istituto 

Nazionale Tumori, Milano, ITALY, 2 Hematology, Oncology and Palliative, HELIOS 

Klinikum Bad Saarow, Bad Saarow, GERMANY, 3 Dept. of Oncology and 

Hematology, Asan Medical Center, Seoul, KOREA, 4 Medical Oncology, Centre 

Léon Bérard, Lyon Cedex, FRANCE, 5 Centrum Onkologii-, Instytut im. Marii 

Sklodowskiej – Curie, Warszawa, POLAND, 6 Medical Oncology, Leiden 

University Medical Center, Leiden, NETHERLANDS, 7 Dept. of Surgery, 

UniversitaetsMedizin Mannheim, Mannheim, GERMANY, 8 The Christie Hospital 

NHS Foundation Trust, Manchester, UNITED KINGDOM, 9 Fox Chase Cancer 

Center, Philadelphia, PA, UNITED STAES OF AMERICA, 10 Dept. of Oncology, 

Helsinki University Central Hospital, Helsinki, FINLAND, 11 U.O. di Oncologia 

Medica, Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone, Palermo, 

ITALY, 12 Mount Sinai Hospital, Toronto, CANADA, 13 Institut Gustave Roussy, 

Villejuif, FRANCE, 14 Universitaire Ziekenhuis Gasthuisberg, Leuven, BELGIUM, 

15 Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, 

New York, NY, UNITED STATES OF AMERICA, 16 307 Hospital of PLA, Beijing, 

CHINA, 17 Osaka Police Hospital, Osaka, JAPAN, 18 Global Clinical Development 

Oncology 2, Bayer HealthCare Pharmaceuticals, Berlin, GERMANY, 19 Ludwig 

Center at Dana-Farber/Harvard Cancer Center and Sarcoma Center, 

Dana-Farber Cancer Institute, Boston, MA, UNITED STATES OF AMERICA 

Background: Regorafenib (REG) therapy significantly improved progression-free 

survival (PFS) in patients (pts) with GIST after failure of both IM and SU (J Clin 

Oncol 2012; 30: suppl; abstr LBA10008). Results of subgroup and post-progression 

analyses are presented here. 

Methods: Pts were randomized (2:1) to receive best supportive care plus either REG 

160 mg or placebo (PL) po once daily (3 wks on/1 wk off). The primary endpoint 

was PFS. Upon progression in either arm, unblinding could occur. Pts on PL were 

eligible for crossover to open-label (OL) REG and progressive pts on REG were 

allowed to continue REG upon local physician’s choice. 

Results: GRID screened 234 pts and randomized 199 (REG: 133, PL: 66), well 

balanced for baseline characteristics. The PFS primary endpoint (according to 

RECIST) was met both per central review (median PFS 4.8 mo for REG vs. 0.9 mo 

for PL), and by investigator assessment (median PFS 7.4 mo for REG vs. 1.7 mo for 

PL). Exploratory sensitivity analyses demonstrate similar positive impact on PFS 

across pre-specified subgroups by number of prior systemic therapy, geographical 

region, age, baseline ECOG score, duration of prior treatment with imatinib, or KIT/ 

PDGFRA mutation. Median overall survival has not been reached in either arm. 

Taking the double-blind and OL periods together, 188 pts received REG. 




Post-progression PFS per investigator assessment was 5.0 mo for pts in the PL arm 

who crossed over to REG (n = 56), and 4.5 mo for pts in the REG arm who 

continued to receive REG after unblinding (n = 41). 

Conclusion: REG induced significant PFS benefit in GIST pts following resistance to 

both IM and SU across all pre-specified subgroups. Interestingly, 41 pts on REG (out 

of 133) whose physicians decided to continue REG after RECIST progression had an 

additional PFS benefit which was in the same range. This suggests that continuous 

kinase inhibition after progression may benefit pts by slowing tumor progression 

and/or that RECIST criteria for progression applied by blind central review have 

clinical shortcomings. 

Disclosure: P.G. Casali: Consultant/advisory: Bayer, MSD, GSK, Infinity, Novartis, 

Pfizer, PharmaMar, Sanofi Honoraria: Novartis, Pfizer, PharmaMar Research 

funds: Amgen Dompe, Bayer, MSD, GSK, Imclone, Infinity, Lilly, Molmed, 

Novartis, Pfizer, PharmaMar, Sanofi. P. Reichardt: Consultant/advisory: Bayer. Y. 

Kang: Consultant/advisory: Bayer Research funding: Bayer. J. Blay: Honoraria: 

Pharmama, Novartis, Pfizer, Roche, GSK Research funding: Pharmama, Novartis, 

Pfizer, Roche, GSK. P. Rutkowski: Consultant/advisory: Novartis, MSD, BMS 

Honoraria: Novartis, Pfizer, BMS, MSD, Roche. M. Leahy: Research funding as 

PI for GRID study at Christie Hospital, Manchester, UK. M. von Mehren 

Consultant/advisory: Novartis, Pfizer, Astex; Honoraria: Novartis, Pfizer. H. 

Joensuu Consultant/advisory: Novartis, Boehringer-Ingelheim. A. Le Cesne 

Honoraria: Novartis, Pfizer, Pharmamar. P. Schöffski: Research funding: Bayer. R. 

Maki: Consultant/advisory: Bayer, Pfizer, Novartis; Honoraria: Bayer, Pfizer, 

Novartis; Research funding: Pfizer; Expert testimony: Pfizer. I. Kuss: Employment: 

Bayer. D. Laurent: Employment: Bayer Stock ownership: Bayer. G.D. Demetri: 

Consultant/advisory: Novartis, Pfizer, GSK, Roche, Deciphra (uncompensated), 

Infinity Research funding: Novartis, Pfizer, GSK, Infinity Expert testimony 

(uncompensated): Infinity, Pfizer, Novartis, Bayer. All other authors have declared 


1479PD MULTI-CENTER PHASE II STUDY OF SUNITINIB IN 

PATIENTS WITH ADVANCED AGGRESSIVE FIBROMATOSIS 

(DESMOID TUMOR) 

J. Jo 1 , K. Kim 1 , Y.S. Hong 1 , J. Lee 1 , J. Lee 2 , Y.S. Park 2 , S.Y. Kim 3 , T.W. Kim 1 

1 Department of Oncology, Asian Medical Center, Seoul, KOREA, 2 Medicine, 

Samsung Medical Center, Seoul, KOREA, 3 Center for Colorectal Cancer, 

National Cancer Center, Goyang, KOREA 

Background: There have been reports on the efficacy of imatinib, a multi-targeted 

tyrosine kinase inhibitor, in the treatment of aggressive fibromatosis (AF, also known 

as desmoid tumor) by inhibiting PDGFRA and PDGFRB rather than KIT. Sunitinib 

has not only PDGFRs, KIT, and FLT3 inhibiting activity but also VEGFRs blockade 

as antiangiogenesis. The aim of this study is to evaluate the efficacy and safety of 

sunitinib for patients with AF. 

Methods: This is a multi-center, phase II study. Nineteen patients with 

pathologically proven AF were accrued between Jun 2008 and Mar 2012. Sunitinib 

was administered with 37.5 mg/day for 4 weeks without break, comprising one cycle. 

Primary endpoint was response rate. 

Results: Ten (53%) patients were female and the median age was 30 years (range, 

22-67). Most of the primary sites were intra-abdominal (12, 63%), and AF associated 

with familial adenomatous polyposis was observed in 9 (47%). The median tumor 

size was 5.0 cm (range, 2.0-14.2), and 8 patients (42.1) had multifocal tumor lesions. 

Of the 15 patients who received two or more cycles of treatment, 6 (40%) required 

dose reductions. With a median 5 cycles per patients (range, 1-47 cycles), 5 (26%) 

achieved a partial response and 8 (42%) had stable disease; the overall response rate 

was 26% (95% CI, 6.3-45.7). With median follow-up time of 11.8 months (range, 

1.4-43.7), the 2-year progression-free survival and overall survival were 70% and 

100%, respectively. Of 10 patients in whom thyroid function test were checked, 1 

(10%) had grade 2 hypothyroidism and 5 (50%) grade 1. Grade 3 or 4 adverse events 

of sunitinib with frequency > 5% of patients included neutropenia (33%), diarrhea 

(5%), and hand-foot syndrome (5%). Intra-abdominal tumor perforation with cystic 

necrosis within first cycle of sunitinib occurred in 3 cases; 2 cases underwent 

palliative tumor resection and 1 case recovered with medical treatment. There was no 

treatment-related death. 

Conclusion: Sunitinib was well-tolerated and showed promising antitumor activity in 

patients with AF. Further investigations on clinical and translational researches of 

sunitinib in these patients are warranted. 


1480PD EFFICACY AND SAFETY OF DENOSUMAB IN GIANT CELL 

TUMOR OF BONE: UPDATED RESULTS WITH 

INDEPENDENT RADIOGRAPHIC ASSESSMENT OF 

RESPONSE 

J. Blay 1 , S. Chawla 2 , E. Choy 3 , R.J. Grimer 4 , S. Ferrari 5 , P. Reichardt 6 , 

P. Rutkowski 7 , D. Thomas 8 , Y. Qian 9 , I. Jacobs 10 

1 University Claude Bernard Lyon I, Centre L, Lyon Cedex 08, FRANCE, 2 Clinical 

Research, Sarcoma Oncology Center, Los Angeles, CA, UNITED STATES OF 

AMERICA, 3 Dana Farber Cancer Center, Harvard University, Boston, MA, 

UNITED STATES OF AMERICA, 4 Orthopaedic Oncology, Royal Orthopaedic 

Hospital, Birmingham, UNITED KINGDOM, 5 Chemotherapy, Istituto Ortopedico 

Rizzoli, Bologna, ITALY, 6 Hematology, Oncology and Palliative, HELIOS Klinikum 

Bad Saarow, Bad Saarow, GERMANY, 7 Centrum Onkologii-, Instytut im. Marii 

Sklodowskiej – Curie, Warszawa, POLAND, 8 Oncology, Peter MacCallum Cancer 

Centre, East Melbourne, AUSTRALIA, 9 Biostatistics, Amgen Inc., Thousand 

Oaks, CA, UNITED STATES OF AMERICA, 10 Clinical Development, Amgen Inc., 

Thousand Oaks, CA, UNITED STATES OF AMERICA 

Giant cell tumor of bone (GCTB) is an aggressive osteolytic tumor that causes 

substantial morbidity. We present data from a second open label phase 2 study of 

denosumab in GCTB. Patients (pts) with surgically unresectable GCTB (Cohort 1), 

resectable GCTB with planned surgery (Cohort 2), and pts who transferred from the 

first phase 2 study (Cohort 3) received SC denosumab (120 mg, Q4W), with 

additional doses on days 8 and 15 (Cohorts 1–2). Prespecified efficacy and safety 

analyses included all pts who received denosumab. Radiographic assessments of 

tumor response included pts with ≥1 evaluable time point response (TPR); 

assessments included RECIST (lesion size), EORTC (PET Standardized Uptake Value 

by Body Weight [SUV bw]), and Density/Size (CT Hounsfield units). Pts (N = 282) 

were 58% women, mean age 36 (SD 13) years; 46% had recurrent unresectable 

disease. AEs were reported in 236 pts (84%); most frequent were arthralgia 20%; 

headache 18%; nausea 17%; fatigue 16%; back pain 15%; and extremity pain 15%. 

Osteonecrosis of the jaw was reported in 3 pts (1%). One pt died of respiratory failure, 

not denosumab-related. Hypocalcemia was reported in 15 pts (5%): 14, grade 1 or 2; 

1, grade 3 not deemed clinically significant by the investigator. Of 100 pts in Cohort 

2, 90% had no surgery or less morbid surgery than planned. Radiologic analyses 

included 190 pts. An objective complete or partial tumor response was observed in 

72% of pts based on best response, any criteria. Of pts with ≥1 objective tumor 

response, response rates were 25% with RECIST, 96% with EORTC, and 76% with 

Density/Size criteria. Among pts with ≥1 evaluable TPR, the median time to objective 

tumor response was 3.1 months (95% CI 2.89, 3.65) based on best response using any 

tumor response criteria. Among pts with ≥2 evaluable TPRs ≥12 weeks apart, 96% 

had tumor control sustained ≥12 weeks based on the best response using any tumor 

response criteria. Eleven pts (6%) had disease progression. Conclusion: Denosumab 

appeared to be well tolerated in pts with GCTB, reduced requirements for morbid 

surgery, and provided a durable objective radiologic response for the majority of pts. 

Denosumab continues to be studied as a potential treatment for GCTB. 

Disclosure: J. Blay: JY Blay has served as an advisory board member for Novartis, 

GSK, Roche, MSD, and Pharmamar. He has conducted corporate-funded research for 

Novartis, GSK, Roche, MSD, and Pharmamar. S. Chawla: Sant Chawla has been an 

advisory board member for and has received corporate-sponsored research funding 

from Amgen, Threshold, Cytrax, Glaxxo, and Berg Pharma. E. Choy: E. Choy has 

served as an advisory board member for Amgen, Sanofi-Aventis, and Biomed Valley 

Discoveries. S. Ferrari: S. Ferrari has received funds from: AMGEN, MOLMED, 

PharmaMar, and Pfizer. He received funds for participation to scientific meetings 

from Takeda. P. Reichardt: P. Reichardt has received honoraria for lectures from 

Amgen Inc. P. Rutkowski: P. Rutkowski has served as an advisory board member for 

Norvartis, BMS, and MSD. He has also received honoraria for lectures and travel 

grants from Novartis, Pfizer, Roche, BMS, and MSD. D. Thomas: David Thomas 

conducts corporate-sponsored research with Pfizer and AMGEN. Y. Qian: Y. Qian is 

an employee and stockholder of Amgen Inc. I. Jacobs: I. Jacobs is an employee and 

stockholder of Amgen Inc. All other authors have declared no conflicts of interest. 


1481PD A PHASE II STUDY OF DOVITINIB IN PATIENTS WITH 

METASTATIC OR UNRESECTABLE GASTROINTESTINAL 

STROMAL TUMORS AFTER FAILURE OF TWO OR MORE 

TYROSINE KINASE INHIBITORS 

Y. Kang 1 , M.H. Ryu 1 , J.J. Lee 2 , I. Park 1 , J.H. Park 3 , B. Ryoo 1 

1 Department of Oncology, Asan Medical Center, University of Ulsan College of 

Medicine, Seoul, KOREA, 2 Department of Nuclear Medicine, Asan Medical 

Center, University of Ulsan College of Medicine, Seoul, KOREA, 3 Department of 

Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 

Seoul, KOREA 

Objectives: This prospective, phase 2 study evaluated the efficacy and safety of 

dovitinib in patients (pts) with advanced gastrointestinal stromal tumors (GISTs) 

who failed previous standard tyrosine kinase inhibitors (TKI). 

Methods: Thirty pts with pathologically proven metastatic or unresectable GIST who 

failed a minimum of both imatinib and sunitinib were accrued between Sep 2011 

and Apr 2012. Dovitinib was administered orally at 500 mg qd for 5 consecutive days 

followed by a 2 day rest period. 

Results: The median age was 57.5 years (range, 35-76). All had metastatic disease in 

the peritoneum (n = 22), liver (n = 20), lung (n = 4), or bone (n = 4). Thirteen pts 

(43%) also failed nilotinib (n = 8), regorafenib (n = 2) or both nilotinib and 

regorafenib (n = 3) after failure of imatinib and sunitinib. By RECIST criteria, there 

were no objective responses, 19 (63.3%) had stable disease (SD), 5 (16.7%) 

progressive disease (PD), and 6 (20.0%) were not evaluable. By EORTC PET criteria 

(at 4 weeks), 3 pts (10.0%) achieved a partial response, 15 (50.0%) had SD, 10 (33.3) 

showed PD, and 2 were not evaluable. With a median follow-up of 4.8 months 

(range, 0.8-7.5), the medi an progression-free survival (PFS) and overall survival were 

3.6 months (95% CI, 2.7-4.4) and 6.2 months (95% CI, 4.9-7.5), respectively. PFS 

could be predicted by PET response (PD vs no PD) at 4 weeks (p = 0.003). Grade 3 

or 4 adverse events of dovitinib with frequency > 5% pts included asthenia (16.7%), 

leucopenia (6.7%), thrombocytopenia (6.7%), and hypertension (6.7%). Those 

toxicities were manageable with dose modification, and there were no 

treatment-related deaths. 

Conclusions: Dovitinib showed antitumor activity with manageable toxicities in this 

heavily pretreated cohort of GIST patients. 

Disclosure: Y. Kang: Honoraria, consultant, and research fund from Novartis. All 


1482PD DASATINIB FIRST-LINE TREATMENT IN 

GASTROINTESTINAL STROMAL TUMORS. A MULTICENTER 

PHASE II TRIAL OF THE SAKK (SAKK 56/07) 

M. Montemurro 1 , J. Domont 2 , P. Rutkowski 3 , A.D. Roth 4 , R. von Moos 5 , 

R. Inauen 6 , D. Dietrich 7 , C. Biaggi 8 , J. Prior 9 , S. Leyvraz 1 

1 Centre Pluridisciplinaire d’Oncologie, Centre Hospitalier Universitaire Vaudois - 

CHUV, Lausanne, SWITZERLAND, 2 Dept. Medical Oncology, Institut Gustave 

Roussy, VILLEJUIF, FRANCE, 3 Department of Soft Tissue/bone Sarcoma and 

Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of 

Oncology, Warsaw, POLAND, 4 Oncology, University Hospitals of Geneva, 

Geneva, SWITZERLAND, 5 Medical Oncology, Kantonal Hospital Graubünden, 

Chur, SWITZERLAND, 6 Dept. of Oncology, Kantonsspital St. Gallen, St. Gallen, 

SWITZERLAND, 7 Statistics, Swiss Group for Clinical Cancer Research SAKK, 

Bern, SWITZERLAND, 8 Trial Coordination, Swiss Group for Clinical Cancer 

Research SAKK, Bern, SWITZERLAND, 9 Nuclear Medicine, University Hospital 

Lausanne CHUV, Lausanne, SWITZERLAND 

Introduction: First line imatinib has improved the outcome of patients (pts) with 

gastrointestinal stromal tumor (GIST), but primary and secondary resistance remain 

a problem. Dasatinib is a second generation tyrosine kinase inhibitor (TKI) of 

bcr-abl, src-family kinases and a number of other oncogenic kinases including kit. 

Dasatinib has shown activity against imatinib-resistant cell lines in vitro. 

18F-fluorodeoxyglucose positron-emission-tomography (FDG-PET) measures tumor 

metabolic activity for early response assessment, which might be of particular use in 

the clinical trial setting. 

Methods: This two-stage phase II trial investigated dasatinib in patients with 

histologically proven, FDG-PET positive, TKI-naïve GIST. Dasatinib starting dose 

was 2x70mg/day. Response evaluation was done by serial CT and FDG-PET using 

EORTC PET response criteria (Young et al. 1999). PET was reviewed centrally. 

Elective surgery was allowed after 6 months of trial treatment. Primary endpoint was 

response (CR + PR) by FDG-PET after one month of dasatinib. 

Results: 47 of planned 52 pts have been enrolled from December 2007 to November 

2011, when the trial was terminated due to slow accrual. 43 pts were eligible. Median 

age was 61 years, 24 pts were male, 19 female. 30 pts had a performance status of 0 

and thirteen of 1. Mutational data are available for 28 pts so far. 20 had a KIT exon 

11, one a KIT exon 9 mutation, and 7 were wild-type. At a median follow-up of 12.4 


months, 15 pts were still on treatment. Pts went off trial for elective surgery (n = 6), 

progression (n = 13), toxicity (n = 4), other reasons (n = 2) and three patients died. 

5% of pts experienced G4, and 38% of pts G3 toxicity, which were most often 

gastrointestinal or pulmonary. 28 pts had their dose reduced or interrupted. The 

primary endpoint, FDG-PET response rate (CR + PR) at 4 weeks was 72% (14 CR, 17 

PR, 7 SD, 3 PD, 2 not evaluable). The response rate in patients with a KIT Exon 11 

mutation was 80%, in wild-type patients 57%. Median progression-free survival is 

11.1 months and median overall survival not yet reached. 

Conclusions: Dasatinib shows promising efficacy in TKI-naïve pts with FDG-PET 

positive GIST. 

Disclosure: M. Montemurro: Speakers fees and travel grants - Bayer, Pfizer, Novartis. 

P. Rutkowski: Consultant - BMS, Novartis, MSD Speakers fees and travel grants - 

Novartis, Pfizer, MSD, BMS, Roche. R. von Moos: Consultant/Advisor - AMGEN, 

Novartis, Roche, BMS, Pfizer, Merck Speakers fees - Roche, Amgen institutional 

Research Funds - AMGEN Expert Testimony - AMGEN. All other authors have 


1483PD INNO-206 IS AN ACTIVE DRUG FOR RELAPSED ADVANCED 

SOFT TISSUE SARCOMA 

S. Chawla 1 , V.S. Chua 1 , A. Hendifar 1 , D. Quon 1 , S. Negre 1 , K.N. Ganjoo 2 , 

K. Sankhala 3 , Y. Lavinski 4 , S. Wieland 5 , D. Levitt 5 

1 Clinical Research, Sarcoma Oncology Center, Los Angeles, CA, UNITED 

STATES OF AMERICA, 2 Medical Oncology, Stanford University Medical School, 

Palo Alto, CA, UNITED STATES OF AMERICA, 3 Medical Oncology, University of 

Texas Health Science Center, San Antonio, TX, UNITED STATES OF AMERICA, 

4 Research, MutualHealth LLC, Newport Beach, CA, UNITED STATES OF 

AMERICA, 5 Clinical Development, CytRx Corporation, Los Angeles, CA, UNITED 


Background: We have studied the safety and tumor response of a doxorubicin 

conjugate, INNO-206, in patients with metastatic STS who progressed on prior 

chemotherapy. INNO-206 is a conjugate of doxorubicin attached to an acid-sensitive 

linker that binds covalently to cysteine-34 in circulating albumin. 

Methods: INNO-206 was administered IV at 350 mg/m 2 (260 mg/m 2 dox. eq.) every 

21 days for up to 8 consecutive cycles. Tumor response was monitored every other 

month and treatment continued until tumor progression or unacceptable toxicity. 

Standard safety monitoring was performed and cardiac function was followed 

periodically using MUGA or cardiac ultrasound. 

Results: As of May 1, 2012, 19 patients were entered in the study. 13/19 patients had 

STS of various types. Of the initial 19 patients treated at the 350 mg/m 2 dose, no 

individuals experienced a grade 3 or 4 non-hematological toxicity during Cycle 

1. The majority of patients demonstrated transient grade 3 or 4 neutropenias that 

resolved prior to the next cycle with and without G-CSF treatment. No patient 

exhibited relevant cardiotoxicity as determined by MUGA or cardiac ultrasound. Of 

19 patients, serious adverse events included febrile neutropenia (3) sepsis (1) and 

mucositis (1). Of the 13 patients with STS, 5 objective partial responses (3 of whom 

received prior doxorubicin) are ongoing as well as 7 patients with stable disease 

(median 6.43 months, range 1-10.7+ months). 1/13 patients had progressive disease 

at the first evaluation. 2/19 patients died with the first cycle (1 PD, 1 sepsis). 

Conclusion: INNO-206 is an active drug for the treatment of patients with advanced 

STS who have failed prior chemotherapy. Cumulative doses of 2000 mg/m 2 of 

doxorubicin equivalents have been achieved, which is over 3½ x the peak cumulative 

dose of standard doxorubicin. Adverse events are primarily hematological and no 

cardiotoxicity has been observed. 

Disclosure: S. Chawla: Corporate sponsored research from CytRx Corporation. 

S. Wieland: Salary and stock ownership from CytRx Corporation. D. Levitt: 

Salaryand stockownership from CytRx Corporation. All other authors have declared 


1484PD SELECTIVE INTERNAL RADIATION THERAPY (SIRT) FOR 

GIST LIVER METASTASES RESISTANT TO TYROSINE 

KINASE INHIBITORS 

P. Hohenberger 1 , N. Rathmann 2 , A. Peschel 2 , J. Schuette 3 , S.O. Schoenberg 2 , 

D. Dinter 2 , S. Diehl 2 

1 Dept. of Surgery, UniversitaetsMedizin Mannheim, Mannheim, GERMANY, 

2 Dept. of Radiology and Nuclear Medicine, UniversitätsMedizin Mannheim, 

Mannheim, GERMANY, 3 Department of Oncology and Hematology, 

Schwerpunktpraxis Haematoonkologie Duesseldorf, Duesseldorf, GERMANY 

Background and aim: The liver is the typical location of metastases from 

gastrointestinal stromal tumors (GIST). Usually, metastases of GIST are treated by 

tyrosine kinase inhibitors (imatinib, sunitinib or others). In patients with multiple 

metastases resistant to drugs and not amenable to surgical resection interventional 



ablation techniques are considered. Selective internal radiation therapy (SIRT), 

delivering 90 Y-loaded particles to liver metastases might offer a new treatment option. 

Material/methods: We evaluated nine patients with liver metastases of GIST being 

progressive under drug (TKI) treatment and referred for SIRT. Five patients had liver 

metastases only, in another four patients extrahepatic disease was present but 

controlled by TKI therapy. One patient had to be excluded from treatment due to a 

hepato-pulmonary shunt volume exceeding 20 %. Depending on intrahepatic tumor 

distribution, either both liver lobes or one lobe were treated using 90 Y spheres. 

Follow-up was done via dynamic MRI, contrast-enhanced (CE)-CT and 

18 F-FDG-PET-CT using modified RECIST criteria at 3 months intervals. All patients 

with targetable mutations in KIT or PD continued with drug to control extrahepatic 

tumor spread. 

Results: In the eight patients, fourteen liver lobes were treated with a mean activity 

of 1.07GBq per lobe. No severe side effects occured in 7/8 patients, while one male 

developed an ulcer of the stomach not responding to high dose antacid therapy. 

Radiation induced liver disease (RILD) was not observed. Three patients showed a 

complete remission (CR) whereas four other patients developed a partial remission 

(PR) and two patients had to be classified as stable disease (SD). Median follow-up 

interval is 16 months (range, 4 - 52 months). The mean progression free interval 

regarding hepatic disease was 9,6 months. 

Conclusion: SIRT offers a safe and effective treatment option in patients with liver 

metastases from GIST being progressive under TKI treatment. 


1485PD CLINICAL SIGNIFICANCE OF SURGERY FOR GASTRIC 

SUBMUCOSAL TUMORS WITH SIZE ENLARGEMENT 

DURING WATCHFUL WAITING PERIOD 

Y. Miyazaki 1 , K. Nakajima 2 , Y. Kurokawa 2 , T. Takahashi 2 , S. Takaguchi 2 , 

H. Miyata 2 , M. Yamasaki 2 , T. Nishida 3 , M. Mori 2 , Y. Doki 2 

1 Gastroenterological Surgery, Osaka University Graduate School of Medicine, 

Suita, JAPAN, 2 Gastroenterological Surgery, Osaka University, Suita, JAPAN, 

3 Department of Surgery, Osaka Police Hospital, Osaka, JAPAN 

Aims: Recent Japanese clinical practice guidelines for gastrointestinal stromal tumor 

(GIST) indicates that surgical resection is optionally considered for small (

1488P ORGANISATION OF SARCOMA PATIENT MANAGEMENT IN 

REFERENCE CENTERS IN NETSARC NETWORK: ANALYSIS 

OF THE QUALITY OF RESECTION 

S. Bonvalot 1 , P. Meeus 2 , E. Stoeckle 3 , B. Bui 4 , A. Le Cesne 5 , N. Penel 6 ,I. 

L. Ray-Coquard 7 , J. Coindre 8 , C. Chemin 9 , J. Blay 7 , On Behalf of The Netsarc 

National Network (www.netsarc.org) 

1 Department of Surgery, Institut Gustave Roussy, Villejuif, FRANCE, 2 Surgery, 

Centre Léon Bérard, Lyon, FRANCE, 3 Surgery, Institute Bergonie, Bordeaux 

Cedex, FRANCE, 4 Medical Oncology, Institute Bergonie, Bordeaux Cedex, 

FRANCE, 5 Dept. Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE, 

6 Medical Oncology, Centre Oscar Lambret, Lille, FRANCE, 7 Medical Oncology, 

Centre Léon Bérard, Lyon Cedex, FRANCE, 8 Anatomopathology, Institute 

Bergonie, Bordeaux Cedex, FRANCE, 9 Medical Evaluation, Centre Léon Berard, 

Lyon, FRANCE 

The French National Cancer Institute suggested the improvement of sarcoma 

management when performed in a multidisplinary expert team. Since 2009, a 

network of 26 reference multidisciplinary boards has been created to improve the 

quality of care of sarcoma patients in France. All patient cases presented are 

uploaded in the NetSarc network collecting patient characteristics, clinical situation 

at the time of the discussion, medical decision, and patient outcome (survival and 

relapse). 

Patients and methods: From January 2010 to April 2012, 8934 patients were 

included on this database. Patients were presented from centers within (N = 5911, 

66%) or outside (N = 2343, 26%) the Netsarc Network (parameter unknown in N = 

679, 8% patient). Patient and disease characteristics and treatment results are 

described. 

Results: There were 4662 women (52%) and 4272 men (48%). Median size of the 

sarcoma was 95mm (range2- > 400). Soft tissue, visceral, and bone represented 6381 

(71%) 1285 (14%) and 1264 (14%) of patients respectively. In soft tissue tumours, 

grade 1, 2, 3 were reported in 44%, 33%, 23% of patients. The most frequent 

histological subtypes were leiomyosarcomas (all sites) (n = 769, 9%), GIST (558, 6%), 

dedifferentiated liposarcomas (n = 439, 5%). Most frequent primary sites were thigh 

(1268, 14%), retroperitoneal (796, 9%), thoracic wall (460, 5%), uterus (405, 4.5%), 

legs (325, 4%). 1052 (11%) patients were reported to have metastases. Clinical and 

disease status at the time of discussion was prior to: biopsy (N = 824, 9%), first 

surgery (N = 1751, 20%), adjuvant treatment (N = 2806, 31%). 6161 (67%) patients 

had a surgery, n = 1472 (24%) in the Netsarc network and outside n = 1843 (30%); in 

n = 2846 (46%) this information is not still documented. Patients whose primary 

surgery was performed in Netsarc centers had R0, R1, R2, and fragmented primary 

surgery in 61%, 31%, 5%, 2% vs 37%, 40%, 16%, 7% in primary care centers 

non-Netsarc centers (p < 0.000001). 

Conclusions: This first analysis of the NetSarc database shows that more patients 

had optimal surgery in reference centers than in primary care centers. This tool will 

ensure the monitoring of dedicated action to improve the management of sarcoma 

patients in the future. 


1489P FINAL RESULTS OF A FRENCH SARCOMA GROUP (FSG) 

RETROSPECTIVE REVIEW OF 110 PATIENTS WITH PRIMARY 

LOCALIZED GASTROINTESTINAL STROMAL TUMORS (GIST) 

OF THE DUODENUM 

F. Duffaud 1 , T. Huynh 1 , P. Cassier 2 , E. Boucher 3 , O. Bouché 4 , A. Le Cesne 5 , 

B. Landi 6 , J. Mancini 7 , F. Marchal 8 , J. Blay 2 

1 Medical Oncology, C.H.U. La Timone Adultes, Marseille Cedex, FRANCE, 

2 Medical Oncology, Centre Léon Berard, Lyon, FRANCE, 3 Medical Oncology, 

Centre Eugène Marquis, Rennes, FRANCE, 4 Gastroenterology, University 

Hospital, Reims, FRANCE, 5 Dept. Medical Oncology, Institut Gustave Roussy, 

Villejuif, FRANCE, 6 Gastroenterology, Hopital Européen Georges Pompidou, 

Paris, FRANCE, 7 Biostatistics, la Timone University Hospital, Marseille, FRANCE, 

8 Surgery, Centre Alexis Vautrin, Nancy, FRANCE 

Background: Duodenal GISTs represent 3-5% of all GISTs, with limited 

understanding of patient outcomes from small series. We conducted a retrospective 

analysis of localized duodenal GISTs over the past 18 years. 

Methods: Patients (pts) were identified in 2 ways: a group of 101 pts reported via 

survey from 20 FSG centers, and a group of 9 pts included in the BFR14 trial. 

Results: Pts were: 55 females, 55 males, with a median age of 57 years (30-84), and 

median ECOG 0 (0-3). Abdominal pain, anemia, and overt GI bleeding were the 

most common symptoms. Tumors (T) originated mainly in D2 (41%), or D3 (27%), 

with a median size of 5 cm (1.5-30). All pts except four had resection of the primary 

T. Surgical procedures were: local resection (LR) [segmental duodenectomy (n = 31), 

wedge local resection (n = 31), local excision (n = 6)], and duodenopancreatectomy 

(DP, n = 20). Resections were R0 in 84 pts (79%), R1 in 6 pts (6%). T characteristics 

included: KIT+ (n = 100), CD34 + (n= 54), mitoses/50 HPF ≤ 5 (n= 70), or > 5 (n = 

24), Miettinen low-risk (n = 37), and high-risk (n = 19), necrosis (n = 29), spindle cell 

(n = 84). Genotype was evaluated in 36 cases: KIT exon 11 mutant (n = 30), no 

mutation (n = 4), and KIT exon 9 mutant (n = 2). 12 pts received neoadjuvant 


imatinib (IM) therapy resulting in 6 PR, 3 SD, 1 PD. 17 pts received adjuvant IM 

therapy. With a median FU of 32 months (1-250), 95 pts (86%) are alive. 

Twenty-eight (26%) pts relapsed: 6 LR, and 26 metastases. The 4-year OS and EFS 

rates were 89.5% and 68.2 %. The 6-year OS and EFS rates were 89.5% and 36.5%. 

Univariate analysis showed that: age and ECOG PS have an impact on OS (p= 0.008, 

p


1491P RESPONSE TO SORAFENIB IN PDGFRA-D842V MUTATED 

METASTATIC GASTROINTESTINAL STROMAL TUMOR 

(GIST), SUPPORTED BY BIOMOLECULAR FUNCTIONAL 

ANALYSES 

E. Fumagalli1 , S. Pilotti2 , E. Conca2 , R. Bertulli1 , M. Fiore3 , C. Morosi4 , F. Bozzi2 , 

P.G. Casali1 , E. Tamborini2 1 

Adult Mesenchymal Tumour Medical Oncology Unit, Fondazione IRCCS Istituto 

Nazionale dei Tumori, Milan, Milan, ITALY, 2 Laboratory of Molecular Pathology, 

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ITALY, 3 Department of 

Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori Milan, Milan, ITALY, 

4 

Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, 

Milan, Milan, ITALY 

Background: In GIST, KIT/PDGFRA mutations correlate with response to TKI. The 

exon 18 PDGFRA-D842V mutation is known to be resistant to imatinib and 

sunitinib. Activation of PDGFRA involves two main signal transduction pathways, 

RAS/MEK/ERK, which involves BRAF, and PI3K-AKT. We used sorafenib in three 

pts with a PDGFRA-D842V mutated metastatic GIST. 

Methods: Since January 2010, 3 PDGFRA-D842V mutated GIST pts (age: 57, 71, 72 

yrs) have been treated with sorafenib 400 mg twice daily, on an individual use basis. 

Two pts were progressing on imatinib in association to mTOR inhibitors (sirolimus 

and everolimus), while the third had four previous lines of therapy. Molecular/ 

biochemical analyses were performed on cryopreserved material taken before 

sorafenib treatment in two of the three patients (one biopsy and one surgical 

specimen). A primary cell culture was obtained from one patient. 

Results: One pt had a Choi’s response 3 mos after starting the treatment; the others 

a RECIST response at 2 mos. The first pt had a tumor progression after 12 mos from 

starting therapy and 9 mos from tumor response. The second pt had a partial 

response lasting 15 mos. Treatment was relatively well tolerated, with G3 skin toxicity 

in one pt, causing a dose reduction. Biochemical analyses on pretreatment tumors 

revealed activated S6K and S6, both downstream mTOR, as well as ERK1/2 strong 

activation. The primary cell culture was treated with sorafenib 0.5 and 1 µM and 

phosphorylation switch-off of both S6K and S6 (Ser 240/244), associated with a 

retained ERK1/2 expression/activation, was observed. Further analyses are ongoing to 

verify which pathways converging on mTOR are inhibited by sorafenib. 

Conclusions: In the unresponsive PDGFRA-D842V mutated GIST we saw clinical 

signs of antitumor activity of sorafenib in 3 pts. This was consistent with biochemical 

analyses, which showed an inhibitory effect downstream mTOR. This clinical setting 

constitutes a high-priority unmet medical need, since very few clinical data are 

known and no functional analyses on sorafenib activity have been reported so far. 

Disclosure: P.G. Casali: Advisory role and honoraria for lectures: Novartis Pharma, 

Pfizer. Advisory role: Bayer. All other authors have declared no conflicts of interest. 

1492P MONITORING OF PATIENTS WITH GASTROINTESTINAL 

STROMAL TUMOUR: SHOULD THE CHEST BE SCANNED? 

A. Findlay 1 , T. Ishfaq 1 , A. Raja 1 , A. Thacoor 1 , P. Hall 2 , M. Marples 3 

1 School of Medicine, University of Leeds, Leeds, UNITED KINGDOM, 2 Leeds 

Institute of Health Sciences, University of Leeds, Leeds, UNITED KINGDOM, 3 St 

James’s Institute of Oncology, St James’s University Hospital, Leeds, UNITED 

KINGDOM 

Introduction: Thoracic CT scanning is often used for monitoring patients with 

sarcoma and upper gastrointestinal carcinoma, but its role in monitoring 

gastrointestinal stromal tumour (GIST) is variably defined in guidelines. In line with 

study protocols, it has been our practice to include chest CT for monitoring patients 

with GIST, and we now report the role of these scans. 

Method: We reviewed the electronic records of all patients diagnosed with GIST at St 

James’s Institute of Oncology, Leeds, UK, between 1 January 2001 and 1 January 

2011. Primary site, stage at diagnosis, pattern of metastatic disease and frequency of 

CT scans were recorded. 

Results: We identified 176 patients diagnosed with GIST. All patients had CT scans 

of the chest, abdomen and pelvis performed at intervals agreed by the Yorkshire 

Sarcoma Network. Primary site was stomach in 96 patients (55%), small bowel in 27 

(15%), rectum in 5 (3%), other sites in 38 (22%), and unknown in 10 (6%). Median 

follow-up was 34.3 months. Of the 139 patients who had no metastases at 

presentation, five developed local recurrence and 11 developed metastases. 27 

patients had metastases at presentation, and the status of 10 was unknown. All 

patients with metastases had disease below the diaphragm, and only two had lung 

involvement as well (one at recurrence, one at initial presentation). Thirty-seven 

patients with metastatic disease were treated with imatinib. Of the 31 patients who 

progressed on imatinib, all had progression below the diaphragm; the patient with 

lung and abdominal metastases progressed in both areas. Four of these patients also 

developed lung metastases at the time of progression elsewhere. 

Conclusions: We observed synchronous progression in lungs and abdomen in 5/31 

patients progressing on imatinib (16%), but no patients in our cohort relapsed or 

progressed in the lungs alone. We conclude that progression confined to the lungs is 

rare in GIST. Patients being monitored for recurrence or progression should have CT 

scans of the abdomen and pelvis only, with completion CT of the thorax being 

reserved for baseline and progression of disease. 

Disclosure: M. Marples: Dr Marples has accepted sponsorship to research meetings 

from Novartis. Novartis support mutation testing for GIST at Dr Marples’ 

institution. All other authors have declared no conflicts of interest. 

1493P RESULTS OF HRQOL DATA FROM PALETTE: A 

RANDOMIZED DOUBLE BLIND PHASE III TRIAL OF 

PAZOPANIB VERSUS PLACEBO IN METASTATIC SOFT 

TISSUE SARCOMA (STS) PATIENTS. AN EORTC STBSG 

GLOBAL NETWORK STUDY (EORTC 62072) 

C. Coens 1 , W.T.A. van der Graaf 2 , J. Blay 3 , S.P. Chawla 4 , D. Kim 5 , 

R. Sanfilippo 6 , S. Manson 7 , M. Ouali 8 , S. Marreaud 9 , A. Bottomley 1 

1 Quality of Life Department, EORTC HQ, Brussels, BELGIUM, 2 Medical 

Oncology /452, Radboud University Medical Centre NijmegenUniversity Medical 

Center St. Radboud, Nijmegen, NETHERLANDS, 3 University Claude Bernard 

Lyon I, Centre L, Lyon Cedex, FRANCE, 4 Clinical Research, Sarcoma Oncology 

Center, Los Angeles, CA, UNITED STATES OF AMERICA, 5 Internal Medicine, 

Seoul National University Hospital, Seoul, KOREA, 6 Cancer Medicine 

Department, Istituto Nazionale dei Tumori, Milano, ITALY, 7 R&D, 

GlaxoSmithKline, Uxbridge, UNITED KINGDOM, 8 Statistical Department, EORTC 

HQ, Brussels, BELGIUM, 9 Medical Department, EORTC HQ, Brussels, 

BELGIUM 

Background: HRQoL was an important secondary endpoint in this global 

double-blind, randomised phase III trial of pazopanib 800 mg QD versus placebo as 

second or later line treatment for advanced STS patients (N = 369) where progression 

free survival was significantly improved in the pazopanib arm (median: 4.6 versus 1.6 

months; hazard ratio = 0.31; P < 0.001), but no statistically significant difference was 

observed in overall survival. Toxicity of pazopanib consisted mainly of fatigue, 

diarrhea, nausea weight loss and hypertension. 

Methods: HRQoL was assessed using EORTC QLQ-C30 at baseline, week 4, 8 and 

12 in patients who were progression free. The primary HRQoL endpont was the 

QLQ-C30 global health scale, analyzed using linear mixed modeling supplemented 

with sensitivity analyses using alternative scales, methods and imputation of missing 

data. 

Results: Compliance of HRQoL was good in this trial, ranging from 94% at baseline 

to 81% at week 12. Placebo patients completed fewer questionnaires, largely due to a 

higher progression rate (median number of completed questionnaires- pazopanib: 3 

vs placebo: 2). Differences in the global health scale between the two treatment arms 

assessed at weeks 4, 8 and 12 were not significant and did not exceed the 

pre-determined minimally important difference of 10 points (P = 0.291; average 

difference = 2.6 points). The EQ-5D data and sensitivity analyses mainly confirmed 

this finding. Among the other scales, the pazopanib arm reported significantly worse 

symptom scores for diarrhea (P < 0.001), loss of appetite (P < 0.001), nausea/vomiting 

(P < 0.001) and fatigue (P = 0.012). On the pazopanib arm, 74.8% of patients 

reported at least one minimally important worsening in any of those four symptom 

scales, compared to 51.2% on the placebo arm. In general, HRQoL scores tended to 

decline over time in both arms, indicative of the underlying disease. Exploratory 

factor analysis revealed that global health was associated mainly with functioning 

scales (Physical, Role and Social) and less with symptom scales except for fatigue. 

Conclusion: The toxicity profile of pazopanib is reflected in the patients’ 

self-reported symptoms but did not translate into worse overall global health while 

on-treatment, as patients maintained continued good functioning. 

Disclosure: J. Blay: research support and honoraria from GSK, Novartis, Roche, 

MSD, PharmaMar. S.P. Chawla: consultant GSK. D. Kim: consultant GSK, MEK 

Advisory Board. R. Sanfilippo: Honoraria from GSK. S. Manson: employee of GSK, 

holds GSK shares. A. Bottomley: Funding for EORTC research projects from Roche, 

Genentech, BMS. All other authors have declared no conflicts of interest. 

1494P IMATINIB MESYLATE IN DESMOPLASTIC SMALL ROUND 

CELL TUMOUR 

A.F. Bertuzzi 1 , G. Bisogno 2 , M. Carli 2 , A. Ferrari 3 , A. Comandone 4 , M. Gasco 1 , 

R. De Sanctis 1 , C. Gnocchi 5 , A. Santoro 1 

1 Medical Oncology and Hematology, Humanitas Cancer Center, IRCCS, 

Rozzano, ITALY, 2 Pediatric Medical Oncology and Hematology, Clinica di 

Onco-Ematologia Pediatrica, Padova, ITALY, 3 Pediatric Oncology Unit, 

Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, ITALY, 4 Medical 

Oncology, Ospedale Gradenigo, Torino, ITALY, 5 Novartis Farma, Novartis, 

Origgio, ITALY 

Introduction: Desmoplastic small round cell tumor (DSRCT) is a very rare and 

aggressive mesenchymal neoplasia with an extremely poor prognosis. The typical 

translocation t(11;22) determines the overexpression of PDGF-Rα and β, responsible 

of clinical stromal fibrosis reaction constantly detected in abdominal lesions. We 

investigated the role of imatinib, as tyrosine kinase inhibitor of PDGF-R, in DSRCT. 


Patients and methods: From August 2005 to June 2009 we enrolled patients (pts) 

with histologically proven diagnosis of DSRCT, refractory to conventional treatment. 

Inclusion criteria comprised immunohistochemical positivity of imatinib targets 

(PDGF-Rα and β). Treatment consisted of imatinib 400 mg p.o. daily. Primary 

endpoint of the study was objective response rate. Secondary endpoint was safety and 

tolerability assessment. 

Results: Of the 13 enrolled patients, 8 pts were evaluable for response (4 screening 

failure and 1 never treated). Median age was 20 years (range, 9-32). M/F ratio was 7/ 

1. ECOG PS was 0 in 6 pts. Median time from diagnosis was 24.5 months (range, 

6-148). 75% of pts had metastatic disease. The primary site was abdominal-pelvic for 

all pts. PDGFRα and β were expressed with an heterogeneous intensity pattern. 

Objective responses at first radiological evaluation at 3 months were: stable disease in 

one pt (12.5%) and progressive disease in 7 (87.5%) pts. Treatment-related adverse 

events were G1-2 nausea/vomiting, fatigue and periorbital oedema. 

Conclusions: In our limited case series, imatinib showed no efficacy in the treatment 

of DSRCT pts unresponsive to conventional therapy, despite molecular-based 

selection of pts. Probably to identify responder pts, it is necessary a more complex 

evaluation comprehensive of both levels of expression and activation of PDGFRα and 

β. Furthermore, enrolled pts were affected by advanced refractory disease, probably 

less responsive to target therapies. It would be hopeful a global effort to define a new 

combined approach based on the association of conventional chemotherapy and 

biological drugs. 

Disclosure: C. Gnocchi: Novartis Patient Advocacy Manager. All other authors have 


1495P SUNITINIB THERAPY IN ADVANCED ALVEOLAR SOFT PART 

SARCOMAS 

H.M. Kosela, K. Wiater, T. Switaj, A. Klimczak, S. Falkowski, P. Rutkowski 

Soft Tissue/bone Sarcoma and Melanoma, MSC Memorial Cancer Centre and 

Institute Maria Sklodowska-Curie, Warsaw, POLAND 

Background: Alveolar soft part sarcoma (ASPS) is a rare entity making up < 1% of 

soft tissue sarcomas (STS). It is characterized by slow, indolent growth but with a 

high frequency of metastatic disease especially to lungs. Chemotherapeutic regimens 

used for the treatment of other soft tissue sarcomas lack efficacy in ASPS. The 

purpose of our analysis was to assess sunitinib activity in ASPS. 

Methods: Since July 2009, 7 patients with metastatic ASPS have been treated with 

sunitinib continuous daily dosing 37,5mg (1 pts started treatment at 50mg/d on a 4/2 

week schedule). All patients’ initial performance status according to ECOG was 0-1. 

Median age at time of diagnosis was 23 yrs (range 18-57), gender distribution M/F was 1/ 

6. Primary localization of the tumor was: lower extremity (3), trunk (2), retroperitoneum 

(1), pelvis (1). Primary tumor size ranged from 5 to 12 cm (median 7cm). All patient had 

unresectable metastases to the lungs. 57% of thepatientswerepreviouslytreatedwith 

standard chemotherapy. Median time from diagnosis to start of sunitinib therapy was 6 

months (range: 2-156). Responses were evaluated after 2 months from baseline, then 

every 3 months by CT scan and/or MRI, according to RECIST criteria. 

Results: At the time of present analysis 3 of the patient continue therapy. After 2 

months of treatment 2 patients had RECIST PR, 5 SD. Median PFS was 15 months 

with 86% patients free of progression of the disease at 6 months. Median therapy 

duration was 18 months (range: 5-31). Median OS was 15 months; 3 patients died due 

to disease progression at the time of analysis. One of the patients had SD after 4 

months of treatment, interrupted treatment for 3 months and experienced progression 

of the disease, after restarting therapy she again gained SD lasting 12 months. Toxicity 

was rather moderate. All the patients experienced some side effects, 4 patients (57%) 

had toxicity grade 3/4 CTC. The common treatment toxicity was neutropenia, 

hypothyroidism, arterial hypertension, hand and foot syndrome. 2 patients required 

dose reduction. There was one death related to the treatment (sepsis). 

Conclusion: Our analysis shows efficacy of sunitinib in patients with advanced ASPS. 

Disclosure: P. Rutkowski: honoraria: Pfizer and Novartis. All other authors have 


1496P SUNITINIB MALATE IN CLEAR CELL SARCOMA 

S. Stacchiotti 1 , E. Palassini 1 , T. Negri 2 , C. Morosi 3 , A. Messina 3 , R. Patuzzo 4 , 

A. Gronchi 4 , S. Pilotti 2 , P.G. Casali 1 

1 Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 

ITALY, 2 Pathology and Molecular Biology, Fondazione IRCCS Istituto Nazionale 

dei Tumori, Milan, ITALY, 3 Radiology, Fondazione IRCCS Istituto Nazionale dei 

Tumori, Milan, ITALY, 4 Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, 

Milan, ITALY 

Background: Clear cell sarcoma (CCS) is a rare soft tissue sarcoma, characterized in 

most cases by the t(12;22), resulting in the EWS-ATFE1 fusion protein. It has a high 


metastatic potential. CCS is poorly sensitive to chemotherapy. We already reported 

on the activity of sunitinib (SM) in one case of CCS. 

Methods: Since September 2009, 9 patients with progressive, metastatic CCS (M/ 

F 3/6; median age 36 yrs; translocated/ non translocated: 6/3; site of primary: 

extremities 6, other 3; pretreated: 9) have been treated with continuous SM 37.5 

mg/day, on a named basis. PET response was assessed in 6 cases. Responses 

were evaluated after 2 months from baseline, then every 3 months by CT scan 

and/or MRI, according to RECIST. Pre-treatment PDGFRB and VEGFR status 

analysis by immunohistochemistry, western/blotting and phospho-RTK array is 

ongoing in evaluable cases. 

Results: At the time of the present analysis, 6/9 pts are evaluable for response (1 

early interruption; 2 just started), and 4 patients are still on treatment. After 3 

months of SM, 3 patient had a RECIST partial response (PR) (50%), along with 

subjective improvement in symptoms, 1 stable disease (SD), 2 progressive disease 

(PD). PET was consistent. One patient had a complicated major response 

characterized by an ulcer to the site of previous surgery; thus she underwent surgery 

with evidence of pathologic partial response, marked by extensive necrosis. The 

median PFS is 5 months (range 2-7). 

Conclusions: SM is active in a proportion of CCS. Prospective studies are needed. 

Disclosure: S. Stacchiotti: Pfizer: reseach grant for studies in which my Institution is 

involved; honoraria. E. Palassini: Pfizer: research grant for studies in which my 

Institution is involved. P.G. Casali: Pfizer: research funds for studies in which my 

Institution is involved; Compensated Advisory; Honoraria. All other authors have 


1497P SIMULTANEOUS TARGETING OF THE INSULIN-LIKE 

GROWTH FACTOR 1 RECEPTOR (IGF-1R) AND ANAPLASTIC 

LYMPHOMA KINASE (ALK) IN EMBRYONAL AND ALVEOLAR 

RHABDOMYOSARCOMA 

J.C. van Gaal 1 , Y.M.H. Versleijen-Jonkers 1 , M.H.S. Roeffen 1 , U.E. Flucke 1 , 

G. van der Heijden 1 , A.J.H. Suurmeijer 2 , E.S.J.M. De Bont 3 , W.T.A. van der 

Graaf 4 

1 Department of Medical Oncology, Radboud University Nijmegen Medical 

Centre, Nijmegen, NETHERLANDS, 2 Pathology, University Medical Center 

Groningen, Groningen, NETHERLANDS, 3 Pediatric Oncology, University Medical 

Center Groningen, Groningen, NETHERLANDS, 4 Medical Oncology /452, 

Radboud University Medical Centre MijmegenUniversity Medical Center 

St. Radboud, Nijmegen, NETHERLANDS 

Introduction: Rhabdomyosarcoma (RMS) is an aggressive soft tissue tumour that 

occurs predominantly in children and adolescents. Its two most common forms 

are embryonal (eRMS) and alveolar RMS (aRMS). Although survival has increased 

over the past decades after the introduction of multi-agent chemotherapy, the 

survival for the high-risk subpopulation remains poor (not exceeding 50%). 

Therefore, there is an urgent need for new systemic treatment options. The aim of 

the current study is to investigate the insulin-like growth factor-1 receptor 

(IGF-1R) and anaplastic lymphoma kinase (ALK) pathway as potential targets in 

RMS. 

Methods: A total of 112 paraffin-embedded RMS tumor specimens (eRMS n = 86; 

aRMS n = 26) were collected on a tissue microarray. IGF-1R and ALK expression was 

evaluated by immunohistochemistry. A binary scoring system was used in which 

staining was scored positive when present in at least 10% of the tumour cells. The 

effect of the ALK small molecule inhibitor NVP-TAE684 (Novartis), the IGF-1R 

monoclonal antibody R1507 (Roche) and combined treatment was investigated by 

cytotoxicity assay MTT in four RMS cell lines (aRMS Rh30 and Rh41; eRMS Rh18 

and RD). 

Results: Expression of IGF-1R was seen in 72% of aRMS and 62% of eRMS, 

respectively. ALK expression was observed in 92% of aRMS and 39% of eRMS. 

Co-expression of IGF-1R and ALK was observed in 68% of aRMS and 32% of eRMS. 

In vitro, inhibition of the IGF-1R by R1507 resulted in diminished cell growth only 

in aRMS cell line Rh41 (IC50 11 ng/ml). NVP-TAE-684 resulted in diminished cell 

growth in aRMS cell lines Rh41 (IC50 103 nM) and Rh30 (IC50 211 nM), and to a 

lesser extent in eRMS cell lines Rh18 (IC50 585 nM) and RD (IC50 734nM). 

Simultaneous treatment could be assessed in aRMS cell line Rh41 by using different 

concentrations of R1507 and NVP-TAE684, and revealed a synergistic effect 

(combination index


1498P A PROGNOSTIC SCORE TO GUIDE APPROPRIATE DELIVERY 

OF FIRST LINE PALLIATIVE CHEMOTHERAPY FOR 

ADVANCED SOFT TISSUE SARCOMA 

N. Gough 1 , C. Smith 1 , J.R. Ross 1 , J. Riley 1 , I. Judson 2 

1 Palliative Care, Royal Marsden Hospital, London, UNITED KINGDOM, 2 Sarcoma 

Unit, Royal Marsden HospitalCR UK Centre for Cancer Therapeutics, Sutton, 


Objective: The study investigated predictive variables of overall survival (OS) in 

patients treated with first line palliative chemotherapy for locally advanced/ 

metastatic soft tissue sarcoma (STS) from 1998-2008. Poor performance status (PS) 

has been identified as a powerful risk factor for early death in this population. 

Establishing additional objective variables may further aid decision making when 

considering the risk/benefit ratio of systemic chemotherapy. 

Methods: Pre-treatment demographic, STS-specific and biochemical variables of 501 

patients were reviewed retrospectively. Patients with chemo-sensitive subtypes 

gastro-intestinal stromal tumour, rhabdomyosarcoma, desmoplatic small round cell 

tumour were excluded. Significant prognostic factors in univariate analysis were 

further evaluated using multivariate analysis (Cox regression). 

Results: Median OS was 11.4 months, 90-day mortality 17% and the 1, 2 and 5 year 

survival was 43, 23 and 2% respectively. The Cox model identified age >60 years 

[Hazard ratio: 1.35 (95% confidence interval 1.01-1.80) p = 0.04], >2 sites of 

metastases [HR: 1.47 (1.14- 1.90) p =0.003], presence of soft tissue metastases [HR 

1.23 (0.99 -1.51) p= 0.054] together with lymphocytes

chemotherapy respectively. At a median follow-up of 47 mths, median relapse-free 

survival (RFS) for R0/R1 resected pts was 49 mths (2yr RFS 68%). In the univariate 

analysis, primary tumor site originating in the extremities (p = 0.019) and use of 

adjuvant radiation (p = 0.008) were significantly associated with improved RFS. 

Notably, pts with axial LPS had significantly higher rates of relapse, 58% vs 37%, (p 

= 0.043) with a significantly higher proportion being local-only relapses, 77% vs 44% 

(p = 0.028) compared with extremity LPS. Median overall survival (OS) of pts with 

localized LPS was 113 mths. For pts with metastatic disease, median OS was 21 

mths. In univariate analysis, use of palliative chemotherapy (p = 0.046) was 

significantly correlated with superior OS. LPS sub-type did not significantly influence 

RFS or OS. 

Conclusions: Our study demonstrates that primary tumor site and use of adjuvant 

RT but not LPS sub-type are important prognostic factors for RFS in pts with 

localised LPS. This knowledge may potentially guide local treatment decisions 

including the use of more aggressive surgery, adjuvant radiation and even 

chemotherapy in selected patients. 


1502P VINORELBINE IS AN ACTIVE DRUG IN DESMOID TUMORS / 

AGGRESSIVE FIBROMATOSIS: INSTITUT GUSTAVE ROUSSY 

EXPERIENCE 

C. Rahal 1 , A. Cioffi 2 , J. Domont 3 , S. Bonvalot 4 , C. Le Pechoux 5 , L. Vilcot 1 , 

P. Terrier 1 ,F.Fayard 1 , A. Rahal 1 , A. Lecesne 1 

1 Dept. of Medicine, Institut de Cancérologie Gustave Roussy, Villejuif Cedex, 

FRANCE, 2 Dept of Medecine - Sarcoma Division, Institut Gustave Roussy, 

Villejuif, FRANCE, 3 Dept. Medical Oncology, Institut Gustave Roussy, Villejuif, 

FRANCE, 4 Department of Surgery, Institut Gustave Roussy, Villejuif, FRANCE, 

5 Radiotherapy, Gustave Roussy, villejuif, FRANCE 

Background: Desmoid tumors /aggressive fibromatosis (AF) are locally aggressive 

neoplasms with frequent relapses despite optimal loco-regional treatments. In 

case of disease progression, non loco-regional therapeutic options include non 

steroidal agents, hormonal therapy and systemic chemotherapy including 

Anthracyclins or Vinca Alkaloids. Vinorelbine (VNR) has been poorly 

investigated in AF. 

Methods: This is a retrospective review of patients with recurrent/progressive AF 

treated with single agent oral VNR between April 2006 and April 2012 at Institut 

Gustave Roussy. 

Results: Seventeen patients (pts) received oral VNR (90 mg weekly). There were 3 

males and 14 females with a median age of 35 years (14-58 yrs). Eleven pts 

(65%) showed PD according to RECIST before inclusion while 6 pts (29%) were 

stable but with progressive symptoms. VNR was given as monotherapy in 7 pts, 

in combination with hormonal therapy (Tamoxifen plus LHRH agonist) in 9 pts 

and with COX 2 non-steroidal anti-inflammatory drugs in 2 pts. The median 

tumor size was 11cm (3.7-29cm). AF were extra-abdominal in 12 pts (extremity: 

3, superficial trunk: 5, girdle 4) and intra abdominal in 5 pts. Prior therapy 

included surgery (53%), radiation therapy (12%), hormonal therapy (53%), 

Imatinib (12%) and chemotherapy (6%). The median duration of VNR treatment 

was 6 months (2-23m). Tolerance was excellent with no grade III-IV toxicities. 

Twelve pts had a tumor shrinkage including 7 RECIST PR (41%), 5 during VNR 

and 2 others few weeks after drug discontinuation. Nine pts (53%) achieved a 

RECIST disease stabilisation and one pt (6%) progressed during chemotherapy. 

Symptomatic relief during treatment was observed in 75% of pts. After a median 

follow-up of 3 years, the 1 and 3-yr PFS rates were 94% (72-99%) and 87% 

(62-96%) respectively. VNR was rechallenged in 3 progessing pts and a PR was 

seen in 2 cases. 

Conclusion: Weekly oral VNR is a well tolerated regimen and highly effective in 

achieving significant and durable clinical benefit in AF. Tumor shrinkage can be 

observed after drug discontinuation .VNR can be rechallenged in previously 

responding pts. This regimen deserves further developments. 



1503P METRONOMIC ORAL CYCLOPHOSPHAMIDE IN THE 

TREATMENT OF METASTATIC SOFT TISSUE SARCOMA: IS 

THERE A ROLE FOR MAINTENANCE THERAPY? 

A.C.R. Ferrari, V.P. Camargo, G.M. Bariani, M.S. Goncalves, P.M. Hoff, G. De 

Castro, Jr. 

Medical Oncology, Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, 

BRAZIL 

Background: Metronomic chemotherapy has been demonstrated to improve DFS in 

advanced STS. Here we aimed to analyze the efficacy and safety of metronomic oral 

cyclophosphamide (M-CTX) as maintenance or salvage therapy in these patients 

(pts). 

Methods: It is a retrospective study of all advanced/metastatic STS pts (RMS, GIST, 

bone sarcomas excluded) treated in our institution between Feb/2009 and Jan/2012 

with M-CTX 100 mg PO daily 21 out of 28 days, until disease progression (DP). 

Tumor response (RECIST 1.1) was assessed every 2 cycles. The primary endpoint of 

the study was time to treatment failure (TTF). Toxicity was graded according to the 

NCI-CTC v.3.0. criteria. 

Results: 27 pts were consecutively included in this analysis. Thirteen pts received 

M-CTX as maintenance chemotherapy after presenting best response: median age 60 

y, 9 female; 5 LMS, 3 HGUPS, 2 PNET, 3 others. Median number of previous 

chemotherapy regimens 2; 9 previously treated with doxorubicin and 4 with 

ifosfamide; 4 presented PR as best response. Median TTF (mTTF) was 9.2 mo, 4 pts 

(2 PNET, 1 LMS, 1 HGUPS) had mTTFs ≥ 6 mo and no deaths were observed in a 

median follow-up of 7 mo. 14 pts received M-CTX as salvage chemotherapy after 

DP: median age 45.5 y, 8 female; 3 LMS, 3 HGUPS, 3 synovial, 2 ASPS, 3 others. 

Median number of previous chemotherapy regimens 1.5; 11 previously treated with 

doxorubicin and 6 with ifosfamide; 1 PR as best response. mTTF 3.3 mo, 1 ASPS 

had mTTFs ≥ 6 mo, and 9 deaths (HR 1.403, 95%CI 0.608-3.236, p = 0.409, in 

comparison with maintenance strategy). In general, M-CTX was well tolerated, and 

the most common toxicity (>10%) included nausea G1 (5 pts), renal failure (3 pts), 

anemia G1 (4 pts), anemia G2 (3 pts), lymphopenia G1 (12 pts). 

Conclusions: Metronomic oral cyclophosphamide seems to be a valid option as 

maintenance chemotherapy after presenting best response in advanced/metastatic 

STS, with acceptable toxicity. This compares favorably with historical controls (mPFS 

around 4 months). However, after disease progression, it is a futile chemotherapy 

regimen. 

Disclosure: A.C.R. Ferrari: Travel expenses covered: Roche. G.M. Bariani: Novartis: 

lecture fee, travel expenses covered. Roche: travel expenses covered. All other authors 


1504P ISOLATED LIMB PERFUSION IN LOCALLY-ADVANCED LIMB 

SOFT TISSUE SARCOMAS: RETROSPECTIVE STUDY OF A 

23-YEAR EXPERIENCE 

M. Rastrelli 1 , L.G. Campana 1 , A. Vecchiato 1 , P.L. Pilati 2 , S. Valpione 3 , R. Spina 1 , 

C. Falci 4 , A. Sommariva 1 , A. Zanon 2 , C.R. Rossi 1 

1 Sarcoma and Melanoma Unit, Veneto Region Oncology Research Institute 

(IOV-IRCCS), Padova, ITALY, 2 Gastroenterological and Surgical Sciences, 

University of Padova, Padova, ITALY, 3 Medical Oncology School, University of 

Padova, Padova, ITALY, 4 Medical Oncology-ii, Veneto Region Oncology 

Research Institute (IOV-IRCCS), Padova, ITALY 

Background: Hyperthermic isolated limb perfusion (HILP) is a cytoreductive 

treatment to avoid amputation in limb soft tissue sarcomas (LSTS). HILP drug 

schedule has been modified to balance treatment activity and toxicity. 

Methods: From 1988 to 2011, 117 patients with unresectable primary or recurrent 

LSTS underwent HILP. Tumor characteristics, HILP parameters and drugs 

(doxorubicin; doxorubicin plus TNFa; TNFa plus L-PAM), postoperative plasma 

myoglobin, tumor response, systemic chemotherapy (CT), site of recurrence and 

outcome were analyzed. 



Results: The 3 treatment groups were homogeneous for clinical pathological features. 

The tumor response (necrosis in resected specimen) was comparable (P = .473) 

(Table) and was correlated with myoglobin (P < .05). Locoregional toxicity was 

similar in the three groups (P = .233) (Table). Surgical resection was radical in 83.2% 

of cases. The 5-year LDFS was 70.2%, with no differences according to HILP 

schedule (P = .475). 22.2% of patients required limb amputation, for complications 

(n = 1), unresponsiveness (n = 17) or recurrence (n = 8). The amputation rate was 

higher in upper LSTS (P = .049). Systemic metastases occurred in 47 patients (40.2%) 

after a median of 14.6 months; their occurrence inversely correlated with post-HILP 

necrosis (P = .001). Five-year OS was 48.1%. The avoidance of amputation (P = .044), 

CT (P = .003) and lung as site of systemic recurrence (P = .018) were associated with 

longer OS. Lung metastases were predictors for longer OS in case of systemic 

progression (OR 3.81,95% CI 1.74-8.34,P < .001). Prognosis was not influenced by 

CT (P = .087). 

Conclusions: Doxorubicin, doxorubicin + TNFa and TNFa + L-PAM schedules are 

equally active, with comparable toxicity profiles. Upper LSTS and poor post-HILP 

necrosis were related with higher amputation rates. Despite preserving limb function, 

40% of HILP patients develop a systemic recurrence, particularly when achieving 

lower responses. Lung relapses lung have a relatively better prognosis. 

Drug schedule 

DOXO 

n=47 

TNFa + DOXO 

n=30 

TNFa + L-PAM 

n=40 

Tumor necrosis, 

median % 

(range) 

Locoregional toxicity 

according to Wieberdink 

n° of pts (%) 

1-2345 

54 (7-91) 38 (80.9) 8 (17.0) 1 (2.1) 0 

64 (10-100) 24 (80.0) 4 (13.4) 1 (3.3) 1 (3.3) 

57 (4-91) 37 (92.5) 1 (2.5) 2 (5.0) 0 


1505P COMPARISON OF TWO CHEMOTHERAPY REGIMENS (AI VS. 

EIA) COMBINED WITH REGIONAL HYPERTHERMIA (RHT) IN 

HIGH-RISK SOFT-TISSUE SARCOMA (HR-STS) 

P.O. Aubele 1 , E. Kampmann 1 , G. Schuebbe 1 , S. Abdel-Rahman 1 , N. Dieterle 1 , 

R. Laubender 2 , R. Issels 3 , L. Lindner 1 

1 Dept Internal Medicine III Hematology/Oncology, University Hospital Munich – 

Grosshadern, Munich, GERMANY, 2 University of Munich, Institute of Medical 

Informatics, Biostatistics, and Epidemiology, Munich, GERMANY, 3 German 

Research Center for Environmental Health, Helmholtz Zentrum München, 

Neuherberg/Munich, GERMANY 

Introduction: A phase III study showed that RHT combined with EIA (E = 

etoposide, I = ifosfamide and A= doxorubicin) is effective in HR-STS (Lancet Oncol, 

2010). EIA + RHT significantly improved tumor response and prolonged local 

progression-free (LPFS) and disease-free survival (DFS). Due to the mutagenic 

potential of etoposide the EIA-regimen was modified thereafter. Here we report a 

retrospective single center sequential analysis of EIA vs. AI both combined with 

RHT. 

Methods: Patients (pts) with localized HR-STS received EIA (E:125mg/m2; I:6g/m2; 

A:50mg/m2) or AI (A:60mg/m2; I:9g/m2) with RHT (T max. 42°C; 60min.). Inclusion 

criteria and procedures were equivalent to the protocol of the phase III study. 

Response was evaluated according to RECIST and survival parameters were analysed 

using cox regression models, Kaplan-Meier and chi-square test. Possible confounders 

were selected by backward elimination using the likelihood ratio test. 

Results: 106 Patients (median age 48 years; 19 - 70) were treated with EIA (42pts; 

from 2006 – 2008) or AI (64pts; 2009 – 2012) with a median follow up of 28 months 

for EIA and 10 months for AI. Best clinical response rate (CR + PR + SD) for EIA + 

RHT was 89% compared with 97% for AI + RHT (p = 0,59). Risk for local disease 

progression or death was not significantly different (Hazard ratio (HR) 0.896; 95% CI 

0.433 -1.855; p= 0,767). 1-year rates of LPFS and DFS were 73% [95% CI 0.60 - 0.87] 

and 73% [95% CI 0.60 - 0.87] for EIA and 77% [95% CI 0.65 - 0.89] and 63% [95% 

CI 0.49 - 0.77] for AI. Accordingly, for DFS HR was 0.739 (95% CI 0.382 - 1.428; p 

= 0.368) and for OS HR was 1.011 (95% CI 0.306 - 3.339; p = 0.958). There was also 

no significant difference in HRs for LPFS, DFS or OS after adjustment for 

confounders. 

Conclusion: Combining both regimens with RHT, AI is an equally effective regimen 

if compared to the EIA regimen. The efficacy of both regimens combined with RHT 

is comparable to the published results of the phase III study. P. Aubele, 

E. Kampmann, G. Schuebbe contributed equally; this work contains parts of the 

doctoral thesis of G. Schuebbe. 


1506P SUPERIORITY OF CHOI VS RECIST CRITERIA IN 

EVALUATING OUTCOME OF ADVANCED SOFT TISSUE 

SARCOMA (STS) PATIENTS TREATED WITH SORAFENIB 

R. De Sanctis 1 , A.F. Bertuzzi 1 , P. Magnoni 2 , L. Giordano 3 , M. Gasco 1 , 

R. Lutman 2 , A. Santoro 1 

1 Medical Oncology and Hematology, Humanitas Cancer Center, IRCCS, 

Rozzano, ITALY, 2 Radiology, Humanitas Cancer Center, IRCCS, Rozzano Milan, 

ITALY, 3 Biostatistics Unit, Humanitas Cancer Center, IRCCS, Rozzano Milan, 

ITALY 

Background: Objective tumor response may be underestimated by RECIST criteria, 

since biological agents can cause metabolic response (necrosis) not related to tumor 

size. For this reason, CHOI criteria were designed to evaluate both tumor density 

and size. We compared CHOI and RECIST criteria in evaluating response to 

sorafenib in patients with advanced STS, treated within a phase II trial. The objective 

was to compare CHOI and RECIST criteria and to relate response to progression-free 

(PFS) and overall survival (OS). 

Patients and methods: Sixty one advanced STS patients received sorafenib 400 mg 

twice daily for progressive or relapsed disease after anthracycline-based 

chemotherapy. Treatment was continued until progression or major toxicity. 

Contrast-enhanced CT was performed every 3 months. Thirty patients were 

evaluable for response, according to both RECIST and CHOI criteria. 

Results: A total of 30 patients were included in the analysis. According to RECIST, 

we observed 1 (3%) complete response (CR), 1 (3%) partial remission (PR), 18 (60%) 

stable diseases (SD) and 10 (34%) progressive diseases (PD) at 3 months. According 

to CHOI, we observed 1 (3%) CR, 10 (34%) PR, 5 (16%) SD and 14 (47%) PD. The 

agreement between the two techniques was low (cohen Kappa: 0.36; CI 95%, 

0.17-0.55). Of the 18 pts with SD according to RECIST, a total of 13 (72%) pts were 

reallocated to responder (8 PR, 44%) and non-responder (5 PD, 28%) groups, while 

only in 5 cases SD was confirmed using CHOI criteria. Median PFS and OS for SD 

RECIST pts were 8.3 and 22.7 months, respectively. In these 18 pts, we compared 

median PFS and OS of responders (CR + PR, n= 8) vs non-responders (SD + PD, n= 

10) according to CHOI criteria. PFS was 11.2 vs 7.9 (p= 0.05), and OS 23.3 vs 15 

months (p= 0.21). 

Conclusions: Our analysis suggests that CHOI criteria may be helpful to define 

response to a biological treatment in STS. According to CHOI criteria, SD pts as 

defined by RECIST could be better divided in two subgroups (responders and 

non-responders) with a different outcome. Therefore, CHOI criteria may have an 

early significant predictive value for PFS in STS pts treated with biological 

agents. 


1507P CORRELATION BETWEEN TUMOUR NECROSIS AND 

OVERALL SURVIVAL IN ADULTS WITH OSTEOSARCOMA 

TREATED WITH NEOADJUVANT CISPLATIN AND 

DOXORUBICIN 

G. Rivalland, D. Porter 

Cancer and Blood Service, Auckland City Hospital, Auckland, NEW ZEALAND 

Purpose: The degree of tumour necrosis following neoadjuvant chemotherapy has 

crucial prognostic significance in methotrexate containing regimens. We examined 

whether a similar relationship exists for a non methotrexate containing regimen in a 

cohort of adult patients treated at the Auckland Regional Cancer Service between Feb 

1996 and Feb 2011. 

Methods: We retrospectively identified 35 patients with high grade osteosarcoma 

using data recorded prospectively in the New Zealand Bone Tumour registry 

and regional pathology laboratories. All patients received neoadjuvant cisplatin 

and doxorubicin, without high dose methotrexate. Reported necrosis rates 

following surgery clustered into 3 groups: >90%, 30-65% and

of this group Those with relapsed disease have significant benefit from surgery for 

metastases. 

Disclosure: D. Porter: Previous consulting fro Pfizer. Current consulting for GSK. 

Previous travel grant from Novartis. All other authors have declared no conflicts of 

interest. 

1508P MIFAMURTIDE (L-MTP-PE) FOR METASTATIC AND 

RECURRENT OSTEOSARCOMA (OS): SURVIVAL AND SAFETY 

PROFILE FROM A PATIENT ACCESS STUDY 

P. Anderson 1 , P. Meyers 2 , E. Kleinerman 1 , C. Oliva 3 ,Y.Liu 4 

1 Pediatrics, MD Anderson Cancer Center, Houston, TX, UNITED STATES OF 

AMERICA, 2 Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 

UNITED STATES OF AMERICA, 3 Oncology Mdc, Takeda Global Research & 

Development (Europe) Ltd, London, UNITED KINGDOM, 4 Biostatistics, 


AMERICA 

Introduction and research objectives: Liposomal muramyl tripeptide phosphatidyl 

ethanolamine (L-MTP-PE; mifamurtide) is approved for treatment of non-metastatic 

osteosarcoma (OS) in Europe, Israel, and Mexico. The primary objective of 

MTP-OS-403 was to collect information regarding the safety and tolerability of MTP 

in patients with high-risk OS. The open label access study called for L-MTP-PE 

2mg/m2 twice /week x 24 doses, then weekly (total doses= 48 in 9 months). OS 

patients could receive MTP as a single agent or with appropriate chemotherapy. 

Results: As of April 2012, 202 patients were registered at 8 participating centers. 

Most had metastases at initial presentation or recurrent OS. Median age was 16 yr. 

Time from initial diagnosis to L-MTP-PE treatment was 29 +/- 23 months (median 

24 mo). Although >88% had metastases, 27% had been resected to no evidence of 

disease (NED) before study entry. The most common Infusion related AE (IRAE) 

within 24 hours of infusion were chills (37%), fever (25%), nausea (21%), headache 

(19%), and fatigue (15%). The most common AE (grade 3-4) other than IRAE were 

chemotherapy-related and included thrombocytopenia (22%), neutropenia (19%), 

leukopenia (18%), febrile neutropenia (16%), lymphopenia (15%), and anaemia 

(15%). At MDACC, there was 1 episode of pleural effusion and one episode of 

pericardial effusion that were possibly L-MTP-PE related. The median number of 

L-MTP-PE doses given was 34 (mean 30.1 +/- 17.5); 32% of these high risk OS 

patients received 48 doses. As of April 2012 45% (90/202) of these high risk OS 

patients continue to be followed for survival. 

Conclusion: The safety profile of L-MTP-PE in high-risk OS patients is consistent 

with the known toxicity of the product. The infusion related AEs were generally mild 

to moderate. Since survival benefit in high-grade OS from MTP may be related to 

disease burden (i.e. achieving NED status using local control measures such as 

surgery and/or radiotherapy), L-MTP-PE may be more effective when used in the 

adjuvant setting. A randomized multi-institutional clinical trial in OS patients 

presenting with metastases at diagnosis should be considered. 

Disclosure: C. Oliva: Cristina Oliva is a Takeda employee. Y. Liu: I am a Millennium 

employee. All other authors have declared no conflicts of interest. 

1509P CHEMOTHERAPY IS EFFECTIVE IN PRIMITIVE 

NEUROECTODERMAL TUMOR (PNET) / EWING SARCOMA 

(EWS) OF THE KIDNEY 

E. Risi, R. Iacovelli, A. Palazzo, A. Passaro, G. Campennì, F. Morano, K. Truscelli, 

P. Trenta, S. Mezi, E. Cortesi 

Department of Radiology, Oncology and Human Pathology, Sapienza University 

of Rome, Rome, ITALY 

Background: PNET/EWS is a rare tumor that occurs most commonly in bone and 

soft tissues of children and young. PNET/EWS arise rarely as a primary renal 

neoplasm and exhibits highly aggressive biological behavior. Since its first description 

in 1975, less than 100 cases of EWS/PNET have been published in medical literature. 

We aim to collect and to analyze clinical and pathological features of this tumor. 

Patient and methods: All cases reports of PNET/EWS published from 1975 to 

February 2012 were collected. When available, clinical and pathological data were 

extracted for each case such as previously reported (Iacovelli et al. BJU Int 2012). 

Survivals were estimated with Kaplan-Meier method and compared with log-rank 

test with 95% CI. 

Results: A total of 117 cases were found, 55% were male and the median age was 

28.0 y (IQR: 20.0 – 42.0). All patients (pts) had clinical symptoms as first 

presentation of disease such as pain (54%), hematuria (29%) and bulky renal mass 

(28%); whereas dysuria, fever, weight loss fatigue and abdomen swelling were 

reported rarely. 66% of pts had stage IV at diagnosis and the main sites of metastases 

were lung (60%), liver (37%), abdominal lymph-nodes (20%), bone and local relapse 

(


metastatic STS patients in the population. These patients were characterized and 

followed to determine treatment patterns. 

Results: For first line (1L) metastatic patients, 25.4% (n = 35/138) of patients entered 

a clinical trial. 68.4% of patients received at least one off-label drug (table 1). 

Doxorubicin was the most common 1L therapy (63%). In the 2L, 25.8% of patients 

entered a clinical trial and 51.6% received at least one off-label drug. Doxorubicin 

was still the most common therapy (29%), but there was no clear standard of care. 

Median time to relapse was 250, 123 and 110 days, for 1, 2 and 3L. Median 

treatment free interval (TFI) between 1L and 2L was 89 days and reduced to 30 days 

between 2L and 3L. 

Conclusions: STS is a rare and heterogeneous disease with a high use of unapproved 

treatments and short TFIs between two treatment lines. The lack of clear standard of 

care, particularly in patients receiving 2L therapy demonstrates important medical 

need for new agents in this therapeutic area Table 1: treatment mainly used at 1 st 

and 2 nd metastatic treatment lines, either given alone or in combination. 

1st metastatic line 2nd metastatic line 

Therapeutic option N = 145, MD* = 7 N = 83, MD = 4 

Systemic Treatment 95 (68.8%) 62 (78.5%) 

Drugs administered N = 95 N = 62 

Doxorubicin 60 (63.2%) 18 (29.0%) 

Ifosfamide 28 (29.5%) 

7 (11.3%) 

Fully combined with Doxo 

42.8% combiend with Doxo 

Dacarbazine 18 (18.9%) 2 (3.2% 

fully combined with Doxo 

Docetaxel‡ 12 (12.6%) 14 (22.6%) 

Gemcitabine‡ 12 (12.6%) 14 (22.6%) 

of which >80% use was Gemcitabine-Docetaxel regimen 

Trabectedine 7 (7.4%)‡ 8 (12.9%) 

Ate least 1 off-label drug 65 (68.4%) 35 (56.5%) 

*MD: Missing Data‡: off-label use in STS treatment 

Disclosure: B. Tehard: GlaxoSmithKline Employee GlaxoSmithKline funded the data 

analyses leading to resultst mentionned in this abstract. I. Ray-Coquard: Isabelle 

Ray-Coquard received fees and Grants from GSK GlaxoSmithKline funded the data 

analyses leading to resultst mentionned in this abstract. N. Ladarre: GlaxoSmithKline 

Employee GlaxoSmithKline funded the data analyses leading to resultst mentionned 

in this abstract. S. Manson: GlaxoSmithKline Employee GlaxoSmithKline funded the 

data analyses leading to resultst mentionned in this abstract. J. Blay: Jean-Yves Blay 

received fees from GSK GlaxoSmithKline funded the data analyses leading to resultst 

mentionned in this abstract. All other authors have declared no conflicts of interest. 

1512 CIRCULATING TUMOR CELLS IN SOFT TISSUE SARCOMAS 

PATIENTS 

B. Vincenzi 1 , E. Rossi 2 , A. Zoccoli 1 , M. Iuliani 1 , F. Pantano 1 , A.M. Frezza 1 , 

M. Silletta 1 , G. Tonini 1 , R. Zamarchi 3 , D. Santini 1 

1 Medical Oncology, University Campus Bio-Medico, Rome, ITALY, 2 Department 

of Surgery, Oncology and Gastroenterology, University of Padova, Padova, 

ITALY, 3 Immunology and Molecular Oncology, IOV-IRCCS, Padova, ITALY 

Introduction: Soft tissue sarcomas (STSs) are an heterogeneous group of highly 

malignant mesenchymal tumors with only few recognised prognostic and predictive 

factors. Circulating tumor cells (CTCs) are considered a prognostic marker classically 

associated with poor prognosis in epithelial solid cancer patients. The purpose of this 

study was to explore the possibility to detect CTCs in blood samples of STSs 

metastatic patients. 

Methods: Patients with histologically confirmed STSs and known metastases treated 

at Campus Bio-Medico Hospital of Rome from June 2011 to February 2012 were 

included. Blood was collected from patients who progressed on previous 

chemotherapy (1st, 2nd or 3rd line). All patients signed informed consent before 

phlebotomy. CTCs were assessed with CellSearchSystem (Veridex, USA). After 

immunomagnetic enrichment with an anti-Epcam-antibody, cells were labelled with 

anti-Ck8/18/19 and anti-CD45 antibodies to distinguish between epithelial cells and 

leukocytes. Wilcoxon rank-sum test was used to test for associations between CTC 

assay results and specific histotype, number of previous treatment, number and 

localization of metastatic disease sites. 

Results: Twenty-three patients with metastatic STSs were evaluated. CTCs were 

detectable in 10/23 (43%) patients with CTC counts in the range of 0-4 cells/7.5 mL. 

The median number of CTCs was significantly lower in patients with only one site of 

metastasis compared to those with two or more metastatic sites (0 vs 2; P = 0.003). 

There was no statistically significant difference (P = 0.210) in median CTC counts 

between patients who received only a first line regimen (0, range 0-4) vs patients who 

previously received more anticancer therapies (1, range 0-3). Finally, no statistically 

significant correlation was identified between the number of CTCs and the 

histological grading evaluated according to the FNCLCC grading system (P = 0.468). 

Conclusions: To our knowledge this is the first detection of circulating Epcam/Ck8/ 

18/19+ cells in STSs patients, even if the identified circulating cells could be epithelial 

cells due to direct tumour invasion of the blood vessel from the surrounding tissue or 

tumor cells at the moment of mesenchymal-epithelial transition. 


1513 PRIMARY SARCOMAS OF THE HEART AND GREAT VESSELS 

K. Wiater, H.M. Kosela, M. Zdzienicki, P. Rutkowski 

Department of Soft Tissue/Bone Sarcoma and Melanoma, MSC Memorial 

Cancer Centre and Institute Maria Sklodowska-Curie, Warsaw, POLAND 

Background: Primary sarcomas of the heart and great vessels are rare entities, 

accounting for less than 25 % of all primary cardiac tumors. They are characterized 

by an aggressive course and poor prognosis. The aim of the study was to analyze 

treatment and outcomes in the group of patients referred to sarcoma center. 

Methods: We retrospectively analyzed 12 patients (8 male, 4 females) treated at our 

institution between 2003 – 2011. Median age at the time of diagnosis was 33 years 

(range: 27-73). The histological types included angiosarcoma (n = 4), pleomorphic 

sarcoma (n = 4), leiomyosarcoma (n = 3), desmoplastic small round cell tumour (n = 

1). Primary tumors were located in right atrium (n = 6), left atrium (n = 5) and 

pulmonary artery (n = 1). The median tumour size was 50 mm (range 25-112). Four 

patients (33%) had a metastatic disease at diagnosis. Nine patients (75%) underwent 

curative intended surgery, including one patient who had a heart transplantation. 

Five patients (42%) received a perioperative anthracycline-based chemotherapy. 

Results: The median overall survival (OS) was 19.5 months (range: 3-42). There was 

a significant improvement in overall survival for patients who underwent surgical 

resection versus those who did not (median OS 24.5 versus 6 months, respectively). 

Even better results were observed in patients receiving perioperative chemotherapy. 

The median OS for these patients was 32 months (range 27-42). Despite the curative 

intention of surgery, 90% of patients have subsequently developed local recurrence. 

Conclusion: Complete surgical excision in combination with chemotherapy improves 

overall survival in patients with primary sarcomas of heart and great vessels. 

It underlines significance of close cooperation of cardiac surgery centers with tertiary 

cancer centers in treatment of patients with these rare entities. 


1514 BRAIN METASTASES(BM) IN PATIENTS (PTS) WITH SOFT 

TISSUE AND BONE SARCOMA (SARCOMA): A 

RETROSPECTIVE STUDY OF 107 PTS 

A. Cioffi 1 , A. Italiano 2 , R.G. Maki 1 , M.L. Keohan 3 

1 Department of Medicine and Pediatrics, Mount Sinai School of Medicine, 

New York, NY, UNITED STATES OF AMERICA, 2 Medical Oncology, Institute 

Bergoni, Bordeaux Cedex, FRANCE, 3 Department of Medicine - Melanoma and 

Sarcoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, 


Introduction: Data related to management and outcome of BM of sarcoma are 

scarce. 

Methods: From 1991 to 2010, from over 4500 sarcoma pts treated at MSKCC, 107 

developed BM. 

Results: Highest relative frequency came from ASPS (26%,7/27 pts), with an absolute 

number highest for LMS(37%). BM metachronous in 96 cases (90%). Median time 

between diagnosis of metastatic sarcoma and the diagnosis of BM was 9 months 

(range 5.5–12.5). Locoregional treatment (surgery ± RT) in 83 pts (78%). Systemic 

CT in 18 pts (17%) after diagnosis of BM. One PR (EWS) in 15 evaluable pts. One 

hundred-one pts died (94%), 6 still alive. Two living pts with follow-up >24 months 

had complete surgery of BM. Deaths related to BM progression were 54 (54%), 

related exclusively to systemic PD were 47 (46%). Median OS was 3.6 months (95% 

CI: 2.9-4.3). One-year OS rate was 16% (95% CI 9–23). On univariate analysis, 

histology, delay between the diagnosis of sarcoma and BM relapse, number of 

lesions, disease status and PS were significantly associated with OS. Surgery was 

significantly related to improved OS while RT was not. On multivariate analysis, time 

between diagnosis of sarcoma and BM relapse and disease status were 

pre-therapeutic prognostic factors associated with OS. 

Conclusions: SARCOMA pts with BM have poor outcome. RT was not associated 

with improved survival. Long-term survival is achieved in small proportion of pts 

managed by surgery. CT had little activity after BM, consistent with the advanced 

nature of the pts’ sarcomas. 



1515 PREDICTORS OF SURVIVAL IN ADOLESCENTS AND YOUNG 

ADULTS WITH NON METASTATIC EXTREMITY 

OSTEOSARCOMA- CANCER INSTITUTE (WIA), A TERTIARY 

CANCER CENTER EXPERIENCE FROM SOUTH INDIA 

R. Rajendranath 1 , K. Narayanaswamy 2 , S.G. Tenali 1 

1 Medical Oncology, Cancer Institute (WIA), Chennai, INDIA, 2 Surgical Oncology, 

Cancer Institute (WIA), Chennai, INDIA 

Osteosarcoma one of the highly curable malignancy is the most common primary 

malignant neoplasm of bone in adolescents and young adults. The purpose of this 

study was to determine the predictors of survival in patients with non metastatic 

Extremity Osteosarcoma. 

Methods: The study was a retrospective analysis of 272 consecutive patients 

diagnosed between 1998 and 2008 and 232 of them who had undergone protocol 

treatment was included for predictors of survival anal. 

Results: Median age of the patients was 17 years (6-52) and males constituted 

60 % (n = 163). Distal femur was the commonest site, 49.4% (n = 134) followed by 

proximal tibia 39.5% (n = 107). Classical osteosarcoma was the commonest subtype 

56% (n = 152) followed by Pleomorphic 21% (n = 57) and chondroblastic variant 

16.6%9 (n = 45). Majority of the tumours were high grade 96.3% (n = 262).156 

(57.6%) patients received Neoadjuvant Chemotherapy and 184 (65%) received ≥ 4 

cycles of planned Chemotherapy. 116 (42.4%) of patients underwent limb salvage 

surgery (LSS). The proportion of patients undergoing LSS improved from 45.3% 

to 53.2% during the time periods 1998-2002 and 2003-2008 respectively. Febrile 

Neutropenia was noted in 15 % and 3 patients died due to Chemotherapy related 

toxicities. Of 156 patients who received neoadjuvant chemotherapy 100 % necrosis 

was seen in 20 (12.8%) and >90% necrosis in 31 (19.8%). 5 year Disease free 

survival and overall survival among non metastatic osteosarcoma was 52.9% and 

55% respectively.Significant factors for predictors of survival included Age 90% necrosis (79.8% v/s 42.2% p = 0.001). Among 

Neoadjuvant Chemotherapy patients who received 3-4 cycles of Preoperative 

Chemotherapy did significantly better than those whoreceived ≥ 5cycles. (62.4% v/s 

46.1% p = 0.036). 

Conclusions: Predictivefactors that implicate adverse survival in non metastatic 

osteosarcoma in our patients include Age


Methods: This phase 4 study will assess osteosarcoma patients who are candidates 

for mifamurtide therapy at European centres. (EudraCT: 2009-017204-89; 

NCT01194284). Eligible patients are aged 2–30 years, with a confirmed diagnosis of 

high-grade osteosarcoma. Approximately 150 patients are planned to be entered, and 

recruited over a 2-year period. Patients will receive the standard schedule of 2 mg/m 2 

IV mifamurtide, administered twice weekly for 12 weeks then once weekly for 24 

weeks (total 36 weeks). The primary objectives are to assess the short- (during 

treatment) and long-term (≤5 years from last mifamurtide dose or until death) safety 

profile of mifamurtide, including evaluation of AEs of special interest (defined as 

important identified and potential risks) to take into account the risk of recurrence 

and comorbidities with chemotherapy. Secondary objectives include assessment of 

disease status, disease-free survival and overall survival. 

Disclosure: C. Oliva: Employment: Takeda. Y. Liu: Employment: Millennium. All 



abstracts 

small cell lung cancer and other 

thoracic malignancies 

1519PD PHASE II STUDY OF AMRUBICIN IN PATIENTS WITH 

REFRACTORY OR RESISTANT RELAPSED SMALL-CELL 

LUNG CANCER: JAPAN CLINICAL ONCOLOGY GROUP 

STUDY (JCOG0901) 

H. Daga 1 , H. Murakami 2 , N. Yamamoto 2 , T. Shibata 3 , M. Endo 4 , H. Watanabe 5 , 

Y. Ichinose 6 , N. Yamamoto 7 ,Y.Ohe 8 , T. Tamura 7 

1 Department of Clinical Oncology, Osaka City General Hospital, Osaka, JAPAN, 

2 Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, JAPAN, 3 Regulatory 

Science Section Multi-institutional Clinical Trial Support Center, National Cancer 

Center Hospital, Tokyo, JAPAN, 4 Department of Radiology, Shizuoka Cancer 

Center, Shizuoka, JAPAN, 5 Department of Radiology, National Cancer Center 

Hospital, Tokyo, JAPAN, 6 Department of Thoracic Oncology, National Kyushu 

Cancer Center, Fukuoka, JAPAN, 7 Department of Thoracic Oncology, National 

Cancer Center Hospital, Tokyo, JAPAN, 8 Thoracic Oncology, National Cancer 

Center Hospital East, Kashiwa, JAPAN 

Background: Standard therapy for refractory or resistant relapsed small-cell lung 

cancer (SCLC) has not yet been established. We conducted an open-label, 

multicenter, non-randomized phase II study to confirm the efficacy and safety of 

amrubicin, a topoisomerase inhibitor, in the treatment of refractory or resistant 

SCLC. 

Material and methods: Patients with SCLC that is refractory or relapsed within 90 

days of completing previous treatment received amrubicin at a dose of 40 mg/m 2 for 

3 consecutive days, every 21 days.The study treatment was repeated until disease 

progression or intolerable toxicity. The primary end point was overall response rate 

(ORR), and secondary end points were progression-free survival (PFS), overall 

survival (OS), and safety. Planned sample size was 80 patients to achieve power of at 

least 80% with one-sided alpha of 0.05, and expected and threshold value for 

primary endpoint as 20% and 10%. All patients were followed-up until one year after 

the last patient enrollment. 

Results: Between November 2009 and February 2011, 82 patients were enrolled from 

25 institutions. The median number of treatment cycles was four (range, one to 22 

cycles).The ORR was 32.9% (p < 0.0001 by the exact binomial test for null hypothesis 

that ORR =


1522PD A MULTI-CENTER PHASE II CLINICAL TRIAL OF THE 

CHIMERIC ANTI-MESOTHELIN MONOCLONAL ANTIBODY 

AMATUXIMAB IN COMBINATION WITH CHEMOTHERAPY 

FOR FRONTLINE THERAPY OF MALIGNANT PLEURAL 

MESOTHELIOMA: UPDATED CLINICAL OUTCOMES AND 

CORRELATIVE STUDIES 

M. Reck 1 , R. Hassan 2 , T. Jahan 3 , H.L. Kindler 4 , L. Bazhenova 5 ,P.Fatato 6 ,J. 

W. Heyburn 6 , J. Parno 6 , J.D. Maltzman 6 , B. Wallin 6 

1 Thoracic Oncology, Krankenhaus Grosshansdorf, Grosshansdorf, GERMANY, 

2 Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, MD, 

UNITED STATES OF AMERICA, 3 Division of Hematology/Oncology, University of 

California - San Francisco, San Francisco, CA, UNITED STATES OF AMERICA, 

4 University of Chicago, Division of Oncology, Chicago, IL, UNITED STATES OF 

AMERICA, 5 Health Sciences, UCSD Moores Cancer Center, La Jolla, UNITED 

STATES OF AMERICA, 6 Oncology, Morphotek, Exton, PA, UNITED STATES OF 

AMERICA 

Background: Amatuximab (MORAb-009) is a chimeric monoclonal antibody to 

mesothelin, a cell surface glycoprotein highly expressed in malignant mesothelioma 

(MPM). Based on amatuximab results in a phase I clinical trial and pre-clinical 

studies showing synergy in combination with chemotherapy, a single arm phase II 

study of amatuximab plus pemetrexed (P) and cisplatin (C) was initiated in MPM 

patients (Pts). 

Methods: Eligibility criteria: unresectable epithelial or biphasic MPM, no prior 

chemotherapy and Karnofsky Performance Status (KPS) >70%. Pts received 

amatuximab 5 mg/kg on days 1 and 8 with P 500 mg/m 2 and C 75 mg/m 2 (PC) 

given on day 1 of each 21-day cycle for 6 cycles. Pts with objective response or stable 

disease received amatuximab monotherapy until disease progression. Primary 

endpoint: progression-free survival (PFS) at 6 months (mo). Secondary endpoints: 

overall survival (OS), objective response rate (ORR), pulmonary function (PFT), and 

safety of amatuximab with PC. 

Results: 89 pts with unresectable MPM were enrolled at 26 sites. Pt characteristics: 

median age 67 yrs (range 46-80); 78% male; 70% with KPS >90%; 89% epithelial 

MPM, 11% biphasic MPM; 88% had stage III/IV disease. Median PC-amatuximab 

cycles: 5 (range 1-6). 56 (63%) pts subsequently received single agent amatuximab. In 

addition to expected toxicities from PC, hypersensitivity reactions (12.4%; Grade 3/4 

= 5%) from amatuximab were noted. By independent radiological review, 30 pts 

(39%) had a partial response and 39 (51%) had stable disease. PFS at 6 mo: 52% 

(95% CI: 39.5-63.5). Median PFS = 6.1 mo (95% CI: 5.4-6.5). Median OS = 14.8 mo 

(95% CI: 12.4 – 19.2). 29 pts are alive and 5 pts are still receiving maintenance 

amatuximab. The mean Forced Vital Capacity (FVC) change from baseline was 

132ml. The proportion of pts with an FVC improvement of > 400ml was 23%. 

Conclusions: Amatuximab in combination with PC was generally well-tolerated in 

this study in MPM pts with a disease control rate of 90%. The median OS of 14.8 

months compares favorably with historical controls. 

Disclosure: M. Reck: Advisory Board (compensated): Hoffmann-La Roche, Lilly, 

AstraZeneca, Pfizer, Daiichi-Sankyo, BMS. Honoraria for lectures: Hoffmann-La 

Roche, Lilly, AstraZeneca, Daiichi-SankyoT. Jahan: research funding from Genentech, 

Lilly and PfizerH.L. Kindler: research funding for morphotekP. Fatato: Employee of 

MorphotekJ.W. Heyburn: Employee of MorphotekJ. Parno: Employee of MorphotekJ. 

D. Maltzman: Employee of MorphotekB. Wallin: Employee of MorphotekAll other 


1523P THE 8.1 ANCESTRAL HAPLOTYPE IS STRONGLY 

ASSOCIATED WITH THE RISK OF SMALL CELL LUNG 

CANCER 

J. Kocsis 1 ,L.Graf 1 , A. Szilagyi 2 , B. Dome 3 , L. Tamasi 4 , G. Galffy 4 , Z. Orosz 5 , 

Z. Prohaszka 2 , G. Fust 2 , Z. Bartfai 6 

1 3rd Dept of Internal Medicine, Oncology, Semmelweis University, Budapest, 

HUNGARY, 2 3rd Dept of Internal Medicine, Semmelweis University, Budapest, 

HUNGARY, 3 Tumor Biology, National Koranyi Institute of Pulmonology, 

Budapest, HUNGARY, 4 Pulmonology, Semmelweis University, Budapest, 

HUNGARY, 5 Radiology and Oncotherapy, Semmelweis University, Budapest, 

HUNGARY, 6 Pulmonology, Erzsebet Hospital, Sopron, HUNGARY 

Background: It is well established that the risk of lung cancer is related to the 

individual genetic background as it is reflected in the increased incidences among 

first degree relatives. The discovery of these genetic variations can lead to the 

identification of those individuals who are at high risk of developing lung cancer. 

AH8.1 is a haplotype which extends through the whole MHC region in the short 

arm of chromosome 6. It is the most frequent and a very conservative haplotype in 

the Caucasian population. Previously we have reported a strong association between 

AH8.1 and colorectal cancer with an odds ratio higher than any risks reported for 

SNPs in genome-wide association studies or candidate gene studies. Published data 

indicate that AH8.1 is a strong risk factor for ovarian cancer and for non-Hodgkin 

lymphoma as well. 

Aim/methods: Here we have determined the carrier state of AH8.1 in 102 

patients with small cell lung cancer (SCLC) (62 + 7.8 years), 94 patients with 

non- SCLC (NSCLC) (59+ 8.6 years) and in 248 age-matched control subjects 

(66.7 + 6.5 years). Subjects carrying all the four marker alleles of AH8.1 (C allele 

of AGER 429T > C, G allele of HSP70-2 1267A > G, A allele of TNFalpha -308G 

> A, as well as G allele of LTA 252A > G polymorphisms) were considered as 

AH8.1 carriers. 

Results: 23% (23/102) of SCLC patients, 13.8% (13/94) of NSCLC patients, and 13% 

(32/248) of healthy controls carried the AH8.1 haplotype. We have found a 

significant increased risk for SCLC in those people carrying AH8.1 with an odds 

ratio of 1.94 (1.01-3.73; p = 0.046) (for men: 3.09, 1.07-8.82; p = 0.031). However, 

there was no significant increase in the risk for NSCLC. 

Summary: These findings indicate that carriers of the AH8.1 haplotype are at 

increased risk for SCLC and it can be due to the altered immune response that is 

characteristic for 8.1 AH. 


1524P COMBINATION OF THREE CYTOTOXIC AGENTS IN SMALL 


G. Stathopoulos 1 , D. Traphalis 1 , J. Dimitroulis 2 , C. Kosmas 3 , J. Stathopoulos 1 , 

D. Tsavdaridis 4 

1 A’ Oncology Clinic Errikos Dunant, Dr. Georgios Stathopoulos, Athens, 

GREECE, 2 6th Pneumonic Clinic, Hospital for Thoracic Disease, Athens, 

GREECE, 3 Oncology Clinic, Anticancer Hospital Piraeus, Piraeus, GREECE, 

4 Oncology Clinic, Anticancer Hospital, Thessaloniki, GREECE 

Background: Small-cell lung cancer treatment has been tested by using combinations 

of several cytotoxic agents. For quite a number of years, the established treatment has 

been cisplatin and etoposide as the most effective chemotherapy regimen. Paclitaxel 

has also been used in combination with cisplatin and etoposide; the latter three - 

drug treatment has been effective but unacceptable due to toxicity. 

Patients and methods: In the present trial we tested the aforementioned three-drug 

combination and avoided the toxicity in the majority of the patients by administering 

all 3 drugs on day 1 instead of on the established three days of treatment. Fifty patients 

were recruited from 5 oncology clinics. All patients had histologically- or cytologicallyconfirmed 

small-cell-lung cancer with limited and extensive disease in 40% and 60% of 

the patients respectively. Treatment was as follows: cisplatin 75mg/m 2 , etoposide 

120mg/m 2 with no dosage higher than 200mg/m 2 and paclitaxel 135mg/m 2 . The agents 

were administered on day 1 and repeated every three weeks for 6 cycles in total. 

Results: The median survival was 14 months (95% CI 10.6-17.4) Forty-five patients 

(90%) achieved a response: 20(40%) patients a complete response and 25 (50%) a 

partial response. Adverse reactions was grade 3 and 4 neutropenia in 12% and 2% of 

the patients, respectively. Other side effects involved very low toxicity. 

Conclusion: The one-day three-agent (cisplatin, etoposide, paclitaxel) treatment of 

small-cell lung cancer is beneficial with respect to response rate and survival, and has 

low and well-tolerated toxicity. 


1525P THIRD-LINE CHEMOTHERAPY IN SMALL CELL LUNG 

CANCER: AN INTERNATIONAL ANALYSIS 

D. Simos 1 , G. Sajjady 2 , M. Sergi 3 , M.S. Liew 4 , R. Califano 5 ,C.Ho 2 , N.B. Leighl 3 , 

S. White 4 , Y. Summers 5 , P. Wheatley-Price 1 

1 Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, CANADA, 

2 Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, CANADA, 

3 Medical Oncology, Princess Margaret Hospital, Toronto, ON, CANADA, 4 Austin 

Health, Joint Austin-Ludwig Oncology Unit, Victoria, AUSTRALIA, 5 Medical 

Oncology, The Christie NHS Foundation Trust & University Hospital South 

Manchester NHS Foundation Trust, Manchester, UNITED KINGDOM 

Background: Small cell lung cancer (SCLC) is an aggressive disease and 

chemotherapy (CT) is the mainstay of treatment. Despite good response rates most 

patients (pts) will relapse and die of this disease. Standard 1st-line CT in limited 

(LD) and extensive stage disease is usually etoposide with platinum (P) or CAV 

(cyclophosphamide, doxorubicin, vincristine). At progression, 2nd-line CT may 

involve re-challenging with the 1st-line regimen. For pts who progress after 2 lines of 

CT, there is little evidence to guide treatment decisions, and the benefit of 3rd-line 

CT is unclear. 

Objective: To determine the clinical benefit of 3rd-line CT for SCLC. 

Study design: An international multi-centre retrospective analysis of pts who 

received 3 lines of CT for SCLC from 2001-2011 was performed. Baseline 

demographics, known prognostic factors and CT details were recorded. The main 

end-points were response rate (RR) and overall survival (OS) after 3rd-line CT. 

Results: A total of 124 eligible pts were identified; 59% male, median age 61, 89% 

ECOG 0-1, 40% LD. First-line P-based CT was given to 99% of pts, with a RR of 

90%. In the 2nd-line, 70 pts (56%) were re-challenged with similar CT, with the 


emaining receiving either CAV or topotecan based CT, with an RR of 50%. In the 

3rd-line, 35 pts (28%) were re-challenged with CT similar to a prior regimen. Only 

27 pts (22%) received 3 distinct lines of CT. Median progression free survival (PFS) 

in the 1st, 2nd and 3rd-lines were: 9.0, 4.6 and 2.0 months respectively. The RR in 

the 3rd-line was 17%, with no complete responses. Median 3rd-line OS was 4.8 

months. Factors associated with longer OS were: normal baseline serum LDH (p = 

0.02), response to 2nd-line CT (p = 0.04) and PFS >3 months after 2nd-line CT (p = 

0.05). Age, sex, initial disease stage, and CT re-challenges did not predict longer 

survival. After the 3rd-line, 35 pts received further CT. 

Conclusions: In 5 cancer centres, over 10 years, few SCLC pts received 3 lines of CT. 

Most who received 3 lines had been re-challenged with a similar regimen at least 

once. OS and RR in the 3rd-line are modest. Lack of response to, or progression after 

2nd-line CT may predict particular lack of benefit in the 3rd-line. Prospective 

research in this area is needed. 


1526P HYPONATRAEMIA AS A MARKER OF INFERIOR OUTCOMES 

IN SMALL CELL LUNG CANCER (SCLC) 

N.J. Coleman 1 , J. Clince 2 , W.M. Grogan 2 , O.S. Breathnach 1 

1 Medical Oncology, Beaumont Hospital Cancer Centre, Dublin, IRELAND, 

2 Medical Oncology, Beaumont Hospital, Dublin, IRELAND 

Introduction: Small cell lung cancer (SCLC) represents approximately 15% of all 

lung cancer diagnoses and is reducing in incidence. Hyponatremia is a common and 

debilitating electrolyte disorder, frequently documented in SCLC. Its occurrence is 

typically attributed to paraneoplastic syndrome- induced syndrome of inappropriate 

antidiuretic hormone hypersecretion (SIADH). The influence of hyponatremia on 

the survival of patients with lung cancer remains poorly understood. Aim: The aim 

of this retrospective study is to investigate clinical features and the prognostic value 

of hyponatremia in an unselected Irish patient population with small cell lung cancer 

(SCLC) with limited disease (LD) and extensive disease (ED). 

Method: The data of patients diagnosed with SCLC in Beaumont hospital over a 

3-year period was analysed retrospectively. Patients were identified from analysis of 

all lung cancers biopsies via the pathology department databank. Data was collected 

from clinical notes on identified patients including clinical performance status, serum 

sodium values, disease stage, chemotherapy regimens and response, radiotherapy, 

palliative care input and survival. 

Results: 48 patients (22 male, 26 female) with a median age 64 yrs (range 41-87yrs), 

29.17%(n = 14) with limited stage were identified. The standard chemotherapy was 

carboplatin–etoposide. 7 patients received 2 nd line treatment with irinotecan. 16.6% 

patients did not receive chemotherapy (n = 8) due to poor performance status. 

Hyponatraemia (plasma sodium [P-Na]


treatment options. There are few data on how delivered treatment has changed 

during the past decade in routine clinical practice and how this has effected overall 

survival. 

Methods: We retrospectively analyzed all patients diagnosed with SCLC at our 

institution (lung cancer center certified by the German Cancer Society (DKG)) since 

2002. Analysis included lines of treatment delivered, progression free survival (PFS) 

at each therapy line, use of radiotherapy, overall survival (OS), and use of PET-CT. 

Results: Preliminary analysis included 102 patients, of which 41 % had limited 

disease (LD) and 59 % had extensive disease (ED). For all patients, platinum doublet 

with etoposide has remained standard first line therapy. For patients with LD, the 

use of simultaneous thoracic radiochemotherapy replaced sequential chemotherapy 

followed by thoracic radiotherapy. In order to achieve a smaller radiation field, 

simultaneous radiochemotherapy was usually preceded by 2 cycles of chemotherapy. 

For patients with extensive disease, the use of cisplatinum instead of carboplatin 

increased in good performance status patients due to improved antiemesis 

(apprepitant). As second line therapy, oral topotecan has largely replaced EpiCO 

(epirubicin, cyclophosphamide, vincristin). One patient with early recurrence of 

brain metastasis after radiotherapy and topotecan was treated successfully with oral 

temozolomide. Since August 2007, all ED patients responding to first line therapy 

received prophylactic cranial radiation. OS tended to increase throughout the study 

period (LD: from 14 to 17 months, ED: from 6.7 to 10.1 months). 

Conclusions: New treatment options were successfully implemented in routine 

clinical practice and resulted in improved survival. However, survival remains 

unsatisfactory emphasizing the need for early detection and development of 

additional treatment strategies. 


1530P EPIDERMAL GROWTH FACTOR RECEPTOR MUTATION IN 

SMALL CELL LUNG CANCER PATIENTS DETECTED BY 

MUTANT-ENRICHED LIQUIDCHIP TECHNOLOGY FROM 

PLASMA 

H. Lu 1 , W. Mao 2 , Q. Cheng 3 , J. Cai 1 , X. Wang 1 , Y. Zhang 4 , C. Lou 1 , J. Qin 1 , 

L. Lei 1 , H. Yang 5 

1 Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, CHINA, 

2 Department of Thoracic Surgery, Key Laboratory Diagnosis and Treatment 

Technology on Thoracic Oncology (Zhejiang Province, China), Zhejiang Cancer 

Hospital, Hangzhou, CHINA, 3 Department of Traditional Medicine, Zhejiang 

Institute for Food and Drug Control, Hangzhou, CHINA, 4 Oncology, Zhejiang 

Cancer Hospital, Hangzhou, CHINA, 5 Department of Research, SurExam 

Bio-Tech Co. Ltd., Guangzhou, CHINA 

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been 

widely used in non-small cell lung cancer (NSCLC), and the incidence of EGFR 

mutation in NSCLC is higher in China than in the United States and European 

countries. Mutations of EGFR exons 19 and 21 in NSCLC is related to response of 

tumors to EGFR TKIs, suggesting their usefulness as biomarkers. Some case studies 

reported a gefitinib-responsive small cell lung cancer (SCLC) with EGFR mutation. 

However, there are few large studies which reported the mutation status of SCLC 

patients. It is difficult to obtain tumor tissues to detect EGFR mutations in SCLC 

patients especially from surgery. The aim of this study was to determine the EGFR 

mutation status in SCLC patients in China, and evaluate the feasibility of EGFR 

mutation detection from plasma by mutant-enriched liquidchip (MEL) technology. 

From September 2011 to March 2012, plasma from 35 cases of SCLC were collected 

at the Zhejiang Cancer Hospital, Hangzhou, China. There were 7 female, 28 male; 

age from 46 to 74 years old and median age of 60 years old. The stage (Veterans 

Administration Lung Study Group, VALSG): limited disease (LD) 8 cases, extensive 

disease (ED) 27 cases. Smoking history: non-smoker 10 cases, light smoker 0 cases, 

moderate smoker 3 cases and heavy smoker 22 cases. MEL technology was used to 

detect EGFR exon 19 and exon 21 mutations from plasma of 35 SCLC patients. One 

of 35 cases was found with mutation in exon 19 of the EGFR gene. The patient with 

EGFR exon 19 mutation was a female and non-smoker. EGFR mutation is rare in 

SCLC patients, and may more easily occur in females and non-smokers. It is feasible 

to detect EGFR mutation for SCLC from plasma by MEL technology. 


1531P NUCLEAR FACTOR-KAPPA B AS A MOLECULAR TARGET IN 

MALIGNANT PLEURAL MESOTHELIOMA 

K.A. Gately 1 , E. Jennions 2 , P. Godwin 3 , M. Barr 3 , S. Heavey 3 , K. Umezawa 4 , 

J. Edwards 5 , S.G. Gray 3 , K.J. O’Byrne 6 

1 Clinical Medicine, St James’s Hospital, Dublin, IRELAND, 2 Oncology, University 

of Leicester, Leicester, UNITED KINGDOM, 3 Clinical Medicine, Trinity College 

Dublin, Dublin, IRELAND, 4 Oncology, Keio University, Yokohama, JAPAN, 

5 Department of Cardiothoracic Surgery, Sheffield Thoracic Institute, Sheffield, 

UNITED KINGDOM, 6 Hope Directorate, St James’s Hospital, Dublin, IRELAND 

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer 

associated with exposure to asbestos. Currently rates of MPM are rising and 

estimates indicate that the incidence of MPM will peak within the next 10-15 years 

for the western world. Untreated, MPM has a median survival time of 6 months, and 

most patients die within 24 months of diagnosis. Nuclear Factor kappa B (NFkB) is a 

pro-inflammatory transcription factor often described as the master regulator of 

pro-inflammatory responses within the cellular setting. We and others have shown 

that NFκB is linked to cisplatin resistance (abstract 2307). Several lines of evidence 

also link NFkB to the pathogenesis of MPM. 

Using IHC we examined the expression of NFkB in a cohort of MPM patients (n = 

200) and correlated expression with various clinicopathological variables. 

Cytoplasmic or membranous immunostaining was seen in the majority of tumour 

samples (96.5%), but nuclear localisation of NFkB was seen in only 11% cases. There 

was no significant correlation between the level of expression of NFkB and standard 

clinicopathological prognostic factors. Kaplan-Meier Survival analysis showed that 

nuclear NFkB expression correlated with reduced survival with (p = 0.05). NFkB was 

expressed in all MPM cell lines tested to a varying extent (n = 20), with no 

associations to histology. Although small-molecule inhibitors of NFkB have been 

proposed as single-agent therapies for cancers with aberrant NFkB activity, most 

classic NFkB inhibitors are poorly selective and result in off-target effects. 

Dehydroxymethyl-epoxyquinomicin (DHMEQ) is a novel NFkB inhibitor of low 

molecular weight designed from the structure of the antibiotic epoxyquinomicin 

C. When bound DHMEQ irreversibly inhibits NFkB and prevents its translocation to 

the nucleus. A series of MPM cell lines including a panel of isogenic parent/cisplatin 

resistant cell lines were treated with various concentrations of DHMEQ. The effects 

of DHMEQ on cellular viability were examined using various methodologies 

(including multi-parametric High Content Screening) and the results will be 

presented at the meeting. 


1532P HIGH EXPRESSION OF MACROPHAGE STIMULATING 

PROTEIN (MSP) CORRELATES WITH SURVIVAL BENEFIT IN 

MALIGNANT PLEURAL MESOTHELIOMA 

D. Easty 1 , A. Baird 1 , K.J. O’Byrne 2 , A. Soltermann 3 , D. Nonaka 4 , D. Fennell 5 , 

L. Mutti 6 , H.I. Pass 7 , I. Opitz 8 , S.G. Gray 9 

1 Clinical Medicine, Trinity College Dublin/St. James’s Hospital, Dublin, IRELAND, 

2 Hope Directorate, St James’s Hospital, Dublin, IRELAND, 3 Institut für Klinische 

Pathologie, Universitätsspital Zürich, Zurich, SWITZERLAND, 4 Pathology, The 

Christie NHS Foundation Trust, Manchester, UNITED KINGDOM, 5 Medicine, 

University of Leicester, Leicester, UNITED KINGDOM, 6 Dept. of Medicine, 

Vercelli Hospital, Vercelli, ITALY, 7 Thoracic Surgery, NYU Langone Medical 

Center, New York, UNITED STATES OF AMERICA, 8 Thoracic Surgery, University 

Hospital Zurich, Zurich, SWITZERLAND, 9 Clinical Medicine, Trinity College 

Dublin, Dublin, IRELAND 

Introduction: RON/MST1R is a member of the MET tyrosine kinase family and has 

a putative role in several cancers. Macrophage stimulating protein (MSP) is the only 

known ligand for RON/MST1R. The MSP-RON signalling pathway has been 

implicated in a variety of cellular functions such as macrophage activity and wound 

healing. We have previously identified MST1R/RON as frequently activated in MPM, 

and high positivity for RON staining was an independent predictor of favourable 

prognosis. 

Methods: A panel of mesothelioma cell lines were screened for the expression of 

MSP and RON at the mRNA and protein level. The proliferative response of Ju77, 

H226 and Met5A (non-malignant transformed human pleural mesothelial cells) to 

MSP treatment was determined. A phospho-kinase array was utilised to detect the 

downstream signalling pathways activated upon MSP stimulation. The effect of 

two MST1R/RON inhibitors (a) a pre-clinical monoclonal antibody (RON8, 

Imclone) and (b) a small molecule inhibitor on proliferation and migration was 

assessed. In addition, a series of MPM TMAs were stained for MSP and 

macrophage markers. 

Results: MSP and MST1R expression varied between the mesothelioma cell line 

panel at both the mRNA and protein level. Treatment with MSP reduced the 

proliferative capacity of the Met5A cell, with a modest effect on the Ju77 MPM line. 

However, MSP stimulation modified the expression of the SRC family of kinases. In 

terms of targeting MST1R/RON, the small molecule inhibitor resulted in a 

significant decrease in proliferation and migration. Although treatment with RON8 

had no effect on proliferation, it did affect the migration capacity of the MPM cells. 

High expression of MST1R/RON or MSP correlated with better survival by 

univariate analysis. In multivariate analysis, MSP was identified as an independent 

prognosticator for survival in MPM. We observed no correlation with macrophage 

(CD 68) staining and survival. 

Conclusion: RON /MST1R comprises of a number of isoforms, the most common of 

which are flRON (full length) and sf (short form). Our results indicate that although 

high levels of RON and MSP correlate with increased survival, in vitro observations 

would indicate that this may be isoform dependant. Experiments are ongoing to 

further elucidate the RON-MSP axis in MPM, including in vivo studies. 



1533P EXPRESSION OF WILM⍰TUMOUR GENE (WT1) IS 

ASSOCIATED WITH SURVIVAL IN MALIGNANT PLEURAL 

MESOTHELIOMA: RETROSPECTIVE ANALYSIS IN A SINGLE 

CENTER SERIES 

S. Cedres 1 , D. Torrejon Castro 2 , N. Stjepanovic 2 , P. Martinez 2 , A. Martinez 2 , 

M. Salcedo 2 , M.A. Montero 2 , E. Felip 2 

1 Medical Oncology, Vall d`Hebron University Hospital Institut d’Oncologia, 

Barcelona, SPAIN, 2 Medical Oncology, Vall d´ Hebron University Hospital, 


Background: Calretinin and Wilmśtumour gene (WT1) are mesothelial markers 

used to confirm the diagnosis of malignant pleural mesothelioma (MPM). Recently, 

calretinin score assessed by immunohistochemistry (IHC) was implicated with poor 

prognosis in MPM. We investigated the prognostic value of calretinin and WT1 

expression in predicting survival in a series of patients (p) diagnosed of MPM in our 

institution 

Methods: Fifty two patients diagnosed of MPM in Vall d ´ Hebron University Hospital 

were retrospectively reviewed. Potential prognostic factors analyzed were age, 

performance status (PS), neutrophil to lymphocyte ratio (NLR), clinical stage, histology, 

calretinin and WT1 expression. Survival data were calculated by Kaplan-Meier. 

Results: Patient’s characteristics: median age 68 years (31-88 years), males 75.5%, PS 

1: 67.3%, asbestos exposure 53.1%, clinical stage III: 55.1%, epithelial subtype 71.4% 

and NLR > 5 in 44.9% of all patients. Calretinin and WT1 IHC expression were 

available in 47 p and 32 p, and were positive in 41 p (83.7%) and 25 p (78.1%) 

respectively. All patients were considered initially unresectable and 71.4% received 

CT. We found a significant association of calretinin and WT1 expression with 

epithelial histology (p= 0.030 and p = 0.010). The median survival (OS) was 15.2 

months. We found a significant increase in OS in patients with epithelial subtype 

(23.4 vs 5.0 months in epithelial vs no-epithelial, p < 0.001), PS1 (14.7 vs 2.2 m in PS 

1 vs PS 2, p = 0.036) and NLR ≤5 (26.5 vs 13.4 m, p = 0.025). In the IHC markers 

analysis we found a significant increase in OS for p with WT1 positive expression 

(16.4 vs 2.3 m, p= 0.013), but not differences for calretinin expression (16.6 m vs 5.0 

months, p = 0.37). In the multivariate analysis epithelial histology and WT1remained 

as significant prognostic factors for survival (HR 22.8; 95%CI,2.7-190, p = 0.004 and 

HR 9.5; 95%CI 1.7-52.3, p = 0.010 respectively). 

Conclusion: In our series of 52 MPM patients, epithelial histology, PS, NLR and 

WT1 expression are significant prognostic factors for survival. The prognostic role of 

WT1 is worth of prospective validation in future studies on MPM. 


1534P EFFICACY AND TOXICITY OBSERVED IN MALIGNANT 

PLEURAL MESOTHELIOMA PATIENTS TREATED IN PHASE I 

TRIALS AT A SINGLE INSTITUTION 

J. Raphael 1 , A. Hollebecque 2 , G. Le Teuff 3 , C. Massard 2 , R. Bahleda 2 , 

J. Margery 4 , B. Besse 1 , J. Soria 1 , D. Planchard 1 

1 Thoracic Group, INSERM U981, Institut Gustave Roussy, Villejuif, FRANCE, 

2 Medical Oncology Department, Institut Gustave Roussy, Villejuif, FRANCE, 

3 Department of Statistics and Epidemiology, Institut Gustave Roussy, Villejuif, 

FRANCE, 4 Pulmonary Department, Percy Hospital, Paris, FRANCE 

Background: Malignant Pleural Mesothelioma (MPM) is a locally aggressive disease 

with a poor prognosis. After failure of first line platinum-based chemotherapy, there 

is no widely approved salvage regimen. New strategies for treatment are needed and 

phase I trials appear as a rationale alternative. The results of such an approach have 

been evaluated. 

Materials and methods: MPM patients, were enrolled in 20 different phase I trials 

between March 2005 and January 2012, and their data analysed retrospectively. The 

primary endpoint was response rate and secondary endpoints were toxicity profile, 

Overall Survival (OS) and Progression Free Survival (PFS). Median follow-up of 

patients was estimated through Schemper’s method. The cut-off date for the analysis 

was April 2012. Adverse events were assessed by NCI-CTC v.3.0 and response rate 

according to RECIST 1.1 criteria. 

Results: Forty-six patients with a confirmed histology of MPM were included in the 

analysis with a median follow up of 20 months. The median age and the sex ratio 

(M/F) were 61 years old and 2.29 respectively. Radiological disease progression was 

observed in 50% of pts, clinical progression in 28%, and dose limiting toxicity in 

22%. The best tumour response was as follows: 7% of pts had a RECIST partial 

response, 59% had stable disease for a median duration of 2.8 months and 24% had 

progressive disease. The median treatment duration in the phase I was 1.9 months. 

Median OS and PFS were 6 months (95% CI= [4.3-10.7]) and 2.1 months (95% CI= 

[1.3-2.8]), respectively. The most common grade 3/4 adverse events (41%) were 

haematological (11%), gastro-intestinal (4%), cutaneous (7%), renal (4%) and hepatic 

(4%). All adverse events were reversible and no death due to toxicity was reported. 

Conclusion: Including MPM pts in phase I trials beyond first line of treatment can 

result in clinical benefits with an acceptable toxicity profile. Several molecular 

pathways involved in MPM have been identified and further novel biologic therapies 

might be tested in a phase I setting in a biology-oriented approach rather than a 


stochastical one. We are currently offering a tumour molecular profiling in our pts 

(MOSCATO trial) for a better selection of phase I trial. 


1535P MULTIMODALITY THERAPY IN MESOTHELIOMA: AN 

EPIDEMIOLOGICAL AND EFFECTIVENESS ANALYSIS 

M.A. Damiano 1 , A.K. Patané 2 , M. Chacon 1 , R. Chacon 1 , V. Vilchez 1 , A. Rosales 2 , 

A. Falco 1 , C. Poleri 3 , M. Rosenberg 2 , C. Martin 1 

1 Clinical Oncology, Instituto Alexander Fleming, Buenos Aires, ARGENTINA, 

2 Surgical Oncology, Instituto Alexander Fleming, Buenos Aires, ARGENTINA, 

3 Patology, Hospital Ferrer, Buenos Aires, ARGENTINA 

Introduction: Malignant pleural mesothelioma (MPM) is a rare and aggressive 

disease arising from the pleural mesothelium, with a reported survival (OS) of less 

than 12 months. However, patients with early-stage disease and good-performance 

status are suitable for multimodality ther¬apy (MT) involving surgery, radiotherapy 

(PORT), and chemotherapy. 

Objective: Epidemiological description and analysis of effectiveness in patients with 

MPM who performed MT. Methods Retrospective study of patients treated by 

multimodality therapy between April 1990 and April 2011 in three institutions from 

Argentina. 

Results: Of 110 patients, 24 (22%) went to MT. Median (Md) follow-up of 21 

months (2-139). Of 21 patients with complete data, 90.5% were epithelioid. 67% 

male, Md age 54, 95% PS 0, 43% smokers, mean of 7.6 packs/year, 29% had contact 

with asbestos. 60% presented with chest pain or pleural effusion, 3 month (R: 0-38) 

Md time to diagnosis. 60% in the right pleura. Treatment: 90.5% extrapleural 

pneumonectomy, 9.5% pleurectomy/decortications, by single surgical team 92%. 

Perioperative mortality 8%, morbidity 63%, 32% bleeding complications (32%). 52% 

T3N0M0 postoperative staging. 15 performed neoadjuvant, 3 adjuvant chemotherapy 

and 10 PORT. 67% received pemetrexed associated with platinum. 57% relapse after 

MT, 80% locoregional, 80% performed chemotherapy. Md disease free survival (DFS) 

20.7 months (95% CI 8-46). OS 34.3 months (95% CI 17-43). 

Conclusions: Epidemiological and efficiency data obtained are similar to reported 

series. The present work shows that MT achieves higher DFS and OS than those 

obtained with other treatments that do not include surgery. 


1536P MULTICENTER INSTITUTIONAL EXPERIENCE OF 

SURGICALLY RESECTED THYMIC EPITHELIAL TUMORS 

(TETS): AN OBSERVATIONAL REPORT ON BEHALF OF F.O.N. 

I.C.A.P. (FORZA OPERATIVA NAZIONALE 

INTERDISCIPLINARE CONTRO IL CANCRO DEL POLMONE) 

G. Genestreti 1 , M.A. Burgio 1 , L. Ampollini 2 , S. Sanna 3 , M. Monti 1 , A. Santo 4 , 

M. Mezzetti 5 , G. Gavelli 6 , A. Verlicchi 7 , R. Buosi 8 

1 Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura 

dei Tumori (I.R.S.T.), Meldola, Meldola (FC), ITALY, 2 Department of Thoracic 

Surgery, University Hospital, Parma, Italy, Parma, ITALY, 3 Department of Thoracic 

Surgery, Morgagni-Pierantoni Hospital, Forlì, Italy, Forlì, ITALY, 4 Department of 

Medical Oncology, University Hospital, Verona, Italy, Verona, ITALY, 5 Department 

of Thoracic Surgery, San Carlo Clinic, Milan, Italy, Milan, ITALY, 6 Department of 

Radiology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei 

Tumori (IRST), Meldola (FC), ITALY, 7 Dipartimento Di Oncologia/ematologia, 

Ospedale Civile di Ravenna - S.ta Maria delle Croci, Ravenna, ITALY, 

8 Department of Clinical Oncology, Civil Hospital, Novara, Italy, Novara, ITALY 

Purpose: thymic epithelial tumors (TETs) are a rare neoplasms. Due to their rarity, 

large-scale prospective trials are lacking. The present retrospective multicenter 

analysis aimed to evaluate clinical outcome and clinical-pathological features of TETs 

after complete surgical resection and adjuvant treatments (Adj) such as 

chemotherapy (CHT) or radiotherapy (RT). 

Patients and methods: Patients who underwent a complete surgical resections for 

TETs between 2000 and 2007 were reviewed. WHO histological classification criteria 

and Masaoka staging system were used. Adj were: anthracycline- and platin-based 

CHT, RT on irradiation fields covering the primary tumor bed. Overall survival (OS) 

was calculated from the date of diagnosis until patient death or last follow-up visit. 

Disease free-survival (DFS) was defined as the interval between surgery and date of 

first documentation of recurrence. OS, DFS and 95% Confidence Interval (95% CI) 

were estimated by Kaplan-Meier method. 

Results: 62 patients were analyzed: 30 patients (48%) male and 32 (52%) female. 

Median age was 60 years (range: 33 - 86). At the beginning of their cancer history 20 

(32%) patients had myasthenia. Clinical staging showed: 31 (50%) stage I disease, 19 

(30%) stage II, 5 (8%) stage III, 2 (4%) stage IVa, 5 (8%) stage IVb. Histologies were: 

11 (19%) A tumor type, 18 (29%) AB type, 7 (12%) B1 type, 11 (17%) B2 type, 11 

(17%) B3 type and 3 (6%) C type. Pathological staging were: 30 (48%) stage I, 22 

(35%) stage II, 3 (6%) stage III, 2 (3%) stage IVa, 5 (8%) stage IVb. 3 (5%) patients 



received Adj-CHT and 16 (26%) Adj-RT. Median follow-up was 71 months (range 

1-145), DFS and OS are the following: 

% DFS (95% CI) % OS (95% CI) 

Events 48 mo 60 o0 72 mo Events 48 mo 60 mo 72 mo 

9 89 (80-97) 89 (80-97) 86 (76-96) 7 97 (92-100) 95 (88-100) 92 (85-100) 

mo, months. 

Conclusions: TETs are rare and indolent tumors. Surgery offers good results which 

can be further improved by Adj such as CHT and/or RT. Supported by GIPO. 


1537P PROGNOSTIC FACTOR FOR SURVIVAL IN PATIENTS WITH 

ADVANCED THYMIC CARCINOMA 

Y. Okuma 1 , Y. Hosomi 1 , Y. Nakahara 1 , M. Yomoda 1 , Y. Takagi 2 , M. Iguchi 1 , 

M. Shibuya 1 , T. Okamura 1 

1 Department of Thoracic Oncology and Respiratory Medicine, Tokyo 

Metropolitan Cancer and Infectious Diseases, Tokyo, JAPAN, 2 Department of 

Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and 

Infectious Diseases Center Komagome Hospital, Tokyo, JAPAN 

Background: Thymic carcinoma is a rare cancer that represents an incidence of 0.15 

per 100,000 persons per year. Thus, clinical characteristics and prognostic factors 

have not been investigated in detail. In this study, we tried to elucidate the disease 

profiles, outcomes, and prognostic factors for survival among patients with advanced 

thymic carcinoma treated with palliative-intent chemotherapy. 

Patients and methods: This study was a retrospective review of medical records of 

38 patients treated with palliative-intent chemotherapy for advanced thymic 

carcinoma between 1991 and 2011. Clinical demographics, histology, overall survival, 

and factors expected to predict survival were analyzed. Differences in survival were 

assessed using Kaplan-Meier analysis and uni- and multivariate Cox proportional 

hazards regression analyses. 

Results: The study included 20 males (52.6%) and 18 females (47.4%). The median 

age at diagnosis was 59.5 years. The most common metastatic sites at diagnosis were 

lung (44.7%), liver (15.8%), lymph nodes (15.8%), bone (13.2%), and brain (5.7%). 

The most common histological subtypes were squamous cell carcinoma (73.7%), 

followed by neuroendocrine carcinoma (15.8%), and mucoepidermoid carcinoma 

(7.9%). The median survival time was 25.4 months. Overall survival rates at 1- and 

2-years were 73.6% and 52.6%, respectively. In univariate and multivariate analyses, 

the only favorable prognostic factor for overall survival was response to first-line 

chemotherapy (p = 0.009). 

Conclusion: Response to first-line chemotherapy may be a prognostic factor for 

overall survival in patients with advanced thymic carcinoma. 


1538P ACUTE EXACERBATION OF PRE-EXISTING INTERSTITIAL 

LUNG DISEASE (ILD) IN PATIENTS (PTS) WITH LUNG 

CANCER UNDER VARIOUS TREATMENTS 

H. Asahina1 , S. Oizumi1 , Y. Fujita2 , K. Takamura3 , T. Kojima4 , T. Harada5 , 

Y. Kawai6 , H. Dosaka-Akita7 , H. Isobe4 , M. Nishimura1 1 

First Department of Medicine, Hokkaido University School of Medicine, 

Sapporo, JAPAN, 2 Department of Respiratory Medicine, National Hospital 

Organization Asahikawa Medical Center, Asahikawa, JAPAN, 3 First Department 

of Medicine, Hokkaido P.W.F.A.C Obihiro-Kosei General Hospital, Obihiro, 

JAPAN, 4 Department of Medical Oncology and Respiratory Medicine, KKR 

Sapporo Medical Center, Sapporo, JAPAN, 5 Center for Respiratory 

Disease, Hokkaido Social Insurance Hospital, Sapporo, JAPAN, 

6 

Department of Respiratory Medicine, Oji General Hospital, Tomakomai, JAPAN, 

7 

Department of Medical Oncology, Hokkaido University School of Medicine, 

Sapporo, JAPAN 

Background: Acute deterioration of ILD for unknown causes, sometimes called as 

acute exacerbation (AE), can occur at any point in the course of ILD. However, little 

is known about its incidence and prognostic significance in lung cancer pts with 

pre-existing ILD, who receive various treatments; chemotherapy, surgery, palliative 

radiotherapy, and best supportive care (BSC). 

Methods: A total of 242 subjects (6.9% of all) were retrospectively identified to have 

pre-existing ILD by computed tomography (CT) from a sum of 3524 pts who had 

been hospitalized for lung cancer treatment at 8 institutions during 2004 to 2009. CT 

images of all the eligible pts were centrally reviewed. Univariate and multivariate 

analyses were performed using a Cox proportional hazard model to examine the 

potential role of any prognostic factors for overall survival (OS) from the initial lung 

cancer diagnosis. 

Results: Pts’ characteristics were: male/female = 217/25; median age (range) = 73 

(42-98) yrs.; smoking status: ever/never = 223/19; Performance Status: 0/1/2/3/4 = 74/ 

121/23/19/5; Stage I/II/III/IV = 48/10/98/86; Histology: adeno/squamous/large/NOS/ 

small = 90/75/6/19/52; CT pattern: usual interstitial pneumonia (UIP)/non-UIP = 

118/124; extent of normal lung on baseline CT: 10-50%/60-90% = 154/88; 

pre-existing emphysema: yes/no = 178/64. AE occurred in 71 of 242 pts (29%) 

overall; 56 of 147 pts (38%) with chemotherapy, 6 of 38 pts (16%) with surgery, 2 of 

17 pts (12%) with palliative radiotherapy, and 5 of 36 pts (14%) with BSC alone, and 

chemotherapy was an independent risk factor for the occurrence of AE (P < 0.001). 

When separated by histology, in NSCLC, multivariate analysis revealed that age (≥70 

yrs., hazard ratio [HR]: 1.84, 95%CI: 1.25-2.71, p = 0.002), PS (≥2, HR: 2.90, 95%CI: 

1.80-4.68, p < 0.001), stage (≥3, HR: 4.03, 95%CI: 2.42-6.71, p < 0.001), and AE (HR: 

1.84, 95%CI: 1.26-2.69, p = 0.002) were significantly associated with OS, while in 

SCLC, AE was the only significant prognostic factor (HR: 2.26, 95%CI: 1.08-4.73, p = 

0.032). 

Conclusions: The occurrence of AE is not rare in the lung cancer treatment, 

particularly during chemotherapy, and it is a factor for poor prognosis in pts with 

pre-existing ILD. 


1539P PRIMARY MEDIASTINAL GERM CELL TUMOUR IN 

PAKISTANI POPULATION; A SINGLE CENTER EXPERIENCE 

K. Das, S. Imtiaz, S. Kumar, I.A. Muazzam, N. Siddiqui, S.A. Kazmi, 

N. MuzzafarMedical Oncology, Shaukat Khanum Memorial Cancer Hospital and 

Research Center, Lahore, PAKISTAN 

Introduction: Primary mediastinal germ cell tumor (PMGCT) constitutes a rare 

malignancy and is a diagnostic challenge because of the difficult approach and often 

small size of the biopsy specimen. These tumours have a worse prognosis than their 

gonadal counterparts. This study was performed to review clinical characteristics, 

therapeutic strategies and outcome of patients with PMGCT at Shaukat Khanum 

Memorial Cancer Hospital and Research Center Lahore Pakistan. 

Patient and method: Medical records of patients treated in our hospital during 1996 

to 2012 were retrospectively studied. 

Results: Of 25 patients, 23 were males with a median age of 23 years (range 16–48). 

Forty percent were seminoma and 60% were nonseminoma. More than 80% of 

nonseminoma had raised baseline alpha feto protein. The clinical presentation in 

order of frequency included; dyspnea (72%), cough (68%), chest pain (56%), pleural/ 

pericardial effusion (44%), weight loss (32%), fever (28%), superior vena-caval 

obstruction (24%), cervical node metastasis (20%) and pulmonary metastasis (12%). 

All were treated with initial standard platinum based chemotherapy. Eighty percent 

of our patients achieved biochemical complete response and 80% achieved 

radiological response (67% Partial response, 13% complete response). Median 

survival of patients with seminoma was 37 months with three year survival rate of 

60%. Median survival of patients with nonseminoma was 13 months with three year 

survival rate of 31%. During study period eleven patients died (seven had disease 

progression, 02 had bleomycin lung toxicity and two had neutropenic sepsis). 

Conclusion: Nonseminoma constitutes the majority of primary mediastinal germ cell 

tumors, with prominent male preponderance. Seminomas had a better outcome than 

nonseminomas. Cisplatin based chemotherapy continues to be an effective treatment 

for these tumours. 


1540 COMPARISON OF SECOND LINE TREATMENT OUTCOMES 

BETWEEN SENSITIVE AND REFRACTORY SMALL CELL LUNG 

CANCER PATIENTS: A RETROSPECTIVE ANALYSIS 

T. Korkmaz 1 , S. Seber 2 , E. Sari 2 , M. Canhoroz 3 , B. Oven Ustaalioglu 1 , U. Kefeli 1 , 

O. Balvan 1 , M. Gumus 4 , N. Yasar 1 , S.N. Turhal 5 

1 Medical Oncology Department, Dr Lutfi Kirdar Kartal Research and Educational 

Hospital, Istanbul, TURKEY, 2 Medical Oncology Department, Marmara University 

Hospital, Istanbul, TURKEY, 3 Medical Oncology Department, Uludag University 

Hospital, Bursa, TURKEY, 4 Dept. Medical Oncology, Kartal Research and 

Training Hospital Division of Medical Oncology, Istanbul, TURKEY, 5 Medical 

Oncology, Marmara University Hospital, Istanbul, TURKEY 

Introduction: Small cell lung cancer (SCLC) has a high relaps rate despite being very 

chemosensitive. The prognosis of these patients is generally poor. The efficasy of 

second line treatment is dismal when compared to other chemosensitive tumors such 

as germ cell tumor or lymphoma. Our aim was to evaluate the outcome of second 

line treatment and to delineate the prognostic factors that would effect the survival 

times and response rates. 

Methods: Results we retrospectively assesed 120 SCLC patients who who failed 

firstline platinum-etoposide chemotherapy and went on to receive second line 

chemotherapy at 3 medical oncology centers. 

Results: Median age of the study group was 58 (33-78) and %80 percent of our 

patients were below 65 years old. %84 patient were male, %82 had an ECOG PS of 

0-1. %61 were at extensive stage at the time of diagnosis. Patients who progressed 


more than 3 months after first line therapy were labelled as platin sensitive (%64). 

The patients who received platin based combination based treatment was % 27. 

Median PFS and OS starting from the initiation of second line treatment were 4 and 

7 months respectively. Multivariate analysis identified PS (P= 0.006), extent od 

disease at inital stage(0.014) and platin sensitivity (0.001) as the independent 

prognostic factors for survival. Subgroup analyses of the platin sensitive patients 

indicated platin re challenge yields higher PFS, OS and RR . There was no difference 

was found between irinotecan and topotecan in the refractory patient group in terms 

of treatment outcomes. 

Conclusion: Patients with good PS, who are platin sensitive or initially staged as 

limited disease derive the most benefit from second line chemotherapy in the setting 

of relapsed SCLC. Platin combination therapy should be the treatment of choice in 

the platin sensitive patients. 


1541 EXPRESSION OF C-KIT (CD 117) IN EPITHELIAL THYMIC 

MALIGNANCIES 

M. Wollner 1 , E. Flechter 1 , O. Vaisman 2 , O. Ben Itzhak 2 

1 Department of Oncology, Rambam Health Care Center, Haifa, ISRAEL, 

2 Department of Pathology, Rambam Health Care Center, Haifa, ISRAEL 

Study objectives: The expression of c-kit (CD117) was investigated to evaluate its 

usefulness as a marker supporting differential diagnosis and choice of therapy. In 

thymic epithelial tumors the expression of c-kit may explain a new model of tumor 

biology, and support the use of determinate target therapy as a new optional 

approach. 

Methods: We examined the immunohistochemical expression of c-kit in 28 cases of 

thymic epithelial tumors diagnosed in our department between 2003-2010, that had 

been classified on the basis of the World Health Organization histologic classification 

system: 24 thymoma and 4 thymic carcinoma (1 type A, 4 type AB, 1 type B1, 12 

type B2, 6 type B3 and 4 type C). 

Results: c-kit expression showed immunoreactivity positive in 18% of the all cases (5 

patients). In this subgroup, 1 type B2, 1 type B3 and 3 type C. In contrast no 

immunoreactivity was found in the thymoma cases (types A, AB and B1). No 

differences were found in the c-kit expressing group between the genders (12 females, 

16 males). All c-kit expressing cases were older than 61 years old. 

Conclusion: Expression of c-kit is an immunohistochemical marker for the diagnosis 

of thymic carcinoma, and represent a new model of tumor biology with potential 

development of new targeted therapies as an option for the treatment of thymic 

carcinoma on the basis of the kit pathways. Clinical trials are necessary to 

demonstrate the efficacy of these new theoretical strategies. 


1542TiP VINORELBINE IN MESOTHELIOMA (VIM): A RANDOMISED 

PHASE II TRIAL OF ORAL VINORELBINE AS SECOND-LINE 

THERAPY FOR PATIENTS WITH MALIGNANT PLEURAL 

MESOTHELIOMA (MPM) EXPRESSING BRCA1 – A STUDY 

IN PROGRESS 

D.A. Fennell 1 , A. Casbard 2 , L. Nixon 2 , J. Lester 3 , G. Griffiths 2 

1 Department of Thoracic Medical Oncology, University of Leicester & Leicester 

University Hospitals, Leicester, UNITED KINGDOM, 2 Wales Cancer Clinical Trials 

Unit, School of Medicine, Cardiff University, Cardiff, UNITED KINGDOM, 3 Cancer 

Centre, Velindre Hospital, Cardiff, UNITED KINGDOM 

Background: Mesothelioma is increasing worldwide. However there is no approved 

therapy in the second-line setting. Vinorelbine exhibits promising activity, however 

there has been no randomised evaluation or validation of biomarkers to support 

patient stratification. We have recently reported that BRCA-1 is an essential regulator 

of mesothelioma sensitivity to vinorelbine, and its expression is lost in approximately 

38% 1 . The Cancer Research UK VIM trial is to be sponsored by the University of 

Leicester in collaboration with the Wales Cancer Clinical Trials Unit. 

Aims: To evaluate the efficacy of second-line vinorelbine plus active symptom 

control (ASC), versus ASC. Secondary endpoints: tolerability, response rate, change 

in tumour volume and overall survival. BRCA1 expression IHC will be evaluated as a 

stratification factor. 


Methods: An open label, randomised trial of weekly vinorelbine 80mg/m 2 plus 

ASC versus ASC alone. The control arm of ASC will be defined by local practice. 

Both study arms will be continued until documented evidence of radiological 

progression or unacceptable toxicity. The sample size has been calculated using 

the parameters; α = 0.2, β = 0.1 (90% power), hazard ratio 0.65, 1-sided logrank 

test and 2:1 randomisation favouring vinorelbine. This requires recruitment of 114 

patients. However, as we hypothesis that BRCA-1 expression is required for 

vinorelbine activity and have estimated its absence in one third of patients, the 

sample size may be inflated to 171 patients depending on the results of an 

interim analysis. We aim to open the study in Q1 2013 and recruit over 18 

months. The results of this study will be used to inform the design of a future 

phase III study, with stratification of patients to optimise efficacy. BRCA1 is an 

essential mediator of vinorelbine-induced apoptosis in mesothelioma. Busacca S 

et al J Pathol. 2012 Jun; 227(2):200-8 


1543TiP PHASE I/II STUDY TO ASSESS THE SAFETY, 

PHARMACOKINETICS (PK) AND EFFICACY OF 

LORVOTUZUMAB MERTANSINE (LM, IMGN901) IN 

COMBINATION WITH CARBOPLATIN/ETOPOSIDE IN 

PATIENTS WITH SOLID TUMORS INCLUDING SMALL-CELL 

LUNG CANCER (SCLC) 

D.R. Spigel 1 , J. Bendell 1 , A.C. Mita 2 , A. Argiris 2 , C. Kurkjian 3 , C.L. Hann 4 , 

Z. Segota 5 , R. Guild 6 , R. Mastico 6 , M.E. Guiterrez 5 

1 Gi Oncology Research/drug Development Unit, Sarah Cannon Research 

Institute, Nashville, TN, UNITED STATES OF AMERICA, 2 Oncology, University of 

Texas Health Sciences Center, San Antonio, TX, UNITED STATES OF AMERICA, 

3 Cancer Center, The Univesity of Oklahoma Cancer Inst., Oklahoma City, OK, 

UNITED STATES OF AMERICA, 4 Cancer Center, Johns Hopkins Sidney Kimmel 

Comprehensive Cancer Center, Baltimore, MD, UNITED STATES OF AMERICA, 

5 Cancer Center, Holy Cross Hospital, Fort Lauderdale, FL, UNITED STATES OF 

AMERICA, 6 Pharmacokinetics Lab, ImmunoGen, Inc., Waltham, MA, UNITED 


Purpose: SCLC expresses CD56 almost universally. LM is a CD56-targeting 

antibody-drug conjugate. This study was initiated to evaluate LM for the treatment 

of SCLC when used in combination with carboplatin (C) and etoposide (E). Its phase 

1 portion was designed to establish the recommended phase 2 dose (RP2D) of LM 

with C and E. PK data with the combination also was obtained. 

Methods: Patients (pts) with advanced solid tumors were accrued to a standard 3 + 3 

dose-escalation study design. Successive cohorts received escalating doses of LM IV 

on days 1 and 8 in combination with C IV on day 1 and E IV on days 1-3 every 21 

days. LM PK was measured by an ELISA-based method. C and E levels were 

measured using optimized LC-MS/MS assays. PK parameters were determined by 

noncompartmental analysis. 

Results: 33 patients (13M, median age = 57.3) were treated in 5 cohorts (2 using C 

AUC6; 3 using C AUC5) at LM doses ranging from 60-112 mg/m 2 . The RP2D was 

defined as LM 112 mg/m 2 with C AUC5 and E 100 mg/m 2 . PK samples were 

analyzed for Cycle 1, first dose. At the RP2D, LM exposure and maximum 

concentration were similar to those observed in single-agent trials, with the t1/2 of 

LM approaching 1 day (24.2 hours). PK findings for C/E were similar to published 

reports (Oguri, 1988; D’Incalci, 1982) with the observed AUC of C = 5.1 ± 0.7 

min*mg/mL and E = 6921 ± 1231 min*µg/mL. The most common treatment-related 

adverse events (AEs) were anemia, thrombocytopenia, nausea, peripheral neuropathy, 

decreased lymphocytes and neutrophils, and fatigue. The majority of related grade 3/ 

4 AEs were cytopenias which, while known to occur with C/E regimens, typically 

have not been associated with LM monotherapy. Among 13 pts with SCLC accrued 

to phase 1, 6 (46%; 4 previously treated) achieved PR after at least one response 

assessment. 

Conclusion: The combination is well tolerated with no apparent drug-drug 

interactions. Preliminary signs of activity have been observed in this predominantly 

pre-treated population. The randomized phase 2 portion of the study in chemo-naïve 

patients with SCLC has opened to accrual. Updated data will be presented. 

Disclosure: R. Guild: Employee of ImmunoGen, Inc.R. Mastico: Employee of 

ImmunoGen, Inc.All other authors have declared no conflicts of interest. 


supportive care 

1544O COMPARISON OF NUTRITIONAL ASSESSMENT WITH A NEW 

DEFINITION OF CACHEXIA IN DETERMINING OUTCOMES 

OF ADVANCED CANCER PATIENTS 

S. Clarke 1 ,C.Tan 2 , J. Read 3 , V. Phan 4 , J.K. Peat 5 and P. Beale 4 

1 Medical Oncology Department, Royal North Shore Hospital, Sydney, NSW, 

AUSTRALIA, 2 Nutrition and Dietetics Department, Concord Hospital, Sydney, 

NSW, AUSTRALIA, 3 Prince of Wales Hospital, Sydney, NSW, AUSTRALIA, 

4 Medical Oncology Department and Sydney Cancer Center, Concord Hospital, 

Sydney, NSW, AUSTRALIA, 5 Consultant Biostatistician, Concord Hospital, 

Sydney, NSW, AUSTRALIA 

Background: An international consensus statement providing a definition and 

diagnostic criteria for cancer cachexia was recently published. This study aimed to 

compare the relative prognostic utility of this definition with nutritional status as 

defined by the Patient-Generated Subjective Global Assessment (PG-SGA) tool. 

Methods: A prospective cohort study was conducted in a tertiary hospital where 

chemotherapy naive patients with life expectancy ≥3 months were recruited by 

medical oncologists and a research dietitian. Kaplan-Meier survival analyses were 

used to determine the median survival of patients with advanced cancer in the 

cohort study, and a subset of patients who met the criteria for cancer cachexia as 

defined in the international consensus (Fearon 2011). The log rank chi-square test 

was used to evaluate the strength of predictors of overall survival (OS). A P value of 

12, 1:]12-10], 2:]10-9], 3:]9-8], 4: < 8. Scores linear (mean) and 

non-linear (polynomial) were calculated using for F: grades from start to end 

CT and for anemia: mean grade per cycle. OS was calculated from CT initiation 

to death or censured at last contact. 

Results: 1279 pts entered the program, 662 (equivalent to 4327 CT cycles) had 

at least 1 assessment of (fatigue + Hb). Excluded pts (617) due to lacking Hb 

results did not differ from the 662 (log-Rank = 0.98). Median age = 64.9y, 

sex-ratio = 1.1, more frequent localization: lung (23%), breast (21%), prostate 

(13%), ovary (10%). 229 and 433 pts had respectively at least 1 or 2 Hb results 

at each cycle. There were 5376 episodes of fatigue in total (PSS > 0), 694 pts 

experienced at least 1 episode. 516, 232, 101 and 35 pts experienced at least 1 

anemia episode on scale 1, 2, 3 and 4 respectively. Median linear F score = 1.08 

[0-3], non-linear = 1.57 [0-200.7]. Median linear anemia score = 0.78 [0-1.5], 

non-linear = 0.78 [0-1.6]. OS was 24.8m IC95%|21.6-30.4]. Linear scores were 

normally distributed and non-linear were discarded since much skewed. As 

expected, anemia and fatigue were correlated (ANOVA, p < 0.0001). Linear F 

score (LFS) was good predictor of OS (L: HR = 2.5, IC95% [2.0-3.1], p < 0.0001). 

Patients with LFS > 2 (N = 72) had an increased death risk of 4.65 (IC95%| 

3.15-6.88]) with respect to LFS < 1 (N = 247). Hb mean and linear anemia score 

were good predictors for OS, respectively HR = 1.45 IC95% [1.31; 1.6] and HR = 

1.86 IC95% [1.57; 2.19]). 

Conclusion: A linear score of anemia and fatigue PSS were simple and efficient 

predictors of overall survival. They could be monitored to help clinicians in fatigue 

and anemia management. 

Disclosure: S. Oudard: honoraria: Sanofi, Roche, Bayer. All other authors have 


1547PD G-CSF AS SECONDARY PROPHYLAXIS OF 

CHEMOTHERAPY-INDUCED NEUTROPENIA IN PATIENTS 

WITH SOLID TUMORS: RESULTS OF A PROSPECTIVE, 

OBSERVATIONAL STUDY 

G. Freyer 1 , N. Jovenin 2 , G. Yazbek 2 , C.B. Villanueva 3 , A. Hussain 4 , A. Bethune 5 , 

M. Rotarski 6 , H. Simon 7 , V. Boulanger 8 and M. Hummerlsberger 9 

1 Medical Oncology, Centre Hospitalier Lyon Sud, Pierre- Bénite, FRANCE, 

2 Medical Oncology, Institut Jean Godinot, Reims, FRANCE, 3 Medical Oncology, 

Centre Hospitalier Universitaire, Besançon, FRANCE, 4 Medical Oncology, Centre 

Hospitalier Quimper, Quimper, FRANCE, 5 Medical Oncology, Centre René 

Huguenin, Saint Cloud, FRANCE, 6 Medical Oncology, Centre Oncologie du Pays 

Basque, Bayonne, FRANCE, 7 Oncologie Médicale, Hôpital Augustin Morvan, 

Brest, FRANCE, 8 Medical Oncology, Centre Hospitalier de Carcassonne, 

Carcassonne, FRANCE, 9 Medical Oncology, Centre de Radiothérapie et 

Oncologie Médicale, Béziers, FRANCE 

Background: There are little available data on secondary prophylaxis of 

chemo-induced neutropenia. We designed this multicentre, prospective and 

observational study to identify predictive factors of occurrence of neutropenic events 

(NE) subsequent to a previous episode, in patients with solid tumors (primary 

objective). Secondary objectives were to determine the incidence of NE, describe 

prophylactic strategy: cycle delay, dose reduction, G-CSF prescription, and its impact 

on the recurrence of NE. 

Patients and methods: Patients ≥ 18 years were included if they experienced a NE 

during any previous cycle (reference cycle A), with no prior G-CSF administration. 

Neutropenic events were defined as any neutropenia grade 1-4, febrile or not, that 

impacts on the subsequent cycles (cycle delay and/or dose reduction and/or use of 

G-CSF). Patients were followed for a total of 5 cycles. Risk factors of febrile 

neutropenia (FN), and prophylactic strategies (with or without G-CSF) were included 

in univariate and multivariate analyses to assess their predictive value on recurrence 

of NE. 

Results: 625 patients included, 548 (87.7%) evaluable.378 (69%) female, mean 

(SD) age (years) 61.7 (12.3), WHO PS 0-1 88.3%, breast: 40%, colorectal: 15.7%, 

lung: 11.9%. Metastatic disease: 53.3%. During cycle A, 88 patients (16.1%) 

experienced FN, 42 (7.7%) neutropenic fever and 418 (76.3%) neutropenia (any 

grade w/o fever). 44.5% had cycle delay, 22.3% dose reduction and 466 (85%) 

received prophylactic G-CSF (pegfilgrastim 59.7%, lenograstim 27.3%, filgrastim 

10.3% and biosimilar 2.1%). Incidence of NE in subsequent cycles and 

prophylactic strategies are shown in the table below. In multivariate analysis, 

G-CSF use (HR:0.32 (0.24; 0.43; p < 0.001) was an independent predictor of 



abstracts

lower recurrence rate of NE. Pegfilgrastim seemed to offer the highest protection 

(HR: 0.23 (0.16; 0.32; p < 0.001). 

Conclusion: Prophylactic strategy with G-CSF has significant efficacy in reducing the 

incidence of NE, and should be considered as the best option in the secondary 

prophyalxis setting. 

Cycle A 

(no G-CSF) 

N = 548 

Cycle B 

N = 548 

Cycle C 

N = 548 

CycleD 

N = 442 

Cycle E 

N = 344 

Febrile 

neutropenia 

88 (16.1%) 3 (0.5%) 4 (0.7%) 0 1 (0.3%) 

Neutropenic fever 42 (7.7%) 2 (0.4%) 4 (0.7%) 1 (0.2%) 0 

Neutropenia w/o 

fever 

418 (76.3%) 111 (20.3)% 95 (17.3%) 50 (11.3%) 47 (13.7%) 

Cycle delay - 244 (44.5%) 44 (8.0%) 23 (5.2%) 18 (5.2%) 

Dose reduction - 122 (22.3%) 27 (4.9%) 17 (3.8%) 12 (3.5%) 

use of 

Prophylactic 

G-CSF 

- 466 (85.0%) 413 (75.4%) 332 (75.0%) 247 (71.8%) 

Disclosure: G. Freyer: Consultant for Amgen. All other authors have declared no 


1548PD ABSOLUTE NEUTROPHIL COUNTS IN A STUDY OF 

LIPEGFILGRASTIM COMPARED WITH PEGFILGRASTIM IN 

PATIENTS WITH BREAST CANCER WHO ARE RECEIVING 

CHEMOTHERAPY 

O.A. Gladkov 1 , I.M. Bondarenko 2 , R. Elsaesser 3 , A. Buchner 4 and P. Bias 4 

1 Chemotherapy, Regional Oncology Center, Chelyabinsk, RUSSIAN 

FEDERATION, 2 Oncology, Dnipropetrovsk State Medical Academy, 

Dnipropetrovsk, UKRAINE, 3 Biostatistics, Teva Ratiopharm, Ulm, GERMANY, 

4 Clinical Research, Teva Ratiopharm, Ulm, GERMANY 

Background: Cancer chemotherapy frequently causes neutropenia, leading to an 

increased risk of infections and delays in subsequent chemotherapy treatments. In a 

randomized, double-blind, phase 3, active-controlled, noninferiority trial, the efficacy 

and safety of lipegfilgrastim, a glycosylated and pegylated recombinant granulocyte 

colony stimulating factor (G-CSF), was compared with pegfilgrastim, a pegylated 

recombinant G-CSF. Here we report the results of the absolute neutrophil counts 

(ANC) from this study. 

Methods: Patients with high-risk stage II, III, or IV breast cancer and an absolute 

neutrophil count ≥1.5x10 9 cells/L were randomly assigned to lipegfilgrastim 6 mg (n 

= 101) or pegfilgrastim 6 mg (n = 101). Study medication was injected 

subcutaneously on day 2 of the chemotherapy cycle (4 cycles maximum). The 

primary efficacy endpoint, the duration of severe neutropenia, was reported 

previously. Secondary endpoints included ANC nadir and time to ANC recovery and 

were analyzed using a Poisson regression. The intent-to-treat (ITT) analysis 

population included all randomized patients. 

Results: ANC nadir and time to ANC recovery for cycle 1 (ITT population) are 

summarized in the table. 

Measurement 

Lipegfilgrastim 

(n = 101) 

Pegfilgrastim 

(n = 101) 

LS Mean Difference 

(95% CI), p value 

Depth of ANC nadir 

(10 9 /L) 

Mean (SD) 1.2 (1.3) 1.0 (1.2) 0.146 (-0.169 to 0.461) 

Median (range) 0.6 (0.0 to 5.5) 0.4 (0.0 to 5.2) p = 0.3610 

Time to ANC 

recovery (days) 

Mean (SD) 5.8 (3.3) 7.4 (3.6) −1.570 (-2.547 to −0.592) 

Median (range) 7.0 (0.0 to 12.0) 8.0 (0.0 to 21.0) p = 0.0018 

Conclusions: Patients who received lipegfilgrastim had significantly faster time to 

ANC recovery than those who received pegfilgrastim. 

Disclosure: O.A. Gladkov: Investigator in Teva-sponsored studies, I.M. Bondarenko: 

Investigator in Teva-sponsored studiesR. Elsaesser: Employee of Teva 

Pharmaceuticals and own Teva Pharmaceuticals stock, A. Buchner: Employee of Teva 

Pharmaceuticals and own Teva Pharmaceuticals stock, P. Bias: Employee of Teva 

Pharmaceuticals and own Teva Pharmaceuticals stock. 


1549PD TREATING DIABETIC PATIENTS WITH CHEMOTHERAPY: 

SINGLE CENTRE EXPERIENCE OF TOXICITY AND 

OUTCOMES 

J.F. Seligmann1 , A. Young2 , G. Heath2 , D. Cairns3 , A. Anthoney2 , G. Hall2 , 

M. Seymour2 and D. Swinson2 1 

Medical Oncology, St. James Institute of Oncology, Leeds Teaching Hospitals 

NHS Trust, Leeds, UNITED KINGDOM, 2 Medical Oncology, The Leeds Teaching 

Hospital NHS Trust St. James University Hospital, Leeds, UNITED KINGDOM, 

3 

Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UNITED 

KINGDOM 

Background: Diabetes is a common comorbidity in cancer patients, and is associated 

with poorer survival in colorectal cancer (CRC). However, there is little data to 

describe the experience of diabetic patients during chemotherapy. We have compared 

a diabetic population of cancer patients with matched controls receiving 

chemotherapy in a single centre. 

Methods: We performed a retrospective case note analysis using an electronic patient 

record database (Patient Pathway Manager) and chemotherapy prescription software 

(ChemoCare) between 2001 and 2011. Diabetic patients starting first line 

chemotherapy for advanced CRC and advanced gynaecological cancers (GC) were 

identified. For each case a non-diabetic control was selected, matched for age (


pruritus recurrence, with a median interval of 7-weeks from first aprepitant 

administration. No potentially aprepitant-related toxic effects were registered. 

Conclusions: This single-center phase-II study showed a new therapeutic activity of 

aprepitant in treating biological therapy-induced pruritus, both after standard 

antipruritic-medication failure and as a first-line therapy. 


1551PD ROLE OF TEMPORARY OVARIAN SUPPRESSION OBTAINED 

WITH GNRH ANALOG IN REDUCING PREMATURE OVARIAN 

FAILURE (POF) INDUCED BY CHEMOTHERAPY IN 

PREMENOPAUSAL CANCER PATIENTS: A META-ANALYSIS 

OF RANDOMIZED STUDIES 

L. Del Mastro 1 , A. Levaggi 2 , F. Poggio 2 , S. Giraudi 2 , C. Bighin 2 ,A.D’Alonzo 2 , 

M. Lambertini 2 , P. Pronzato 2 and P. Bruzzi 3 

1 Ss Sviluppo Terapie Innovative, IRCCS AOU San Martino - IST-Istituto Nazionale 

per la Ricerca sul Cancro, Genova, ITALY, 2 Oncologia Medica A, IRCCS AOU 

San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genova, ITALY, 

3 Clinical Epidemiology, IST-San Martino, Genoa, ITALY 

Background: premenopausal cancer patients treated with chemotherapy (CT) are at 

risk of POF. The role of GnRHa in the prevention of CT-induced POF is still 

controversial. We performed a pooled analysis of randomized studies that evaluated 

the role of GnRHa as strategy to prevent POF. 

Methods: studies were retrieved by searching the PubMed database and the 

proceedings of major conferences. Odds ratios (OR) and 95% CIs for CT induced 

POF were extracted from each trial and averaged to obtain pooled estimates using an 

inverse-variance model. 

Results: we included in the meta-analysis 7 randomized trials involving 745 

premenopausal women randomly assigned to receive chemotherapy or 

chemotherapy + GnRHa: five trials were carried out in breast cancer patients and two 

trials in patients with lymphoma. The pooled OR estimate for CT induced POF was 

0.46 (95% CI, 0.3-0.72). 

Conclusion: temporary ovarian suppression obtained with the use of GnRH 

analogues reduces the incidence of chemotherapy induced POF in premenopausal 



1552P EVALUATION OF THE QUALITY OF LIFE AND ECONOMIC 

BURDEN WITH GRANULOCYTE-COLONY STIMULATING 

FACTOR IN CHINESE BREAST CANCER PATIENTS 

RECEIVING DOCETAXEL, EPIRUBICIN AND 

CYCLOPHOSPHAMIDE 

M. He 1 , S. Huang 1 ,L.Yu 1 , G. Shi 1 , J. Deng 1 , X. Zhang 1 , X. Wang 1 , J. Chen 1 , 

X. Nong 2 and P. Shen 1 

1 Medical Oncology, First Affiliated Hospital, Zhejiang University School of 

Medicine, Hangzhou, CHINA, 2 Department of Medical Oncology, 1st Affiliated 

Hospital of ZhejiangUniversity School of Medicine, Hangzhou, CHINA 

Background: Docetaxel, Epirubicin, cyclophosphamide (TEC) has been accepted as 

the standard care in the treatment of Chinese patients with breast cancer. However, 

little is known about the impact of primary prophylactic granulocyte-colony 

stimulating factor (G-CSF) on the quality of life(QOL) and economic burden in 

these patients. 

Patients and methods: This was a randomized control study to compare G-CSF as 

primary prophylactics or not while breast cancer patients receiving TEC 

chemotherapy. Primary prophylactic G-CSF (PPG) was: filgrastim 3mcg/kg/day on 

day 3-8 (n = 53 patients); G-CSF for treatment was: filgrastim 5mcg/kg/day on the 

occasion that grade 3-4 neutropenia, febrile neutropenia, and delayed recovery of 

absolute neutrophil count on day 21 till the neutrophil recovery (n = 54 patients). A 

total of 107 patients from single centre in China were included in the trial. 

Side-effects, costs and the scores of the EORTC QLQ-C30 questionnaires were 

compared in the two groups. 

Results: The addition of PPG to TEC significantly reduced the incidence of 

neutropenic fever (15.32% vs 6.94%, P = 0.0482), grade 3–4 neutropenia (52.3% vs 

12.2%, P < 0.001) and anaemia, asthenia, stomatitis, anorexia, myalgia and dysgeusia. 

Patient’s QOL decreased during chemotherapy, more in TEC without PPG than TEC 

with PPG, but returned to baseline afterwards. The addition of PPG significantly 

reduced the percentage of patients with clinically relevant Global Health Status 

deterioration at the end of treatment (60% versus 47%, P =0.0331). The average cost 

of each cycle was quite approaching in the two groups (CNY 16432.01 in TEC with 

PPG vs CNY 16059.24 in TEC without PPG, P > 0.05), but the cost of G-CSF was 

increased at the end of chemotherapy without PPG. 

Conclusions: The addition of PPG significantly reduces the incidence of 

neutropenic fever as well as that of some TEC-induced haematological and 

extrahaematological side-effects. The QOL is elevated during chemotherapy by 

using PPG, particularly in the end of treatment. Economically speaking, primary 

prophylactic G-CSF is cost-effective in Chinese breast cancer patients receiving 

TEC chemotherapy. 


1553P COST-EFFECTIVENESS OF PRIMARY PEGFILGRASTIM 

PROPHYLAXIS IN BREAST CANCER PATIENTS AT RISK OF 

FEBRILE NEUTROPENIA 

M.J. Aarts 1 , J.P. Grutters 2 , F.P. Peters 3 , C.M. Mandigers 4 , M.W. Dercksen 5 ,J. 

M. Stouthard 6 , J.W. Nortier 7 , H.W. van Laarhoven 8 , L.J. van Warmerdam 9 and 

V.C. Tjan-Heijnen 1 

1 Department of Medical Oncology, Grow-school for Oncology and 

Developmental Biology, Maastricht University Medical Centre+ (MUMC+), 

Maastricht, NETHERLANDS, 2 Department of Health Service Research, School 

for Public Health and Primary Care (caphri), Maastricht University, Maastricht, 

NETHERLANDS, 3 Medical Oncology, Orbis Medical Centre, Sittard, 

NETHERLANDS, 4 Medical Oncology, Canisius Wilhelmina Hospital, 

Nijmegen, NETHERLANDS, 5 Medical Oncology, Maxima Medical 

Centre, Veldhoven, NETHERLANDS, 6 Medical Oncology, Maasstad Medical 

Centre, Rotterdam, NETHERLANDS, 7 Medical Oncology, Leiden University 

Medical Centre, Leiden, NETHERLANDS, 8 Medical Oncology, Radboud 

University Nijmegen Medical Centre and Academic Medical Centre, University of 

Amsterdam, Nijmegen, NETHERLANDS, 9 Medical Oncology, Catharina Hospital, 

Eindhoven, NETHERLANDS 

Purpose: Guidelines advise primary G-CSF prophylaxis during chemotherapy if risk 

of febrile neutropenia (FN) is more than 20%, but this comes with considerable costs. 

We investigated the incremental costs and effects between two treatment strategies of 

primary pegfilgrastim prophylaxis. 

Methods: Our economic analysis, using a health care perspective, was based on a 

randomized study in breast cancer patients with increased risk of FN comparing 

primary G-CSF prophylaxis throughout all chemotherapy cycles (G-CSF 1-6 cycles 

arm) with prophylaxis during the first two cycles only (G-CSF 1-2 cycles arm). 

Primary outcome was the cost-effectiveness expressed as costs per patient with 

episodes of FN prevented. 

Results: The incidence of FN increased from 10% (8 out of 84 patients) in the G-CSF 

1-6 cycles arm to 36% (30 out of 83 patients) in the G-CSF 1-2 cycles arm, whereas the 

mean total costs decreased from € 20,658 (95%CI € 20,049 to € 21,247) to € 17,168 

(95%CI € 16,239 to € 18,029) per patient, respectively. Chemotherapy and G-CSF 

largely determined total costs: 83% in the G-CSF 1-6 cycles versus 78% in the G-CSF 

1-2 cycles arm. As expected, FN-related costs were higher in the G-CSF 1-2 cycles 

arm. The incremental cost-effectiveness ratio for the G-CSF 1-6 cycles compared to 

the G-CSF 1-2 cycles arm was € 13,112 per patient with episode of FN prevented. 

Conclusion: We conclude that G-CSF prophylaxis throughout all chemotherapy 

cycles is more effective, but more costly, compared to prophylaxis limited to the first 

two cycles. Whether G-CSF prophylaxis throughout all chemotherapy cycles is 

considered cost-effective depends on the willingness to pay per patient with episode 

of FN prevented. 


1554P TRENDS IN G-CSF USE IN GERIATRIC ONCOLOGY: 2011 

AFSOS SOFOG SURVEY 

C. Falandry 1 , I. Krakowski 2 , H. Curé 3 , E. Carola 4 , P. Soubeyran 5 , O. Guérin 6 and 

G. Freyer 7 

1 Oncologie Médicale, CHU Lyon Sud, Pierre Bénite, FRANCE, 2 Service 

d’Oncologie Médicale, Centre Alexis Vautrin, Vandoeuvre-les-Nancy, FRANCE, 

3 Oncologie Médicale, Institut Jean Godinot, Reims, FRANCE, 4 Oncologie 

Médicale, CH Senlis, Senlis, FRANCE, 5 Department of Medical Oncology, Institut 

Bergonié and Université Bordeaux Segalen, Bordeaux, FRANCE, 6 Gériatrie, CHU 

Nice, Nice, FRANCE, 7 Oncologie Médicale, CHU Lyon Sud, Lyon, FRANCE 

Background: Age is a risk factor for chemo-induced febrile neutropenia (FN). 

According international guidelines, it should be considered when discussing G-CSF 

use for regimens with FN risk between 10% and 20%. Prophylactic G-CSF remains 

controversial for regimens with a lower risk. 

Patients and methods: A survey was undertaken in France to describe current 

treatment practices in patients aged 70 years and older with gynaecologic cancer. 

Individual data from 791 chemo-treated patients were collected (breast 74%, ovary 

21%, uterus 5%, adjuvant 30%). 

Results: According 101 practitioners, important factors to be considered for GCSF use 

are previous FN /neutropenic events (96%), bone radiotherapy (92%) or chemotherapy 

(86%), comorbidities (91%), performance status (PS) ≥2 (87%), recent septic event 

(92%), anemia (54%). In routine practice, GCSF was prescribed in 51% of the cases, ie 

41% and 9% as primary and secondary prevention respectively and 0.4% in curative 

setting. Prophylactic GCSF prescription rates for regimens with FN risk ≥20%, 10-20% 

and

egimens (HR = 2.5, p < 0.001). Physicians performing geriatric assessments were more 

prone to prescribe GCSF (HR = 1.5, p = 0.015), notably those involved in a 

comprehensive geriatric assessment network ((HR = 1.5, p = 0.007). However proven 

risk factors for FN were rarely considered: PS ≥2 (HR = 0.7, p = 0.05), comorbidities 

(HR = 1.3, p = 0.2), anemia < 12g/dL (HR = 1.0, p = 0.8), malnutrition (albumin < 35g/L, 

HR = 0.7, p = 0.03). In metastatic disease, previous FN (HR = 2.6, p < 0.001), or 

chemotherapy (HR = 1.9, p < 0.001) were significantly associated with higher rates of 

prophylactic GCSF, but not previous irradiation (HR = 1.1, p = 0.5); a limited number of 

daily G-CSF injections were given in most cases (mean: 4.9, 64% patients). 

Conclusion: Our study suggests a trend to overtreatment in some cases, in 

comparison to international guidelines, and insufficient use of validated risk factors 

in treatment decision making. 

Disclosure: C. Falandry: membership on an advisory board Chugaï, I. Krakowski: 

membership on an advisory board Chugaï, H. Curé: membership on an advisory 

board Chugaï, E. Carola: membership on an advisory board Chugaï, P. Soubeyran: 

membership on an advisory board Chugaï, O. Guérin: membership on an advisory 

board Chugaï, G. Freyer: membership on an advisory board Chugaï 

1555P BIOSIMILAR FILGRASTIM INITIATION IN PATIENTS 

ENROLLED IN THE MONITOR G-CSF OBSERVATIONAL 

STUDY RELATIVE TO EORTC GUIDELINES 

M.S. Aapro 1 , P. Gascon 2 , H. Ludwig 3 , C. Bokemeyer 4 , M. Boccadoro 5 , 

M. Turner 6 , M. Muenzberg 6 , K. Denhaerynck 7 , I. Abraham 7 and K. Macdonald 7 

1 Institut Multidisciplinaire d’Oncologie, Clinique de Genolier, Genolier, 

SWITZERLAND, 2 Medical Oncology, Hospital Clinic y Provincial de Barcelona, 

Barcelona, SPAIN, 3 1st Department of Medicine, Wilhelminenspital, Wien, 

AUSTRIA, 4 Head of The Department for Oncology, Haematology and Bone 

Marrow Transplantation, UKE II. Medizinische Klinik und PoliklinikMedizinische 

Klinik II., Hamburg-Eppendorf, GERMANY, 5 Section of Hematology, Università 

degli Studi di Torino, Torino, ITALY, 6 Sandoz International Gmbh, Sandoz 

Biopharmaceuticals, Holzkirchen, GERMANY, 7 Matrix 45, Tucson, AZ, UNITED 


Introduction: MONITOR G-CSF is a prospective observational study of practice 

patterns and outcomes for prophylaxis of chemotherapy-induced febrile neutropenia 

(FN) with biosimilar filgrastim (Zarzio®, Sandoz Biopharmaceuticals). 

Methods: This analysis describes treatment initiation with biosimilar filgrastim in the 

788 patients enrolled to date (target 1500) in the MONITOR G-CSF study relative to 

the 2010 EORTC G-CSF guidelines. Patients were enrolled at 134 centres (199 open) 

across 12 European countries. 

Results: In this mainly female (62%) and older (61.6 ± 11.9 years) cohort with 

predominately solid tumours (79%), FN risk based on chemotherapy (CT) regimen 

was 20% in 39% of patients. All patients with 

20% 

10-20% 

< 10% 

Prophylaxis (%) Initiation (%) Duration (%) 

Primary Secondary 24-72 h Days 5-8 3 days 5 days 

70 

70 

76 

74 

56 

30 

30 

24 

26 

44 

Table 2. FN risk 10-20% 

Prophylaxis (%) 

Patient-related risk factors Primary Secondary 

Age >65 years 79 21 

Advanced disease (Stage IV) 74 26 

History of prior FN 29 71 

No antibiotic prophylaxis 73 24 

Poor performance (ECOG >2) 83 17 

Female 76 24 

Hb 20% or 10-20% in combination with other risk factors did not receive 

primary prophylaxis as recommended. The trend to initiate filgrastim in regimens 

with


neutropenia in patients with cancer. These consisted of two large multicentre 

observational studies plus three small single-centre studies conducted across 12 

European countries. All studies were conducted in Europe and reflected real-life 

clinical use of biosimilar G-CSF. Patients receiving biosimilar G-CSF for 

interventional treatment were excluded from this analysis. 

Results: Data from 1302 patients treated with biosimilar G-CSF were available for 

analysis. The most frequent types of cancer were breast cancer (n = 541; 42%), lung 

cancer (n = 212; 16%) and lymphoma/leukaemia (n = 201; 15%). Thirty-six percent 

of patients had a febrile neutropenia risk of >20% while 39.6% had a risk of 10 − 

20% based on chemotherapy regimen. A further 12.1% of patients received biosimilar 

G-CSF despite a febrile neutropenia risk of

1561P PREDICTIVE DIAGNOSTICS FOR RESPONSE TO THERAPY 

OF CHEMOTHERAPY ASSOCIATED ANEMIA WITH 

DARBEPOETIN ALFA +/- INTRAVENOUS IRON IN CANCER 

PATIENTS: PFAD-3 A MULTICENTRE COHORT STUDY IN 

OUTPATIENTS 

H..T. Steinmetz 1 , K. Kuhr 2 , M. Hellmich 2 , M. Heinz 1 , M. Neise 3 , J. Mittermüller 4 , 

H.W. Tessen 5 , M. Reiser 6 , K. Severin 1 and S. Schmitz 1 

1 Hematology and Oncology, Outpatient Clinic, Cologne, GERMANY, 2 University, 

Institut für Medizinische Statistik, Informatik und Epidemiologie, Cologne, 

GERMANY, 3 Hematology and Oncology, Outpatient Clinic, Krefeld, GERMANY, 

4 Hematology and Oncology, Outpatient Clinic, Germering, GERMANY, 

5 Hematology and Oncology, Outpatient Clinic, Goslar, GERMANY, 6 Hematology 

and Oncology, PIOH - Outpatient Clinic, Cologne, GERMANY 

Introduction: Seven randomized studies have demonstrated a benefit of combining 

erythropoiesis stimulating agents (ESA) with intravenous iron (iv Fe) in the 

treatment of chemotherapy-associated anemia in cancer patients (pts). Because, so 

far there is no proven recommendation for the best pretherapeutic diagnostics to 

select optimal therapy (ESA, iron or both), we conducted a multicenter cohort study. 

Methods: Cancer pts were included and eligible for response if they had a 

symptomatic anemia (hemoglobin (Hb) < 11g/dl), received a chemotherapy, gave 

written informed consent, and had a pretherapeutic diagnostics of anemia: Ferritin 

(F), transferrin saturation (TSAT), endogenous erythropoietin (eEPO) and soluble 

transferrin-receptor (sTFR) on day 1 and 14. All pts were treated with Darbepoetin 

alfa (DA, 500 µg, q3w) with or without iv Fe-III-hydroxyd-saccharose (200mg in 

250ml NaCl 0.9% q3w). The use of iv Fe based on the recommendations of the 

NCCN guidelines at the discretion of the oncologists. Pts with an absolute iron 

deficiency (F m < 30ng/ml, f < 15ng/ml) were excluded. 

Results: Between 03/07 - 08/10 in 9 outpatient clinics 331 pts received DA on day 

0. Mean age was 66.3 years, 58% were women. 202 pts (61%) received at least one 

dose iv Fe additionally to DA on day 0. Baseline Hb was 9.53g/dl (SD 0.78) and 

increased in average 1.23g/dl (SD 1.34) and 1.53 g/dl (SD 1.49) til weeks 6 and 9, 

respectively. Transfusion rate in weeks 3-9 was 15.1%. Associations of relevant 

criteria with response are shown in the table. 

Conclusion: The results confirm the increase of Hb within the first 3 weeks as strong 

predictor for response to DA in week 6. Pts with Hb-increase ≥ 0.6 g/dl have a 6-fold 

higher chance of being responders than those without. Ferritin is a stronger predictor 

for response to iv Fe than TSAT. Supported by Amgen, Munich, Germany. 

Disclosure: H..T. Steinmetz: Member of advisory boards for Amgen, Janssen, 

Medice, Novartis, Roche, Vifor. Investigator in studies for Amgen, Janssen, Novartis, 

Roche, Vifor., M. Neise: Investigator in studies with Amgen, J. Mittermüller: 

Investigator in studies with Amgen, H.W. Tessen: Investigator in studies with 

Amgen, M. Reiser: Investigator in studies with Amgen, K. Severin: Ivestigator in 

studies with Amgen, Roche, Vifor, S. Schmitz: Investigator in studies with Amgen, 

Novartis, Roche, Vifor. All other authors have declared no conflicts of interest. 

1562P A PROSPECTIVE DATA AUDIT OF THE MANAGEMENT OF 

CHEMOTHERAPY-INDUCED ANEMIA WITH DARBEPOETIN 

ALFA – THE APRIORI STUDY 

P. Boguradzki 1 , K. Boér 2 , A. Cipková 3 , E. Wojciechowska-Lampka 4 , 

M. Schützová 5 , J. Ocvirk 6 and E. Tóth 7 

1 Hematology, Warsaw Medical University, Warsaw, POLAND, 2 Oncology 

Department, Szent János Kórház és Észak-budai Egyesített Kórházak, Budapest, 

HUNGARY, 3 Radiotherapy and Oncology, East Slovakian Cancer Institute, 

Košice, SLOVAK REPUBLIC, 4 Department of Lymphoma, The Maria 

Sklodowska-Curie Memorial Cancer Centre and Institute, Warsaw, POLAND, 

5 Hemato-oncologic Department, Faculty Hospital, Plzen-Lochotín, CZECH 

REPUBLIC, 6 Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, 

SLOVENIA, 7 Amgen Slovakia s.r.o., Piešt´any, SLOVAK REPUBLIC 

Background: Darbepoetin alfa (DA, Aranesp®) is an erythropoesis-stimulating agent 

(ESA) used to treat chemotherapy (CT) induced anaemia (CIA). In 2008 EORTC 

Table: 1561P 

guidelines changed to recommend starting ESA treatment at haemoglobin (Hb) 9 - 

11 g/dL and stopping ESA if Hb was > 13 g/dL. In February 2008, the SmPC for DA 

was revised to recommend treatment start at Hb ≤ 10 g/dL and Hb be maintained in 

the 10 - 12 g/dL range. APRIORI was a prospective, noninterventional, observational, 

longitudinal, multicentre study collecting data from patients (pts) in Central and 

Eastern Europe with CIA receiving DA and CT. The aims were to evaluate the 

compliance with international guidelines and EU label for use of DA in treating CIA, 

to assess effectiveness of DA, and describe DA dosing characteristics. 

Methods: This study collected clinical data of cancer pts over 4 consecutive years 

(11/2006 – 12/2010), at 120 centers in Poland, Czech Republic, Slovakia, Slovenia, 

Hungary, and Russia. Pts were enrolled before the label change (BLC) as well as after 

the label change (ALC). The data were collected at enrolment and at follow-up visits 

during CT until the first follow-up visit after the end of CT. 

Results: Out of 6408 pts enrolled (mean (sd) age of 59.9 (±12.57) years, 44.4% 

male), 929/1648 (56.4%) pts enrolled BLC had Hb in the target 9 - 11 g/dL range, 

while 4284/4760 (90.0%) pts enrolled ALC had Hb in the target range of ≤ 10 g/dL. 

Total 666 (40.4%) pts had Hb < 9 g/dL and 53 (3.2%) pts had Hb > 11 g/dL BLC, 

while 476 (10.0%) pts had Hb > 10 g/dL ALC. BLC, 38 (35.8%) pts had any DA 

dosing withheld while exceeding the 13 g/dL Hb concentration limit, at any time 

during the study and ALC, 55 (7.8%) pts had the doses reduced while exceeding the 

12 g/dL Hb concentration limit, at any time during the study. DA effectively 

increased Hb concentrations; mean Hb after achieving the target anaemia Hb level 

BLC 11.94 g/dL vs. 11.29 g/dL ALC. Only 4.9% of pts required RBC transfusion after 

5 weeks of DA initiation. Out of 9 ADRs no serious and no fatal ADRs was reported 

during the study. Mortality was 4.9% (305 pts). 

Conclusion: Based on these data, the patients are being treated in accordance with 

the current European SmPC for darbepoetin alfa. This study was sponsored by 

Amgen GmbH CEE Headquarters. 

Disclosure: P. Boguradzki: Corporate-sponsored research - Amgen APRIORI, K. Boér: 

Corporate sponsored study - APRIORI study Amgen, A. Cipková: Corporatesponsored 

research - Amgen APRIORI, E. Wojciechowska-Lampka: 

Corporate-sponsored research - Amgen -APRIORI, M. Schützová: Corporatesponsored 

research - Amgen; member of advisory board - Amgen, J. Ocvirk: 

Corporate-sponsored research - Amgen APRIORI, E. Tóth: Amgen contract worker. 

1563P THE USE OF BIOSIMILARS IN THE MANAGEMENT OF 

CHEMOTHERAPY-INDUCED ANAEMIA (CIA) IN SOLID 

TUMOURS, LYMPHOMA AND MYELOMA: THE ORHEO 

STUDY 

M. Michallet 1 , P. Soubeyran 2 , H. Albrand 3 and E. Luporsi 4 

1 Service d’Hématologie, Pavillon Marcel Bérard 1g, Centre Hospitalier Lyon Sud, 

Lyon-Pierre Bénite, FRANCE, 2 Department of Medical Oncology, Institut 

Bergonié and Université Bordeaux Segalen, Bordeaux, FRANCE, 3 Medical 

Director, Laboratoire HOSPIRA France, Meudon La Forêt, FRANCE, 4 Medical 

Oncology, Centre Alexis Vautrin, Vandœuvre-lès-Nancy, FRANCE 

The approval of epoetin biosimilars in the European Union requires extensive 

scientific evaluation and stringent regulatory procedures, including post-marketing 

studies. The ORHEO (place of biOsimilaRs in the therapeutic management of 

anaemia secondary to chemotherapy in HaEmatology and Oncology) study was an 

observational, longitudinal, multicentre study performed in France to evaluate the 

efficacy and safety of biosimilar epoetins for the treatment of CIA in the clinical 

setting. Patients >18 years with CIA (haemoglobin [Hb] 5 mg/l : FI ≤ 2 *** Odds ratio, confidence intervall, 

and number of pts with … 


… DA therapy conform with protocol, 

treatment response and predictive 

factors evaluable 



7.4% myeloma. Of those patients with solid tumours, 30.1% of patients had a stage III 

and 21.6% had a stage IV tumour. Almost all patients received the biosimilar epoetin 

zeta (Retacrit®, Hospira UK Ltd., median dose 30,000 IU/week). Mean baseline Hb 

level across all patients was 9.6 g/dL, with 35.6% of patients having moderate anaemia 

(Hb 8–9.5 g/dL). Following treatment, Hb response was achieved in 81.6% and 86.5% 

of patients at 3 and 6 months, respectively. The overall mean change in Hb level was 

1.5 ± 1.6 g/dL at 3 months and 1.72 ± 1.61 g/dL at 6 months. Transfusion rates were 

9.4% and 5.8%, while the rate of thromboembolic events was 2.4% and 1.5%, at 3 and 

6 months respectively. In conclusion, Retacrit was effective and well tolerated in the 

management of CIA in patients with solid tumours, lymphoma and myeloma. 

Disclosure: M. Michallet: I received honoraria from Hospira for advisory boards and 

consulting, P. Soubeyran: I received honoraria from Hospira for advisory boards and 

consulting, H. Albrand: Employed by Hospira, E. Luporsi: I received honoraria from 

Hospira for advisory boards and consulting. 

1564P ANAEMIA-RELATED FATIGUE IN PATIENTS WITH SOLID 

TUMOURS: A MULTICENTER, OBSERVATIONAL AND 

PROSPECTIVE STUDY (PACS STUDY) 

P. Gascon 1 , A. Casas 2 , J. Muñoz 3 , J. De Castro 4 , V. Alberola 5 , M. Cucala 6 and 

F. Barón 7 


2 Medical Onology Department, Hospital Virgen del Rocío, Sevilla, SPAIN, 

3 Medical Oncology Department, Hospital Dr. Peset, Valencia, SPAIN, 4 Medical 

Oncology Department, Hospital La Paz, Madrid, SPAIN, 5 Medical Oncology 

Department, Hospital Arnau de Vilanova, Valencia, SPAIN, 6 Medical Advisor, 

Vifor Pharma España, Barcelona, SPAIN, 7 Medical Oncology Department, 

Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de 

Compostela, SPAIN 

Background: Quality of life in cancer patients is significantly reduced by anaemia 

and associated fatigue. Fatigue is one of the most common symptoms of cancer 

and cancer therapy. The aim of the present study was to evaluate fatigue in 

treatment-naive patients with solid tumours and after four months of cancer 

therapy using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) 

questionnaire. 

Methods: Multicenter, prospective and observational study that included newly 

diagnosed cancer patients. Patients completed the FACT-F questionnaire at 

baseline and after four months of cancer therapy. Anaemia status (haemoglobin 

Methods: A prospective multicentre observational study conducted in Germany 

enrolling 1,066 patients (pts) with non-myeloid malignancies, symptomatic 

chemotherapy-induced anaemia and planned treatment with DA. The primary 

endpoint was a haemoglobin (Hb) level of 10–12 g/dL at week (wk) 9 or, if earlier, at 

the end of treatment. Red blood cell (RBC) transfusion needs and quality of life 

(QoL) were also assessed. 

Results: In total, 984 pts met the protocol criteria and were included into the 

analysis. Cancer types included breast (n = 260; 26%), lung (n = 118; 12%), ovarian 

(n = 103; 10%), colorectal (n = 95; 10%) and other (n = 408; 41%). Median Hb 

levels rose from 9.6 g/dL at baseline (BL) to 10.8 g/dL at wk9. 519 pts (53%) 

reached the primary endpoint over 3.7 wks (median; IQR 0.1–7.1) of DA 

treatment. Median time to Hb level ≥10 g/dL was 14 days (IQR 0–32 days). RBC 

transfusion was required by 32% of pts from wk1 to wk9; 16% of pts required 

RBC transfusion in the first 3 wks from DA initiation. QoL improved (measured 

using FACIT questionnaires and the Linear Analog Scale Assessment); however, a 

clinically important difference was only found using FACIT-F. Of 30 reported 

adverse drug reactions, the investigators classified 12 as DA related. Of these, 1 

was fatal. 

Conclusion: Overall, DA use was in line with the current label and guidelines; most 

pts started DA at Hb levels of ≤10 g/dL and were treated to the Hb target level of 

10-12 g/dL. DA seems to be effective in enhancing Hb response and improving QoL. 

Study sponsor: Amgen Europe (GmbH). Editorial support: archimed medical 

communication ag. 

Median (IQR) or n (%). Information available for 984°, 588∞, 726 a , 978¤ or 980^ 

pts. *Primary endpoint or rise of 2 g/dL from BL. 

Baseline 

Age, years 66 (57–73)° 

Female 617 (63%)° 

Hb level, g/dL 9.6 (9–10.1)° 

Hb level ≤10 g/dL 716 (73%)° 

Performance status 1–2 818 (83%)° 

Disease stage III–IV 350 (59%)∞ 

Prior chemotherapy 387 (53%) a 

Anaemia treatment in 4 wks before BL 

Wk9 

161 (16%)° 

Hb level, g/dL 10.8 (9.8–11.8)¤ 

Met primary endpoint (Hb 10–12 g/dL) 519 (53%)¤ 

Met modified response* 660 (67%)¤ 

Hb level >12 g/dL 178 (18%)¤ 

Required RBC transfusion 312 (32%)¤ 

Chemotherapy cycles 5 (3–6)^ 

Disclosure: H.T. Steinmetz: Consultation and advisory boards: Amgen, Roche, 

Janssen/Ortho-Biotec, Vifor, Medice, Hexal. Funding for scientific research: Amgen, 

Roche, VIifor. Travel costs: Amgen, Roche, Vifor., A. Kuhn: Employee and 

shareholder of Amgen., E. Hellebrand: Employee of Amgen. All other authors have 


1568P THE USE OF BIOSIMILAR EPOETINS IN THE MANAGEMENT 

OF CHEMOTHERAPY-INDUCED ANAEMIA (CIA) IN PATIENTS 

WITH BREAST CANCER: A SUBANALYSIS OF THE ORHEO 

STUDY 

M. Michallet 1 , E. Luporsi 2 , P. Soubeyran 3 and H. Albrand 4 

1 Service d’Hématologie, Pavillon Marcel Bérard 1G, Centre Hospitalier Lyon Sud, 

Lyon-Pierre Bénite, FRANCE, 2 Medical Oncology, Centre Alexis Vautrin, 

Vandœuvre-lès-Nancy, FRANCE, 3 Department of Medical Oncology, Institut 

Bergonié and Université Bordeaux Segalen, Bordeaux, FRANCE, 4 Medical 

Director, Laboratoire HOSPIRA France, Meudon La Forêt, FRANCE 

ORHEO (place of biOsimilaRs in the therapeutic management of anaemia 

secondary to chemotherapy in HaEmatology and Oncology) is an observational, 

longitudinal, multicentre study performed in France to evaluate the efficacy and 

safety of biosimilar epoetins for the treatment of CIA in the clinical setting. The 

study included a total of 2310 patients (mean age 66.5 years) of whom 79.6% 

(n = 1838) had solid tumours, 13.0% (n = 171) had lymphoma and 7.4% (n = 

301) myeloma. Here we report a subanalysis of the study assessing the efficacy 

and safety of biosimilar epoetins in patients with breast cancer. A total of 266 

patients >18 years with CIA (haemoglobin [Hb] 18 years with CIA (haemoglobin [Hb]


bladder bleeding: 1). Platelet transfusions were administered for 8 cycles. No 

life-threatening bleeding occurred in any patient. Thrombocytopenia was associated 

with more than five previous chemotherapy cycle (p = 0.03), previous radiotherapy 

(p = 0.0001), disseminated disease (p = 0.006), distant metastatic disease (p = 0.02) 

and poor performance status (p = 0.0001). Clinical bleeding was associated with 

previous radiotherapy (p = 0.003), distant metastatic disease (p = 0.03) and poor 

performance status (p = 0.02). Both clinical bleeding were not related with age, bone 

marrow metastases or platinum-based regimens. Febrile neutropenia was complicated 

with 35% of thrombocytopenia cycles and 43% of clinical bleeding cycles. 

Conclusions: By estimating risk factor of clinical bleeding such as progression of 

disease and poor bone marrow reserve, safe management of chemotherapy-induced 

thrombocytopenia without unnecessary platelet transfusion may be possible in 

patients with gynecologic malignancy. 


1571P PREVENTION OF DELAYED NAUSEA (DN): A POOLED 

ANALYSIS OF 562 WOMEN RECEIVING HIGHLY 

EMETOGENIC CHEMOTHERAPY (HEC) IN PROSPECTIVE 

CLINICAL TRIALS OF PALONOSETRON (PALO) 

L. Celio 1 , F. Longo 2 , S. Brugnatelli 3 , G. Mansueto 4 , E. Bonizzoni 5 , F.G.M. De 

Braud 1 , F. Ricchini 1 and M.S. Aapro 6 

1 Medical Oncology, Fondazione IRCCS “Istituto Nazionale Tumori”, Milan, ITALY, 

2 Medical Oncology, Policlinico Umberto Primo, Rome, ITALY, 3 Medical 

Oncology, Policlinico San Matteo, Pavia, ITALY, 4 U.O.C. Oncologia Medica, 

Ospedale Fabrizio Spaziani, Frosinone, ITALY, 5 Section of Medical Statistics and 

Biometry, Faculty of Medicine, University of Milan, Milan, ITALY, 6 Institut 

Multidisciplinaire d’Oncologie, Clinique de Genolier, Genolier, SWITZERLAND 

Purpose: Chemotherapy-induced nausea occurs more frequently than vomiting, and 

women are particularly prone to experience DN instead of delayed vomiting. We 

conducted a pooled analysis to evaluate the efficacy of three regimens for preventing 

DN: 1-day regimen (n = 241): Palo plus dexamethasone 8 mg IV (Day 1); 3-day 

regimen (n = 209): Palo plus dexamethasone 8 mg (Day 1) and dexamethasone 8 mg 

PO (Days 2 and 3); triple regimen (n = 112): Palo plus dexamethasone 12 mg and 

aprepitant (Day 1) and dexamethasone 8 mg PO plus aprepitant (Days 2 and 3). 

Methods: The analysis was based upon outcomes in 562 chemo-naïve women (mean 

age 52.7 years; PS ECOG 0: 93%; metastatic disease: 11%) with solid tumors (90% 

breast cancer) enrolled in two Phase III and two Phase II trials of HEC (AC-based: 

91%; cisplatin: 9%). The pre-specified primary end point was the proportion of 

patients with no nausea during the delayed period (Days 2-5) after the first cycle of 

chemotherapy. The two primary comparisons were 3-day regimen vs. 1-day regimen, 

and triple regimen vs. 3-day regimen. Penalized multivariable logistic regressions 

were also performed adopting the Firth’s correction in order to adjust estimates for 

potential over-fitting, skewed data and multi-collinearity. Results were reported as 

adjusted odds ratios (OR) with two-sided probability values. 

Results: The 3-day to 1-day regimen comparison was not statistically significant 

(DN, 46.4% vs. 44.4%, two-sided Fisher’s exact test, P = 0.777). The triple regimen to 

3-day regimen comparison was significant (DN, 58.9% vs. 46.4%; P < 0.0001). For no 

nausea end point in the overall phase (Days 1-5) adjusted ORs (95% CI) were: 3-day 

regimen vs. 1-day regimen: OR 1.19 (0.80 - 1.77), P = 0.398; triple regimen vs. 3-day 

regimen: OR 2.86 (1.44 - 5.83), P = 0.003. 

Conclusions: This analysis suggests that Palo plus 1-day or 3-day dexamethasone 

have similar effects on DN. The addition of aprepitant to 3-day regimen improves 

the prevention of DN in women receiving HEC. Complete results accounting for risk 

factors (age and alcohol consumption) will also be presented. 


1572P SAFETY AND EFFICACY OF ORAL PALONOSETRON IN 

PREVENTING CHEMOTHERAPY-INDUCED NAUSEA AND 

VOMITING (CINV) OVER MULTIPLE CYCLES OF 

MODERATELY EMETOGENIC CHEMOTHERAPY (MEC) 

D. Voisin1 and S. Grunberg2 1 

Clinical R&D, Helsinn Healthcare, Pambio Noranco, SWITZERLAND, 

2 

Hematology/Oncology Unit, Fletcher Allen Health Care, Burlington, UNITED 


Background: Palonosetron (PALO), a pharmacologically distinct 5-HT3 receptor 

antagonist (RA) offers superior CINV prevention compared with other 5-HT3 RAs 

when administered as a single IV dose. Oral PALO doses 0.25, 0.50, 0.75 mg were 

clinically comparable to the approved 0.25 mg IV dose in a pivotal phase 3 

single-cycle trial, with 0.50 mg being the FDA/EMA approved dose. A dose of 0.75 

mg was selected for the present study to best evaluate safety of oral PALO in multiple 

cycles of chemotherapy (CT). 

Methods: In this multicenter, open-label study, patients received a single 0.75 mg 

dose of oral PALO (with [at investigator discretion] or without concomitant 

dexamethasone [DEX]) 60 min prior to MEC (up to a maximum of 4 consecutive 

cycles). The primary safety and efficacy assessments were adverse event (AE) 

reporting and the proportion of cycles showing patients complete response (CR: no 

emesis, no rescue medication) in the acute and delayed intervals. 

Results: 217 patients (75% female; 61% white, 36% Hispanic; 66% CT-naive) 

received a total of 654 cycles of MEC (median 3 cycles).The median number of 

cycles was 3 with ∼ half of patients receiving 4 cycles. Concomitant DEX (8 mg Day 

1) was administered in 483 cycles while PALO was given alone in 171 cycles. 

Generally, antiemetic efficacy was maintained across the CT cycles (Table) with 

higher CR rates when DEX was given concomitantly vs PALO alone (acute: 74% vs 

61%; delayed: 63% vs 60% respectively, all cycles combined). 

CR (%) 

Time Period, hrs 

Cycle 1 

(n = 217) 

Cycle 2 

(n = 186) 

Cycle 3 

(n = 143) 

Cycle 4 

(n = 107) 

Acute (0-24h) 75 70 72 60 

Delayed (24-120h) Overall (0-120h) 63 57 62 58 63 60 60 55 

The majority of AEs were mild, with headache the most common related AE in 3.5% 

cycles PALO alone and 5.4% cycles PALO + DEX. In both the PALO alone and 

PALO + DEX groups, AEs decreased slightly from cycle 1 to 3 and remained about 

the same for cycle 4. There were few severe or serious AEs and the profile raised no 

safety concerns. 

Conclusion: Oral PALO was well tolerated and effective in preventing CINV over 

multiple cycles in patients receiving MEC. 

Disclosure: D. Voisin: Yes. Daniel Voisin is a Helsinn employee, S. Grunberg: Yes 

Steven Grunberg is an Helsinn Helathcare consultant. 

1573P THE DOPAMINE D2/D3 RECEPTOR ANTAGONIST APD421 IN 

COMBINATION WITH ONDANSETRON EFFECTIVELY 

PREVENTS ACUTE CISPLATIN-INDUCED NAUSEA AND 

VOMITING (CINV) 

J. Herrstedt 1 , Y. Summers 2 , G. Daugaard 3 , T.B. Christensen 4 , K. Holmskov 1 , 

P.D. Taylor 2 ,G.Fox 5 and A. Molassiotis 6 

1 Onkologisk Afdeling R, Odense University Hospital, Odense, DENMARK, 

2 Pulmonary Oncology Unit, University Hospital South Manchester NHS 

Foundation Trust, Manchester, UNITED KINGDOM, 3 Department of Oncology 

5073, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DENMARK, 

4 Oncology Department RA65 C8, Herlev Hospital, Herlev, DENMARK, 5 Clinical 

Development, Acacia Pharma Ltd, Cambridge, UNITED KINGDOM, 6 School of 

Nursing, Midwifery and Social Work, Manchester University, Manchester, 


Conventional dopamine D 2 antagonists are among the oldest antiemetics and are 

considered to be of only moderate efficacy in CINV. Central dopamine D 3 receptors 

have recently been demonstrated to be involved in the emetic reflex arc, but so far no 

clinical data have been published for any agents acting at these receptors. In preliminary 

testing, APD421, a potent D2 and D3-antagonist, showed some single-agent efficacy in 

preventing vomiting and especially nausea caused by cisplatin. We therefore investigated 

its efficacy in combination with ondansetron at preventing acute-phase CINV. 

Methods: Chemotherapy-naïve patients receiving cisplatin ≥ 50 mg/m 2 were given 

single IV doses of APD421 (20 mg) and ondansetron (8 or 16 mg) 30 minutes prior 

to the cisplatin. Complete response (CR) was defined as no emetic episodes and no 

rescue medication in the first 24 h after cisplatin infusion. Prospective nausea scores 

were measured on a 100 mm visual analogue scale at times 2, 4, 8 and 24 h. After the 

initial 24 h patients received standard antiemetics. 

Results: 17 subjects (15M:2F) have taken part so far, receiving a mean cisplatin dose 

of 71 mg/m 2 (range 64-82 mg/m 2 ), of whom 15 have had CR (88%; 95% CI 

72-100%). The mean nausea score is 0.7/100 (range 0-8). 57/66 nausea scores 

collected have been zero. There have been no clinically-significant APD421-related 

adverse events. Recruitment will continue until the desired sample size of 23 subjects 

is reached (expected to be completed July 2012). Final results will be presented. 

Conclusions: The acute-phase efficacy of APD421 in combination with ondansetron 

in CINV compares favourably with historical data on other 5-HT 3-based 

combinations. Randomised trials in acute and delayed phase CINV are merited. 

Disclosure: G. Fox: The author is an employee and stock-holder of Acacia Pharma. 


1574P BIOEQUIVALENCE AND ABSOLUTE BIOAVAILABILITY OF A 

SINGLE ORAL DOSE OF TWO FORMULATIONS OF 0.75 MG 

PALONOSETRON IN HEALTHY VOLUNTEERS (HV) 

D. Voisin 1 , C. Giuliano 2 and S. Baumann 3 

1 Clinical R&D, Helsinn Healthcare, Pambio Noranco, SWITZERLAND, 2 Preclinical 

R&D, Helsinn Healthcare SA, Lugano, SWITZERLAND, 3 Clinical Research, CRS 

Clinical Research Services, Mannheim, GERMANY 

Background: Palonosetron HCl (PALO) is a potent 5-HT 3 receptor antagonist 

(5HT3-RA) with a stronger receptor binding affinity and unique mechanism of action 


Table: 1574P 

Pharmacokinetic 

parameter palonosetron Ratio 

AUC(0-t) [ng h/L] b1 / b3 

b2 / b3 

AUC(0-inf) [ng h/L] b1 / b3 

b2 / b3 

Cmax [ng/L] b1 / b3 

b2 / b3 

compared to older 5HT 3-RAs. The primary objectives were to investigate the 

bioequivalence of two oral PALO 0.75 mg formulation(s) (F (s)) b 1 and b 2 and their 

absolute bioavailability when compared to b 3 PALO 0.75 mg i.v F (see table for: b 1, b 2 

and b 3). Secondary objective was to evaluate the safety profile of the three PALO F (s). 

Methods: 36 male and female hv were randomized in this open-label, 3-treatment, 

cross-over study. 30 subjects received treatments b1, b2 and b3 in a 3- period 

randomized order (14-day interval set between periods). Treatments b 1 and b 2 were 

analyzed for bioequivalence by ANOVA CVs and defined bioequivalent if the 90% 

confidence intervals (CI) for the AUC 0-∞, AUC 0-t and C max treatment ratios lie 

within 80% to 125% range CI Absolute Ratios. Absolute bioavailability of the oral 

F (s) was calculated using the extent of exposure measure AUC 0-∞ and AUC 0-t. 

Results: The oral 0.75 mg F(s) b1 and b2 showed bioequivalence in terms of rate and 

extent of absorption: The 90% CI for PALO AUC0-t, AUC0-∞ and Cmax are 97.91% 

to 109.47%, 96.47% to 107.76% and 93.40% to 103.59%, respectively. All CI’s are well 

within the 80-125% equivalence limits. The absolute bioavailability of both oral and 

the i.v. F (s), calculated using AUC 0-t is essentially not different (97% for b1, and 99% 

for b2 F (s)). All study F (s) were safe and well tolerated: constipation and headache 

were the main adverse events. No clinical influence was observed on safety laboratory 

or vital signs variability. No drop out was due to safety issue. 

Conclusions: The study has shown bioequivalence of two PALO 0.75 mg oral 

formulations. No significant changes were observed in the absolute bioavailability 

between the two oral formulations and the i.v. 0.75 mg. All tested formulations 

showed a good safety profile. 

Disclosure: D. Voisin: The Author is an Helsinn Employee, C. Giuliano: The Author 

is an Helsinn Employee, All other authors have declared no conflicts of interest. 

1575P ADME STUDY OF [14C]NETUPITANT ADMINISTERED AS AN 

ORAL 300 MG SUSPENSION TO HEALTHY MALE SUBJECTS 

C. Giuliano 1 , S. Calcagnile 1 , S. Mair 2 , L. Stevens 2 and I. Nisbet 2 

1 Clinical Operation, Helsinn Healthcare, Lugano, SWITZERLAND, 2 Radiology, 

Quotient Bioresearch, Nottingham, UNITED KINGDOM 

Background: Netupitant (NETU) is a highly selective neurokinin 1 receptor 

antagonist developed to provide protection from nausea and vomiting induced by 

emetogenic chemotherapy. The objectives of the study were to investigate the 

pharmacokinetic (PK) profile, the mass balance recovery, the excretion pathways and 

the metabolism of [ 14 C]NETU in an open-label study in 6 healthy male subjects 

receiving a single-nominal-dose of 300 mg as oral suspension. 

Methods: Plasma, urine and feces samples were collected up to 336h after dosing, 

plus two additional 24h excreta collections until 696h. Total radioactivity was 

measured by liquid scintillation counting (liquid samples) and after combustion in 

oxygen (non-liquid samples). PK parameters for NETU and its metabolites were 

analyzed by liquid chromatography-tandem mass spectrometry. 

Results: [ 14 C]-NETU is rapidly absorbed with peak in plasma concentration ranging 

between 2h and 5.5h post dose. Elimination is mainly via the feces, with approximately 

71% of the total radioactivity recovered at 696h. Urinary elimination accounts for less 

than 4% of total radioactivity. Cumulative percent of total radioactivity suggests that 

approximately half of the administered dose was recovered within 120h and, based on 

an extrapolation, elimination was completed by 696h. NETU undergoes extensive 

metabolism forming phase I and II metabolites. The main metabolites of NETU are M1 

(N-demethylated NETU), M2 (NETU N-oxide) and M3 (monohydroxy NETU) which, 

on average, account respectively for 29%, 14% and 33% of the NETU plasma exposure. 

Phase I metabolites observed include those formed through N-demethylation, mono 

and di-hydroxylation, N-oxidation, desaturation, N-formylation, oxidation and 

reduction to a keto group and oxidation to an acid. Phase II metabolites include those 

formed by glucuronidation and conjugation to a hexose group. 

Conclusions: These data indicate that the hepatic/biliary route, rather than renal 

clearance is the major elimination route for drug-related entities. NETU undergoes 

extensive metabolism via phase I and II metabolic reactions with M1, M2 and M3 as 

the main circulating metabolites. NETU was well tolerated. 

Disclosure: C. Giuliano: Helsinn employee, S. Calcagnile: Helsinn employee, 


Point estimate 

Test/Ref. ratio 

96.56 

99.88 

97.26 

98.99 

72.60 

71.71 

b1: oral administration of 0.75 mg palonosetron as a softgel capsule (formulation A, clinical trial formulation). 

b2: oral administration of 0.75 mg palonosetron as a softgel capsule (formulation B, Proposed commercial formulation). 

b3: intravenous administration of 0.75 mg palonosetron (3 x 0.25 mg i.v. Aloxi® - reference for the bioavailability analysis). 

ANOVA and 90% CIs for l0g-transformed. 


90% 

Confidence Interval 

91.47 - 101-93 

94.61 - 105.44 

92.33 - 102.45 

93.98 - 104.27 

67.01 - 78.67 

66.18 - 77.70 

1576P SAFETY AND PHARMACOKINETIC EVALUATION OF 

PALONOSETRON GIVEN ON DAY 1 AND 3 FOR PATIENTS 

WHO ARE TO RECEIVE A HIGH OR MODERATE RISK OF 

CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING (CINV) 

Y. Ikari, Y. Nakasima, E. Sato, M. Masaki, H. Katsuya, A. Shirahashi, T. Tanaka, 

K. Ishitsuka, Y. Takamatsu and K. Tamura 

Department of Medicine, Division of Medical Oncology, Hematology and 

Infectious Diseases, Fukuoka University, Fukuoka, JAPAN 

Aim: To assess safety, pharmacokinetics and tolerability of repeated dosing of 

palonosetron in patients receiving chemotherapy categorized as having a high or 

moderate emetic risk. 

Method: Nineteen patients undergoing high or moderate emetic risk for CINV were 

given palonosetron 0.75mg intravenously once daily for 30 min on day 1 and 

3. Blood samples for the first 6 patients were obtained for pharmacokinetics analysis 

from day 1 through 5. To evaluate safety profiles, serial complete blood cell counts, 

blood chemistry tests and electrocardiograms were also performed. 

Result: The pharmacokinetic studies of 6 patients showed mean Cmax values on 

day1 and 3 were 2.05 and 2.90ng/mL, respectively, with coefficients of variation (CV) 

of 30.9% and 34.2%. Mean AUC0-48hr values were 42.4 and 58.3 ng•hr/mL on day1 

and 3, with a CV of 21.2% and 23.2%, respectively. T1/2 of palonosetron was 

approximately 40 hours and was constant in day1 and 3. Accumulation of 

palonosetron on day3 was 1.42-fold for Cmax and 1.37-fold for AUC0-48hr. 

Treatment-related adverse events for 19 patients including above 6 patients were 

constipation and loss of appetite which might be secondary to antineoplastic agents, 

but were mild and transient. Complete response defined by no emesis and no rescue 

antiemetics was 100% for acute and 73% for delayed CINV, respectively. 

Conclusions: Repeated dosing of palonosetron on day1 and 3 was safe and well 

tolerated in patients who received high to moderate emetic risk chemotherapy. 


1577P EVALUATION OF SUBCUTANEOUS (SC) VERSUS 

INTRAVENOUS (IV) PALONOSETRON IN CANCER PATIENTS 

TREATED WITH PLATINUM-BASED CHEMOTHERAPY: A 

RANDOMIZED PHARMACOKINETIC ASSAY 

E. Arevalo, A. Del Barrio, B. Sadaba, M.A. Campanero, J.R. Azanza, A. Gurpide, 

J.M. Lopez Picazo, S. Martin Algarra and J.L. Perez Gracia 

Clinical Oncology, Clinica Universitaria de Navarra, Pamplona, SPAIN 

Background: 5-HT3 antagonists are one of the more effective antiemetic preventions 

in patients who are receiving platinum-based chemotherapy. Some of these 5-HT3 

antagonist are available for oral use, however the therapeutic formulations with more 

bioavailability and middle course which have been traditionally administrated by the 

intravenous route, have a limited use in the hospital environment. Up to now, no 

study has examined the pharmacokinetics of these drugs when administered 

subcutaneously. We have compared pharmacokinetics of palonosetron in the two 

different routes, SC and IV. 

Methods: Patients under platinum-based chemotherapy were randomized to receive 

before the first cycle of chemotherapy, palonosetron by the SC or the IV route. In 

the second cycle, the drug was administrated by the other route. The main endpoint 

was Area Under the Curve between 0-24 hours (AUC 0–24h). Blood samples were 

drawn at 10, 15, 30, 45, 60, 90 min and 2, 3, 4, 8, 12, 24 h after palonosetron. Drug 

levels were determined by HPLC with fluorescence detection after liquid extraction of 

the samples, with a quantitation limit of 0.1 ng/ml. 

Results: We included 26 patients, from October 2009 to May 2010. We found no 

statistically differences in the Area Under Curve at 24 hours after the drug 

administration (AUC 0-24) between both routes. Maximum concentration (Cmax) 

reached after its administration was significantly lower via the SC route than by IV. 

The time to reach the Cmax (Tmax) by the SC route was superior than the IV route. 

The elimination of unmetabolized drug in urine (Ae 24h) was similar in both routes, 



in the first 24 hours, about 20% of the administered dose. The prevention of early 

and late emesis was equivalent with both alternatives. 

Conclusions: Palonosetron SC administration showed similar AUC0-24h to that of 

the IV route, with the same exposure to the drug, and good control in the prevention 

of early and late emesis, which can benefit the management of outpatient treatments. 

i.v. (mean ± SD) 

s.c. 

(mean ±SD) p-value 

AUC 0-24h (ngxh/ml) 14,10 ± 6,73 12,68 ± 9,70 0,160 

Cmax (ng/ml) 11,88 ± 7,38 1,91 ± 1,09 < 0,001 

Tmax (h) 0,04 ± 0,04 0,26 ± 0,13 < 0,001 

Ae24h (%) 19,48 ± 9,99 22,24 ± 8,50 0,660 


1578P CORRELATION BETWEEN CYCLOPHOSPHAMIDE-INDUCED 

HYPONATRAEMIA AND THE USE OF APREPITANT 

Y. Tono, T. Mizuno, K. Saito, S. Tamaru, Y. Yamashita, H. Oda, S. Kageyama 

and N. Katayama 

Medical Oncology, Mie University Hospital, Tsu, JAPAN 

Background: For prevention of emesis during anthracyline (A)/cyclophosphamide 

(CPA) therapy for breast cancer, use of aprepitant(AP) combined with serotonin 

receptor antagonist(5HT3) and dexamethasone(DEX) is recommended. AP, known 

to function as a CYP3A4 inhibitor, has been reported to interfere with metabolism of 

chemotherapeutic drugs. It has been also reported that AP does not influence the 

AUC’s of 4-OH and DCE. Although, in the previous clinical reports for AC, the 

toxicities were not significant in patients who were given AP, compared to those 

without AP, we have experienced a cases of severe hyponatremia probably related to 

AP. Thus, we investigated an impact of AP on Na metabolism during chemotherapy 

using CPA for breast cancer. 

Material and methods: We investigated serum levels of Na in primary breast cancer 

patients who received CPA-combined therapy with the use of AP as anti-emesis, or 

not. They all received 600mg/m 2 of CPA combined with either of anthracycline or 

docetaxel. Their ages were to be less than 65 years, and their GFR’s were more than 

60 ml/min/1.73m 2 . Their prior electrolytes were to be within normal range. In the 

first cycle, we evaluated serum Na levels before the CPA start and that at 24 hours 

after. We defined serum Na level lower than 135 mEq/L as “hyponatremia” based on 

previous study. We enrolled 81 patients, in whom 52 were given AP and 29 were 

without AP, between December 2010 and April 2012. 

Results: The background between the two groups, with AP and without AP, were 

comparable, in whom the median ages were 53.0(33-64) and 53.2(38-65), and the 

prior Na levels were139.84 ± 1.89 mEq/L, and 140.25 ± 1.82 mEq/L, in the AP-group 

and in non-AP-group, respectively. The uses of 5HT3 and DEX were similar between 

the two groups. The incidence of CPA-induced hyponatremia was significantly 

higher in AP-group than in non-AP-group (26.9% v 6.9%; P =0.04). The average Na 

level at 24 hours after chemotherapy was 136.32 ± 3.73 mEq/L in AP-group, and 

138.60 ± 2.92 mEq/L in non-AP-group. Among 14 patients who developed 

hyponateremia in AP-group, they were resolved without any intervention in 13, and 

one needed Na replacement. The patient did not develop hyponatremia without AP 

in the third cycle. 

Conclusions: According to our cohort study, AP cause hyponatremia more 

frequently in the CPA-combined chemotherapy. 


1579P THE EFFICACY OF TRIPLET ANTIEMETIC THERAPY FOR 

CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING IN 

LUNG CANCER PATIENTS RECEIVING HIGHLY EMETOGENIC 

CHEMOTHERAPY: PALONOSETRON (PALO), APREPITANT 

(APR), AND DEXAMETHASONE (DEX) 

H. Yoshizawa 1 ,K.Sato 2 , M. Makino 3 , O. Kobayashi 4 , H. Tanaka 5 , S. Miura 6 , 

S. Watanabe 1 , J. Tanaka 7 , H. Kagamu 6 and N. Ichiei 6 

1 Bioscience Medical Research Center, Niigata University Medical and Dental 

Hospital, Niigata, JAPAN, 2 Department of Respiratory Medicine, Nagaoka Red 

Cross Hospital, Nagaoka, JAPAN, 3 Department of Internal Medicine, Niigata 

Prefectural Shibata Hospital, Shibata, JAPAN, 4 Department of Internal Medicine, 

Niigata Prefectural Central Hospital, Jyoetsu, JAPAN, 5 Department of Internal 

Medicine, Niigata Cancer Center Hospital, Niigata, JAPAN, 6 Department of 

Medicine (II), Niigata University Medical and Dental Hospital, Niigata, JAPAN, 

7 Department of Health Promotion Medicine, Niigata University Graduate School 

of Medical and Dental Sciences, Niigata, JAPAN 

Background: Chemotherapy-induced nausea and vomiting (CINV) is one of the 

most problematic symptoms experienced by patients undergoing cancer treatments. 

Triplet therapy with PALO, APR, and DEX, is a guideline-recommended antiemetic 

prophylaxis for highly emetogenic chemotherapy (HEC). However, the efficacy and 

safety of this therapy for lung cancer patients has not yet been well investigated. 

Methods: Chemotherapy naïve lung cancer patients scheduled to receive HEC were 

enrolled in this study. The eligible patients were pretreated with the triplet therapy 

(PALO 0.75 mg day 1, APR 125 mg day 1 and 80 mg day 2-3, DEX 9.9 mg day 1 and 

8 mg day 2-4) before receiving HEC. The efficacy and safety of these substances were 

assessed during an observation period starting from the administration of HEC to 

120 hours. A questionnaire diary documented patients’ complaints. The primary 

endpoint was the proportion of the patients who did not experience emesis or rescue 

antiemetic (Complete Response rate; CR rate) during any part of the whole 

observation period. The secondary endpoints were (1) the CR rate during the acute 

phase (0-24hrs) and the late phase (24-120hrs), (2) the proportion of patients who 

experienced no emetic episodes and significant nausea with no rescue medication 

(Complete Control rate; CC rate), and (3) safety. 

Results: A total of 72 patients were enrolled with 65 assessable patients at the time of 

submission. The median age was 64 years. The CR rate during the whole observation 

period, the acute and late phase was 78.5 %, 95.4% and 80.0%, respectively. The CC 

rate in the late phase was 62.9%. No severe side effects were observed. In the subset 

analysis, the CC rate in late phase was significantly lower in female subset (71.4% vs. 

45.0%). Another subset analysis regarding to chemotherapy regimen, the proportion 

of vomiting event was higher in the pemetrexed used regimen. 

Conclusion: Triplet therapy using PALO, APR and DEX, was shown to be safe and 

effective in preventing CINV in lung cancer patients treated with HEC. Further 

investigation is needed for to reduce nausea in the late phase. 


1580P PAIN INTERFERENCE OUTCOMES IN A RANDOMIZED 

PHASE 3 CLINICAL TRIAL OF DENOSUMAB VS ZOLEDRONIC 

ACID (ZA) IN PATIENTS WITH SOLID TUMORS AND BONE 

METASTASES 

C. Cleeland1 , L. Fallowfield2 , R. von Moos3 , D. Patrick4 , D.H. Henry5 , V. Hirsh6 , 

K. Zarogoulidis7 , A. Feng8 , Z. Cong9 and A. Braun10 1 

Symptom Research Division of Internal Medicine, MD Anderson Cancer Center, 

Houston, TX, UNITED STATES OF AMERICA, 2 Sussex Health Outcomes 

Research & Education In Cancer (shore-c), University of Sussex, Brighton, 

UNITED KINGDOM, 3 Medizinische Onkologie und Hämatologie, Kantonsspital 

Graubünden, Chur, SWITZERLAND, 4 Health Services, University of Washington, 

Seattle, WA, UNITED STATES OF AMERICA, 5 Joan Karnell Cancer Center, 

Pennsylvania Hospital, Philadelphia, PA, UNITED STATES OF AMERICA, 

6 7 

Oncology, McGill University Health Centre, Montreal, QC, CANADA, G. 

Papanikolaou Hospital, Pulmonary Department, Aristotle University of 

Thessaloniki, Thessaloniki, GREECE, 8 Global Biostatistical Science, Amgen Inc., 

Thousand Oaks, UNITED STATES OF AMERICA, 9 Global Health Economics, 

Amgen Inc., Thousand Oaks, CA, UNITED STATES OF AMERICA, 

10 

Hematology/Oncology, Amgen Inc., Thousand Oaks, CA, UNITED STATES OF 

AMERICA 

Background: In patients with advanced cancer, bone metastases cause pain and may 

lead to skeletal-related events (SREs). Subcutaneous (SC) denosumab prevented SREs 

more effectively than intravenous (IV) ZA in patients with solid tumors and bone 

metastases in a phase 3 clinical trial (n = 1597; Henry D, J Clin Oncol. 2010. Abstr 

9133). We now describe pain interference outcomes for patients with solid tumors in 

this trial (ClinicalTrials.gov NCT00330759; May 25, 2006; sponsor Amgen Inc.). 

Methods: Patients received 120 mg of denosumab SC or 4 mg of ZA IV every 4 

weeks in a randomized, multinational, double-blind, double-dummy trial. 

Patient-reported pain interference (overall, activity, and affect) was assessed by the 

Brief Pain Inventory (0: does not interfere-10: completely interferes) at baseline (BL) 

and upon each monthly visit. Analyses included time to clinically meaningful 

(≥2-point increase or decrease from BL) worsening or improvement in pain 

interference, and percentage of patients reporting clinically meaningful worsening in 

pain interference by visit. Analyses were conducted for patients with no/mild pain 

(worst pain 0-4) at BL and all patients at risk. 

Results: In patients with no/mild pain at BL, denosumab delayed the median time to 

clinically meaningful worsening in pain interference compared with ZA (overall 3.4 

months, P = 0.0213; activity 1.8 months, P = 0.0124; affect 0.9 months, P = 0.0518). 

Similarly, fewer of these patients treated with denosumab vs ZA reported clinically 

meaningful worsening in pain interference over all visits (average relative difference: 

overall 13%; activity 16%; affect 10% fewer). Time to clinically meaningful 

improvement in pain interference was similar between treatment groups. Pain 

interference outcomes were similar among all patients at risk compared to those with 

no/mild pain at BL. 

Conclusion: In patients with solid tumors, denosumab delayed time to worsening of 

pain interference, and fewer patients reported worsening in pain interference over 

time, compared with ZA. Greater effects on pain interference were seen for patients 

with no/mild pain at BL, suggesting the benefit of early intervention with 

denosumab. 

Disclosure: C. Cleeland: Advisory board member for Amgen, Genentech, Merck, 

and Exelixis, L. Fallowfield: Consultancy honoraria for serving on an advisory board 

for Amgen Inc., R. von Moos: Advisory board member for Amgen, Roche, & 


Novartis and unrestricted research grants from Amgen and Roche, D. Patrick: 

Research funding from Amgen Inc., D.H. Henry: Advisory board member, served on 

the speakers bureau, and received research funding from Amgen Inc., V. Hirsh: 

Advisory board member for Amgen Inc., A. Feng: Employed by and owns stock/ 

stock options in Amgen Inc., Z. Cong: Employed by and owns stock/stock options in 

Amgen Inc., A. Braun: Employed by and owns stock/stock options in Amgen Inc., 


1581P A RANDOMIZED PHASE II TRIAL COMPARING STANDARD 

PAIN CONTROL WITH OR WITHOUT GABAPENTIN FOR THE 

TREATMENT OF PAIN RELATED TO RADIATION-INDUCED 

MUCOSITIS IN HEAD AND NECK CANCER 

T. Kataoka 1 , N. Kiyota 2 , T. Shimada 2 , M. Toyoda 2 , Y. Fujiwara 2 , K. Nibu 3 , 

T. Komori 4 , R. Sasaki 5 , T. Mukohara 2 and H. Minami 2 

1 Division of Oral and Maxillofacial Surgery, Shizuoka Cancer Center, Shizuoka, 

JAPAN, 2 Medical Oncology and Hematology, Kobe University Hospital, Kobe, 

JAPAN, 3 Otolaryngology and Head and Neck Surgery, Kobe University Hospital, 

Kobe, JAPAN, 4 Oral and Maxillofacial Surgery, Kobe University Hospital, Kobe, 

JAPAN, 5 Radiation Oncology, Kobe University Hospital, Kobe, JAPAN 

Background: Radiation-induced mucositis (RIM) in chemoradiation (CRT) for 

head and neck cancer (HNC) causes severe pain and worsens CRT 

compliance and outcome. Following retrospective reports that gabapentin 

might improve RIM-associated pain during CRT, we conducted a randomized 

phase II trial to analyze the safety and efficacy of gabapentin for 

RIM-associated pain. 

Methods: HNC patients (pts) receiving CRT were randomized to receive standard 

pain control (SPC) or SPC plus gabapentin (SPC + G). Pts in the SPC arm received 

acetaminophen and opioids as analgesic, while those in the SPC + G arm received 

gabapentin in addition to SPC. Gabapentin maintained at dose of 900 mg/day till 4 

weeks after CRT. The prescribed RT dose was 66-70 Gy/33-35Fr. Concurrent 

chemotherapy consisted of a three-week cycle of cisplatin. Primary endpoint was 

maximum VAS score during CRT. Secondary endpoints were total dose of opioids, 

change in QOL (EORTC QLQ-C30 and EORTC QLQ-HN 35) from base line to 4 

weeks after CRT, and adverse events. 

Results: From Apr 2010 to Oct 2011, 22 eligible pts were randomly assigned to 

receive SPC (n = 11) or SPC + G (n = 11). All pts were Stage III or IV. Twelve were 

treated in a locally advanced setting and 10 in a postoperative setting. No statistically 

significant differences were seen in median maximum VAS scores between arms (47 

in SPC vs. 74 in SPC + G; p = 0.517). Median total dose of opioids at maximum VAS 

and total dose of opioids at 4 weeks after CRT did not statistically differ but 

appeared higher in the SPC + G arm (215 mg vs. 745.3 mg; p = 0.880, 1260 mg vs. 

1537.5 mg; p = 0.9438). QOL analysis showed significantly worse scores in the SPC + 

G arm for weight gain (p = 0.005). Adverse events related to gabapentin were 

manageable. One-year survival rate in both arms was equivalent. 

Conclusions: This is the first prospective randomized trial to analyze the safety and 

efficacy of gabapentin for RIM-associated pain. While survival data was equivalent in 

both arms, gabapentin may have detrimental effects for RIM and further 

investigation is warranted. 

Disclosure: N. Kiyota: an advisory board member on proper usage of cetuximab for 

head and neck cancer in Japan (Merck Serono) All other authors have declared no 


1582P PAIN AND BOWEL FUNCTION EVOLUTION, IN CANCER 

PATIENTS TREATED WITH STRONG OPIOIDS AT THE FIRST 

TIME THAT THEY REPORT MODERATE-SEVERE PAIN. C2 

STUDY 

I. López Calderero 1 , L. Zugazabeitia Olabarria 2 , M.Á. Nuñez Viejo 3 , J.M. 

García Bueno 4 , E. Blanco Campanario 5 , J. Contreras Martínez 6 ,M. 

López Mata 7 , J.L. Marti Ciriquian 8 , D. Isla Casado 9 and M. Provencio Pulla 10 

1 Radio-Oncology Service, Hospital Virgen del Rocío, Sevilla, SPAIN, 2 Oncology 

Service, Hospital Povisa, S.A, Vigo, SPAIN, 3 Oncology Service, Hospital Santa 

María Nai, Ourense, SPAIN, 4 Oncology Service, Hospital General de Albacete, 

Albacete, SPAIN, 5 Oncology Service, Hospital Infanta Cristina, Badajoz, SPAIN, 

6 Radio-Oncology Service, Complejo Hospitalario Regional Carlos Haya, Málaga, 

SPAIN, 7 Radio-Oncology Service, Hospital Clínico Universitario Lozano Blesa, 

Zaragoza, SPAIN, 8 Oncology Service, Hospital General Universitario de Alicante, 

Alicante, SPAIN, 9 Oncology Service, Hospital Clínico Universitario Lozano Blesa, 

Zaragoza, SPAIN, 10 Oncology Service, Hospital Universitario Puerta de Hierro de 

Majadahonda, Madrid, SPAIN 

Introduction and objectives: Opioids remain the cornerstone of analgesic treatment 

for cancer patients, but gastrointestinal side effects have a great impact on their 

quality of life. The aim of this analysis was to evaluate the use of strong opioids in 


these patients, and if oxycodone/naloxone combination provides benefits in terms of 

analgesia, without compromising bowel function. 

Material and methodology: Interim analysis of an observational multicentre study, 

in which patients reporting moderate-severe pain, at 1 st time in the oncology 

services, were treated following investigator criteria. We present results of the patients 

treated with strong opioids during 1 month (N= 298). 

Results: Baseline characteristics: 65% male, mean ± SD age: 66 ± 13 years (27% ≥ 75 

years old), ECOG 1: 54%; receiving chemotherapy 64% and radiotherapy 41%. Main 

location of the primary tumor: lung (28%), colon/rectum (12%), head and neck 

(11%). Metastatic cancer: 79%; 67% of patients reported pain secondary to 

metastases. Comparison between patients treated with oxycodone/naloxone (n= 217) 

with those treated with other strong opioids (n= 81) showed a good pain control in 

both groups (NRS0-10-2.7 and -2.2 points respectively, p = 0,08). It was confirmed a 

significant improvement of bowel function (


1584P HOME-BASED ZOLEDRONIC ACID (ZOL) INFUSION 

THERAPY IN PATIENTS WITH SOLID TUMOURS: 

COMPLIANCE AND PATIENT-NURSE SATISFACTION 

T. Lebret 1 , J. Mouysset 2 , A. Lortholary 3 , C. El Kouri 3 , L. Bastit 4 , M. Ktiouet 5 , 

K. Slimane 5 , X. Muracciole 6 and S. Guérif 7 

1 Urology, Hôpital Foch, Suresnes, FRANCE, 2 Oncology, Polyclinique Parc 

Rambot-Provençale, Aix en Provence, FRANCE, 3 Medical Oncology, Catherine 

de Sienne Institute, Nantes, FRANCE, 4 Radiothérapie, Centre de Radiothérapie, 

Evreux, FRANCE, 5 Oncology, Novartis Pharmaceuticals, Rueil-Malmaison, 

FRANCE, 6 Service de Radiotherapie, CHU La Timone APHM Marseille, Marseille, 

FRANCE, 7 Radiothérapie, CHU Poitiers, Poitiers, FRANCE 

Objective: To explore patient and nurse satisfaction, compliance with practice 

guidelines, technical feasibility, and safety of home infusion of the bisphosphonate 

ZOL. 

Methods: This was a prospective longitudinal 1-year survey of home ZOL therapy in 

patients with bone metastases secondary to a solid malignancy. Randomly selected 

physicians prescribed home ZOL therapy (4 mg Zometa®, 15-min IV infusion, every 

3-4 weeks). Three questionnaires were administered at 3 time points: physician 

questionnaire, nurse satisfaction and feasibility questionnaire, and patient satisfaction 

questionnaire. The main end-points were patient and nurse satisfaction with home 

ZOL therapy. 

Results: Of the 154 physicians who agreed to participate, 87 (56.5%) enrolled 818 

patients for whom 788 case report forms were received of which 763 met inclusion 

criteria. Overall, 343 nurses (97.5% community) took part. Patient characteristics 

were: median age 68 yrs (30-95); male-female ratio 40/60; primary cancer: breast 

55.2%, prostate 28.4%, lung 7.2%, other 9.4%; ECOG-PS 0 or 1: 78.6%. Overall, 

90.9% of nurses were either highly satisfied or satisfied with how home ZOL therapy 

was run; 96.7% found the infusion either very easy or easy to perform; 97.5% felt that 

home therapy promoted a good relationship with patients, and 73% were either 

highly satisfied or satisfied with their hospital contacts. Among patients, 95.3% were 

either very satisfied or satisfied with home ZOL therapy. Causes for satisfaction were 

quality of the nurse-patient relationship (57.6%) in addition to expected reasons (e.g. 

less time travelling/waiting (68.8%), less disruption to daily routine (36.6%)). ZOL 

therapy was well tolerated (discontinuation due to adverse events 6.1%; osteonecrosis 

of the jaw 0.6%, fractures 0.2%). Practitioner compliance with recommendations was 

73% for dental hygiene checks at inclusion and 48-56% thereafter, 66% for 

pre-infusion patient hydration, and often undocumented for calcium/vitamin D 

supplementation. 

Conclusions: There was a very high level of both patient and nurse satisfaction with 

home ZOL therapy. However, improved compliance with practice guidelines should 

be encouraged. 

Disclosure: T. Lebret: Consulting fees : Amgen, Novartis Advisory board : Amgen, 

Novartis Honorarium study Novartis, J. Mouysset: Honorarium study Novartis, A. 

Lortholary: Honorarium study Novartis, C. El Kouri: Honorarium study Novartis, L. 

Bastit: Honorarium study NovartisM. Ktiouet: Novartis EmployeeK. Slimane: 

Novartis Employee, X. Muracciole: Advisory board Novartis Consulting fees 

Novartis, S. Guérif: Consulting fees Novartis. 

1585P A PROSPECTIVE MONO-INSTITUTIONAL STUDY ON THE 

IMPACT OF A SYSTEMATIC PREVENTION PROGRAM ON 

THE INCIDENCE AND OUTCOME OF OSTEONECROSIS OF 

THE JAW (ONJ) IN PATIENTS (PTS) TREATED WITH 

BISPHOSPHONATES (B) FOR BONE METASTASES 

N.M. La Verde, A. Bramati, S. Piva, M.C. Dazzani, S. Girelli, A. Moretti, D. Mihali, 

M. Dimaiuta, A. Pinto and G. Farina 

Oncology, A.O. Fatebenefratelli e Oftalmico, Milan, ITALY 

Background: B are commonly used to treat bone metastases in cancer pts, who have 

a higher risk of developing ONJ. The elective involvement of the jaw can have an 

anatomic rationale, since this region has a thin mucosa and microbiological 

contamination. The jaw is exposed to dental microtraumatisms and infections, so 

reparation mechanisms are essential. B inhibits bone turnover and since the 

increased demand for bone repair isn’t satisfied, the bone is exposed to osteonecrosis. 

To reduce this risk we have developed a specific prevention program focused 

primarily on reducing its incidence and, wherever it develops, the need for 

demolitive surgery with permanent sequelae. 

Patients and methods: All consecutive pts with bone lesions, that were eligible for 

treatment with B (either zoledronic or pamidronic acid) were prospectively evaluated. 

Before starting B, each patient was referred to an specialized odontoiatric team that 

performed: 1. dental examination; 2. orthopantomography; 3. professional dental 

hygiene. If the oral conditions weren’t satisfactory (i.e., tooth decay, dental plaque, 

broken teeth), the dentist completed the necessary intervention before starting B. 

Results: From April 2007 to April 2012 we collected data of 254 pts, 243 of which 

were treated with zoledronic acid and 9 with pamidronic acid. The median age was 

74 years old (range 37-95), 92 male and 162 female. All pts had bone involvement: 

74 pts had breast cancer, 39 lung cancer, 36 prostate cancer, 33 multiple myeloma 

and 72 others. On average the pts received 9.7 cycles (range 1-48). No case of ONJ 

was recorded. 

Conclusions: Our study demonstrates that ONJ can be effectively prevented with a 

serious program that involves a multidisciplinary team. The odontoiatric basal 

evaluation is necessary to identify pts with oral pathologies or inadequate oral 

hygiene who must undergo preventive dental treatment. When reparative 

phaenomena are compromised by B, the healthy oral environment prevents 

infections and subsequent morbidity. In our opinion, this type of preventive program 

should be mandatory for all pts starting B. 


1586P QOL AND SURVIVAL SURVEY OF CANCER CACHEXIA IN 

ADVANCED NSCLC PATIENTS - JNUQ-LC STUDY, TORG0912 

S. Atagi 1 , F. Imamura 2 , A. Yokoyama 3 , K. Minato 4 , T. Harada 5 , N. Katakami 6 , 

T. Yokoyama 7 , Y. Ohashi 8 , K. Watanabe 9 and K. Eguchi 10 

1 Department of Thoracic Oncology, Kinki-chuo Chest Medical Center, Osaka, 

JAPAN, 2 Department of Thoracic Oncology, Osaka Medical Center for Cancer 

and Cardiovascular Diseases, Osaka, JAPAN, 3 Department of Internal Medicine, 

Niigata Cancer Center Hospital, Niigata, JAPAN, 4 Department of Respiratory 

Medicine, Gunma Prefectural Cancer Center, Ohta, JAPAN, 5 Center for 

Respiratory Disease, Hokkaido Social Insurance Hospital, Sapporo, JAPAN, 

6 Division of Integrated Oncology, Institute of Biomedical Research and Innovation 

Hospital, Kobe, JAPAN, 7 Department of Respiratory Medicine, Kyorin University 

Hospital, Tokyo, JAPAN, 8 Department of Biostatistics, School of Public Health, 

The University of Tokyo, Tokyo, JAPAN, 9 Department of Respiratory Medicine, 

Yokohama Municipal Citizen’s Hospital, Yokohama, JAPAN, 10 Internal Medicine, 

Division of Medical Oncology, Teikyo University School of Medicine, Tokyo, 

JAPAN 

Background: Cancer cachexia, mainly characterized by muscle atrophy and 

subsequent cancer induced weight loss (CIWL), is attributed to about a third of 

cancer deaths. Despite worsening prognoses with the symptoms, clinical factors 

involved and the effect of CIWL to the overall status remain unexplained. We 

planned a prospective cohort study, Japan Nutrition and QOL survey in patients 

with advanced NSCLC study to investigate changes in CIWL in relation to grip, 

QOL, and clinical parameters to understand their effects on prognosis. 

Method: Untreated stage IV NSCLC patients with ECOG PS of 0-2 were registered. 

Their body weight (BW), grip, QOL, Karnofsky Performance Scale, biochemical 

assay, and survival were recorded every four weeks for one year from the start of 

cancer treatments. Patients were classified by BW loss ≥ 5% and cachexia diagnosis 

by BW loss, fatigue, anorexia, and abnormal assay results. Estimated survival curves 

were drawn by Kaplan-Meier method, and Log-rank test was applied. To evaluate the 

effect of cancer cachexia attribution to QOL, we performed principal component 

analysis, factor analysis, and analysis on time course data using generalized 

estimating equation (GEE). 

Results: Out of 466 patients registered, 406 were evaluable and analyzed. Patient 

characteristics were: median age: 67 (33-87) years, male/female ratio: 280/126, 

median BW: 56.5kg, PS 0: 39.2%, and PS 1: 51.5%. The patients with BW loss of ≥ 

5% (n = 219) reported more early deaths than those without (n = 166, p < 0.0001). 

Patients with cachexia (n = 169) reported more early deaths than those without (n = 

216, p < 0.0001). All correlations between principal component scores estimated from 

the variables considered the signs of cancer cachexia (cancer cachexia attributions: 

more weight on anorexia, fatigue, BW and grip) and each factor scores of QOL 

domains estimated from QOL factor analyses were significant (p < 0.01). From the 

time course data analyses using GEE, cancer cachexia attributions of each visit are 

shown as useful variables for all QOL domains (p < 0.01). 

Conclusion: Cancer cachexia decreased QOL and possibly affected prognoses. 

Cachexia preventions and treatments based on the further elucidation of its 

pathology are needed. 


1587P SARCOPENIA AFFECTS TREATMENT TOXICITY IN 

METASTATIC COLORECTAL CANCER PATIENTS: RESULTS 

OF A PROSPECTIVE MULTICENTER STUDY 

M. Barret 1 , C. Dalban 2 , J. Taieb 3 , D. Malka 4 , T. Mansourbakht 5 ,E.Latko 6 and 

S. Antoun 7 

1 Gastroenterology, Hopital Européen Georges Pompidou, Paris, FRANCE, 

2 Department of Biostatistics and Epidemiology (ea4184), Centre Georges 

François Leclerc, Dijon, FRANCE, 3 Gastroenterology and Digestive Oncology, 

Hopital Européen Georges Pompidou, Paris, FRANCE, 4 Oncology, Institut 

Gustave Roussy, Villejuif, FRANCE, 5 Gastroenterology, Hopital de la Pitié 

Salpetriere, Paris, FRANCE, 6 Nutricia Advanced Nutrition, Danone, St Ouen, 

FRANCE, 7 Emergency Department, Institut Gustave Roussy, Villejuif, FRANCE 

Background: Malnutrition reduces tolerance to treatment, quality of life, and survival 

in numerous cancers, including metastatic colorectal cancer (mCRC). Previous 


studies have shown that chemotherapy toxicity may be linked to low muscle tissue 

(sarcopenia). Our study evaluated the effect of sarcopenia on chemotherapy toxicity 

among mCRC patients. 

Methods: In this prospective, cross-sectional, multicenter study, demographic, 

oncological, and nutritional data were collected in all consecutive mCRC patients 

in three hospitals. Computed tomography (CT) images were analyzed using 

Slice-O-Matic software V4.3 (Tomovision) to evaluate cross-sectional areas (cm 2 ) 

of muscle tissue (MT), visceral adipose tissue (VAT), and subcutaneous adipose 

tissue (SAT). The 3 rd lumbar vertebra (L3) was chosen as a reference, since L3 

and whole-body measurements are linearly related. Indexed on height, MT, VAT 

and SAT (cm 2 /m 2 ), were described, after stratification on sex. Sarcopenia was 

defined as MT 90% for all assessments during treatment. CTCAE consistently resulted in 



lower sensitivity and correlation compared to PNQ (weighted kappa coefficients of 

sensory and motor components were 0.50 and 0.38). Sensory and motor component 

grades of PNQ were significantly correlated with the FACT/GOG Ntx-subscale (r = 

0.63 and 0.45). The test-retest reliability of PNQ sensory and motor components 

demonstrated Spearman correlation coefficients of 0.81 and 0.59. PNQ sensory 

grades increased similarly with CTCAE. PNQ motor grades were worse compared to 

CTCAE. 

Conclusions: The PNQ has adequate feasibility and validity to prospectively assess 

oxaliplatin neurotoxicity. The PNQ is a convenient, accurate and reliable assessment 

tool for oxaliplatin neurotoxicity. 


1591P PHASE II STUDY OF TOPICAL MENTHOL FOR 

CHEMOTHERAPY-INDUCED PERIPHERAL NEUROTOXICITY 

(CIPN) 

M. Nakamura, K. Nakamura, T. Onikubo, H. Kamikawa and K. Tauchi 

Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, JAPAN 

Background: Chemotherapy-induced Peripheral Neurotoxicity (CIPN) is a major 

dose-limiting toxicity of many commonly used chemotherapeutic agents that can 

limit successful disease control in cancer care. Although some systemic agents have 

been available, a significant proportion of patients are left with long-term pain and 

disability which is difficult to treat. Transient Receptor Potential Melastatin-8 

(TRPM-8) is distributed in peripheral nerves and has been shown to associate with 

cold hypersensitivity, noxious cold, sensory disturbance, and impaired 

thermoregulation. Menthol is a compound derived from mint leaves that functions as 

an agonist of TRPM-8. Preclinical and clinical works have shown the effect of topical 

menthol on CIPN. We conducted a phase II study to investigate the effects of 

menthol on CIPN. 

Methods: 27 patients with CIPN caused by treatment with oxaliplatin (n = 22), 

paclitaxel (n = 3), capecitabine (n = 1), and irinotecan (n = 1) applied 1% topical 

menthol, twice daily to affected skin areas. CIPN symptoms were assessed separately 

for the hands and feet using the Numerical Rating Scale (NRS) and modified 

Peripheral Neuropathy Scale (PNS) based on patient questionnaires at baseline, 4 and 

8 weeks after treatment. Responders and good responders were defined as 10% and 

30% reduction in NRS respectively. 

Results: Three patients (11%) could not continue the study due to adverse events 

(skin swelling, desquamation and aggravation of Hand-Foot Syndrome). Efficacy of 

topical menthol was evaluated in 24 patients. Eighteen patients (75%) showed over 

10% decrease of NRS, and 12 patients (50%) showed over 30% decrease of NRS. 

Median scores of NRS of baseline, 4 and 8weeks were 4.3, 4.1 and3.6 in hands (p = 

n.s.; paired t test); 5.4, 4.9 and 4.4 in feet respectively (p = 0.03; paired t test). In 

modified PNS that assessed the severity of neurological symptoms and functional 

disabilities caused by CIPN, a decrease of score was observed in 19 of 24 patients 

(79.2%). 

Conclusions: Topical menthol was well tolerated and demonstrated significant 

therapeutic response for CIPN. 


1592P CHEMOTHERAPY INDUCED PERIPHERAL NEUROPATHY: 

THE ROLE OF THE MODIFIED TOTAL NEUROPATHY SCORE. 

S. Vasquez 1 , M. Guidon 2 , E. McHugh 2 , O. Lennon 2 and O.S. Breathnach 3 

1 Physiotherapy, Beaumont Hospital Cancer Centre, Dublin, IRELAND, 

2 Physiotherapy, Royal College of Surgeons in Ireland, 2, IRELAND, 3 Medical 

Oncology, Beaumont Hospital Cancer Centre, Dublin, IRELAND 

Background: Chemotherapy induced peripheral neuropathy (CIPN) is a common, 

potentially reversible side-effect of some chemotherapeutic agents. Common toxicity 

scales used in clinical practice are subjective, insensitive to change, and may 

underreport this phenomenon. The use of nerve conduction studies is invasive and 

impractical in routine practice. The modified total neuropathy score (mTNS) 

provides a comprehensive non-invasive measure of CIPN. CIPN is associated with 

decreased balance, function and quality of life (QoL). This association has to date 

been under-investigated. 

Methods: All patients receiving neurotoxic chemotherapy regimes over a seven week 

period during July / August 2011 were identified using the hospital pharmacy 

database and once screened for inclusion/exclusion criteria, were invited to complete 

the mTNS, Berg Balance Scale (BBS), Timed Up and Go (TUG), and the FACT-G 

QoL questionnaire. mTNS scores were profiled and correlated with BBS, TUG and 

FACT-G using Spearmans correlation coefficient. All assessments were carried out 

under the supervision of a Senior Physiotherapist. 

Results: A total of 29 patients undergoing a variety of neurotoxic chemotherapy 

regimes (taxanes n = 9, vinca-alkaloids n = 3, platinums n = 13, combination 

platinum/taxane regimes n = 4) were assessed. The patients mTNS scores ranged 

between 1 and 12 (median score = 5), indicating that all patients had some signs of 

neuropathy on mTNS, and 93% (n = 27) had scores indicative of CIPN. No 

significant correlations were found between mTNS and BERG (r = -.289; p = 0.05), 

TUG (r = .136; p = 0.05), or FACT-G (r = 0.050; p = 0.05). 

Conclusion: This study found a high prevalence of CIPN in patients treated with 

neurotoxic chemotherapy regimes as assessed by the mTNS. The mTNS provided a 

clinically applicable, sensitive screening tool for CIPN which could prove useful in 

clinical practice. mTNS did not correlate with BERG, TUG or FACT-G in this study, 

which may be due to relatively mild levels of CIPN and consequent subtle 

impairments which were not adequately captured by gross functional assessments. 


1593P INFLUENCE OF BASELINE OXIDATIVE STRESS LEVEL ON 

CHANGES IN LEFT VENTRICLE ECHOCARDIOGRAPHIC 

PARAMETERS IN PATIENTS WITH BREAST CANCER 

RECEIVING ANTHRACYCLINE CHEMOTHERAPY 

L. Petruzelka 1 , M. Kocik 2 , M. Zimovjanova 1 , J. Kodytkova 3 ,L.Vavrova 3 , 

O. Mestek 4 , K. Gorican 2 and A. Zak 5 

1 Oncology, First Faculty of Medicine Charles University, Prague, CZECH 

REPUBLIC, 2 4thdepartment of Internal Medicine, First Medical Faculty Charles 

University, Prague, CZECH REPUBLIC, 3 Institute for Clinical Biochemistry and 

Laboratory Diagnostics, First Medical Faculty Charles University, Prague, CZECH 

REPUBLIC, 4 Department of Analytical Chemistry, Institute of Chemical 

Technology, Prague, CZECH REPUBLIC, 5 4st Department of Internal Medicine, 

First Medical Faculty Charles University, Prague, CZECH REPUBLIC 

Introduction: Breast cancer (BC), like other malignancies, is associated with 

chronic increase of oxidative stress (OS). Anthracyclines (ANTS), potent 

inductors of OS, represent first-line therapy of advanced BC. OS induction by 

ANTS is believed to be the key factor in ANTS- related left ventricle dysfunction 

and the subsequent development of heart failure, which are major complications 

of ANTS therapy. The aim of the present study is to establish the role of 

malignancy-related OS present before ANTS therapy in the development of 

changes in echocardiografic (ECHO) parameters after chemotherapy in patients 

with breast cancer. 

Patients and methods: The study population consists of 99 adult female suffering 

from breast cancer (mean age 52 ± 12 years) receiving ANTS chemotherapy. Catalase 

(CAT) activity as a surrogate marker of OS level and ECHO examination were 

established at the baseline in all patients. Follow-up ECHO examinations were 

performed at the end of therapy and again one year after the start of therapy. The 

correlations between baseline CAT activities and changes in ECHO parameters were 

evaluated. 

Results: Statistically significant correlation between baseline CAT activity and 

unfavorable change in end-diastolic left ventricle diameter ( r = 0.24; p = 0.02) was 

observed soon after the ANTS therapy. Statistically significant correlation between 

baseline CAT activities and unfavorable change in end-diastolic left ventricle 

diameter (r = 0.30;p = 0.003) was found at one year following the start of ANTS 


Conclusion: The results of our study suggest a possible correlation between baseline 

OS level and the future development of morphological cardiac changes after ANTS 

chemotherapy in patients with breast cancer. Whether pre-treatment levels of OS can 

predict ANTS induced left ventricle dysfunction and/or the development of heart 

failure will be shown by a further follow-up of the study population. The study was 

supported by the grant awarded by Ministry of Health, Czech republic, IGA MZ ĆR 

NS 9774-4 


1594P PREVENTION STRATEGIES FOR CHEMOTHERAPY INDUCED 

HAND-FOOT SYNDROME: A META-ANALYSIS OF 

PROSPECTIVE RANDOMISED TRIALS 

L. Traldi Macedo 1 and A. Sasse 2 

1 Medical Oncology, State University of Campinas (UNICAMP), Campinas, 

BRAZIL, 2 Cevon Centre for Evidences in Oncology, UNICAMP - Universidade 

Estadual de Campinas, Campinas, BRAZIL 

Introduction: Hand-foot syndrome (HSF) is a distinctive adverse event relatively 

frequent to some chemotherapeutic agents as capecitabine, pegylated liposomal 

doxorubicin, docetaxel or sorafenib, and often recognized as a dose-limiting 

reaction. The prevention of HSF would be therefore crucial to avoid treatment 

interruptions, and many studies have been developed in the attempt to reach this 

purpose. The aim of this meta-analysis is to analyze the clinical efficacy of current 

prevention strategies. 

Methods: A wide search through PubMed/MEDLINE was performed using the terms 

related to hand-foot syndrome, erythrodysesthesia and random in all fields. ASCO 

and ESMO Meeting Abstracts from 2000 to 2011 were also scanned. Randomized 

trials comparing intervention versus observation or placebo were selected and had 

their data collected. The end-points evaluated were the dichotomic data for mild 


(Grade 1) and moderate to severe (Grades 2 to 3) HSF. Meta-analysis was calculated 

through RevMan v5.1 software. 

Results: Amongst 195 potential articles, only six matched the inclusion criteria, 

with details described on the table below. In regards to mild HSF, the use of 

celecoxib presented statistical benefit (OR 0.35, 95% CI 0.22 to 0.58, p < 0.0001), 

while pyridoxine (OR 0.58, 95% CI 0.56 to 4.01) and topical urea/lactic acid 

(OR 1.6, 95% CI 0.5 to 5.16) failed to prove efficacy. The same pattern was 

observed for moderate to severe HSF, where celecoxib significantly reduced the 

number of events (OR 0.38, 95% CI 0.2 to 0.7, p = 0.002), unlike pyridoxine 

(OR 0.99, 95% CI 0.65 to 1.52) or topical urea/lactic acid (OR 1.55, 95% CI 

0.69 to 3.45). 

Author Year N Intervention Blinding 

Köhne 2008 44 Celecoxib 800 mg Yes 

Zhang 2012 139 Celecoxib 400 mg No 

Zhang 2011 110 Celecoxib 400 mg No 

von Gruenigen 2010 34 Pyridoxine 200 mg Yes 

Kang 2010 389 Pyridoxine 200 mg Yes 

Wolf 2010 137 Urea/lactic acid-based topic agent Yes 

Conclusions: From all available possibilities for prevention of HSF, celecoxib appears 

to be the most promising agent, with statistically significant results. Larger, 

multicentric studies would be ideal to reinforce this hypothesis. 


1595P TOPICAL APPLICATION OF TJ-14 (HANGESHASHINTO) IN 

THE TREATMENT OF CHEMOTHERAPY-INDUCED ORAL 

MUCOSITIS: A RADOMIZED, PLACEBO-CONTROLLED, 

DOUBLE-BLIND, PHASE II TRIAL 

N. Nagata 1 , C. Matsuda 2 , Y. Munemoto 3 , M. Oshiro 4 , M. Kataoka 5 , Y. Shindo 6 , 

S. Morita 7 , T. Kono 8 , J. Sakamoto 9 and H. Mishima 10 

1 Surgery, Kitakyushu General Hospital, Kitakyushu, JAPAN, 2 Surgery, Osaka 

General Medical Center, Osaka, JAPAN, 3 Surgery, Fukui Saiseikai Hospital, 

Fukui, JAPAN, 4 Surgery, Toho University Sakura Medical Center, Sakura, 

JAPAN, 5 Surgery, Nagoya National Hospital, Nagoya, JAPAN, 6 Digestive 

Surgery, Nakadori General Hospital, Akita, JAPAN, 7 Biostatistics and 

Epidemiology, Yokohama City University Medical Center, Yokohama, JAPAN, 

8 Advanced Surgery Center, Higashi-Tokusyukai Hospital, Sapporo, JAPAN, 

9 Young Leaders Program, Nagoya University, Nagoya, JAPAN, 10 Clinical 

Oncology, Aichi Medical University, Nagakute, JAPAN 

Background and aims: Although chemotherapy-induced oral mucositis (COM) is a 

common side effect of many anticancer therapies, the optimal treatment for this 

condition is not well established. Recent studies showed that one of the traditional 

Japanese herbal medicines (Kampo) called TJ-14 (hangeshashinto) may be useful for 

COM via downregulating pro-inflammatory prostaglandins in the cyclooxygenase 

pathway (ASCO-GI2011, AGA2012). The efficacy of TJ-14 for the prevention and/or 

treatment of COM was exploratively tested in a randomized, double-blind, 

placebo-controlled trial in colorectal cancer patients. 

Methods: Ninety-three patients who developed COM during FOLFOX, FOLFIRI or 

XELOX treatment for advanced colorectal cancer were centrally randomized to 

receive either a topical application of TJ-14 or placebo. Patients were advised to 

dissolve 2.5 g of TJ-14 or placebo in 50 mL of tap water and rinse their oral cavity 

three times daily for 10 seconds with the solution before expectorating it. Patients 

followed this oral care throughout the treatment before the next course of 

chemotherapy began. The COM grade was evaluated using the Common 

Terminology Criteria for Adverse Events (CTCAE) version 4 and a self-administered 

questionnaire before and after the 2-week treatment with the TJ-14 or placebo 

solution. The study endpoints included the incidence of worst grade COM, the 

incidence of grade 2 or higher COM, the duration of grade 2 or higher COM, and 

the healing time of COM. 

Results: Ninety patients (43 in the TJ-14 group, 47 in the placebo group) were 

included in the statistical analysis. The incidence of grade 3 COM was 9.5% vs. 17%, 

while no significant difference in the incidence of grade 2 or higher COM was found 

between the two groups. The median duration of grade 2 or higher COM was 5.5 

days vs. 10.5 days (p = 0.018). No significant difference was observed between the 

two groups with regard to the incidence of grade 2 or higher adverse events. 

Conclusions: Topical TJ-14 rinse appears to have a significant ability to treat grade 2 

or higher COM and reduce the risk of developing grade 3 COM. Our results are 

encouraging and warrant further phase III trials. 



1596P MAINTENANCE OF QUALITY OF LIFE IN PATIENTS WITH 

MALIGNANT ASCITES DURING TREATMENT WITH THE 

TRIFUNCTIONAL ANTIBODY CATUMAXOMAB: RESULTS 

FROM THE PHASE III B CASIMAS TRIAL 

F. Lordick 1 , J. Sehouli 2 , I.B. Vergote 3 , P. Rosenberg 4 , A. Schneeweiss 5 , 

A. Block 6 , C. Salat 7 , G. Scambia 8 , D. Berton-Rigaud 9 and P. Wimberger 10 

1 Medizinische Klinik III, Staedtisches Klinikum Braunschweig, Braunschweig, 

GERMANY, 2 Department of Gynecology, Charite Medical University, Berlin, 

GERMANY, 3 Obstetrics & Gynaecology, BGOG and University Hospital Leuven, 

Leuven, BELGIUM, 4 Onkologiska Kliniken Universitetssjukhuset, University 

Hospital Linköping, Linköping, SWEDEN, 5 Heidelberg, National Center for Tumor 

Diseases, Heidelberg, GERMANY, 6 Internal Medicine, UKE Universit, Hamburg, 

GERMANY, 7 Munich, Hematology Oncology Clinic, Munich, GERMANY, 

8 Department of Gynecologic Oncology, Catholic University, Rome, ITALY, 

9 Oncology, Centre René Gaducheau, Nantes, FRANCE, 10 University of 

Duisburg-essen, AGO and Department of Gynecology and Obstetrics, Essen, 

GERMANY 

Background: Malignant Ascites (MA) is associated with a poor prognosis and a 

major deterioration in quality of life (QoL). To demonstrate the value of a new 

treatment the assessment of QoL is of particular importance. Results from the pivotal 

study demonstrated catumaxomab’s potential to stabilize QoL and prolong the time 

to first deterioration of QoL in these patients. Observations from the two-arm, 

open-label, multicentre CASIMAS trial now give evidence that QoL remains 

unaffected during catumaxomab treatment 

Methods: In our trial, 219 patients were randomized to receive catumaxomab plus 

premedication of 25 mg prednisolone (CP, 111 pts) or catumaxomab alone (C, 108 

pts). QoL was measured using the EQ-5D visual analogue scale (EQ-VAS). The 

EQ-VAS reports the respondent’s self-rated health on a vertical scale where the 

endpoints are labelled “Best imaginable health state” (100) and “Worst imaginable 

health state” (0). This information is used as a quantitative measure of health 

outcome. Patients were asked to complete the EQ-VAS during the treatment period 

(d 0, 3 and 10) and follow-up (d8, 28). Descriptive analyses were performed 

according to EQ-5D User Guide (Version 4.0). In addition, ascites-related symptoms 

were measured with a disease specific patient questionnaire (Functional Assessment 

of Chronic Illness Therapy, FACIT). 

Results: Longitudinal analysis of the EQ-VAS for the pooled population (CP and C) 

showed no relevant changes in mean score during the treatment period with 

catumaxomab (d0: 51.5; d3: 50.9; d10: 51.0) and compared to screening (52.7). 

During the follow-up period (d8: 53.9, d28: 57.1), an increase in mean values was 

observed. Descriptive comparison of both treatment groups revealed no major 

differences in QoL and ascites-related symptoms during the treatment and follow-up 

period, indicating that prednisolone has no impact on patient’s self-rated health. 

Conclusions: Quality of Life as measured by EQ-VAS remains unchanged during 

treatment with catumaxomab and improves after the treatment period. The 

improvement is plausible due to the prolonged-puncture-free survival and is 

consistent with previous observations of QoL changes during and after 

intraperitoneal treatment with catumaxomab. 

Disclosure: F. Lordick: consultant for Fresenius Biotech GmbH, J. Sehouli: 

consultant for Fresenius Biotech GmbH and financial support for clinical studies, I.B. 

Vergote: consultant for Fresenius Biotech GmbH, P. Rosenberg: financial support for 

clinical studies from Fresenius Biotech GmbH, A. Schneeweiss: financial support for 

clinical studies from Fresenius Biotech GmbH, A. Block: financial support for clinical 

studies from Fresenius Biotech GmbH, C. Salat: financial support for clinical studies 

from Fresenius Biotech GmbH, G. Scambia: financial support for clinical studies 

from Fresenius Biotech GmbH, D. Berton-Rigaud: financial support for clinical 

studies from Fresenius Biotech GmbH, P. Wimberger: consultant for Fresenius 

Biotech GmbH 

1597P PROPHYLACTIC TOPICAL ADAPALENE AND ORAL 

MINOCYCLINE FOR PANITUMUMAB-INDUCED SKIN 

TOXICITY 

T. Yanai 1 , H. Hashimoto 1 , N. Yamazaki 2 , H. Yasui 3 , G. Sakai 4 , S. Akatsuka 5 , 

K. Ogawa 6 , S. Hirai 7 , H. Yamamoto 1 and T. Hamaguchi 8 

1 Division of Pharmacy, National Cancer Center Hospital, Tokyo, JAPAN, 2 Division 

of Dermatological Oncology, National Cancer Center Hospital, Tokyo, JAPAN, 

3 Medical Oncology, Kyoto Medical Center, Kyoto, JAPAN, 4 Division of 

Gastrointestinal Medicine, Saiseikai Utsunomiya Hospital, Utsunomiya, JAPAN, 

5 Division of Medical Oncology, Yokohama Rosai Hospital, Yokohama, JAPAN, 

6 Gastroenterology, University of Toyama, Toyama, JAPAN, 7 Division of 

Gastrointestinal Medicine, Toyama Prefectural Central Hospital, Toyama, JAPAN, 

8 Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, JAPAN 

Background: Panitumumab (Pmab) has been associated with a high incidence of 

skin toxicity. The STEPP study evaluated whether prophylactic treatment with a 

topical steroid and oral doxycycline during the first 6 weeks of Pmab-containing 



therapy reduced incidence of grade 2 or higher skin toxicities compared to reactive 

treatment. Prophylactic treatment resulted in skin toxicity incidence of 29% 

compared with 62% in the reactive treatment arm. 

Purpose: The aim of this study was to evaluate the efficacy of combination 

prophylactic therapy with topical adapalene and oral minocycline in patients 

receiving Pmab. 

Methods: Patients with KRAS wild-type unresectable/recurrent colorectal cancer 

enrolled in a prospective phase II clinical trial of third-line Pmab plus irinotecan 

(CPT-11) or Pmab monotherapy were included. Prophylactic therapy with 

topical adapalene, a third-generation topical retinoid used in the treatment of 

mild-to-moderate acne, and oral minocycline were started from one day prior to 

the first Pmab dose and continued for 6 weeks. Adapalene was administered 

once daily in the evening, along with oral minocycline 100 mg twice per day. 

Skin toxicity was evaluated according to NCI CTCAE, version 4. The primary 

endpoint was incidence of grade 2 or higher skin toxicities during the 6-week 

skin treatment period. 

Results: Between January 2011 and December 2011, 48 patients were included in this 

study (27 men, 21 women; median age, 62.0 years; 43 CPT-11 + Pmab, 5 Pmab 

alone). During the 6 weeks of prophylactic therapy, incidence of skin toxicities (rash, 

dry skin, and paronychia) was 83.3%. The incidence of skin toxicities of grade 2 or 

higher was 29.2%, similar to STEPP trial results (29%). The median adherence to 

topical adapalene was 90% (range, 0-100%), while minocycline was 100% (range, 

17-100%). In the good adapalene adherence group (≥median), the incidence of skin 

toxicity of grade 2 or higher was 20.8% compared to 37.5% in the poor adherence 

group (

declined to relatively lower level of QOL and then steadily back to moderate QOL“. 

The third type of QOL covered 39.6% of patients and represented “steadily moderate 

level of QOL“. The factors significantly related to the first type of QOL trajectory 

were physical function, pain, poor appetite, uncertainty, and self efficacy; pain, 

uncertainty and self-efficacy were related to the second type of QOL trajectory; and 

depression and uncertainty were related to the third type of QOL trajectory. 

Conclusion: Based on the QOL trajectories and identified factors, the timely and 

tailoring interventions should be developed, applied to and tested for their clinical 

effectiveness in enhancing advanced lung cancer patients’ QOL during the most 

distressful first 6 months of having lung cancer. Acknowledge This study is 

supported by National Health Research Institute (NHRI) in Taiwan. 


1601P PATIENT DIGNITY INVENTORY (PDI) QUESTIONNAIRE: THE 

VALIDATION STUDY IN ITALIAN PATIENTS WITH SOLID AND 

HAEMATOLOGICAL CANCERS ON ACTIVE ONCOLOGICAL 

TREATMENTS 

C.I. Ripamonti 1 , L. Buonaccorso 2 , A. Maruelli 3 , E. Bandieri 4 , M.A. Pessi 5 , 

S. Boldini 6 , C. Primi 7 and G. Miccinesi 8 

1 Supportive Care in Cancer, Fondazione IRCCS, Istituto Nazionale Tumori, 

Milano, ITALY, 2 Psychology, AMO Association of Oncological Patients from nine 

towns and villages in the Northen Area of Modena, Mirandola, ITALY, 

3 Psychology Unit, LILT and Centre for Oncological Rehabilitation CERION of 

Florence, Firenze, ITALY, 4 Oncological Unit, Azienda USL Modena CeVEAS 

Modena, Mirandola Modena, ITALY, 5 Supportive Care In Cancer, Fondazione 

IRCCS, Istituto Nazionale dei Tumori Milano, Milano, ITALY, 6 Supportive Care in 

Cancer, Fondazione IRCCS, Istituto Nazionale dei Tumori Milano, Milano, ITALY, 

7 Psycology, University of Florence, Florence, ITALY, 8 Epidemiology, Cancer 

Prevention and Research Institute ISPO Florence, Florence, ITALY 

Background: In Oncology, little is known about the dignity – related distress and the 

issues that influence the sense of dignity for patients. W validated the Patient Dignity 

Inventory (PDI) questionnaire in Italian patients on oncological active treatments. 

Methods: After the translation procedures, the PDI was administered to 266 patients 

along with other questionnaires to assess the psychometric properties of the Italian 

version of PDI. Factor structure was tested by both explorative and confirmatory 

factor analyses. Concurrent validity was tested through convergent and divergent 

validity with validated questionnaires inquiring about physical and psychological 

symptoms, and religiosity. The test/retest reliability was assessed through the 

concordance coefficient of Linn (two weeks interval, 80 patients). 

Results: The explorative analysis suggested one factor only loading highly on all the 

25 items (>.45) and explaining the 48% of variance; confirmative analysis and 

Cronbach alpha (0.96) confirmed the adequacy of the one-factor model. In the 2 

weeks test-retest study a concordance coefficient of 0.73 (95% C.I.:0.64; 0.83) was 

found. High correlations of problems with dignity were found with both physical and 

psychological symptoms (0.52 and 0.64 rho coefficient, respectively), and moderate 

inverse correlation with spiritual well being (-.40). The dignity construct, as 

measured by PDI; showed to be orthogonal to that of religiosity (-.02). 

Conclusions: The Italian version of PDI is a valid and reliable tool to evaluate the 

dignity related-distress in out-patients with either solid and haematological cancers, 

on active oncological treatments, in non advanced stage of the disease. 


1602P HOPE HERTH INDEX (HHI): A VALIDATION STUDY IN ITALIAN 

PATIENTS WITH SOLID AND HAEMATOLOGICAL 

MALIGNANCIES ON ACTIVE ONCOLOGICAL THERAPIES 

C.I. Ripamonti 1 , L. Buonaccorso 2 , A. Maruelli 3 , E. Bandieri 4 , S. Boldini 1 , 

M.A. Pessi 1 , F. Chiesi 5 and G. Miccinesi 6 

1 Supportive Care in Cancer, Fondazione IRCCS, Istituto Nazionale Tumori, 

Milano, ITALY, 2 Psychology, AMO Association of Oncological Patients from nine 

towns and villages in the Northen Area of Modena, Mirandola, ITALY, 

3 Psychology Unit, LILT and Centre for Oncological Rehabilitation CERION of 

Florence, Firenze, ITALY, 4 Oncological Unit, Azienda USL Modena CeVEAS 

Modena, Mirandola Modena, ITALY, 5 Psychology, University of Florence, 

Florence, ITALY, 6 Epidemiology, Cancer Prevention and Research Institute ISPO 

Florence, Florence, ITALY 

Aims and background: Although Hope is a term widely used, the experience of 

hope in patients with chronic diseases or even life threatening is often disregarded 

due to the scarcity of assessment tools carefully crafted and validated. The aim of the 

study was to validate the Hope Herth Index (HHI) questionnaire in the Italian 

population of patients with solid or haematological cancers during oncological active 

treatment. 

Methods: After the translation procedures, the psychometric properties of the Italian 

version of the Hope Herth Index (HHI) were evaluated in 266 patients with 

non-advanced cancer cared for in four different settings. Summative scores ranged 


from 12-48, with a higher score denoting greater hope. Confirmative factorial 

analysis to assess dimensionality was performed. The test/retest reliability was 

assessed by means of the Linn concordance coefficient (two weeks interval, 80 

patients). Concurrent validity was assessed through the following questionnaires: 

Hospital Anxiety and Depression Scale (HADS), Functional Assessment of Chronic 

Illness Therapy-Spiritual Well-Being (FACIT-Sp), Edmonton Symptom Assessment 

Scale (ESAS) and System Belief Inventory (SBI-15R). 

Results: A total of 266 patients were enrolled. Confirmative Factor analysis did not 

confirm the original three factors solution, whereas a one factor solution did perform 

well. Cronbach alpha was 0.84. Test-retest reliability was 0.64 (95% C.I.: 0.51; 0.76). 

Large convergence was found with spiritual well being as measured by the FACIT-Sp 

(0.69) and with anxiety-depression as measured by the HADS (inverse correlation: 

-0.51). Physical symptoms and religiousness were only slightly correlated, as 

expected. 

Conclusions: The Italian version of Herth Hope Index (HHI) is a valid and reliable 

assessment tool, useful to initiate conversation with someone who is troubled but 

finds it difficult to talk, in cancer patients on active oncological treatment during the 

non advanced stage of the disease, with either solid and haematological cancers. 


1603P SERUM PLASMA LEPTIN LEVELS AND LIFE EXPECTANCY 

IN CANCER PATIENTS WITH TERMINAL ILLNESS 

C. Spoto, M. Iuliani, A. Zoccoli, F. Pantano, F.M. Guida, S. Intagliata, V. Limetti, 

B. Vincenzi, G. Tonini and D. Santini 

Medical Oncology, University Campus Bio-Medico, Rome, ITALY 

Introduction: Excess body fat (assessed by Body Mass Index, BMI) is an established 

risk factor in various cancers and high BMI is directly associated with elevated levels 

of leptin. Leptin, in addition to its neuroendocrine function involved in the 

regulation of appetite, can act as a mitogen and an angiogenic factor and it seems 

also associated with cancer cachexia and chronic inflammation. However, data on the 

association between leptin levels and cancer progression are contradictory and not 

definitive. The objective of the present prospective study was to investigate the 

relationship between leptin and life expectancy in advanced cancer patients, 

regardless of the primitive tumor. 

Methods: We assessed Palliative Prognostic (PaP)-Score in cancer patients from the 

Medical Oncology Unit at CampusBio-MedicoHospital in Rome. PaP-score ranked 

patients into three groups with a different 30-day survival probability (A = 82%; B = 

52.7%; C = 9.6% respectively). We enrolled 20 patients for each PaP-Score subgroup. 

For each patient, leptin serum levels were measured by ELISA (Enzyme-Linked 

ImmunoSorbent Assay) using commercially available kit (R&D System). Statistical 

analysis was performed using Mann-Whitney U-test. 

Results: The mean leptin serum concentration in PaP-Score C subgroup was 

significantly higher compared to PaP-Score A patients subgroup (P = 0.046) with an 

increase in mean leptin levels of 115%. No statistically significant difference was 

observed in mean leptin serum levels beetwen PaP-Score B vs PaP-Score A patients 

(increase of 7%). 

Conclusions: This study showed for the first time a correlation between leptin serum 

levels and life expectancy in end-stage cancer patients according to PaP-Score. 

Further studies in larger populations are warranted to clarify the weight of these 

preliminary results. 


1604P CASE-CONTROL PHASE II CLINICAL TRIAL TO ASSESS 

EFFICACY AND SAFETY, OF THE SAME ANTINEOPLASTIC 

TREATMENT(S) IN ELDERLY “FIT” COMPARED TO ADULT 

PATIENTS WITH CANCER AT DIFFERENT SITES 

G. Mantovani, E. Massa, A. Dessi’, M. Dessi’, L. Orgiano and F.M. Tanca 

Department of Medical Oncology, University of Cagliari, Cagliari, ITALY 

Background: We designed a case-control phase II open, prospective non-randomized 

trial in elderly “fit” (≥65 yo) cancer patients (pts) compared to well-matched adult 

(45-65 yo) cancer pts to assess whether the same standard antineoplastic treatment 

could achieve comparable results as for efficacy and safety. Planned sample size: 125 

pts per arm. Endpoints: safety, QoL, PFS, ORR, dose intensity. 

Patients and methods: Only elderly “fit” pts at MGA were included. Inclusion 

criteria for elderly: histological diagnosis of cancer with either advanced disease with 

measurable lesions or radically resected (adjuvant setting); life expectancy >3 mo.; 

adequate baseline functional parameters; written informed consent. Inclusion criteria 

for adults: the same as for elderly plus ECOG-PS 0-1. 

Results: At September 2011, 254 pts were enrolled, 127 elderly and 127 adults, all 

evaluable for toxicity. Elderly pts clinical characteristics: M/F ratio 69/58; mean age 

70.8 ± 4.5 y. Adult pts: M/F ratio, 58/69; mean age 53 ± 5.4 y. Tumor sites: colo-rectal 

(23.5%), head and neck (16.4%), breast (14.1%), lung (11.7%), ovarian (9.3%); 

prostate (6.2%), NHL (4.7%), gastric (4.7%), liver (4.7%), uterus (3.9%), pancreas 

(0.8%); 92.1% of pts were stage IV, 5.9% stage III and 2.0% stage II. In the elderly no 



grade 4 toxicity were observed, hematological and non hematological grade 3 

toxicities were observed in 12.21% and 13.8% of pts, respectively. In the adults, grade 

4 hematological and non hematological toxicity were observed in 3.8% and 1.9% of 

pts, respectively; grade 3 hematological toxicity in 23.2% and non hematological 

toxicities in 21.3% of pts. The difference was statistically significant (p = 0.042) in 

favor of the elderly. At September 2011, 234 pts were assessable for response: the 

ORR was 50.7% for elderly and 51.1% for adults. No differences were observed for 

quality of life and dose intensity between the two groups. PFS was 10.6 mo. (3-12 + 

mo) for elderly and 9.05 mo. (3-12 + ) for adults. 

Conclusion: The promising results of this single Institution study warrant to be 

confirmed by a larger clinical trial. 


1605P OPINIONS OF NURSES ON THE APPLICATION AND 

IMPLICATIONS OF DNR/DNI ORDERS 

I.C. Glitza 1 , H.J. Conter 1 , R. Turner 2 , S.K. Reddy 3 and E. Bruera 4 

1 Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, 

UNITED STATES OF AMERICA, 2 Palliative Care, Albert Einstein Medical Center, 

Philadelphia, PA, UNITED STATES OF AMERICA, 3 Department of Palliative Care 

and Rehabilitation Medicine, MD Anderson Cancer Center, Houston, TX, 

UNITED STATES OF AMERICA, 4 Palliative Care and Rehabilitation Medicine, M. 

D. Anderson Cancer Center, Houston, TX, UNITED STATES OF AMERICA 

Background: Although do not resuscitate (DNR)/ do not intubate (DNI) orders have 

a technically limited mandate, the implication of such orders may be broad. 

Moreover, the patient factors that may influence healthcare providers’ decisions may 

be debated. This study aimed to evaluate nurses’ opinions on DNR/DNI orders. 

Methods: The study was conducted as an anonymous, single institution survey. 

Fulltime nurses (RNs) were identified by payroll and received a questionnaire. 

Nurses’ demographics and background, their rating of factors leading to DNR/DNI 

and rating of appropriateness of treatments were obtained. 

Results: Of the 350 distributed surveys, 83% were returned. Work locations included 

general floors (47%), intermediate care (21%) and ICU (32%). Sixty-seven percent 

were ≤ 40 years old, 88% were female, and 73% had ≤ 10 years of work experience. 

204 RNs felt that DNR/DNI orders influence treatment choices of physicians, 81% 

felt they should be more included in the discussion process. Female RNs were more 

likely to change the amount of time spent at bedside (OR 0.32, 95%CI 0.12-0.92) and 

they felt that physician’s treatment choices were influenced by DNR orders (OR 0.36, 

95% CI 0.17-0.74) compared to males. From an RN view, most important factors 

leading to a DNR/DNI order were patients’ wishes (99%), untreated/untreatable 

cancer (94%) and quality of life before admission (89%). For less experienced RNs, 

there was a general trend to support the administration of blood products, 

antibiotics, feeding tube placement, invasive procedures, vasopressors, and ICU 

transfer. Their support for hemodialysis was the only variable that was statistically 

significant (OR 1.74, 95% CI 1.03- 2.97). Pooled analysis demonstrated that less 

experienced were more likely to support a more agressive treatment approach (OR 

1.41, 95%CI 1.17-1.71, i^2= 0%). 

Conclusion: Nurses regard patients’ wishes, quality of life, serious diseases as the 

most important factors leading to a DNR/DNI order. Less experienced nurses favor a 

more aggressive treatment approach. Nursing staff feel that they should be a vital part 

of the DNR/DNI discussion. Further continuous education of the whole health care 

team on the meaning and implication of DNR/DNI orders is mandated. 


1606P PARENTAL CANCER: REVIEWING THE CONCERNS OF 

BREAST CANCER PATIENTS WITH CHILDREN 

E. Miura and T. Ishida 

Child Support, St.Luke’s International Hospital, Tokyo, JAPAN 

Background: In recent years, it is estimated that 24% of cancer patients have a child 

under 18 years of age. Affected parents may experience heightened distress related to 

the worries about their illness as well as their inability to perform parenting 

activities. Many parents also struggle with what and how to tell their children about 

their own or their loved one’s illness and future. Since 2008, St. Luke’s International 

Hospital (Tokyo, Japan) started a service called “Child Support”, for these patients to 

discuss their concerns, providing them with appropriate suggestions and useful 

resources. 

Objective: The objective of this research is to review and organize the concerns 

breast cancer patients with children have, and to review the types of support 

provided by the professionals. 

Method: Medical charts of breast cancer patients with under aged children, who 

were offered to a child support service between the period of April 2010 and 

November 2011, were reviewed (n = 172). 

Result: 75% of the child support sessions started from the direct offering by the 

Child Life Specialist (CLS). Nurses were slightly more active in referring the patients 

to the service. 70% of the patients’ concerns were topics that directly related to their 

children. The two most common concerns were “confrontation to the children about 

parent’s illness” (30%), and “how the illness will impact the child” (40%). While less 

than 10% showed absolutely no concern, others showed concerns in topics related to 

one’s own illness (

1609P PHYSICAL ACTIVITY (PA) AND PHYSICAL FITNESS (PF) IN 

LYMPHOMA PATIENTS BEFORE DURING AND AFTER 

CHEMOTHERAPY (PAFILP): A PROSPECTIVE 

OBSERVATIONAL PILOT-STUDY 

P. Wolter 1 , N. Vermaete 2 , D. Dierickx 3 , A. Janssens 3 , P. Schöffski 1 , G. Verhoef 3 

and R. Gosselink 2 

1 Department of General Medical Oncology, University Hospitals Leuven, Leuven, 

BELGIUM, 2 Department of Rehabilitation Sciences, KU Leuven, Leuven, 

BELGIUM, 3 Department of Hematology, University Hospitals, Leuven, BELGIUM 

Background: We performed a prospective longitudinal single-center pilot study to 

investigate physical activity (PA) and physical fitness (PF) in Hodgkin Lymphoma 

(HL) and Non-Hodgkin-Lymphoma (NHL) patients before, during and after 

first-line systemic chemotherapy. Further aims were to correlate different patient-, 

disease-, and treatment-related factors with the possible decline or increase of PA 

and PF and to identify patients at risk of developing a significant decline in PA and 

PF who might be candidates for an individualized exercise training program. 

Methods: PA was assessed with an activity monitor (Dynaport MiniMod McRoberts, 

The Hague, The Netherlands), PF by incremental cycle ergometry and by a 6 minute 

walking test (6MWD). Isometric quadriceps strength was measured using a Cybex II 

dynamometer (Lumex, Bay Shore, United States). Pulmonary function tests, 

electrocardiogram, echocardiography, blood pressure measurements were routinely 

performed. 

Results: The pilot study involved a total of 22 lymphoma patients (♂: 19, ♀: 3, 

median age 57 years, NHL: 14, HL: 8) from 10/2010 to 01/2012. At baseline PA, 

6MWD, maximal inspiratory pressure, quadriceps strenght, diffusion capacity at 

pulmonary function tests were significantly lower than predicted. In contrast, forced 

expiratory volume in one second (FEV1), forced vital capacity (FVC), maximal 

oxygen consumption (VO2max), maximal expiratory force and hand grip force were 

not significantly different. We observed a broad variation in the different test results 

between patients at baseline. After 2-3 cycles of chemotherapy we did not identify a 

significant decrease in PA, whereas VO2max decreased significantly after 2-3 cycles 

but recovered after completion of chemotherapy (6-8 cycles). Importantly, a huge 

interpatient variability could be observed at all different time points. 

Conclusions: Preliminary results of the PAFILP pilot study suggest that levels of PA 

and PF probably evolve very differently between lymphoma patients. The study is 

ongoing to identify possible risk factors predictive for decline in PA and PF. Such a 

screening tool would allow us to identify early in the course of treatment patients at 

risk of developing a significant decline in PA and PF who might benefit from an 

individualized exercise training program. 


1610P SURVEY OF OUTPATIENT CANCER CHEMOTHERAPY: 

OCCURRENCE OF SIDE EFFECTS AND REASONS FOR 

DISCONTINUATION OR DELAY 

H. Kushihara 1 , K. Kawada 2 , T. Kushihara 3 , N. Hamajima 4 , M. Amano 4 , K. Ooji 4 , 

K. Honda 2 , F. Nomura 2 , Y. Ikeda 1 and K. Mori 1 

1 Pharmacy, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, JAPAN, 

2 Medical Oncology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, 

JAPAN, 3 Pharmacy, Japanese Red Cross Nagoya First Hospital, Nagoya, 

JAPAN, 4 Nursing, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, 

JAPAN 

Background: In cancer chemotherapy, patients have various side effects. In general, if 

patients’ quality of life is negatively affected (e.g., toxicity of grade 3 or higher), the 

treatment will be discontinued. On the other hand, if symptoms are mild or 

moderate (e.g., toxicity of grade 2 or lower), the treatment will be continued with 

supportive therapy. Patients with mild or moderate side effects must tolerate such 

adverse effects for a prolonged period. Therefore, to continue chemotherapy safety, it 

is very important to understand the extent of symptoms and to provide suitable 

supportive care as required. We conducted a survey of outpatient cancer 


Methods: We retrospectively investigated the characteristics of side effects and the 

reasons for discontinuation or delay of chemotherapy between July 2009 and March 

2011 at Nagoya Daiichi Red Cross Hospital in Japan. 

Result: Data on 924 patients (8221 cases) were analyzed. The following data are 

presented in the order of grade 2 and grade 3 or higher. Nonhematologic toxicities 

were constipation (32.0, 0.7%), fatigue (21.3, 2.7%), anorexia (17.0, 0.6%), neuropathy 

(15.3, 1.4%), nausea (14.4, 0.6%), pain (13.7, 1.0%), vomiting (7.5, 0.6%), diarrhea 

(6.3, 0.2%), dysgeusia (6.0, − %), oral mucositis (4.1, 0.1%), and nail changes (3.6, 

0.1%). Hematologic toxicities were neutropenia (16.3, 19.1%), thrombocytopenia (4.1, 

2.1%), and anemia (26.1, 7.0%). Nonhematologic toxicities Grade 2 or lower had a 

high average incidence of 44.6%. Chemotherapy was discontinued in 1341 patients 

(16.3%). The reasons for discontinuation or delay were laboratory abnormalities 

(35.4%), chief complaints of patients (34.0%), and others (30.1%). 

Conclusion: In patients with grade 3 or higher toxicity, appropriate care was 

provided, including dose reduction or discontinuation of treatment. In patients with 

grade 2 or lower toxicity, treatment tended to be continued. Our results showed that 

a large proportion of patients tolerate mild or moderate side effects that do not lead 

to discontinuation or delay of treatment. It is necessary to evaluate the extent of 

symptoms and to provide supportive care from an early stage. 


1611P IMPROVING PATIENT ADHERENCE BY USING THE 

FLOWCHART TYPE LEAFLET 


S. Suzuki 1 , M. Yoshida 1 , Y. Yajima 2 , T. Kobayashi 2 , S. Kobayashi 1 , T. Enokida 2 , 

H. Ishiki 2 , K. Endo 3 , K. Izumi 1 and M. Tahara 4 

1 Pharmacy, National Cancer Center Hospital East, Kashiwa, JAPAN, 2 Head and 

Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, 

JAPAN, 3 Drug Safety Management, Meiji Pharmaceutical University, Tokyo, 

JAPAN, 4 Endoscopy & Gi Oncology, National Cancer Center Hospital East, 

Kashiwa, JAPAN 

Background: Most information sheets cover the schedule of chemotherapy sessions 

and the adverse reactions of the respective drugs. However, the leaflets do not 

provide enough information instructing them how to take their supportive 

medications while at home for patients that have adverse drug reactions. We have 

developed a flowchart type leaflet to help improve the patients’ adherence. The 

flowchart consisted of yes/no questions to guide how to take supportive medicine for 

adverse drug reactions or when patients should call to a hospital. 

Objective: This study was designed to evaluate the benefits associated with the 

flowchart type leaflet (FC). [Subjects and methods] Subjects include head and neck 

cancer inpatients who received induction chemotherapy, TPF (docetaxel, cisplatin, 

and 5FU) or TPS (docetaxel, cisplatin, and S-1), from September 2009 to April 2012. 

Group A used FC while Group B did not use FC in their chemotherapy. A 

retrospective study was performed using patient records. The endpoints of this study 

were: (1) To determine the emergency hospital admissions/visits, (2) To determine 

the nonadherence, (3) To determine the telephone calls from patients. 

Results: There were 49 patients and a total of 139 chemotherapy sessions in group A 

while there were 60 patients and a total of 163 chemotherapy sessions in group B with 

no significant differences in age, performance status, and their chemotherapy regimen. 

The results are: (1) Incidence of emergency hospital admission was significantly lower 

in group A compared to group B. (Group A v.s. Group B: 1% v.s. 10%, p < 0.01) (2) 

The nonadherence rate in supportive medication for adverse drug reactions due to 

chemotherapy was significantly lower in group A than group B (Group A v.s. Group 

B: 5% v.s. 23%, p < 0.01). (3) Telephone call rates were statistically significant in group 

A (16%, total 30 calls) compared to group B (7%, total 11 calls) in each chemotherapy 

regimen. Of the 30 telephone calls in group A, 24 calls (80%) were in a situation 

where patients needed to call a hospital and 5 calls (45%) in group B. 

Conclusions: The FC could contribute to reducing emergency hospital admissions to 

prevent nonadherence and encourage patients’ judgments in chemotherapy. 


1612P BREAKTHROUGH PAIN (BTP) IN OPIOID-TOLERANT 

CANCER PATIENTS: A PAN-EUROPEAN OPEN-LABEL 

MULTICENTRE STUDY WITH FENTANYL BUCCAL TABLET 

(FBT) 

S. Mercadante 1 , A. Davies 2 , J. Jarosz 3 , U.R. Kleeberg 4 ,T.O’Brien 5 , P. Poulain 6 

and H. Schneid 7 

1 Anesthesia and Intensive Care Unit & Pain Relief and Palliative Care Unit, La 

Maddacena Cancer Center, Palermo, ITALY, 2 Palliative Medicine, Royal Surrey 

County Hospital NHS Foundation Trust, Guildford, UNITED KINGDOM, 3 Palliative 

Medicine Unit, SCMCC and Institute of Oncology, Warsaw, POLAND, 

4 Hematology and Medical Oncology, H, Hamburg, GERMANY, 5 Palliative 

Medicine, Marymount Hospice, Cork, IRELAND, 6 Palliative Unit, Polyclinique de 

l’Ormeau, Tarbes, FRANCE, 7 Medical Affairs EU, Teva Pharmaceutical, 

Maisons-Alfort, FRANCE 

BTP, a transitory exacerbation of pain that occurs on a background of otherwise 

controlled persistent pain, is a common problem in cancer patients. FBT is indicated 

for the treatment of BTP in adults with cancer already receiving maintenance opioid 

therapy for chronic cancer pain and should be titrated to an effective dose that 

provides adequate analgesia and minimises undesirable events. In this study, patients 

entered a screening period and were randomized during an open-label titration 

period to a starting FBT dose of 100 µg (group A) or 200 µg (group B) to identify 

the FBT effective dose and then treated in an open-label period (for 8 BTP episodes). 

Patients’ inclusion followed the FBT label. 442 patients were screened from 135 

European sites (7 countries) and 330 were enrolled into the titration period [group A 

(156); group B (174)]. Cancer history of the patients: breast (20.3%), lung (14.2%), 

colon/rectum (12.1%), other (24.5%). The most frequent extent of the disease was 

bone metastasis and local disease, for 45.8% and 40.6% of patients, respectively. 312 

(94.5%) received at least one dose of study drug during the titration period [group A 

(145; 92.9%); group B (167; 96.0%). The effective dose rate (primary outcome) was 

75.2% in the group A compared to 81.4% in the group B with non-inferiority 



established. Medication performance was assessed during the treatment period using 

a 5-point scale (0 = poor to 4 = excellent). Responses at 30 min. and at 60 min. post 

dose were “good” to “excellent” for 70.3% (1248/1176 BTP) and 82.4% (1374/1668 

BTP) respectively. Patients’ quality of life and functional status [modified Brief Pain 

Inventory-short version 7 item subscale (BPI-7S)] improved after treatment with FBT 

[BPI-7S global score [mean (SD)] decreased from 39.7 (15.85) before to 31.6 (16.8) 

after treatment. The ease of use of FBT was rated “very easy/convenient” and “easy/ 

convenient” for 82.5% (174/211) of patients. Safety data do not indicate concerns 

with use of FBT and were as expected for cancer patients with opioid treatments. 

These results demonstrate that FBT was safe and efficacious in a real-world clinical 

practice setting with a large number of cancer patients experiencing BTP. 

Disclosure: S. Mercadante: Investigator, A. Davies: Investigator, J. Jarosz: 

Investigator, U.R. Kleeberg: Investigator, T. O’Brien: Investigator, P. Poulain: 

InvestigatorH. Schneid: Teva Pharmaceutical employee. 

1613P ACUTE ONCOLOGY SERVICE AND REDUCTION OF 

INPATIENT LENGTH OF STAY FOR CANCER PATIENTS. A 

REPORT FOR 846 PATIENTS ADMITTED WITH 

ONCOLOGICAL EMERGENCIES 

A. Mostyn-Jones, L. Burton, M. Keni and M. Karina 

Beacon Cancer Centre, Musgrove Park Hospital, Taunton Somerset, UNITED 

KINGDOM 

Background: The Acute Oncology Service (AOS) has been recommended in the UK 

since 2008, when the National Chemotherapy Advisory Group (NCAG), and the 

National Confidential Enquiry into Patient Outcome and Death (NCEPOD) reported 

the results of safety and quality in systemic therapy for cancer patients. The National 

Patient Safety agency (NPSA) recommended that cancer related emergencies be dealt 

in a systematic approach. This abstract refers to the data from patients with known 

or undiagnosed cancer, admitted in Musgrove Park Hospital (MPH) and referred to 

the AOS. 

Materials and method: We collected the data of patients admitted to MPH because 

of cancer or treatment-induced complications or undiagnosed cancer. Patients were 

referred via the inpatient referral system and were registered daily in a purpose built 

database. We recorded patients’ demographics, diagnosis, metastatic sites, treatment 

type, reason of admission and length of in-hospital stay (LOS). 

Results: From June 2010 to April 2012, 846 patients were admitted with oncological 

complications. 48% had multiple metastatic sites, 18% had primary diagnosis of 

breast cancer, 19% urological, 16% lung, 24% upper and lower GI cancers and 5% of 

unknown primary. Only 1% of patients were referred from A&E department, 28% 

from medical assessment unit and 71% from the medical wards. 29% of patients were 

admitted during their chemotherapy period, 8% during their radiotherapy treatment, 

whereas for 38%, the type of treatment was not reported. The reasons of admission 

were: Dyspnoea 14%, Neutropenic sepsis 8%, CNS related 9%, metastatic spinal cord 

compression 6%, pain 12%, miscellaneous/unclear 51%. Admission was attributed to 

cancer and/or treatment in 73% of patients and it was unclear/unknown in 23%. The 

number of referrals has increased from 50 for the first 2 months to 97, the last 2 

months. The LOS ranged from 0-102 days and the median remained stable at 10 

days. 

Conclusion: The majority of cancer patients with complications are admitted in 

medical wards. This real time audit will be used to re-define the appropriate AOS 

model. Further education, communication, recourses and training are mandatory to 

reduce the patients’ LOS and develop a cost-efficient service. 


1614P OCULAR ADVERSE EFFECTS (OAES) OF MOLECULARLY 

TARGETED AGENTS (MTAS) APPROVED IN ONCOLOGY: A 

SYSTEMATIC REVIEW 

O. Huillard 1 , S. Bakalian 2 , C. Levy 2 , L. Desjardins 2 , L. Lumbroso 2 ,S.Pop 2 , 

M. Sablin 1 , V. Diéras 1 and C. Le Tourneau 1 

1 Department of Medical Oncology, Clinical Trial Unit, Institut Curie, Paris, 

FRANCE, 2 Department of Ophthalmology, Institut Curie, Paris, FRANCE 

Background: MTAs display different toxicity profiles than conventional cytotoxic 

agents, with primarily non-hematological toxicity. This study aimed to describe the 

OAEs reported with the use of MTAs approved in oncology. 

Methods: EMEA and FDA product information files (PIFs) were reviewed including 

all MTAs approved in oncology as of January 1st, 2012. Incidence, severity and types 

of OAEs were recorded. OAEs reported in these files were compared to the ones 

described in the publications of the trials that led to drug approval. 

Results: OAEs were reported in the PIFs for 14 out of the 16 reviewed MTAs (88%). 

44 different types of OAEs were reported in the PIFs, 30% and 52% being items 

appearing in the National Cancer Institute Common Terminology Criteria for 

Adverse Events (NCI CTCAE) version 3 and 4, respectively. Common OAEs 

occurring with a frequency ranging from 1 to 10% were reported for 75% of MTAs. 

The most common reported OAEs were increased lacrimation, dry eye, blurred 

vision, ocular hyperemia, eyelash changes, eye pain, eye irritation, eye pruritus, eyelid 

irritation, conjunctivitis, eyelid edema, blepharitis, keratitis, periorbital edema, 

amblyopia, conjunctival hemorrhage, eye hemorrhage, eye infection, eye edema and 

eyelid infection. Serious OAEs (Grade ≥3 or with a warning in the PIFs) were 

reported for 62.5% of the MTAs, and included conjunctivitis, periorbital edema, 

keratitis, eyelid edema, blepharitis, papilledema, uveitis, cataract, irititis, episcleritis, 

scleritis, corneal perforation, and retinal vein occlusion. All these serious OAEs were 

uncommon with a frequency ranging from 0.1% to 1%. Intriguingly, OAEs were 

reported in the publications of the corresponding pivotal trials for only 5 out of the 

14 MTAs for which OAEs were reported in the PIFs. 

Conclusions: MTAs display frequent and varied OAEs that sometimes clearly lack 

precision in their descriptions. These OAEs can be severe and are not well captured 

by the NCI CTCAE. Finally, these OAEs are not well reported in the publications of 

the pivotal clinical trials. Efficient collaboration between clinical trial conductors and 

ophthalmologists should help defining and handling the OAEs occurring in patients 

treated with MTAs. 


1615P THE IMPACT OF ANEMIA IN ADVANCED SOLID TUMORS 

TREATED WITH SORAFENIB (SO) AND SUNITINIB (SU): A 

POOLED ANALYSIS OF 6 TRIALS 

S. Barni 1 , K.F. Borgonovo 1 , M. Ghilardi 2 , M. Cabiddu 1 , F. Maspero 1 , 

M. Cremonesi 1 and F. Petrelli 1 


ITALY, 2 Medical Oncology Division, A.O. Trevilgio-Caravaggio, Treviglio, ITALY 

Introduction: Anemia is a frequent and serious complication experienced by many 

cancer patients, especially those receiving chemotherapy. Targeted therapies are 

associated with a significant risk of anemia too but this data is often underreported in 

clinical trials. We described in a published meta-analysis of 24.310 patients affected by 

solid tumours, that the addition of targeted therapies to standard treatment increased by 

7% the risk of all grades anemia (p = 0.09). Now we perform a pooled analysis to 

evaluate the risk of anemia in patients treated with So and Su as single agent therapy 

Materials and methods: We searched PubMed for published, randomized, 

controlled, Phase II and III trials (RCTs), and we have performed a pooled-analysis 

to calculate the incidence of anemia associated with So and Su. Relative risk (RR) 

with 95% confidence interval has been calculated to quantify the burden of anemia 

in these patients. 

Results: Six studies have been selected, for a total of 2802 patients analysed. Four 

trials included Su and 2 So. Comparison arms were: Axitinib in 1 trial, Bevacizumab/ 

INF or Bevacizumab/Temsirolimus in 1 trial, placebo in 3 trials and no therapy in 1 

trial The overall incidence of anemia was 44% in experimental vs 34% in control 

arms (incidence difference 9.8%; p =

patients were admitted to the oncology day care unit for 8 hours in order to facilitate 

repeated blood testing. Blood samples were obtained before the injection of LMWH 

and 1, 2, 3, 4, 6 and 8 hours after LMWH subcutaneous administration, and tested 

for anti Xa activity as a surrogate marker of bioavailable LMWH levels. The trial was 

approved by the ethics committee of Shaare Zedek Medical Center. ClinicalTrials.gov 

Identifier: NCT00716898. Study funding: Israel Cancer Association. 

Results: Eleven patients were enrolled; one was excluded from analysis due to 

complete remission at time of VTE diagnosis. Peak anti Xa activity was achieved 

after 2, 3, 4, 6, and 8 hours in 2, 3, 2, 2, and 1 patient respectively. 60% of the 

patients (n = 6) did not reach the therapeutic anti Xa activity target (0.6 -1.0 IU/ml) 

at 4 hours after subcutaneous administration of LMWH. Average anti Xa activity at 4 

hours was 0.62 ± 0.29 IU/ml as opposed to 1.1 IU/ml in historical controls of 

non-oncology patients. 

Conclusions: Our results show that a substantial number of cancer patients suffering 

from VTE and treated with standard dose enoxoparin do not reach therapeutic target 

anti Xa activity. If confirmed in a larger study, our results suggests that cancer 

patients suffering from VTE should be tested for anti Xa activity and LMWH dose 

should be titrated accordingly in order to achieve effective anticoagulation. 


1617 EDMONTON SYMPTOM ASSESSMENT SCALE (ESAS) FOR 

ROUTINE SYMPTOM ASSESSMENT OF NON-ADVANCED 

PATIENTS WITH SOLID OR HAEMATOLOGICAL 

MALIGNANCIES ON ONCOLOGICAL THERAPIES 

C.I. Ripamonti1 , S. Boldini2 , L. Buonaccorso3 , E. Bandieri4 , A. Maruelli5 ,M. 

A. Pessi6 and G. Miccinesi7 1 

Supportive Care in Cancer Unit, Fondazione IRCCS - Istituto Nazionale dei 

Tumori, Milano, ITALY, 2 Supportive Care in Cancer, Fondazione IRCCS, Istituto 

Nazionale dei Tumori Milano, Milano, ITALY, 3 Psychology, AMO Association of 

Oncological Patients from nine towns and villages in the Northen Area of 

Modena, Mirandola, ITALY, 4 Oncological Unit, Azienda USL Modena CeVEAS 

Modena, Mirandola Modena, ITALY, 5 Psychology Unit, LILT and Centre for 

Oncological Rehabilitation CERION of Florence, Firenze, ITALY, 6 Supportive Care 

in Cancer, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, ITALY, 

7 

Epidemiology, Cancer Prevention and Research Institute ISPO Florence, 

Florence, ITALY 

The Edmonton Symptom Assessment Scale (ESAS) was developed for use in daily 

symptom assessment of palliative care patients. We used the ESAS validated version in 

Italian Language to assess the presence and intensity of symptoms (not at all = 0; mild 

1-4, not controlled ≥5) in 108 patients with solid and 86 with haematologic malignancies 

and no metastases, on active oncological treatments (156 patients) or during follow-up. 

In haematologic group, dyspnoea was ≥ 5 in 12% of the patients in respect to 3% of solid 

tumour group (chi2 test, p = 0.002). Not controlled fatigue, drowsiness and dyspnoea 

were significantly more frequent in patients on cure (p = 0.041; p = 0.026; p = 0.010 

respectively). The intensity of all the symptoms was higher in patients with a KPS of 

70-90 in respect to those with KPS > 90, and in patients above the clinical HADS cutoff 

(10/11) in respect to those below. The intensity of psychological suffering was higher for 

patients who requested psychological support. The correlation (rho of Pearson) between 

the anxiety and depression items of ESAS with HADs was >.5, whereas the feeling of 

well- being in ESAS inversely strongly correlated with all the other ESAS symptoms (rho 

> .4); anorexia with nausea and drowsiness; drowsiness with fatigue; and anxiety with 

depression. As the ESAS assesses the most frequent symptoms referred to by the patients 

during oncological treatments, its administration to the patients in the routine practice 

before each visit with the oncologist can give him/her the information on the presence 

and intensity of physical and emotional symptoms. 


1618 IN VITRO DRUG-DRUG INTERACTION STUDIES WITH THE 

ANTIEMETIC DRUG NETUPITANT AND ITS MAJOR 

METABOLITES M1 AND M2, INVOLVING SEVERAL HUMAN 

CYTOCHROME P450 ISOENZYMES 

C. Giuliano 1 ,E.Lovati 1 , C. Funk 2 , M. Potthast 2 and C. Pietra 1 

1 Preclinical R&D, Helsinn Healthcare SA, Lugano, SWITZERLAND, 2 Non-clinical 

Drug Safety, Hoffmann La-Roche Ltd., Basel, SWITZERLAND 

Introduction: Nausea and emesis are significant adverse events of chemotherapy. 

Substance P plays a major role in the emetic process especially in the delayed emesis 

occurring 24h after treatment and beyond. Antagonism of substance P effect at the 

neurokinin 1 (NK1) receptor level is a validated target in showing a broad antiemetic 

activity in animal models of emesis and also in humans. Within the new NK1 

antagonists in clinical trials, Netupitant (Netu) has been characterized as an 

antiemetic in vitro and in vivo in various pharmacological experiments against 

emesis induced by chemotherapeutics. In vitro studies have shown that the CYP3A4 

isoenzyme is the major enzyme involved in the oxidative metabolism of Netu. 

Methods: The in vitro inhibition potential of Netu and its major metabolites M1 and 

M2 has been studied for the human cytochrome P450 isoenzymes CYP1A2, 2C9, 

2C19, 2D6 and 3A4 utilizing human liver microsomes and isoform selective 

substrates. 

Results: Netu inhibited the CYP3A4-dependent metabolism of the two isoform 

selective probe-substrates midazolam and testosterone with estimated IC 50 (±S.E.) 

values of 5.9 ± 1 and 1.7 ± 0.2 µM, respectively. For the hydroxylation of diclofenac, 

catalyzed by CYP2C9, IC50 (±S.E.) of 18.0 ± 6 and 22.6 ± 3 µM were calculated in two 

different experiments, utilizing both the free base, and the Netu hydrochloride as 

inhibitors. Netu showed no significant inhibition potential for CYP1A2, 2C19 and 

2D6 (IC 50s >100 µM). 

Conclusions: Significant metabolic drug-drug interactions in human are not 

anticipated for compounds metabolized mainly by CYP1A2, 2C19 and 2D6 and are 

very unlikely for CYP2C9 metabolized drugs based on the expected human plasma 

concentration of Netu in the low μmolar range. However, metabolic drug-drug 

interactions are possible for co-medicated drugs metabolized mainly by CYP3A4, 

based on the high in vitro affinity of Netu for this isoenzyme, as tested with 

testosterone and midazolam (app Ki ∼ 1.1 to 2.2 µM) and for the inhibition potential 

of the metabolites M1 and M2 similar to the parent compound. The in vivo CYP3A4 

interaction has been studied in appropriate designed clinical interaction studies. 

Disclosure: C. Giuliano: Helsinn healthcare employee, E. Lovati: Helsinn Healthcare 

employee, C. Funk: Roche employee, M. Potthast: Roche employee, C. Pietra: Helsinn 

employee. 

1619 CILASTATIN ATTENUATES CISPLATIN-INDUCED 

NEPHROTOXICITY WITHOUT COMPROMISING 

ANTITUMORAL ACTIVITY 


B. Humanes1 , M. Blanco Codesido2 , A. Lázaro1 , S. Camaño1 and A. Tejedor1 1 

Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, SPAIN, 

2 

Servicio de Oncología Médica, Hospital General Univ. Gregorio Marañon, 

Madrid, SPAIN 

Introduction: Cisplatin (CDDP) is a very effective and common treatment in solid 

malignancies used mostly in breast, ovarian, bladder, esophageal, gastric, head and 

neck cancer and germ cell tumors. One of the most important side effects of CDDP 

is the nephrotoxicity, especially with CDDP doses higher than 60 mg/m2, affecting as 

much as 30% of the patients. Nephrotoxicity is a limitating side effect on treatment 

with CDDP, preventing patients with limit kidney function of receiving the drug and 

stopping treatment once kidney function has worsened. Cilastatin (Cls) is a specific 

inhibitor of renal dedydrodipeptidase I (DHP-I) which prevents hydrolysis of 

imipenem and its accumulation in the proximal tubule. In this work we hypothesized 

that Cls acts as a nephroprotector against CDDP-induced damage without 

compromising antitumor activity. 

Methods: Primary cultures of proximal tubular cells (PTCs) and cell lines of different 

malignancies (colon, breast, ovarian, bladder) were cultured with different 

concentrations of CDDP (1, 10 and 30 µM) in the presence or absence of Cls. Cell 

viability was assessed with MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5diphenyltetrazolium 

bromide) assay. Raft staining was measured with toxine B 

choleric and FasL by confocal microscopy. 

Results: Cls interfered with CDDP-induced FasL signalling at raft level on PTCs 

brush border. Concomitant treatment with Cls reduced CDDP-induced changes. 

Several tumoral cell lines were tested with CDDP and Cls together. Cls did not 

increase or decreased tumor growth alone or in combination with CDDP. CDDP 

sensitivity was not affected by Cls. 

Conclusion: By binding a DHP-I, Cls blocks CDDP-induced PTCs apoptosis but it 

does not affect the CDDP antitumoral activity. Our findings suggest that the affinity 

of Cls for renal DHP-I makes this effect specific for proximal tubular cells and may 

be related to a reduction in intracellular drug accumulation. Cls administration might 

represent a novel strategy in the prevention of CDDP-induced acute renal injury. Cls 

treatment could potentially increase the number of patients undergoing CDDP 

treatment or maintaining treatment. Further clinical trials for renal function 

preservation in cancer patients are on development. 


1620 WEIGHT LOSS DESPITE ORAL GLUTAMINE 

SUPPLEMENTATION PREDICTS POOR PROGNOSIS IN 

LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER 

PATIENTS TREATED WITH CONCURRENT 

CHEMORADIOTHERAPY 

C. Parlak 1 , S. Topuk 1 , O. Ozyilkan 2 and E. Topkan 1 




Background: In this retrospective study, we investigated potential impact of weight 

change according to oral glutamine supplementation (GLT) on survival in patients 

with stage IIIB non-small cell lung cancer (NSCLC) treated with concurrent 

chemoradiotherapy. 



Table: 1620 Survival results according to glutamine supplementation (GLT) and wieght loss (WL) 

GLT- and KK+ GLT- and KK- GLT+ and KK+ GLT+ and KK- P-value 

Median OS Months) (95%CI) 15.7 (11.8-19.6) 21,7 (12.1-31.3) 13.5 (9.8-17.2) Not reached yet

Dicarbamin 100 mg/day on day 5 before chemotherapy administration. Treatment 

with Dicarbamin continued for all treatment period. 34 patients of control group 

(202 cycles of chemotherapy) were not giver any prophylaxis of neutropenia. 

Neutropenia was evaluated with Common Toxicity Criteria, Version 3.0. 

Results: Median age was 48 (29 – 55). Grade 4 neutropenia was reported in 6 

(14.2%) patients treated with Dicarbamin and in 11 (32.3%) patients treated without 

Dicarbamin. The beneficial effect of Dicarbamin was also demonstrated by a quick 

recovery of granulocytes levels than in controls. In 15 (35.7%) patients treated with 

Dicarbamin granulocytes levels were normal all period of chemotherapy. The dose 

intensity of chemotherapy was more in group with Dicarbamin prophylaxis. The 

toxicity of Dicarbamin was not observed. 

Conclusions: Dicarbamin is an active agent for prophylaxis of neutropenia without 

specific toxicity. 


1624 NEXT AND VENICE: DESIGN OF TWO MULTICENTRE, PHASE 

IV, PROSPECTIVE, LONGITUDINAL STUDIES EVALUATING 

THE SAFETY PROFILE OF A BIOSIMILAR FILGRASTIM IN 

PATIENTS TREATED WITH CYTOTOXIC CHEMOTHERAPY 

S. Fruehauf 1 , C. Berthou 2 , S. Lepretre 3 , L. Cals 4 , F. Maloisel 5 and D. Kamioner 6 

1 Haemato/Onkologie, Paracelsus Klinik Center for Tumor Diagnostics and 

Therapy, Osnabrück, GERMANY, 2 Département d’Clinique Hématologie, Hôpital 

Morvan, Brest, FRANCE, 3 Département D’Hématologie, 3Centre Henri 

Becquerel, Rouen, FRANCE, 4 Department of Medical Oncology, CHRU de 

Besançon, Besançon, FRANCE, 5 Department of Hematology and Oncology, 

Clinique Saint Anne, Strasbourg, FRANCE, 6 Oncologue Médical et 

Hématologue, Hôpital Privé de l’Ouest Parisien, Trappes, FRANCE 

Introduction: Nivestim is a European Union (EU)-licensed biosimilar filgrastim 

used in the treatment of chemotherapy-induced neutropenia and febrile neutropenia. 

Nivestim has similar pharmacokinetic and pharmacodynamic properties to its 

reference compound Neupogen®, and has demonstrated equivalent safety and efficacy 

in clinical trials. However, the safety of biosimilars in general is closely scrutinised. 

We present designs for two observational phase IV studies that will examine the 

safety profile of prophylactic and curative Nivestim in patients treated with 

cytotoxic chemotherapy in real-world clinical-practice. 

Method: NEXT (Tolérance de Nivestim chez les patients traités par une 

chimiothérapie anticancéreuse cytotoXique en praTique courante) and VENICE 

(VErträglichkeit von NIvestim unter zytotoxischer Chemotherapie in der 

Behandlung malinger Erkrankungen) are multicentre, prospective, longitudinal, 

observational studies that aim to monitor 2000 adult and 700 adult and paediatric 

patients respectively 12 months. The primary objective of the studies is to assess the 

safety of Nivestim in patients undergoing cytotoxic chemotherapy for malignancy 

through the evaluation of adverse events in all organ system classes, as required by 

EU pharmacovigilance guidelines. Secondary objectives include obtaining data on 

efficacy outcomes, lab values, patterns of use of Nivestim, dose intensity, 

indications for treatment, patient characteristics, physician knowledge of filgrastim 

prescribing, and the reasons for choosing Nivestim. VENICE will also include data 

on levels of CD34+ cells to assess predictive value as a marker of response. Data will 

be gathered over 3 patient visits: 1) inclusion visit, 2) first follow-up after first course 

of Nivestim, and 3) second follow-up after completion of chemotherapy. 

Results: Accrual figures as of 1 May 2012 are 630 (NEXT) and 136 (VENICE). 

Completion dates are June 2013 and June 2014 respectively. 

Conclusion: Data from NEXT and VENICE will provide additional information on 

the long-term safety and efficacy of Nivestim in patients receiving cytotoxic 

chemotherapy in clinical practice. 

Disclosure: S. Fruehauf: Receiving support from Hospira for the conduct of the 

VENICE study, C. Berthou: Receives support from Hospira for the conduct of the 

NEXT study, S. Lepretre: Receives support from Hospira for the conduct of the 

NEXT study, L. Cals: Received support from Hospira for the conduct of the NEXT 

study, F. Maloisel: Receive support from Hospira for the conduct of the NEXT study, 

D. Kamioner: Receives support from Hospira for the conduct of the NEXT study. 

1625 NEUTROPENIA IN LUNG CANCER PATIENTS TREATED WITH 

CHEMOTHERAPY IN A ROUTINE CLINICAL PRACTICE – AN 

INSTITUTIONAL EXPERIENCE 

N.T. Hitij 1 , K. Mohorcic 1 , A. Sadikov 2 and T. Cufer 1 

1 Department of Medical Oncology, University Clinic Golnik, Golnik, SLOVENIA, 

2 Department of Artificial Intelligence, Faculty of Computer and Information 

Science Ljubljana, Ljubljana, SLOVENIA 

Background: Febrile neutropenia (FN) is a serious complication of chemotherapy 

(ChT). Lung cancer patients are fragile with much comorbidity mostly receiving 

intermediate FN (iFN) risk ChT schemas and primary prophylaxis with granulocyte 

colony-stimulating factors (ppG-CSF) should be used in a majority of pts according 

to recommendations. A routine use of ppG-CSF in clinical practice seems to be 

variable. Therefore, we conducted a retrospective analysis of lung cancer pts treated 

with ChT in a routine clinical practice at University Clinic Golnik (2009-2011), 

estimating the rate and severity of neutropenia, the rate of FN and treatment 

strategies. 

Patients and methods: A typical collective of 190 pts with advanced lung cancer 

(SCLC 29% and NSCLC 71%) treated with ChT alone were included. Most pts 

received platinum based ChT (cisplatin 64.7%, carboplatin 20.0%), only 15.3% 

received other ChT schemas. For most of the pts it was first line ChT (86.8%). 

Majority of the pts received 6 cycles of ChT (46.3%), 53.7% of pts received 2-6 

cycles. Only one patient received ppG-CSF. 

Results: Neutropenia at any time during ChT was recorded in 100/190 (52.6%) of 

pts, in 60/190 (31.6%) of pts it was grade 3 or 4. FN was recorded in 16/190 (8.4%) 

of pts. Mostly, neutropenia developed after the first three cycles of ChT (76.0%). One 

patient died due to FN. There was no correlation between occurrence of neutropenia 

and cisplatin- vs. carboplatin- based ChT, nor the line of ChT. Secondary 

prophylactic G-CSF was used in 14/190 (7.4%) of pts, 8 of them received G-CSF after 

the episode of FN, and 6 of them due to higher grade neutropenia without FN. All 

pts with FN received standard antibiotic treatment, while secondary prophylaxis with 

G-CSF has not been initiated in 8 pts due to the dose reduction in following cycles 

and death in one case. No patient suffered from recurrent FN episode. 

Conclusion: Despite a negligible use of ppG-CSF in our collective of pts a very low 

rate of FN (8.4%) was observed. Due to retrospective nature of the analysis we 

certainly might have missed some cases of FN, less likely there were some major 

complications due to missed FN. Based on this retrospective analysis we cannot 

neglect the use of ppG-CSF in lung cancer patients receiving iFN risk ChT, though, 

the actual proportion of patients needing ppG-CSF is questionable. 


1626 CHLORHEXIDINE FOR THE PREVENTION OF BLOODSTREAM 

INFECTION (BSI) ASSOCIATED WITH PERMANENTLY 

IMPLANTABLE VENOUS PORTS (PORT-A) IN SOLID CANCER 

PATIENTS: A PROSPECTIVE COHORT STUDY 

H. Kao 1 , I. Chen 1 , S. Chang 2 , M. Hong 2 , S. Chien 3 ,F.Hu 4 , C. Hsu 5 and K. Yeh 6 

1 Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch, 

Yunlin, TAIWAN, 2 Department of Nursing, National Taiwan University Hospital, 

Taipei, TAIWAN, 3 Center for Infection Control, National Taiwan University 

Hospital, Taipei, TAIWAN, 4 Graduate Institute of Clinical Medicine, National 

Taiwan University College of Medicine, Taipei, TAIWAN, 5 Department of 

Oncology, National Taiwan University Hospital, Taipei, TAIWAN, 6 Oncology Dept., 

National Taiwan University Hospital, Taipei, TAIWAN 

Background: Chlorhexidine can prevent surgical wound infection and BSI related to 

central venous catheters, but its effects on preventing BSI associated with Port-A use 

in cancer patients remain obscure. 

Methods: Solid cancer patients who were implanted with a Port-A since Dec 2010 at 

our department for systemic anti-cancer therapies were prospectively followed for the 

occurrence of Port-A-associated BSI (PABSI), defined as BSI without other 

identifiable infection foci. All patients used chlorhexidine for Port-A topical care. 

The time to first PABSI in this cohort was compared with a previous cohort for 

whom iodine was used as topical anti-septic. Risk factors of PABSI were analyzed by 

Cox proportional hazards model. 

Results: The baseline characteristics of the two cohorts were similar (table). The 

PABSI incidence was 0.740 and 1.051 per 1000 catheter-day for the chlorhexidine 

and the iodine cohorts, respectively. The use of chlorhexidine can significantly delay 

the time to first Gram-positive-cocci (GPC) PABSI (hazard ratio (HR) 0.41, 95% CI 

0.20-0.84, p = 0.015). Other Independent predictors of increased GPC PABSI 

occurrence included previous chemotherapy (HR = 13.65, 95% CI = 4.12-45.26), total 

parental nutrition (HR =5.17, 95% CI = 2.51-10.63), chronic steroid use (HR = 7.02, 

95% CI = 2.60-18.90), and postoperative antibiotics (HR = 2.06, 95% CI = 1.02-4.14). 

Chlorhexidine had no significant effects on preventing Gram-negative bacilli or 

fungal PABSI. 

Conclusion: The use of chlorhexidine as topical anti-septic may help prevent 

GPC-related PABSI in cancer patients.(supported by grants NTUH 100-S1805) 

Iodine chlorhexidine p value 

Enrollment Oct 2009-Aug 2010 Dec 2010-Nov 2011 

N 396 487 

M/F 202/194 242/245 0.697 

median age 57.7 59.1 0.121 

Cancer type 0.892 

GI 169 209 

Lung 115 129 

Breast 46 71 

H&N cancer + NPC 20 26 

Others 46 52 

N of stage IV 324 (0.82) 376 (0.77) 0.136 

Total catheter-day 81752 99977 





1627 RETROSPECTIVE ANALYSIS OF CANCER AND 

CHEMOTHERAPY INDUCED ANAEMIA TREATED WITH 

FERRIC CARBOXYMALTOSE ONLY, AN INTRAVENOUS IRON 

THERAPY 

B. Tschechne 1 , S. Broszeit-Luft 2 , O. Harlin 3 , W.O. Jordan 2 and H. Zakaria 4 

1 Haematologisch-Onkologische Praxis Neustadt, Neustadt a. Rbge., GERMANY, 

2 Haematologisch-Onkologische Praxis Lehrte, Lehrte, GERMANY, 3 Vifor Pharma 

Deutschland GmbH, München, GERMANY, 4 NewConceptOncology GmbH, 

Lehrte, GERMANY 

Chemotherapy induced anaemia is often treated with ESAs and/or blood 

transfusions. Oral or intravenous iron substitution represent alternatives for both 

cancer and chemotherapy induced anaemia. Current discussions focus on 

intravenous treatment to increase Hb levels in cancer patients, as oral treatments are 

often associated with limited response rates and gastrointestinal side effects. This 

retrospective, single centre analysis investigates the effectiveness of an iv iron 

compound, ferric carboxymaltose (Ferinject® [FCM]) as the only anaemia treatment 

in an unselected, routinely treated anaemic cancer patient population between 2009 

and 2012. Patients fulfilling the following criteria were included in the analysis: 

malignant cancer diagnosis, anaemia, FCM treatment ≧ 4 weeks, complete available 

documentation ≧ 12 weeks, no ESA or other iron medication and no blood 

transfusion during the observation period. At baseline, sex, age, tumour history, 

anti-tumour treatment and history of anaemia treatment during the four weeks prior 

the retrospective analysis were recorded. Modalities of FCM treatment and serum 

levels of available relevant laboratory parameters (e.g. Hb, transferrin saturation 

[TSAT], ferritin, haematocrit) were recorded at baseline and throughout the 

observation period. Treatment response, tolerability and adverse reactions for a total 

of 59 cancer patients were investigated. The median age was 61 (20-91) years, of 

these 14 were male and 45 female. During the FCM therapy, 52 patients were not 

treated actively for cancer and 7 patients were on anticancer treatment. Median Hb 

increase was 2.0 g/dl compared to baseline (range: 0 to 6.2 g/dl). Patients received on 

average 336 mg iron (range: 100-1700mg). No adverse events related to FCM were 

recorded. The results of our retrospective analysis demonstrate the safety and 

effectiveness of FCM therapy in correction of anaemia in cancer patients prior, 

during or after completed chemotherapy. More long-term data on FCM exposure in 

cancer patients with iron deficiency are needed in order to characterize which 

patients benefit most from this therapy and to determine optimal dosing and 

frequency of FCM use. 

Disclosure: B. Tschechne: I am a member of the Advisory Board of Vifor Pharma 

DeutschlandO. Harlin: employee of Vifor Pharma GermanyH. Zakaria: The data 

analysis shown was sponsored by Vifor Pharma DeutschlandAll other authors have 


1628 ANEMIA POINT PREVALENCE IN PATIENTS RECEIVING 

CHEMOTHERAPY IN 56 CENTERS IN ITALY AND AUSTRIA 

L. Merlini 1 , G. Carteni 2 , S. Iacobelli 3 , C. Stelitano 4 , M. Airoldi 5 , P. Balke 6 , F. Keil 7 , 

F. Haslbauer 8 , L. Belton 9 and B. Pujol 10 

1 Medical Oncology, Ospedale Civile S. Bortolo, Vicenza, ITALY, 

2 Onco-Hematology, Azienda Ospedaliera Cardarelli, Napoli, ITALY, 3 Medical 

Oncology, Ospedale Clinicizzato SS.Annunziata, Chieti, ITALY, 4 Hematology, 

Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria, ITALY, 5 Medical 

Oncology, Azienda Ospedaliero Universitaria Le Molinette, Torino, ITALY, 6 1st 

Medical Department, General Hospital St. Pölten and Karl Landsteiner Institute of 

Oncology, St. Pölten, AUSTRIA, 7 Hematology-Oncology, Landeskrankenhaus 

Leoben, Leoben, AUSTRIA, 8 Internal Medicine, Landeskrankenhaus 

Vöcklabruck, Vöcklabruck, AUSTRIA, 9 Biostatistics, Amgen Ltd, Uxbridge, 

UNITED KINGDOM, 10 Haematology/Oncology, Amgen Europe, Zug, 

SWITZERLAND 

Purpose: To evaluate the point prevalence of anemia in patients with non-myeloid 

tumors being treated with chemotherapy (±radiotherapy) in a clinical practice setting. 

Methods: This was a cross-sectional, observational survey. Centers had to prespecify 

a single day, during a 4-month enrollment window, to report specific data collected 

as part of normal clinical practice for patients attending in relation to chemotherapy 

treatment. Data for all centers/consenting patients were included in the analyses. The 

primary endpoint was the point prevalence of anemia as determined using a 

prespecified algorithm, which defined a patient as anemic based on 1) hemoglobin 

(Hb) ≤10 g/dL on/within 3 days prior to visit, 2) ongoing anemia treatment at visit, 

or 3) physician diagnosis of anemia together with ≥1 anemia symptom at visit. 

Reasons for visit, patient demography, tumor type, systemic chemotherapy, Hb levels, 

and consequences of anemia, were secondary endpoints. Patients provided informed 

consent where required by local regulations. 

Results: Between 18/11/2010-18/3/2011, data for 1412 patients were collected (Italy n 

= 1130 [80%]; Austria n = 282 [20%]). Of these, 49% were men, median age was 65 

years and most (80%) had solid tumors (colorectal: 18%; breast: 18%; lung: 14%; 

prostate: 3%; other solid tumors: 28%). Overall, 57% of patients had received ≤3 

chemotherapy cycles. The point prevalence of anemia was 32% (95% CI: 29.4%, 34.2%); 

14% of patients were deemed anemic based on Hb levels ≤10 g/dL, 9% based on 

evidence of anemia treatment and 8% based on physician assessment of anemia 

together with ≥1 anemia symptom. Overall, 82% of patients had Hb data; the mean 

(SD) Hb level was 11.7 (1.7) g/dL. 32% of patients had anemia symptoms, the most 

common were fatigue (28%), depression (9%) and dyspnea (8%). Few patients (4%) had 

had their current chemotherapy cycle delayed due to anemia. On visit day or ≤28 days 

prior, 6% of patients had evidence of whole blood or red blood cell transfusion, 13% 

had evidence of erythropoiesis-stimulating agent use and 6% had evidence of iron use. 

Conclusions: In this survey one-third of patients with non-myeloid tumors 

undergoing chemotherapy were found to be anemic on the prespecified study day. 

Disclosure: L. Belton: Contract worker for Amgen Ltd, B. Pujol: Employed by 

Amgen EuropeAll other authors have declared no conflicts of interest. 

1629 HIGH PREVALENCE AND INCIDENCE OF ANAEMIA IN 

CANCER PATIENTS IN SPAIN 

P. Gascón 1 , A. Casas 2 , J. Muñoz 3 , J. De Castro 4 , V. Alberola 5 , M. Cucala 6 and 

F. Barón 7 

1 Medical Oncology Department, Hospital Clínic i Provincial de Barcelona, 

Barcelona, SPAIN, 2 Medical Onology Department, Hospital Virgen del Rocío, 

Sevilla, SPAIN, 3 Medical Oncology Department, Hospital Dr. Peset, Valencia, 

SPAIN, 4 Medical Oncology Department, Hospital La Paz, Madrid, SPAIN, 

5 Medical Oncology Department, Hospital Arnau de Vilanova, Valencia, SPAIN, 

6 Medical Advisor, Vifor Pharma España, Barcelona, SPAIN, 7 Medical Oncology 

Department, Complejo hospitalario Universitario de Santiago de Compostela, 

Santiago de Compostela, SPAIN 

Background: Anaemia is a frequent complication in cancer patients. This 

haematological abnormality may be related to cancer itself and/or induced by 

chemotherapy. The objective of the present study was to describe the prevalence of 

anaemia in treatment-naïve patients with solid tumours, the incidence of anaemia 

after four months of cancer treatment and anaemia management. 

Methods: Multicenter, prospective and observational study that included newly 

diagnosed cancer patients. Data on anaemia parameters and its management were 

collected at baseline and after four months of cancer treatment. The primary 

outcome was the proportion of patients with anaemia defined as a haemoglobin (Hb) 

concentration

Results: Anemia was detected in 83.6% (122/146) of pts. 23.8% (29/122) of pts were 

anemic already before ChT and 55.7% (68/122) of all anemic pts experienced anemia 

after the first cycle of ChT. Statistically significant correlation was found between 

chemotherapy induced anemia and Hb value before starting ChT (p= 0.002). ESA 

treatment was administred in 60/122(49.2%) of all anemic pts and targeted value of 

Hb level >110g/L was achieved in 65.5% of those pts. The red blood cell transfusion 

was given to only 19/122 (15%) of anemic patients, half of which were also treated 

with ESA. PFS of patients with anemia before ChT was significantly shorter 

compared to non-anemic pts (p = 0.001). ESA treatment did not affect PFS despite 

the fact that the proportion of trombembolic events was higher in patients receiving 

ESA or not (8.3% vs 3.8%, respectively). 

Conclusions: Our results confirmed that anemia is a frequent complication in lung 

cancer patients treated with ChT. Treatment with ESA was safe but marginally 

effective in our group of patients. 


1631 PHYISICAL AND EMOTIONAL SYMPTOMS IN PATIENTS WITH 

SOLID AND HAEMATOLOGIC MALIGNANCIES WITHOUT 

METASTASES, ON CURE OR FOLLOW-UP: ARE THEY 

OVERLAPPING? 

C.I. Ripamonti 1 , M.A. Pessi 2 , A. Maruelli 3 , S. Boldini 4 , G. Miccinesi 5 , E. Bandieri 6 

and L. Buonaccorso 7 

1 Supportive Care In Cancer Unit, Fondazione IRCCS - Istituto Nazionale dei 

Tumori, Milano, ITALY, 2 Supportive Care in Cancer, Fondazione IRCCS, Istituto 

Nazionale Tumori, Milano, ITALY, 3 Psychology Unit, LILT and Centre for 

Oncological Rehabilitation CERION of Florence, Firenze, ITALY, 4 Supportive Care 

in Cancer, Fondazione IRCCS, Istituto Nazionale dei Tumori Milano, Milano, 

ITALY, 5 Epidemiology, Cancer Prevention and Research Institute ISPO Florence, 

Florence, ITALY, 6 Oncological Unit, Azienda USL Modena CeVEAS Modena, 

Mirandola Modena, ITALY, 7 Psychology, AMO Association of Oncological 

Patients from nine towns and villages in the Northen Area of Modena, Mirandola, 

ITALY 

In a prospective study carried out on 88 patients with solid cancer on cure and 20 on 

follow up (Group A) and 86 patients with haematologic malignancies (68 on cure) 

(Group B), we assessed the presence and intensity of physical and emotional 

symptoms through the Edmonton Symptom Assessment Scale (ESAS). In both 

groups, whereas no correlation was observed between age or religiousness and ESAS 

symptoms, a score above the clinical cut off for HADS (10/11) was associated with 

higher intensity of almost all symptoms. Drowsiness was less reported by patients 

with HADS 90 for group A only. Whereas, for group B the associations with 

low KPS were for uncontrolled anorexia, not-well being and dyspnoea (p = 0.002; p 

= 0.029; p = 0.018 respectively). In both groups patients with higher proportion of 

uncontrolled depression or drowsiness were significantly associated to receiving 

psychological support. Pain, anxiety and not-well being were correlated with 

psychological support for group A only. We believe that the routinary assessment of 

physical and emotional symptom in patients with both malignancies is mandatory to 

recognize all the symptoms with a particular attention to the emotional ones. 

Phyisical and emotional symptoms in patients with solid and haematologic 

malignancies without metastases, on cure or follow-up: are they overlapping 


1632 HEMODIALYSIS IN CERVICAL CANCER PATIENTS: CLINICAL 

ASPECTS AND OUTCOME IN 95 PATIENTS FROM THE 

BRAZILIAN NATIONAL CANCER INSTITUTE (INCA) 

D.G. Candido Reis 1 , L.M.C. Soares 1 , D. Herchenhorn 1 , I.S. Martins 2 and 

E. Rocha 3 

1 Medical Oncology, Brazilian National Cancer Institute, Rio de Janeiro, BRAZIL, 

2 Serviço de Infectologia, Universidade Federal Fluminense, Niterói, BRAZIL, 

3 Departamento de Nefrologia, Hospital Universitário Clementino Fraga Filho- 

UFRJ, Rio de Janeiro, BOUVET ISLAND 

Cervical Cancer is a serious issue in development and underdeveloped countries. It is 

the second most prevalent (18000 new cases expected for 2012) and the fourth 

deadliest cancer among women in Brazil. Most patients (pts) (68,3%) are diagnosed 

with advanced disease- increasing their risk of renal failure due to local progression 

and cisplatin-based chemotherapy. Benefits of hemodialysis in these patients are 

unknown, and it should be better clarified due to its cost and morbidity. 

Material and methods: Data were retrospectively assessed from all 95 consecutive 

patients diagnosed with cervical cancer submitted to renal substitute therapy in the 

years of 2007/2008, with a follow-up until March 2010. Statistical analysis was 

performed using software SPSS v11.0. Median Age of Diagnosis and at 1st 

Hemodialysis (1HD) were, respectively, 50.72y (25.39-95.13) and 52.06y 

(25.41-95.70). 70 pts (73,7%) had stage III or IV at the moment of diagnosis and 81 

pts (85,3%) had disease progression at the moment of the 1HD. Main reason for HD 

was post-renal kidney failure in 84pts (88%). 34 pts (36%) received any kind of 

chemotherapy at the moment of 1HD and 5 pts (5%) developed nephrotoxicity due 

to chemotherapy. 87pts (91,6%) were dead at the moment of analysis, and 67pts 

(77%) died in the first 3 months after the 1HD. The Median Survival for the entire 

cohort was 41 days (CI95% 25-57 days). The main causes of death were cancer 

(83%) and sepsis (5%). In a Multiple Logistic Analysis using Cox Model, a significant 

difference was found in the Median Survival in the following categories: Age at First 

HD (55 years: 25 days (CI95: 9-41), HR = 0.259, 

p = 0.020); Tumor Status at the moment of HD (stable diase/partial response/no 

evidence of disease: 52 days (CI95: 30-74); Disease Progression/active disease: 39 days 

(CI95: 20-58), HR = 0.052, p = 0.003); Renal Drainage (not performed: 20 days (CI95: 

7-33); performed: 67 days (CI95: 39-95), HR = 2.287, p = 0.003). 

Conclusions: Overtreatment is common in oncology, from anti-cancer therapy to 

supportive care, and this can be hazardous to the patients. Most patients who were 

submitted to HD in this cohort had active advanced disease, and renal failure seemed 

to be a surrogate of poor prognosis/outcome. Patients who most benefited from HD 

was those younger than 55y and those with controlled disease. 


1633 BISPHOSPHONATES IN BONE METASTATIC PATIENTS: 

EXPERIENCE OF MEDICAL ONCOLOGY, UNIVERSITY OF 

L’AQUILA OVER 17 YEARS 

E. Ricevuto 1 , A. Irelli 1 , K. Cannita 1 , G. Bruera 1 , P. Lanfiuti Baldi 1 , V. Cocciolone 1 , 

E. Palluzzi 1 , L. Rinaldi 1 , A. Teti 2 and C. Ficorella 1 

1 Medical Oncology Division, S. Salvatore Hospital, University of L’Aquila, 

L’Aquila, ITALY, 2 Department of Experimental Medicine, University of L’Aquila, 

L’Aquila, ITALY 

Three hundred and twenty-nine bone metastatic patients (BMP) followed at Medical 

Oncology Division, San Salvatore Hospital L’Aquila from 1995 were evaluated. 

Primary tumors were: breast 113, 55%; prostate 29, 14%; lung 26, 13%. Treatment 

with bisphosphonates was administered in 204 patients, 62% (male/female, 80/124): 

zoledronic acid and/or intravenous pamidronate 178, 87%; ibandronate 16, 8%; and 

ibandronate followed by intravenous bisphosphonate 10, 5%. Median duration of 

treatment was 7 months (range 1-47months), 19,5 months (range 1-57months) and 

27 months (range 9-44months), respectively. Features of bone metastases: multiple 

bone sites 193 (95%), one bone site 11 (5%); osteolytic 124 (61%), osteosclerotic 

lesions 35 (17%), mixed 28 (14%), undetermined 17 (8%). Involved sites: spinal 

column, 172 (84%); pelvis/hip, 146 (72%); long bones, 102 (50%); other skeletal sites, 

156 (76%). Overall skeletal–related events (SREs) during follow up were 140 (69%): 

pathologic fracture, 45 (22%); spinal cord compression, 6 (3%); bone RT, 120 (59%); 

bone surgery, 14 (7%). The first occurring SRE was: pathologic fracture in 28 patients 

(20%); spinal cord compression, 3 (2%); bone RT, 108 (77%); bone surgery, 1 (1%). 

Number of SREs in individual patient was: 1 in 54%; 2 in 25%; 3 in 17%; 4 in 7%; 6 

in 1%. SREs before onset of treatment with bisphosphonate were 99 (71%), after 

treatment were 41 (29%). A baseline mouth assessment with dental visit and/or 

orthopantomography of the jaws was performed in 58% of patients, 2% also with 

TAC or RMN. Median survival after diagnosis of bone metastases was 32 months. 

Median time to first SRE after diagnosis of bone metastases was 15 days. Median 

survival after first SRE was 29 months. Events related to bisphosphonate were: acute 

phase reactions (first 3 days), 6 (2,5%); pyrexia, 5 (2%); bone pain, 2 (0,8%); 

arthralgia, 1 (0,4%); hypercalcemia, 4 (1,7%); hypocalcemia, 7 (2,9%); toothache, 3 

(1,25%); osteonecrosis of the jaw (ONJ), 6 (2,5%); uveitis, 1 (0,4%). ONJ before and 

after introduction of baseline mouth assessment, 4/65 patients (6.1%) and 2/139 

patients (1,4%), respectively. Our experience confirms the relevance of SREs and 

efficacy of bisphosphonate treatment in BMP. 


1634 MEETING THE CHALLENGE OF ORAL ANTI-CANCER 

THERAPY EDUCATION – AN IRISH PERSPECTIVE 

D.M. Graham, E. Duignan, A. Campbell and K. O’Byrne 

Medical Oncology, St James’s Hospital, Dublin, IRELAND 


Background: Prescription of oral anti-cancer therapy (OAT) is increasing. Safety and 

adherence issues surrounding OAT are causing a shift in the traditional roles and 

responsibilities of oncologists, nurses and pharmacists. The aim of this study was to 

evaluate education provided to patients receiving OAT and to develop a standardised 

tool to improve the education process and its documentation. 

Method: Over a 1-month period patients attending St James’s Hospital oncology 

department for OAT were identified. Charts were reviewed for each of these patients. 

Analysis: Criteria were established to assess standards of documentation. 1. All charts 

should have documentary evidence of patient education for OAT. 2. Documentary 



evidence should include: side effects, schedule of treatment, support services, storage, 

handling, disposal and interactions. 

Results: During the review period, 35 patients receiving OAT were identified. Of 

these, 12 patients had documentation of education by a doctor (34%), 15 (43%) by a 

nurse. Documentary evidence of education about side effects was noted in 22 cases 

(63%), schedule of treatment in 16 cases (46%), support services in 16 (46%), safe 

storage in 3 cases (9%), safe disposal, safe handling and interactions in 2 cases each 

(6%). Recommendations: A standardised tool has been developed to enable 

healthcare staff to accurately document issues discussed during patient education for 

OAT. This is in the form of a checklist to ensure that all elements including safety, 

timing of medication, interactions, monitoring and support are documented 

accurately. All patients prescribed OAT will be referred to a nurse-led OAT clinic to 

facilitate education. Healthcare staff in the oncology department will be educated 

about the tool and clinic and, following a pilot period, a repeat audit will be 

performed to assess the effectiveness of the tool. These results will also be presented. 


1635 INTENSIVE CARE AS A KEY PLAYER IN THE CHANGING 

PARADIGM OF MODERN CANCER CARE: A SINGLE 

INSTITUTION EXPERIENCE 

L.C. Connell 1 , F. Othman 2 , B. Marsh 2 , D.N. Carney 1 , J.A. McCaffrey 1 ,P. 

O Gorman 3 and C.M. Kelly 4 

1 Medical Oncology, Mater Misericordiae University Hospital, Dublin, IRELAND, 

2 Department of Intensive Care, Mater Misericordiae University Hospital, Dublin, 

IRELAND, 3 Haematology, Mater Misericordiae University Hospital, Dublin, 

IRELAND, 4 Medical Oncolgy, Mater Misericordiae University Hospital, Dublin, 

IRELAND 

Background: Many metastatic cancers are now treated similar to other chronic 

diseases. Expanding treatment options, increasing age; co-morbid illness; and 

improving cancer-specific survival means that decisions regarding the timeliness & 

appropriateness of transfer to the Intensive Care Unit (ICU) are complex. We sought 

to examine the clinical, demographic & outcome characteristics of oncology/ 

haematology patients (pts) transferred to ICU at a large academic teaching hospital. 

Methods: Data was extracted from a prospectively maintained database for all pts 

with documented malignancy admitted to ICU between September 2009 & 

December 2011. Clinicopathological variables examined included; cancer type; 

tumour stage; time from diagnosis; age; co-morbidities; and treatment history. The 

Sequential Organ Failure Assessment (SOFA), an ICU-specific scoring system, was 

reviewed for each patient (pt). We report 30 day & 6-month mortality. 

Results: A total of 52 of an eligible 83 pts have been analysed in detail to date. The 

common cancer types were well represented; breast (11.5%),colorectal(11.5%), lung 

(11.5%) & acute leukaemia(19.2%). Mean age at time of ICU admission was 60 years 

(range 29-82). The maximum number of prior lines of chemotherapy (CT) was 5 

(range 0-5). Approximately 50% of pts had metastatic disease at time of ICU 

admission. The most frequent reasons for admission were sepsis (n = 16, 31%) & 

respiratory distress (n = 15, 29 %). Use of mechanical ventilation, vasopressors & 

renal dialysis was 51.9%, 61.5% & 21.1% respectively. Four pts (7.7 %) received CT in 

the ICU setting. ICU-specific mortality was 28.8% (n = 15). Thirty-day and 6-month 

mortality rates were 38.5% & 61.5% respectively. Data on the remaining 31 pts is 

currently being analysed and will be available for presentation at the meeting. 

Conclusions: A significant proportion of pts admitted to ICU had advanced disease 

& had received multiple lines of CT previously. The ICU-specific mortality rate was 

lower than expected at 28.8% and may reflect stringent selection criteria. Pts 

transferred tended to have had long periods of disease remission/stabilisation or had 

a new diagnosis of malignancy with unknown CT sensitivity status. Analysis of pt 

selection at ward level is on-going and will identify other factors influencing ICU 

transfer decisions. 


1636 A PROSPECTIVE STUDY OF SUBACUTE THYROID 

DYSFUNCTION FOLLOWING SUPRACLAVICULAR 

IRRADIATION IN THE MANAGEMENT OF CARCINOMA OF THE 

BREAST 

S. Akyurek 1 , I. Babalioglu 1 , S. Yuksel 2 and S. Cakir Gokce 1 

1 Radiation Oncology, Ankara University School of Medicine, Ankara, TURKEY, 

2 Biostatistic, Ankara University School of Medicine, Ankara, TURKEY 

Purpose: To evaluate the relationship between irradiation and early thyroid 

dysfunction, focusing on radiation dose-volume factors. 

Patients and methods: Between December 2010 and January 2012 a total of 21 

patients with breast cancer received supraclavicular irradiation were evaluated 

Thyroid function tests, including serum thyroid stimulating hormone (TSH), free 

thyroxine (fT4), free triiodothyronine (fT3), were analyzed prior to irradiation and 

every three months the first year and then 18th month after radiotherapy. Based on 

each patient’s dose volume histogram (DVH), total volume of the thyroid, mean 

radiation dose the thyroid and percentages of thyroid volume which received 

radiation doses 10-60Gy (V10-V60) were considered for statistical analysis. 

Results: Mean TSH levels before irradiation, at 3, 6, 9 and 12 months were 1.4 µIU/ 

ml, 1.5 µIU/ml, 1.7 µIU/ml, 3.6 µIU/ml and 4.6 µIU/ml, respectively. Serum TSH 

levels did not change significantly at 3 and 6 months after irradiation (p = 0.1). 

However, a significant elevation was noted at 9 months (p = 0.005). Mean thyroid 

dose was 32 Gy (19-48 Gy) and mean thyroid volume was 35 cc (24-64 cc). Median 

values of V10-20-30-40-50-60 were 68%, 58%, 55%, 53%, 48% and 0%, respectively. 

With a median follow-up was 9 months (range, 3-18 months), only one patient (5%) 

developed clinical hypothyroidism requiring thyroid replacement treatment. 

Conclusion: According to early results of our study, irradiation of the thyroid 

develops early thyroid dysfunction. This damage is initially manifested within 9 

months after radiotherapy. However we could not analyze the radiation dose-volume 

factors of the peak level of serum TSH because of inefficient follow up time. 


1637 COMBINATION OF SERUM PROCALCITONIN AND 

C-REACTIVE PROTEIN LEVEL AS A DIAGNOSTIC MARKER OF 

DISCRIMINATING INFECTION FROM NEOPLASTIC FEVER IN 

FEBRILE LUNG CANCER PATIENTS 

K. Miyamoto 1 , R. Seki 2 , D. Taniyama 1 , H. Kamata 1 and F. Sakamaki 1 

1 Pulmonary Medicine, Saiseikai Central Hospital, Minato-ku, Tokyo, JAPAN, 

2 Pathology, Saiseikai Central Hospital, Tokyo, JAPAN 

Background: Neoplastic fever in lung cancer is assessed on clinical course only, and 

is difficult to discriminate from infection. 

Objective: To evaluate the diagnostic role of procalcitonin (PCT) and C-reactive 

protein (CRP) in discriminating neoplastic fever and infection. 

Methods: We reviewed the medical records of 112 consecutive febrile episodes of 52 

patients (39 males, mean age 67.1y/o), who were diagnosed as lung cancer from 

November 2009 to April 2012 at our Saiseikai Central Hospital in Tokyo, Japan. 

Based on clinical, laboratory, and bacteriological results, patients were classified as 

having neoplastic fever (NF, n = 53), suspected or definite bacterial infection (BI, n = 59). 

Values of white blood cell count (WBC), PCT, and CRP were measured on day 1 of 

onset of fever. Microbiological specimen and radiological imaging study were also 

performed to diagnose infectious diseases or other febrile conditions. 

Results: The most common infection was pneumonia (38.4 %). Mean WBC (12000 

vs. 14800) were not statistically significant. Mean values of PCT were significantly 

higher in patients with BI compared with NF (0.14 vs. 3.95 ng/ml, p < 0.05). Mean 

values of CRP were also significantly higher in patients with BI compared with NF 

(8.6 vs. 15.2 mg/dl, p < 0.05). Combination of CRP level at the threshold value of 

10.2 mg/dl and PCT level at the threshold value of 0.32 ng/ml were the most 

sensitive from ROC curve for discriminating infection to neoplastic fever. 

Conclusions: Combination of PCT and CRP on the day of onset of fever is useful in 

discriminating neoplastic fever from infection in febrile lung cancer patients. 


1639 INCIDENCE OF THROMBOEMBOLIC EVENTS IN PATIENTS 

TREATED WITH CISPLATIN-BASED CHEMOTHERAPY 

A.C. Fernandes 1 , S.R. Meireles 2 , I. Augusto 2 , L. Aguas 2 and M. Damasceno 2 

1 Oncologia Médica, Hospital de São João, Porto, PORTUGAL, 2 Medical 

Oncology Department, Hospital São João, Porto, PORTUGAL 

Introduction: Cancer patients on chemotherapy have higher risk in developing 

thromboembolic events (TEE), with great impact on morbidity and mortality. The 

aim of this study is to determine the incidence of venous and arterial TEE in patients 

treated with cisplatin-based chemotherapy. We also analysed the prognostic value of 

patientś baseline and treatment characteristics in predicting TEE occurrence. 

Methods: We performed a retrospective analysis of all patients with cancer treated 

with cisplatin-based chemotherapy between January 1, 2011, and April 10, 2012, 

with at least 4 weeks of follow-up after their last cisplatin dose. A TEE was 

considered cisplatin-associated if it occurred between the time of the first dose of 

cisplatin and 4 weeks after the last dose. 

Results: Among 141 patients, 27 (19.1%) experienced a TEE. The TEE observed 

were: deep vein thrombosis (DVT) in 9.9% (14), pulmonary embolism (PE) in 5.7% 

(8), DVT plus PE in 0.7% (4) and arterial thrombosis in 2.8%. The majority of 

patients (51.9%) had a TEE after 63 days, and after the 3 rd dose of cisplatin, with a 

cumulative dose of 160 mg/m 2 . By univariate analysis, active smoking (p = 0.016), 

hypertension (p = 0.007), site of cancer (p = 0.025), Khorana site of cancer (p = 

0.001), Khorana score (p = 0.049) and risk group (p = 0.04) were all identified as risk 

factors. However, by multivariate analysis, only hypertension (p = 0.18; HR 3.59; 95% 

CI, 1.25 to 10.34) and Khorana site of cancer (p = 0.03) retained statistic significance. 

Conclusion: As we expected, gastric and pancreatic cancers had the highest 

incidence of TEE. We verified a very high incidence of TEE in patients treated with 

cisplatin-based regimens, also described in other published studies. It is therefore 


important to carry out randomized studies to conclude the need for prophylaxis of 

TEE in these patients. 


1640 ARE THERE FACTORS THAT PREDICT ACUTE CARE 

ADMISSION IN CANCER PATIENTS AGE ≥65 YEARS 

RECEIVING CHEMOTHERAPY? A RETROSPECTIVE ANALYSIS 

M.S. Lung, Y. Yeung, C. Maddison, A. Hutchinson and S. White 

Medical Oncology, Northern Health, Epping, VIC, AUSTRALIA 

Background: There is growing evidence that older patients derive the same benefits 

from chemotherapy as younger patients, but often at the cost of increased toxicity. A 

retrospective analysis was done of cancer patients ≥65 years who received 

chemotherapy, with the aim of identifying patient or treatment factors associated 

with subsequent hospital admission. 

Methods: Medical records and an electronic prescribing system (EPS) were used to 

identify all cancer patients ≥65 years who received chemotherapy at Northern 

Health. For each patient, age, treatment dose at onset, ECOG, presence of metastases, 

cardiac comorbidities, chronic kidney disease stage, liver function tests and reason 

for admission were documented. Univariate and multivariate logistic regression 

analysis was used to assess the association between a factor and subsequent 

hospitalisation. An Odds Ratio greater than or less than 1, and a P value


progression-free survival very useful from the viewpoint of side effects, even in phase 

III clinical trials. 


1705 PROSPECTIVE EVALUATION OF THE EFFECT OF A MANUAL 

FOR DIABETIC PATIENTS WHO RECEIVE CANCER 

CHEMOTHERAPY 

H. Kato1 , T. Mineta2 , K. Chikamori2 , N. Hamajima2 , S. Koyama3 , H. Kushihara3 , 

B. Hiroyuki4 , M. Yamauchi5 , K. Kawada1 and F. Nomura1 1 

Medical Oncology, Japanese Red Cross Nagoya First Hospital, Nagoya, 

JAPAN, 2 Nursing, Japanese Red Cross Nagoya First Hospital, Nagoya, JAPAN, 

3 

Pharmacy, Japanese Red Cross Nagoya First Hospital, Nagoya, JAPAN, 

4 

Nutrition, Japanese Red Cross Nagoya First Hospital, Nagoya, JAPAN, 

5 

Endocrinology and Diabetes, Japanese Red Cross Nagoya First Hospital, 

Nagoya, JAPAN 

Background: How to safely administer cancer chemotherapy to patients with 

diabetes mellitus is an important issue. Our institution is a general core hospital in 

Japan. In 2010, we surveyed the current status of diabetic patients given cancer 

chemotherapy. Adequate medical examinations were not performed. In 2011, we 

designed a manual for diabetic patients who receive cancer chemotherapy. We now 

report an improvement in medical examinations of diabetic patients who receive 

cancer chemotherapy since introducing our manual. 

Methods: We decided that adequate medical examinations should include the 

following: adequate measurement of blood sugar levels; evaluation of the patient by a 

diabetologist; making standards for decreasing the dose of steroids given before 

cancer chemotherapy; and making standards for nutritional guidance. We compared 

the present status (as of March 2012) with that before the introducing our manual 

for diabetic patients receiving cancer chemotherapy. 

Results: The proportion of diabetic patients increased from 12% to 19%. The 

rate of measuring blood sugar levels at the start of new regimens of 

chemotherapy increased from 69% to 72%. The rate of adequate continuous 

monitoring of blood sugar levels increased from 48% to 81%. The rate of 

evaluation by a diabetologist increased from 36% to 50%. The rate of decreased 

premedication with steroids increased from 55% to 66%. The rate of providing 

nutritional guidance was unchanged (23% to 24%). 

Conclusions: The rates of adequate continuous monitoring of blood sugar levels, 

decreasing premedication with steroids, and evaluation by a diabetologist improved. 

The increase in the proportion of diabetic patients was attributed to adequate blood 

sugar examinations. However, the low rate of providing of nutritional guidance 

remains an unsolved problem. 



abstracts 

translational research 

1644PD ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY 

(ADCC) EVOLUTION UNDER TREATMENT BY CETUXIMAB 

AND LINKS WITH TREATMENT OUTCOME IN LOCALLY 

ADVANCED HEAD AND NECK (LAHNSCC) AND IN 

METASTATIC COLORECTAL CANCER (MCRC) PATIENTS 

C. Lo Nigro 1 , M. Monteverde 1 , G. Strola 2 ,M.Maffi 1 , E. Miraglio 1 , L. Lattanzio 1 , 

D. Vivenza 1 , F. Messa 1 , G. Milano 3 , M. Merlano 1 

1 Oncology, S. Croce General Hospital, Cuneo, ITALY, 2 Laboratory, S. Croce 

General Hospital, Cuneo, ITALY, 3 Oncopharmacology Unit, Lacassagne, Nice, 

FRANCE 

Background: ADCC may play a role in antitumor activity of IgG1 mAb by inducing 

immune cell-mediated tumor lysis. We evaluated ADCC ability before and under 

cetuximab treatment and impact on survival in locally advanced Head and Neck 

(LAHNSCC) or metastatic colorectal cancer (mCRC). 

Methods: 82 patients (60 men, 22 women; median age 64, range 39-87), 39 

LAHNSCC and 43 mCRC, treated with chemotherapy (irinotecan or folfiri) plus 

cetuximab, were prospectively enrolled. ADCC ex-vivo was measured before 

treatment and every 2 months (1 to 7 measurements/patient, 44 patients with 

≥2 measurements). 400 000 purified Natural Killer cells (CD3- CD56+) from 

patients were incubated with 10 000 target cells (CAL166 cell line expressing 

EGFR) and 10 µg/ml cetuximab. Cytotoxicity was measured by LDH-release 

assay. ADCC was expressed as % of lysed target cells. Polymorphisms of Fcg 

receptors FcgR2a (131Arg > His) and FcgR3a (158Phe > Val) were analyzed by 

Allelic Discrimination assay. 

Results: The feasibility rate of ADCC measurements was 85-90%. Basal ADCC 

ranged between 30% and 100% (mean 62%, median 66%) and was not 

influenced by gender. A trend for an increased basal ADCC was observed in 

younger patients: median was 66% in the 22 patients < 65 vs 56% in the 22 

patients ≥ 65 years (p = 0.084), with a marked difference by tumour site (H&N 

p = 0.056; colon p= 0.16). FcgR2a and FcgR3a gene polymorphisms were not 

linked to basal ADCC. The evolution of individual ADCC ability before 

treatment and 2 months later revealed a significant drop in ADCC (intra-patient 

comparison, N = 44, p = 0.003, absolute median drop of 20%). 82 patients were 

assessable for survival (43 deaths; median follow up = 10.3 month). Cutaneous 

rash, but not basal ADCC, was related to survival (p = 0.043). There were no 

correlation between ADCC evolution (decrease/increase during the two months) 

vs EGFR status nor vs cutaneous rash. 

Conclusions: A new generation of mAb is currently being developed with the aim to 

amplify ADCC. Present data illustrate the feasibility of ADCC measurement in 

mAb-treated patients and reveal an initial drop in ADCC under treatment that may 

reflect the variable chemotherapy-induced impact on host immunity. 


1645PD MICRORNA-9 AND -224 IN TRASTUZUMAB RESISTANT 

HER2 POSITIVE BREAST CANCER CELLS 

K. Howe, A. Eustace, S. Souahli, B.C. Browne, S. Aherne, N. Barron, N. Walsh, 

J.P. Crown, N. O’Donovan 

National Institute for Cellular Biotechnology, Molecular Therapeutics for Cancer 

Ireland, Dublin City University, Dublin, IRELAND 

HER2 positive breast cancer accounts for approximately 25 % of all breast 

cancer cases. Trastuzumab, a humanised monoclonal antibody, is an approved 

established treatment for HER2 positive breast cancer; however, patients that 

initially respond frequently develop resistance. The aim of this study is to 

investigate microRNAs in cell line models of acquired and innate trastuzumab 

resistance. MicroRNA was extracted from the HER2 positive cells; SKBR3, 

BT474, and the acquired trastuzumab resistant variants SKBR3-T and BT474-T, 

and from a panel of innate trastuzumab sensitive (BT474, EFM-192A, SKBR3 

and MDA-MB-361) or resistant cell lines (UACC-732, JIMT-1, HCC-202, 

HCC-1954, HCC1569 and MDA-MB-453), in triplicate. MicroRNA profiling was 

performed on SKBR3 and SKBR3-T using Taqman Low Density Arrays (TLDA). 



Differentially regulated miRNAs were selected using > 2-fold change and a 

P-value of < 0.05. Individual quantitative RT-PCR (qRT-PCR) was performed to 

confirm alterations in miRNAs. Functional studies were carried out using 

Ambion® Pre-miR miRNA Precursors and Anti-miR miRNA Inhibitors for 

miR-224 in SKBR3 cells. TLDA analysis identified nine differentially regulated 

microRNAs in the SKBR3-T cells. Individual qRT-PCR assays confirmed that 5 

miRNAs were up-regulated and 4 were down-regulated. MiR-9 was 2.2-fold 

up-regulated (p = 0.04), while miR-224 was 1.6-fold down-regulated (p = 0.01) in 

SKBR3-T compared to the SKBR3 cells. Further validation of these targets in the 

BT474 model showed that miR-224 expression is lost in the resistant cells 

compared to the parental BT474 cells. MiR-9 is not significantly altered in the 

BT474-T cells. In the innate resistant models, miR-224 expression is reduced or 

lost in 4/6 resistant cell lines. Expression of miR-9 does not significantly differ 

between the innately sensitive and resistant cell lines. Transfection of SKBR3 

cells with pre-miR-224 significantly decreases cell proliferation by 23.5% (p = 

0.04). 

Conclusions: This is the first report of the involvement of miR-9 and miR-224 in 

trastuzumab resistance in HER2 positive breast cancer. Preliminary functional studies 

suggest that miR-224 may play a role in regulating cell growth in HER2 positive 

breast cancer cells. 


1646PD CUSTOMIZED FIRST LINE CHEMOTHERAPY ACCORDING 

TO ERCC1 AND RRM1 SNPS IN ADVANCED 

NON-SMALL-CELL LUNG CANCER (NSCLC) PATIENTS: A 

PHASE II STUDY 

F. Mazzoni 1 , G. Meoni 1 , F.L. Cecere 1 , C. Giuliani 2 , A. Camerini 3 , G. Allegrini 4 , 

F. Martella 5 , L. Boni 6 , F. Torricelli 2 , F. Di Costanzo 1 

1 Medical Oncology Unit, Azienda Ospedaliero Universitaria Careggi, Firenze, 

ITALY, 2 Genetic Diagnosis Laboratory, AOU Careggi, Firenze, ITALY, 3 Medical 

Oncology Unit, Versilia Hospital, Viareggio, ITALY, 4 Medical Oncology Unit, 

Pontedera Hospital, Pontedera, ITALY, 5 Oncology Unit, Ospedale di S. Maria 

Annunziata, Bagno a Ripoli, ITALY, 6 Centro Coordinamento Sperimentazioni 

Cliniche, ITT-AOU Careggi, Firenze, ITALY 

Introduction: Excision repair cross complementation group 1 (ERCC1) and 

ribonucleotide reductase 1 (RRM1) expression levels are predictive of chemotherapy 

(CT) efficacy in some malignancies. Customized CT has several advantages: patients 

(pts) are more likely to be treated with agents that they will respond to, pts can be 

spared the toxicity of agents that they are resistant to. 

Methods: We planned a phase II multicentric trial in two steps based on Simon 

design. Pts affected by advanced NSCLC are treated with first line CT according 

to Single Nucleotide Polymorphisms (SNPs) of ERCC1 (T118C and C8092A) 

and RRM1 (-37C > A and -524T > C), which are supposed to be correlated with 

specific expression levels. CT is delivered as follow: treatment A (low ERCC1 

and RRM1) Cisplatin plus Gemcitabine; treatment B (low ERCC1, high RRM1) 

Cisplatin plus Docetaxel; treatment C (high ERCC1, low RRM1) Gemcitabine 

plus Docetaxel; treatment D (high ERCC1 and RRM1) Docetaxel plus 

Vinorelbine. 

Results: Here we report the first step analysis for futility: 42 pts were enrolled from 

January 2010 to November 2011; 40 pts received at least 1 cycle of CT; median age 

was 66 years (range 47-72); 30(75%) pts were males; 21(52%) pts showed ECOG PS 

0, 19(48%) PS 1; 36(90%) pts had stage IV and 4(10%) IIIB; 23(58%) pts had 

adenocarcinoma, 14(35%) squamous, 3(7%) other types; 25(62%) pts received 

treatment A, 3(8%) treatment B, 11(27%) treatment C, 1(3%) treatment D. As 

primary end-point we assessed the overall best response and found a 55% response 

rate (RR) [38.7 – 70.4, 95% CI] in the intention to treat population. Subgroups 

analysis showed 46.2% RR in non squamous pts and 71.4% RR in squamous pts. 

Secondary end-points were progression free survival (PFS), overall survival (OS) and 

safety. The median follow-up time is 7.1 months, 12 pts did not show progression 

disease and 23 pts are still alive, then data for PFS and OS are not mature. CT was 

well tolerated: only 17(42%) pts showed grade 3-4 toxicity and there were no 

treatment related deaths. 

Conclusions: We observed an increase of RR in advanced NSCLC pts treated with 

CT according to ERCC1 and RRM1 SNPs status, the treatment strategy overcomes 

the first step of the study. 





1647PD MOLECULAR PROFILING AS AN OUTCOME PREDICTOR IN 

THE GALAXY TRIALTM (NCT01348126): A RANDOMIZED 

IIB/III STUDY OF GANETESPIB (STA-9090) IN 

COMBINATION WITH DOCETAXEL VERSUS DOCETAXEL 

ALONE IN SUBJECTS WITH STAGE IIIB/IV NSCLC 

R. Rosell 1 , S.S. Ramalingam 2 , D. Fennell 3 , C. Manegold 4 , I. El Hariry 5 , 

V. Vukovic 6 , F. Teofilovici 5 , V. Reichert 7 , G. Goss 8 

1 Medical Oncology Service, Catalan Institute of Oncology ICO Badalona Hospital 

Germans Trias i Pujol, Medical Oncology, Badalona, SPAIN, 2 Division of Medical 

Oncology, Emory University Winship Cancer Institute, Atlanta, GA, UNITED 

STATES OF AMERICA, 3 Medicine, University of Leicester, Leicester, UNITED 

KINGDOM, 4 Interdisziplinare Thorakale Onkologie, Klinikum Mannheim GmbH, 

Mannheim, GERMANY, 5 Oncology, Synta Pharmaceuticals, Lexington, MA, 

UNITED STATES OF AMERICA, 6 Clinical Development, Synta Pharmaceuticals 

Corp., Lexington, VA, UNITED STATES OF AMERICA, 7 Oncology, Synta 

Pharmaceuticals, Lexington, MA, UNITED STATES OF AMERICA, 8 Medical 

Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, CANADA 

Background: Inhibition of Hsp90, a key molecular chaperone required for activation 

of many oncoproteins, can lead to cancer cell death. Ganetespib is an Hsp90 

inhibitor that has shown single agent activity in molecularly defined disease, 

including ELM4-ALK rearrangement, KRAS mutations, HER2 amplification and 

BRAF mutations. The AS/RAF/MEK/ERK pathway is a potential therapeutic target 

in non-small cell lung cancer (NSCLC). 

Methods: This randomized trial compares ganetespib (G) + docetaxel (D) to D in 2 nd 

line advanced NSCLC patients. Archival tissue collection was mandatory and 

included formalin-fixed paraffin-embedded (FFPE) 10 unstained slides at 5 or 10 um 

and 1 matching hematoxylin-eosin (HE)-stained slide. The aim of this study is to 

investigate the predictive value of most commonly occurring known mutations in 

NSCLC in association with the efficacy of G + D, including KRAS, EGFR, BRCA, 

MET, BRAF and others. Genetic mutational analysis was analyzed using Affymetrix 

OncoScan FFPE Express platform, which provides information on copy number 

variation, allele ration and somatic mutations, Additionally, KRAS mutations were 

also analyzed separately using real-time PCR based sequencing. Results are correlated 

with baseline demographics and efficacy outcome data. 

Results: Approximately 160 of the 300 planned patients were enrolled by early May. 

Median age was 60 yrs (range 39-86), M/F: 105/53; adeno/other: 91/67; never/ 

former/current smokers: 30/77/51. KRAS mutation was detected in 21 of first 140 

patients (15%). Full genetic profiling is ongoing, and will be correlated with the 

efficacy outcomes from a planned interim analysis in early September, including 

disease control rate, PFS, and OS. 

Disclosure: I. El Hariry: stock ownership. V. Vukovic: Stock options. F. Teofilovici: 

stock options. V. Reichert: stock options. All other authors have declared no conflicts 

of interest. 

1648P NEOADJUVANT ADDITION OF BEVACIZUMAB TO 

CHEMORADIATION IN RECTAL CANCER: IMPACT ON 

ANGIOGENIC BIOMARKERS 

B. Laquente 1 , J. Capdevila 2 , M. Martínez-Villacampa 3 , C. López 4 , M.J. Safont 5 , 

A. Gómez 6 , J.L. Manzano 7 , C. Grávalos 8 , R. Salazar 3 , E. Aranda Aguilar 6 

1 Medical Oncology, ICO. Hospital Duran i Reynals, Barcelona, SPAIN, 2 Medical 

Oncology, Hospital Vall d’Hebrón, Barcelona, SPAIN, 3 Medical Oncology, ICO 

Hospital Duran i Reynals, Barcelona, SPAIN, 4 Medical Oncology, Hospital 

Marqués de Valdecilla, Santander, SPAIN, 5 Medical Oncology, Hospital General 

de Valencia, Valencia, SPAIN, 6 Medical Oncology, Hospital Reina Sofía, 

Córdoba, SPAIN, 7 Medical Oncology, ICO Hospital Germans Trias i Pujol, 

Barcelona, SPAIN, 8 Medical Oncology, Hospital Doce de Octubre, Madrid, 

SPAIN 

Purpose: We report the clinical results of adding bevacizumab (BEV) to preoperative 

chemoradiation (CRT), in patients (pts) with locally advanced rectal cancer (LARC). 

This pre-planned sub-study was aimed to evaluate the evolution of several 

biomarkers and their correlation with downstaging. 

Methods: Patients with LARC were randomized to radiotherapy 45Gy/25f/5 weeks + 

capecitabine (CAP: 825mg/m/bid) + BEV every 2 weeks (5 mg/kg for 3 doses) (arm 

A) or the same schedule without BEV (arm B): surgery was scheduled 6-8 weeks 

after completing CRT. Plasma levels of vascular endothelial growth factor (VEGF), 

VEGF receptor 2 (VEGFR-2) and angiopoietin-2 (Ang-2) were measured at baseline 

(d1), day 15 (d15) and day 57 (d57). Tissue samples (baseline and at surgery) were 

assessed for microvessel density (MVD). Comparisons between concentrations at 

different time points were assessed by using appropriate statistical paired tests. 

Logistic regression model was adopted to estimate and test the biomarkers for their 

association with downstaging. 

Results: Samples for biomarker analyses were obtained for 50 out of 90 randomized 

pts (arm A/B: 22/28): paired plasma samples were available for 18/23 pts at d1 and 

d15, and for 14/17 pts at d57; paired tumor samples were obtained from 12/18 pts. 

Eleven pts in each arm were downstaged (lower pT compared with the pretreatment 

cT). No differences were observed in baseline levels of any biomarker between both 

arms. Ang-2 levels were significantly higher in arm B than in arm A at d15 and d57 

(p = 0.0056 and p = 0.0133, respectively). Ang-2 levels significantly decreased at d15 

only in arm A (p < 0.05 ). Plasma Ang-2 levels decreased in arm A and increased in 

arm B (p < 0.05 at all time points). There were no significant changes in other 

biomarker levels. Overall, decrease in Ang-2 levels from baseline to d57, was 

significantly associated with tumor downstaging (OR: 0.95, p < 0.0001). 

Conclusions: Additional larger tailored studies are needed to corroborate the observed 

association between decreasing Ang-2 levels, tumoral downstaging and the role of 

Bevacizumab in this effect. 

Disclosure: E. Aranda Aguilar: Consultant or Advisory Role: Roche and Merck 

Serono. All other authors have declared no conflicts of interest. 

1649P MUTATIONS IN NRAS CODON 61 AND KRAS CODON 146 

ARE POOR PROGNOSTIC FACTORS IN PATIENTS WHO 

RECEIVED ANTI-EGFR MONOCLONAL ANTIBODY FOR 

METASTATIC COLORECTAL CANCER 

N. Takahashi 1 , Y. Yamada 1 , H. Taniguchi 2 , Y. Honma 3 , S. Iwasa 3 , K. Kato 4 , 

T. Hamaguchi 5 , Y. Shimada 3 


Japan., Tokyo, JAPAN, 2 Division of Pathology, National Cancer Center Hospital, 

Tokyo, JAPAN, 3 Gastrointestinal Oncolgoy, National Cancer Center Hospital, 

Tokyo, JAPAN, 4 Gastrointestinal Oncology, National Cancer Center Hospital, 

Tokyo, JAPAN, 5 Gastrointestinal Oncology Division, National Cancer Center 


Background: Previous studies showed that gene mutations (NRAS, BRAF, PIK3CA) 

are associated with a poor prognosis or resistance of anti-EGFR antibody in 

metastatic colorectal cancer (mCRC) patients with wild type (WT) of KRAS codon 

12/13 (KRAS-WT). However the significance of these biomarkers has not been 

clarified. In addition, EGFR immunohistochemistry (IHC) and EGFR gene 

amplification by DISH to evaluate the efficacy of anti-EGFR antibody treatment has 

not been reported for mCRC. 

Method: We evaluated tumor response and survival in patients who received anti-EGFR 

antibody by mutation analysis of KRAS, NRAS, BRAF, and PIK3CA in KRAS-WT 

patients with mCRC. Tumor DNA samples were obtained from patients treated in our 

hospital with anti-EGFR antibody between August 2008 and August 2011. 

Result: A total of 117 patients were eligible for this analysis, including 100 

KRAS-WT patients. Seventy-one patients (60.7%) were all WT for KRAS, NRAS, 

BRAF, and PIK3CA, and 46 patients (39.3%) had at least 1 mutation or had 

insufficient DNA samples to analyze. Mutations of KRAS codon 61 (2 patients), 

KRAS codon 146 (5), BRAF V600E (2), PIK3CA exon9 (8), NRAS codon 12/13 (2), 

and NRAS codon 61 (5) were detected. No patients had a mutation of PIK3CA exon 

20. Patients with at least 1 mutation had no response. Mutations of KRAS codon 

146, NRAS 61, and BRAF V600E were associated with a shorter progression free 

survival (PFS) compared with all WT patients (p = 0.049, p = 0.004, p = 0.036, 

respectively). Twelve patients (12% of KRAS-WT patients) with a mutation of KRAS 

codon 146, BRAF V600E, NRAS codon 61 had poor prognosis compared with the 

other KRAS-WT patients (PFS, 6.4 vs 2.0 months, p < 0.001; overall survival (OS), 

13.7 vs 7.9 months, p = 0.012). In all WT patients, EGFR IHC 3+ and gene 

amplification by DISH were associated with a better response rate than negative and 

weak IHC and no gene amplification (p = 0.046). Conclusion: Mutations of KRAS 

codon 146, NRAS codon 61, and BRAF V600E were a strong prognostic factor of 

anti-EGFR antibody in patients with mCRC. Combination of IHC and DISH of 

EGFR could identify patients with a tumor response to anti-EGFR antibody in 

patients that are all wild type for KRAS, NRAS, BRAF, and PIK3CA. 


1650P ANALYSIS OF CD40 EXPRESSION ON CIRCULATING 

COLORECTAL CANCER CELLS 

M. Torchio 1 , G. Comolli 2 , M. Danova 1 , G. Mazzini 3 

1 Medical Oncology and Internal Medicine, Azienda Ospedaliera della Provincia di 

Pavia, Ospedale Civile di Vigevano, Vigevano, ITALY, 2 Microbiology and 

Molecular Biology, IRCCS San Matteo Pavia, Pavia, ITALY, 3 IGM-CNR di Pavia, 

Istituto di Genetica Molecolare IGM-CNR, Pavia, ITALY 

Background: In colorectal cancer circulating tumor cells (CTCs) can be clinically 

relevant as: prognostic factor and predictive biomarker for treatment efficacy. The 

detecting and the carachterization of CTCs remains technically challenging. The cell 

surface costimulatory molecule CD40, widely expressed by lymphoid cells and by 

various tumour types, has been indicated as prognostic/predictive biomarker and as a 

potential target for therapy. In the present study we wanted to demonstrate the value 

of a multiparameter flow cytometry (FCM) approach for the detection and the 

characterization of circulating colorectal cancer cells in vivo. 

Methods: SW48 and HCT116 human colorectal cancer cells (highly positive for 

CD40) were serially diluted in normal whole blood to evaluate the sensitivity of the 

method in both the cancer cell identification and characterization for CD40 


expression. Then, we analyzed PB samples from 10 patients with advanced colorectal 

cancer to identify CTCs; PB from normal subjects was utilized as negative control. 

Analyses were performed using a Navios FCM (Beckman Coulter ®) equipped with a 

dedicated software for multidimensional analyses. 

Results: The method was found to have a sensitivity limit of 10(-5). The specificity was 

100%. In 8 patients we were able to differentiate in vivo CTCs from normal mononuclear 

cells based on increased light scatter parameters, cell marker expression (EpCAM+ 

CD45-) and nuclear stain with 4’6-diamidino-2-phenylindole. In half of the patients the 

simultaneous analysis of the CD40 expression revealed significant high levels. 

Conclusions: Multiparameter FCM can detect CTCs in colorectal cancer patients 

and allows simultaneous immunophenotype analysis. CTC identification and 

characterization represent emerging applications of FCM in solid tumor biology. 


1651P SPHINGOSINE KINASE 1 (SPHK1) OVEREXPRESSION 

CONTRIBUTES TO CETUXIMAB RESISTANCE IN HUMAN 

COLORECTAL CANCER MODELS 

L. Formisano 1 , L. Nappi 1 , R. Rosa 1 , V. Damiano 1 , R. Marciano 1 ,C.D’Amato 1 , 

C. Carlomagno 1 , G. Troncone 2 , S. De Placido 1 , R. Bianco 1 

1 Medical Oncology, University Federico II, Napoli, ITALY, 2 Surgical Pathology, 

Università Federico II, Napoli, ITALY 

Purpose: Although the anti-Epidermal Growth Factor (EGFR) monoclonal antibody 

(mAb) cetuximab is an effective strategy in colorectal cancer therapy, its clinical use 

is limited by intrinsic or acquired resistance. Alterations in the ‘sphingolipid rheostat’ 

- the balance between the proapoptotic molecule ceramide and the mitogenic factor 

sphingosine-1-phosphate (S1P) - due to sphingosine kinase 1 (SphK1) overactivation 

have been involved in resistance to anticancer targeted agents. Moreover, cross-talks 

between SphK1 and EGFR-dependent signalling pathways have been described. 

Experimental design: In this study, we investigated SphK1 contribution to 

cetuximab resistance in colorectal cancer in preclinical in vitro/in vivo models and in 

tumor specimens from patients. 

Results: Immunohistochemical analysis on colorectal cancer tissues revealed a 

correlation between SphK1 expression and K-Ras mutations. Moreover, SphK1 was 

found overexpressed and overactivated in colorectal cancer cells with intrinsic or 

acquired resistance to cetuximab. SphK1 contribution to resistance was supported by 

the demonstration that SphK1 inhibition by N,N-dimethyl-sphingosine (DMS) or 

silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas 

exogenous SphK1 overexpression in sensitive cells confers resistance to these agents. 

Finally, treatment of resistant cells with fingolimod (FTY720), a S1P receptor (S1PR) 

inhibitor, resulted in re-sensitization to cetuximab both in vitro and in vivo, with 

significant inhibition of tumor growth, interference with signal transduction, 

induction of cancer cells apoptosis and prolongation of mice survival. 

Conclusion: Our data could contribute to clarify SphK1 role in cetuximab resistance 

and may suggest SphK1 inhibition as a part of novel targeting strategies potentially 

effective also in resistant colorectal cancer patients. 


1652P CYCLOOXYGENASE-2 INHIBITION ENHANCES THE 

ANTI-TUMORAL ACTIVITY OF THE MULTI-TARGET KINASE 

INHIBITOR AEE788 IN COLORECTAL CANCER CELLS 

A.M. Valverde Estepa 1 , A. Cañas 1 , V. Hernández Nieto 2 , C. Lopez Pedrera 2 , 

J. De La Haba Rodriguez 2 , A. Rodríguez Ariza 2 , E. Aranda Aguilar 2 

1 Oncology Department, IMIBIC, Hospital Reina Sofia, Córdoba, SPAIN, 

2 Oncology Deparment, IMIBIC-Hospital Reina Sofía, Córdoba, SPAIN 

Introduction: KRAS and BRAF mutations are common in colorectal cancer and 

confer resistance to anti-EGFR therapy. AEE788 is a multiple kinase inhibitor, with a 

potent inhibitory activity against both EGFR and VEGFR. The aim of this study was 

to determine the efficacy of AEE788 as anti-tumor treatment in colorectal cancer 

cells with different RAS/BRAF mutational status. 

Material and method: The human colorectal cancer cell lines SW48 (KRAS/BRAF 

non-mutated), Caco-2 (BRAF V600E) and HCT-116 (KRAS G13D) were treated 

with AEE788, in the presence or the absence of EGF or VEGF. Cell proliferation was 

measured using a colorimetric XTT assay, cellular apoptosis was measured using 

flow-cytometry and VEGF production was analyzed by ELISA. The expression and/ 

or phosphorylation levels of EGFR, VEGFR, Akt, Erk1/2, and COX-2 were 

determined by western-blot using the corresponding specific antibodies. 

Results: Although AEE788 effectively inhibited EGFR phosphorylation in all three 

cell lines, the more effective inhibition of EGF-dependent growth was observed in 

Caco-2 cells. In these cells AEE788 inhibited the activation of intracellular kinases 

Akt and ERK1 / 2, efficiently induced apoptosis and caused cell cycle arrest at G1/ 

M transition. Furthermore, AEE788 reduced in Caco-2 cells both VEGF 

production and VEGF-dependent growth, effects that were associated with the 

inhibition of ERK1/2 phosphorylation and the increased expression of COX-2 


observed in these cells. Accordingly, the addition of specific inhibitors of COX-2 

(celecoxib and NS-398) significantly enhanced the antitumor effect of AEE788 in 

Caco-2 cells. 

Conclusion: Our results support the notion that that AEE788 can be effective in the 

treatment of colorectal cancer. Besides, its antitumoral efficacy may be potentiated by 

combination with COX-2 inhibitors. 


1653P DICER AND DROSHA EXPRESSION AND RESPONSE TO 

BEVACIZUMAB-BASED THERAPY IN ADVANCED 

COLORECTAL CANCER PATIENTS 

A. Zoccoli 1 , M. Iuliani 1 , F. Pantano 1 , G. Schiavon 2 , R. Ratta 1 , P. Correale 3 , 

A. Onetti Muda 4 , D. Santini 1 , G. Tonini 1 , B. Vincenzi 1 

1 Medical Oncology, University Campus Bio-Medico, Rome, ITALY, 2 Internal 

Oncology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, 

NETHERLANDS, 3 Medical Oncology Unit, Oncology Department, Azienda 

Ospedaliera Universitaria Senese, Siena, ITALY, 4 Pathology Department, 

university campus bio-medico, rome, ITALY 

Introduction: The miRNA-regulating enzyme Dicer and Drosha exhibit aberrant 

expression in several cancer types. Dicer and Drosha play a crucial role during the 

angiogenetic process in vitro and, for Dicer, in vivo. We aimed to investigate the 

potential role of Dicer and Drosha in predicting response to Bevacizumab-based 

therapy in advanced CRC patients. 

Methods: We measured Dicer and Drosha messenger RNA (mRNA) levels in 

formalin-fixed paraffin-embedded specimens of advanced CRC treated with (n = 76) 

or without (n = 28) Bevacizumab-containing regimens and patients with 

diverticulosis (normal mucosa) (n = 20), using a quantitative reverse-transcriptasepolymerase-chain 

reaction assay, and compared the results with clinical outcome. 

Results: We found that lower Dicer levels predicted a longer Progression-Free 

Survival (PFS) (P = .0001) and Overall Survival (OS) (P = .031) in 

Bevacizumab-treated patients. Conversely, Drosha levels were not associated 

with prognosis. Low Dicer levels were associated with better response to 

Bevacizumab-based treatments versus high Dicer levels (2.6% complete 

responses and 43.4% partial responses versus 1.3% and 28.9%, respectively; 

P = .045). Multivariate analysis identified three independent predictors of 

improved OS: high performance status [Relative Risk (RR) 1.56; P = .009], lower 

organs involvement (RR 0.72; P = .025) and low Dicer expression (RR 0.62; 

P = .009). Importantly, Dicer and Drosha expression did not correlate with 

outcome in not Bevacizumab-treated patients. Moreover we analysed Dicer and 

Drosha mRNA levels; our results showed a significantly higher Drosha 

expression in primary tumors than in normal mucosa (P =


stabilisation, but no objective responses were observed. The median PFS and OS were 

2.8 (range 2.1-4.0) and 5.4 (range 4.3-7.0) months (mo), respectively. Pre-treatment 

blood samples and archival tumor tissue were available for analysis in all patients. 

Thirty-three mutations were detectable in the peripheral blood, whereas 7 patients 

had primary tumor mutations and wildtype status according to the blood sample. 

The median level of pKRAS alleles was 900 alleles/ml. When divided into quartiles of 

pKRAS, significantly shorter PFS and OS were revealed with increasing levels of 

alleles. The median PFS was 2.1 mo (95%CI 1.9-2.1) in patients with high levels (> 

median) compared to 4.2 mo (95%CI 2.5-5.1) in those with lower levels (< median) 

(HR = 3.0, p = 0.0002), and the OS 4.1 (95%CI 3.0-5.2) and 8.0 (95%CI 5.1-9.6) mo, 

respectively (HR = 3.0, p = 0.0005). 

Conclusion: A high pre-treatment level of pKRAS alleles had a detrimental effect 

on both PFS and OS, whereas low levels were correlated to a better chance of 

disease stabilisation. This confirms our data from two previous study cohorts and 

pKRAS could therefore serve as a new prognostic marker in KRAS mutant 

mCRC. 


1655P HIGH MRNA EXPRESSION OF LMO4, A BRCA1 

DOWNREGULATOR, CORRELATES WITH BETTER 

PROGNOSIS IN ERLOTINIB-TREATED NON-SMALL-CELL 

LUNG CANCER (NSCLC) PATIENTS (P) WITH EGFR 

MUTATIONS 

N. Karachaliou 1 , C. Costa 2 , A. Gimenez-Capitan 2 , S. Viteri 1 , A. Gasco 1 , 

C. Camps 3 , E. Carcereny 4 , B. Massuti Sureda 5 , J. Souglakos 6 , R. Rosell 4 

1 Oncology, Instituto Oncologico Dr Rosell, USP Dexeus University Institute, 

Barcelona, SPAIN, 2 Laboratoy of Biology Department, Pangaea Biotech, USP 

Dexeus University Institute, Barcelona, SPAIN, 3 Oncology, Hospital General de 

Valencia, Valencia, SPAIN, 4 Medical Oncology Service, Catalan Institute of 

Oncology, Hospital Germans Trias i Pujol, Badalona, SPAIN, 5 Medical Oncology 

Dpt, Hospital General Universitario de Alicante, Alicante, SPAIN, 6 Oncology, 

University Hospital of Heraklion, Crete, GREECE 

Background: High BRCA1 mRNA levels affected progression-free survival (PFS) to 

erlotinib in EGFR-mutant NSCLC p (Rosell et al. CCR 2011). LMO4 is a negative 

regulator of BRCA1 function, and CtIP can bind to BRCA1 and LMO4. We have 

assessed the expression of CtIP, LMO4 and BRCA1 and examined the impact of CtIP 

and LMO4 levels on outcome. 

Methods: mRNA expression of BRCA1, LMO4 and CtIP was examined by RT-PCR 

in the original pretreatment tumor biopsies of 72 erlotinb-treated NSCLC p with 

sensitive EGFR mutations. 

Results: p characteristics: median age, 68; 61.8% female; 98.2% Caucasian; 63.6% 

never-smokers; 81.8% ECOG PS < 2; 95 adenocarcinoma; 94.5% stage IV. BRCA1 

expression correlated with that of CtIP (ρ = 0.31; P = 0.01) and LMO4 (ρ = 0.32; P 

= 0.02). PFS for p with high LMO4 levels was not reached while it was 13 

months (m) for p with low levels (P = 0.006). Overall survival (OS) was not 

reached for p with high levels of LMO4 and was 31 m for p with low levels (P = 

0.17). PFS was not reached for p with low BRCA1 and high LMO4 levels and was 

19 m for p with low levels of both genes (P = 0.04). PFS was 8 m for p with high 

BRCA1 and low LMO4 levels and 18 m for p with high levels of both genes (P = 

0.03). In the multivariate analysis, BRCA1 and LMO4 expression emerged as 

markers of PFS (Table). 

Conclusions: Low BRCA1 and high LMO4 levels were associated with longer 

PFS in erlotinib-treated advanced NSCLC p with EGFR mutations. We 

recommend baseline assessment of BRCA1 and LMO4 mRNA expression to 

predict outcome and provide alternative individualized treatment to patients 

when indicated. 

HR 95%CI P 

BRCA1 

≤4.92 1 ref. 

4.92-10.7 5.32 1.45-19.52 0.03 

>10.7 

CtIP 

5.13 1.25-20.99 0.02 

≤1.21 1 ref. 

1.21-2.1 0.69 0.24-2.02 0.50 

>2.1 

LMO4 

1.10 0.42-2.89 0.84 

≤1.29 6.02 1.51-23.94 0.01 

1.29-1.86 2.81 0.85-9.21 0.09 

>1.86 1 ref. 


1656P BREAST CANCER (BC) AND THE STUDY OF INTRATUMORAL 

HETEROGENEITY THROUGH PI3K PATHWAY-BIOMARKERS 

L. De Mattos-Arruda 1 , J. Cortes 1 , C.M. Aura 2 , J. Gregori 3 , G. Caratú 4 , C. Saura 1 , 

M. Oliveira 1 , J. Tabernero 1 , J. Seoane 5 , A. Vivancos 4 

1 Medical Oncology Department, Vall d’Hebron Institute of Oncology, Vall 

d’Hebron University Hospital, Barcelona, SPAIN, 2 Molecular Pathology, Vall 

d’Hebron University Hospital, Barcelona, SPAIN, 3 Statistics Department, Faculty 

of Biology, Barcelona University, Barcelona, SPAIN, 4 Genomics Laboratory, Vall 

d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, 

SPAIN, 5 Gene Expression and Cancer Laboratory, Vall d’Hebron Institute of 

Oncology, Vall d’Hebron University Hospital, Barcelona, SPAIN 

Introduction: Alterations of the PI3K pathway are BC drivers. Intratumoral 

heterogeneity seems to be key to deal with therapeutic resistance. In this study, we 

analyzed the presence, intratumor distribution and prognostic implications of 

PI3K-pathway biomarkers (PTEN expression and PIK3CA point mutations). 

Methods: 99 BC formalin-fixed, paraffin-embedded (FFPE) tumor-tissues and 20 

matched plasma samples were assessed. PTEN expression was determined by 

immunohistochemistry (IHC); the H-score was calculated by multiplying the percentage 

fraction of positively stained tumor area (TA) by staining intensity (0, 1 + , 2 + , or 3+). 

Sorting the H-scores, with h 1 as the highest and h 3 as the lowest, and normalizing them 

to add to 100, i.e. h` 1 =h 1/(h 1 +h 2 +h 3)*100, and taking the maximum value: Hm = 

max i (h’ i)=h’ 1. The sample was classified as homogeneous (Ho) when either Hm ≥ 90 

or Hm = 0, otherwise as heterogeneous (He). PTEN low: H-score< 50. PIK3CA and its 

% mutant alleles (mA) from FFPE or cell-free DNA (cfDNA) in plasma were 

determined by OncoCarta Panel v1.0 (Sequenom). TA and stromal area (SA) were 

scored by H&E; real tumor area: RTA = TA-SA. Metastatic BC patients (pts) were 

classified: ER + /HER2- (LUM); HER2+ (HER2); triple negative (TN). 

Results: 42% (41/97) of FFPE had PTEN Ho, 29.9% (29/97) PTEN low and 36% (33/ 

96) PIK3CA mutations. For PTEN, there was a trend for less homogeneity among LUM 

vs. non-LUM tumors (41 vs. 59%, p = 0.067). PIK3CA was more homogeneously 

distributed within LUM than non-LUM as there was a significant linear correlation 

between mA and RTA (r = 0.77, p = 0.00008). Prognosis was better for LUM pts (N = 

98, p = 0.0002), but did not differ between Ho vs. He (N = 95, p = 0.123) or PIK3CA 

mutant vs. non mutant pts (N = 89, p = 0.23). CfDNA among PIK3CA mutant pts had 

a concordance of 58% (7/12, 1 st sample for advanced BC pts) and 12.5% (1/8, 2 nd 

matched sample in 1 st follow-up), reflecting changes with treatment as compared with 

the primary/metastatic FFPE. Updated analysis will be presented. 

Conclusions: The intratumoral heterogeneity of PTEN and PIK3CA mutations were 

detected. In the case of LUM tumors, while PIK3CA mutations seemed to be more 

homogeneously distributed, reassuring its driver role, PTEN tended to be more 

heterogeneous. Profiling cfDNA could be essential to mirror the tumor from which 

they derive. 


1657P BIOMARKER (BM) RESULTS FROM THE PHASE III AVEREL 

TRIAL OF 1ST-LINE BEVACIZUMAB (BV), TRASTUZUMAB (H) 

+ DOCETAXEL (T) FOR HER2-POSITIVE LOCALLY 

RECURRENT/METASTATIC BREAST CANCER (LR/MBC) 

L. Gianni 1 , A. Chan 2 , M. Mansutti 3 , X. Pivot 4 , R. Greil 5 , L. Provencher 6 ,S.Prot 7 , 

N. Moore 8 , S.J. Scherer 9 , C. Pallaud 10 

1 Medical Oncology, IRCCS San Raffaele, Milano, ITALY, 2 Breast Clinical Trials 

Unit, Mount Hospital, Perth, AUSTRALIA, 3 Oncology, University Hospital 

S. Maria Misericordia, Udine, ITALY, 4 Service Oncologie Medicale, C.H.U. Jean 

Minjoz, Besancon Cedex, FRANCE, 5 IIIrd Medical Department, Paracelsus 

University Hospital Salzburg, Salzburg, AUSTRIA, 6 Centre Des Maladies Du Sein 

Deschenes-fabia, CHA-Hôpital du Saint-Sacrement, Quebec, CANADA, 7 PDC, F 

Hoffmann-La Roche Ltd, Basel, SWITZERLAND, 8 Biostatistics, F Hoffmann-La 

Roche Ltd, Basel, SWITZERLAND, 9 Pharma Development, Genentech, Inc., 

South San Francisco, CA, UNITED STATES OF AMERICA, 10 Pharma 

Development Oncology Business, F Hoffmann-La Roche Ltd, Basel, 

SWITZERLAND 

Background: AVEREL efficacy and safety results have been reported. We present 

exploratory analyses from the optional BM substudy. 

Methods: Patients (pts) with HER2-positive LR/mBC received 1st-line T (100 mg/m 2 

q3w) + H (8 → 6 mg/kg q3w) ± BV (15 mg/kg q3w). The primary endpoint was 

investigator-assessed PFS. Baseline (BL) blood and tissue samples were collected from 

consenting pts. BL plasma levels of candidate BMs were measured using a novel 

ELISA. Median BL values for each BM were used to define high (> median; H) vs 

low (≤ median; L) BM cohorts and to correlate BMs with PFS using Cox regression 

corrected for prognostic factors. 

Results: Plasma samples were available from 162/424 pts (38%). ICAM-1 correlated 

statistically significantly with PFS at α = 0.05. 

Conclusions: High BL ICAM-1 correlated significantly with greater PFS benefit from 

BV at α = 0.05, consistent with data in lung cancer. VEGF-A, VEGFR-2 and -3 and 

E-selectin showed potential predictive value. VEGF-A and VEGFR-2 results are in 

line with data in HER2-negative mBC and pancreatic cancer. 


Table: 1657P 

TH BV + TH 

HR (95% CI) Interaction p value a 

Subgroup Events/pts, n Median, mo Events/pts, n Median, mo 

All 64/82 11.2 66/80 16.5 0.78 (0.56–1.11) 

E-selectin L H 31/44 32/37 16.4 8.2 30/36 35/43 16.5 16.6 1.01 (0.61–1.68) 0.57 (0.35–0.92) 0.241 

IL-8 L H 35/45 28/36 13.6 8.4 28/35 37/44 16.4 17.8 0.84 (0.51–1.40) 0.74 (0.45–1.22) 0.506 

ICAM-1 L H 30/45 33/36 16.4 10.3 29/35 36/44 16.5 16.2 1.13 (0.68–1.89) 0.49 (0.30–0.80) 0.017 

bFGF L H 32/41 31/40 13.3 11.1 33/39 32/40 16.4 19.1 0.80 (0.49–1.30) 0.80 (0.49–1.32) 0.837 

PDGF-C L H 29/40 35/42 17.1 8.5 32/41 34/39 16.5 16.6 0.87 (0.52–1.44) 0.72 (0.45–1.16) 0.342 

VEGF-A L 33/45 13.6 30/36 16.5 0.83 (0.50–1.36) 0.795 

H 31/37 8.5 35/43 16.6 0.70 (0.43–1.14) 

VEGF-C L H 35/42 29/40 13.5 9.6 32/39 34/41 14.8 19.1 0.70 (0.43–1.15) 0.92 (0.56–1.51) 0.649 

VEGFR-1 L H 30/40 33/41 11.1 13.3 33/40 32/39 16.2 16.6 0.76 (0.46–1.25) 0.84 (0.52–1.37) 0.982 

VEGFR-2 L H 35/44 28/37 11.2 11.0 30/36 35/43 13.7 19.2 0.95 (0.58–1.55) 0.67 (0.40–1.10) 0.174 

VEGFR-3 L H 35/48 28/33 12.2 11.0 25/32 40/47 15.3 16.6 0.88 (0.52–1.47) 0.65 (0.40–1.06) 0.051 

a Model includes prognostic factors. 

Disclosure: L. Gianni: LG acts as a Consultant and has sat on Advisory Boards for Roche, 

Genentech, GSK, Novartis, Pfizer, Boehringer Ingelheim, Astra Zeneca, and Celgene. A. 

Chan: AC has acted as a Consultant, sat on Advisory Boards, and received honoraria and 

research funding from Roche. X. Pivot: XP has acted as a Consultant and sat on Advisory 

Boards for Roche, Eisai and GlaxoSmithKline, and has received honoraria from Sanofi. R. 

Greil: RG has acted as a Consultant for, sat on Advisory Boards for, and received 

honoraria and research funding from Roche. L. Provencher: LP has received a travel grant 

and honoraria from Roche.S. Prot: SP is an employee of F Hoffmann-La Roche Ltd. N. 

Moore: NM is an employee and holds stock in F Hoffmann-La Roche Ltd. S.J. Scherer: SS 

is an employee of Genentech. C. Pallaud: CP is an employee of F Hoffmann-La Roche Ltd. 

.All other authors have declared no conflicts of interest. 

1658P DIFFUSE REFLECTANCE SPECTROSCOPY; TOWARDS 

CLINICAL APPLICATION IN BREAST CANCER 

T.J.M. Ruers 1 , D. Evers 1 , R. Nachabé 2 , M.J. Vranken Peeters 1 , J. van der Hage 1 , 

H. Oldenburg 1 , E. Rutgers 1 , G. Lucassen 2 , B. Hendriks 2 , J. Wesseling 3 

1 Surgery, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, 

Amsterdam, NETHERLANDS, 2 Minimally Invasive Healthcare, Philips Research, 

Eindhoven, NETHERLANDS, 3 Pathology, The Netherlands Cancer Institute 

Antoni van Leeuwenhoek Hospital, Amsterdam, NETHERLANDS 

Background: Diffuse reflectance spectroscopy (DRS) is a promising new technique 

for breast cancer diagnosis. During DRS tissue is illuminated by a selected light 

spectrum. By specific absorption and scattering characteristics of the tissue an 

‘optical fingerprint’ is obtained which represents specific morphological information. 

In this way DRS is able to differentiate normal tissue from tumor tissue. Here we 

compared the diagnostic accuracy of DRS in a cohort of patients and each patient 

individually to the pathology analysis of normal and malignant breast tissue. 

Methods: Breast tissue from 47 female patients was analysed ex-vivo by DRS. A total 

of 1073 optical spectra were collected from fat, glandular tissue and fibroadenoma 

lesions as well as from (pre)-malignant tissue samples. These spectra were analyzed 

for each patient individually as well as for all patients collectively. Results were 

compared to the pathology analysis of biopsies from each measurement location. 

Results: Collective patient data analysis for discrimination between normal and 

malignant breast tissue resulted in a sensitivity of 90%, a specificity of 88% and an 

overall accuracy of 89%. For individual analysis all measurements per patient were 

categorized as either benign or malignant. The discriminative accuracy of this individual 

analysis was nearly 100%. When an arbitrary threshold was used of a 90% agreement 

between all DRS measurements and the pathology analysis for each individual patient to 

ascertain a diagnosis, only in one patient the diagnosis was classified as uncertain. 

Conclusions: Our results demonstrate that diffuse reflectance spectroscopy can be 

considered as an important new optical sensing technique that could improve the 

diagnostic workflow in breast cancer. 


1659P EFFECTS OF SRC INHIBITION ON SURVIVAL, MIGRATION 

AND INVASION OF HUMAN BREAST CANCER CELLS 

RESISTANT TO LAPATINIB 

L. Nappi, L. Formisano, R. Rosa, V. Damiano, T. Gelardi, C. D’Amato, 

V. D’Amato, R. Marciano, A.P. De Maio, R. Bianco 

Medical Oncology, University Federico II, Napoli, ITALY 

Background: HER2, a member of the HER family, is a transmembrane tyrosine 

kinase receptor overexpressed in almost 30% of breast cancer patients. Lapatinib is a 

small molecule HER2 inhibitor approved in metastatic breast cancer patients after 


trastuzumab failure. Unfortunately, the resistance against lapatinib is observed even 

in responding patients. Src is an intracellular kinase involved in tumor growth, 

angiogenesis and migration and it is related to trastuzumab resistance in human 

breast cancer cell lines. 

Materials and methods: We used different HER2 expressing human breast cancer 

cell lines, such as MDA-MB-361, MDA-MB-231 and BT474 (sensitive to lapatinib) 

JIMT-1 and KPL-4 (low sensitivity against lapatinib), and MDA-MB-361-LR 

(acquired resistance to lapatinib). We performed survival, migration and invasion 

assays and WB analysis in all cell lines treated with lapatinib, saracatinib (a Src 

inhibitor) or the combination. We also used nude mice xenografted with JIMT-1 

cells and in vivo artificial metastatic assay. 

Results: We observed that the combination treatment of lapatinib plus saracatinib is 

able to inhibit survival, migration and invasion in vitro and to regulate several 

proteins such as Src, Akt, MAPK, paxillin and FAK in all cancer cell lines tested. In 

nude mice xenografted with JIMT-1 cells, the combined treatment reduced tumor 

growth, prolonged survival and strongly decreased the incidence of lung metastases. 

Interestingly, we observed that Src preferentially binds to HER2 in lapatinib sensitive 

cells and with EGFR in resistant ones. EGFR inhibition, through the use of 

cetuximab or siRNA silencing, strongly enhanced the effect of lapatinib on the 

growth of resistant cancer cells. The combined treatment of lapatinib and cetuximab, 

moreover, significantly reduced the activation of several intracellular transducers. 

Conclusions: We demonstrated that Src plays an important role in the development 

of resistance to lapatinib in breast cancer cell lines, in particular affecting invasion 

and migration, and that EGFR may mediate its activation. These results may suggest 

the clinical development of lapatinib and cetuximab combination in patients resistant 

to lapatinib. 


1660P EPIGENETIC SILENCING OF ARGININO-SUCCINATE 

SYNTHASE (ASS1) DEFINES ARGININE DEPLETION 

THERAPY AS A NOVEL TREATMENT STRATEGY FOR 

BREAST CANCER 

F. Cavicchioli 1 , A. Shia 1 ,K.O’Leary 1 , V. Haley 1 , C. Palmieri 2 ,N.Syed 3 , 

T. Crook 4 , A.M. Thompson 5 , C. Lo Nigro 6 , P. Schmid 7 

1 Oncology, Brighton and Sussex Medical School, Brighton, UNITED KINGDOM, 

2 Hammersmith Campus, Charing Cross HospitalImperial College Healthcare 

NHS Trust, London, UNITED KINGDOM, 3 Faculty of Medicine, Imperial College 

of London, London, UNITED KINGDOM, 4 Dundee Cancer Centre, University of 

Dundee, Dundee, UNITED KINGDOM, 5 Surgery and Molecular Oncology, 

University of Dundee, Dundee, UNITED KINGDOM, 6 Oncology, S. Croce General 

Hospital, Cuneo, ITALY, 7 Clinical Investigation and Research Unit, Brighton and 

Sussex Medical School, Brighton, UNITED KINGDOM 

Background: Loss of argininosuccinate synthetase (ASS1) or lyase (ASL) expression, 

critical for the biosynthesis of arginine in normal tissues, due to 

methylation-dependent silencing sensitises ovarian or glioblastoma cells to arginine 

depletion therapy (ADT). Cells not expressing sufficient levels of ASS1 or ASL 

become auxotrophic for arginine and require exogenous supply. Arginine deiminase 

(ADI), a novel arginine-degrading enzyme, can eliminate arginine from the 

circulation and has shown activity in cancers with low ASS1 and/or ASL activity. 

This study was performed to establish whether ASS1 or ASL are subject to 

methylation-dependent silencing in breast cancer to validate ADT as a novel 

therapeutic strategy for breast cancer. 

Methods: Methylation of ASS1 and/or ASL was analysed by pyrosequencing and 

methylation-specific PCR (MSP) using primer sets validated by bisulphite 

sequencing. We used a panel of 19 breast cancer cell lines and two independent 

series of stage I-III primary breast cancers with linked mature clinical outcome that 



were randomly selected from the Tayside (n = 224) and Cuneo (n = 150) Tissue 

Banks. Tissue samples were subject to histopathological review to ensure adequate 

representation of cancer cells. 

Results: Although ASS1 or ASL methylation could not be verified in breast cancer cell 

lines, ASS1 methylation was evident in a significant proportion of primary or metastatic 

breast cancer samples. In two independent series, aberrant methylation of ASS1 was 

detected in 4.5% and 16% of primary breast cancers. The incidence was even higher in 

metastatic breast cancer, with 47% of resected brain metastases (n = 19) showing 

methylation of ASS1 and 26% showing additional methylation of ASL, a combination 

that has shown to be highly sensitive to ADT. ASS1 methylation status as called by MSP 

agreed with that determined by pyrosequencing in all cases assessed by both methods. 

No significant association with a specific tumour type or outcome was found. 

Conclusions: A significant proportion of primary and metastatic breast cancers show 

methylation-dependent transcriptional silencing of ASS1 or ASL and might be 

candidates for arginine depletion therapy. 


1661P THE PREDICTIVE ROLE OF THE 53BP1 PATHWAY IN 

ADVANCED NON-SMALL-CELL LUNG CANCER (NSCLC) 

PATIENTS (P) TREATED WITH FIRST-LINE 

PLATINUM-BASED CHEMOTHERAPY 

L. Bonanno 1 , C. Costa 2 , M. Majem 3 , A. Gimenez-Capitan 2 , I. Rodriguez 4 ,J. 

J. Sánchez 5 , B. Massuti Sureda 6 , A. Favaretto 1 , M. Rugge 7 , R. Rosell 8 

1 U.o.Oncologia Medica, Istituto Oncologico Veneto IOV-IRCCS, Padova, ITALY, 

2 Laboratoy of Biology Department, Pangaea Biotech, USP Dexeus University 

Institute, Barcelona, SPAIN, 3 Oncology, Hospital de Sant Pau, Barcelona, 

SPAIN, 4 Statistics, USP Dexeus University Institute, Barcelona, SPAIN, 

5 Statistics, Autonomous University of Madrid, Madrid, SPAIN, 6 Medical 

Oncology Dpt, Hospital General Universitario de Alicante, Alicante, SPAIN, 

7 Pathology and Cytopathology Unit, University of Padova, Padova, ITALY, 

8 Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans 

Trias i Pujol, Badalona, SPAIN 

Background: Preclinical and clinical data have shown that low BRCA1 expression 

increases sensitivity to platinum. However, the complexity of DNA repair pathways 

suggests that the BRCA1 function could be modulated by several proteins. MDC1, 

the protein initiating the response to DNA double strand breaks, activates two 

parallel pathways: 53BP1 and BRCA1. We hypothesized that the mRNA expression 

of components involved in the 53BP1 pathway could influence the predictive value of 

BRCA1. 

Methods: mRNA expression levels of BRCA1, MDC1, UBC13, RNF8, 53BP1, PIAS4, 

MMSET and UBC9 were assessed by real-time PCR analysis in 115 

paraffin-embedded tumor samples collected from advanced NSCLC p treated with 

first-line platinum-based chemotherapy without taxanes. 

Results: Expression levels of BRCA1 were correlated with MDC1 (ρ = 0.47, P < 

0.0001), UBC13 (ρ = 0.41, P = 0.001), RNF8 (ρ = 0.41, P = 0.001), 53BP1 (ρ = 0.37, 

P = 0.003), PIAS4 (ρ = 0.51, P < 0.0001), MMSET (ρ = 0.57, P < 0.0001) and UBC9 

(ρ = 0.31,P = 0.01). Median overall survival (OS) was 11 months (m), and 

progression-free survival (PFS) was 7 m. Among p with low levels of BRCA1, median 

OS was 19.3 m and PFS was 10 m for p with low levels of 53BP1, compared to 8.2 m 

and 5.9 m, respectively, for p with high levels of 53BP1 (OS: P = 0.01; PFS: P < 

0.0001). Among p with high levels of BRCA1, no significant differences in OS were 

observed according to 53BP1 expression levels. 

Conclusions: Advanced NSCLC p with low levels of both BRCA1 and 53BP1 showed 

significantly improved outcome to first-line platinum-based chemotherapy. The 

assessment of BRCA1 and 53BP1 can be useful for customizing chemotherapy. 


1662P MCPH1 (BRIT1) AND OUTCOME TO ERLOTINIB IN 

NON-SMALL-CELL LUNG CANCER (NSCLC) PATIENTS (P) 

HARBORING EGFR MUTATIONS 

R. Garcia-Campelo 1 , J.J. Sánchez 2 , C. Costa 3 , C. Queralt 4 , I. De Aguirre 4 , 

M.A. Molina, 3 , M. Majem 5 ,S.Cros 4 , L. Capdevila 4 , R. Rosell 4 

1 Oncology, Complejo Hospitalario Universitario A Coruña, A Coruña, SPAIN, 

2 Statistics, Autonomous University of Madrid, Madrid, SPAIN, 3 Laboratoy of 

Biology Department, Pangaea Biotech, USP Dexeus University Institute, 

Barcelona, SPAIN, 4 Medical Oncology Service, Catalan Institute of Oncology, 

Hospital Germans Trias i Pujol, Badalona, SPAIN, 5 Oncology, Hospital de Sant 

Pau, Barcelona, SPAIN 

Background: Progression-free survival (PFS) in EGFR-mutant NSCLC p treated with 

erlotinib can range from a few months (m) to more than two years, but genetic 

influences on the duration of response remain unclear. The cytotoxic effect of 

erlotinib has been related to several proteins that regulate DNA damage response (eg, 

BRCA1, BRCA2). MCPH1 contains 3 BRCT domains which are conserved in 

important molecules involved in DNA damage signaling, including BRCA1, MDC1 

and 53BP1. MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and 

Rad51 at sites of DNA damage. MCPH1 also regulates the ATP-dependent SWI-SNF 

chromatin remodeling complex during DNA repair. 

Methods: We used the NanoString nCounter gene expression system, which captures 

and counts individual mRNA transcripts, to analyze the expression of 44 selected genes, 

many of which are involved in DNA damage response, in 55 erlotinib-treated NSCLC 

p. We identified MCPH1 and correlated expression levels with clinical outcomes. 

Results: p characteristics: 16 males, 39 females (70.9%); 39 never-smokers (70.9%), 

12 former smokers, 4 current smokers; 34 with EGFR deletion in exon 19 (61.8%), 

21 with L858R mutation (38.2%). PFS was not reached for patients with high 

MCPH1, while it was 19 m for those with intermediate levels and 9 m for those with 

low levels (P = 0.01). Median survival was 31 m for p with high levels, not reached 

for p with intermediate levels and 17 m for p with low levels (P = 0.004). 

Conclusions: The enhanced effect of erlotinib in the presence of elevated MCPH1 

could be due to the fact that MCPH1 can interfere with the function of MDC1 and 

53BP1. The role of MCPH1 merits validation as a predictive marker of erlotinib 

response. 


1663P THE ROLE OF HEDGEHOG (HH) SIGNALING IN THE 

PREDICTION OF CLINICAL OUTCOME FOR ADVANCED 


R. Berardi 1 , A. Santinelli 2 , M. Caramanti 1 , A. Savini 1 , A. Onofri 1 , T. Biscotti 2 , 

A. Brunelli 3 , P. Mazzanti 1 , I. Bearzi 4 , S. Cascinu 1 



Riuniti Ancona Università Politecnica delle Marche, Ancona, ITALY, 3 Thoracic 

Surgery, AOU Ospedali Riuniti Ancona, Ancona, ITALY, 4 Anatomia Patologica, 

AOU Ospedali Riuniti Ancona Università Politecnica delle Marche,, Ancona, 

ITALY 

Background: NSCLC lacks validated biomarkers to predict clinical outcome. The Hh 

pathway is critical for cell growth and differentiation. The aim of our study is to 

evaluate the role of the Hh signaling pathway in determining prognosis of NSCLC 

patients. 

Methods: In this single-center prospective study, the expression of Hh-related 

molecules including Ptch1 and Gli1 (nuclear and cytoplasmic) was determined by 

immunohistochemistry in 35 histologic samples (biopsies and surgical specimens) of 

advanced NSCLC patients. All the neoplastic area included in the slides was 

considered and both cytoplasmic and nuclear stainings were evaluated, according to 

the positive neoplastic cells. The intensity of the staining was considered and scored 

as 0 (absent), 1+ (low), 2+ (medium) and 3+ (high). 

Results: We analyzed 18 adenocarcinomas and 17 squamous cell carcinomas. 

Positivity of Gli1-cytoplasmic expression and Gli1-nuclear expression were expressed 

in adenocarcinoma at a significantly higher level and more frequently than compared 

to squamous cell carcinoma (p < 0.05), while Ptch1 did not differ significantly in the 

two histotypes. Overall survival was higher in Gli1 and Ptch1 negative tumor samples 

compared to the positive group (p = 0.02). The 18 patients with adenocarcinoma 

received erlotinib as second line therapy and those presenting a lower Gli1 and Ptch1 

expression experienced a significantly better progression free survival. 

Conclusion: At our best knowledge this is the first study investigating the role of HH 

in NSCLC patients. The results suggest that the Hh pathway might play a major 

prognostic role in NSCLC with significant differences between the histotype. 

Furthermore it might predict the efficacy of erlotinib as second-line treatment in 

patients with advanced lung adenocarcinoma. 


1664P PROTEOMIC AND CIRCULATING FREE DNA ANALYSIS 

OUTCOME PREDICTORS IN THE GALAXY TRIALTM 

(NCT01348126): A RANDOMIZED PHASE IIB/III STUDY OF 

GANETESPIB (STA-9090) IN COMBINATION WITH 

DOCETAXEL VERSUS DOCETAXEL ALONE IN SUBJECTS 

WITH STAGE IIIB/IV NSCLC 

D. Fennell 1 , E. Petricoin 2 , J. Shaw 3 , I. El Hariry 4 , V. Vukovic 5 , F. Teofilovici 5 , 

V. Reichert 4 , R. Rosell 6 

1 Medicine, University of Leicester, Leicester, UNITED KINGDOM, 2 Applied 

Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 

UNITED STATES OF AMERICA, 3 Cancer Studies & Molecular Medicine, 

University of Leicester, Leicester, UNITED KINGDOM, 4 Oncology, Synta 

Pharmaceuticals, Lexington, MA, UNITED STATES OF AMERICA, 5 Clinical 

Development, Synta Pharmaceuticals Corp., Lexington, VA, UNITED STATES OF 

AMERICA, 6 Medical Oncology Service, Catalan Institute of Oncology ICO 

Badalona Hospital Germans Trias i Pujol, Medical Oncology, Badalona, SPAIN 

Background: Inhibition of Hsp90, a key molecular chaperone required for activation 

of many oncoproteins, can lead to cancer cell death. Ganetespib (G) is an Hsp90 

inhibitor that has shown single agent activity in molecularly defined disease, 

including ELM4-ALK rearrangement, KRAS mutations, HER2 amplification and 


BRAF mutations. Circulating free DNA (cfDNA) is present at low levels in plasma of 

healthy individuals, whereas its increased concentration was observed in patients 

with malignant tumors including non-small cell lung cancer (NSCLC). Cancer gene 

somatic mutations can be detected in cfDNA. 

Methods: This is a randomized trial, comparing G+ docetaxel (D), to D in 2 nd line 

advanced NSCLC patients. This study aimed at investigating the potential usefulness 

of plasma DNA concentration in NSCLC patients for efficacy of therapy. We 

performed a prospective exploratory analysis to identify serum biomarkers as 

predictors of improved outcomes with G. Plasma samples were collected from 160 

pts at baseline prior to initiation of treatment, and at end of cycles 1 and 2. cfDNA 

was evaluated using the Ion Torrent platform to survey mutations in 46 cancer 

genes. Serum levels were correlated with progression free survival (PFS) and overall 

survival (OS) in both treatment arms. Upfront enrichment using both nanoparticle 

capture and phosphoprotein capture technologies were coupled to high resolution 

Orbitrap-LTQ MS/MS analysis followed by spectral counting for each samples. 

Results: By early May approximately half of the 300 planned patients were enrolled. 

Baseline characteristics were balanced. Full proteomic profiling and cfDNA analysis 

is ongoing, and will be correlated with the efficacy outcomes from a planned interim 

analysis in early September, including disease control rate, PFS, and OS. 

Disclosure: I. El Hariry: stock ownership. V. Vukovic: stock ownership. F. Teofilovici: 

stock option. V. Reichert: stock options. All other authors have declared no conflicts 

of interest. 

1665P INTER-OBSERVER AGREEMENT OF THE RESPONSE TO 

THERAPY ASSESSMENT IN ADVANCED LUNG CANCER 

WITHIN A NORMATIVE MEASUREMENT ENVIRONMENT 

H. Beaumont 1 , E. Oubel 1 , A. Iannessi 2 , D. Wormanns 3 

1 Science, MEDIAN Technologies, Valbonne, FRANCE, 2 Radiology, Centre 

Antoine Lacassagne, Nice, FRANCE, 3 Department of Radiology, ELK Berlin 

Chest Hospital, Berlin, GERMANY 

Purpose: Image-based biomarkers play an increasing role in the assessment of 

response to therapy. The value of a biomarker comes, in part, from its ability to 

guarantee reproducibility in a varying context. This study aims at evaluating the 

impact of workflow normalization and automation on the reproducibility of 

volume-based response assessment. This impact is measured in terms of inter-reader 

agreement (IRA). 

Method: A retrospective study was performed on 10 patients with Non-Small Cell Lung 

Cancer (NSCLC) lesions followed over 7 time points (TP) on average with Computed 

Tomography. Five imaging scientists measured sequentially the volume of each lesion at 

each TP and the time required to perform segmentations. We relied on a software 

providing semi-automatic segmentation capabilities and follow-up (FU) display. After 6 

months, a second reading session used no automation for segmentation. The response 

to treatment was assessed according to +/-30% thresholds as recommended by the 

Quantitative Imaging Biomarker Alliance (QIBA). The IRA was measured by using 

Kappa coefficient. From the initial reading, where the same reader reviewed 

consecutively all TPs from the same patient, additional IRA assessments where 

performed by random mixing of measurements from different readers. Different types 

of mixing patterns simulated several deviations from normalization, this corresponding 

to FUs involving more than one radiologist or method. 

Results: The IRA of a normalized and automated workflow yielded a significantly 

higher kappa = 0.69 [0.59; 0.79] compared to mixed manual segmentations where 

kappa was 0.24 [0.06; 0.42]. Analyzed separately, both single-reviewer assessment and 

semi-automated segmentation led to higher reproducibility. The recourse to 

semi-automated segmentation reduces the average segmentation time by a factor of 4. 

Conclusions: Normalization and automation of the measurements improved 

significantly the IRA. Both normalization and automation contribute to improved 

reproducibility. Even small deviations from a normalized review may impair the 

global reliability of FUs. Single-reviewer reading and automation must be considered 

for a highly reproducible assessment of response to therapy. 


1666P UTILITY OF A NOVEL QUANTITATIVE EGFR MUTATED 

PROTEIN ANALYSIS USING AQUA SYSTEM FOR EGFR-TKI 

TREATMENT IN NON-SMALL CELL LUNG CANCER 

PATIENTS 

K. Goto 1 , G. Ishii 2 , K. Fujimoto-Ouchi 3 , M. Shirane 4 , H. Ohmatsu 1 , S. Niho 1 , 

K. Yoh 1 , S. Umemura 1 , K. Nagai 5 ,Y.Ohe 1 

1 Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, 

JAPAN, 2 Department of Pathology, National Cancer Center Hospital East, 

Kashiwa, JAPAN, 3 Discovery Pharmacology Department 2, Chugai 

Pharmaceutical Co., Ltd., Kanagawa, JAPAN, 4 Medical Affairs Devision, Chugai 

Pharmaceuticals Co. Ltd, Tokyo, JAPAN, 5 Department of Thoracic Oncology, 

National Cancer Center Hospital East, Kashiwa, JAPAN 

Background: Lung cancer carrying EGFR mutation (muEGFR) expresses good 

response to EGFR tyrosine kinase inhibitors (TKIs). However, not all patients (pts) 


with mutation showed similar clinical benefits from EGFR-TKIs. Heterogeneity of 

tumor cells is considered to be one plausible reason. MuEGFR was usually genotyped 

in qualitative manner in present clinical practice. In addition, new technology of 

AQUA system enables us to measure protein levels objectively with considering 

expression heterogeneity in tissues. Here we investigated the correlation between 

AQUA score obtained from each specimen and the response and the response 

duration by EGFR-TKIs. 

Methods: Slice sections from genotyped 105 pts with muEGFR and 33 pts with 

wild-type EGFR were stained by E746-A750 deletion (6B6)- and L858R 

(43B2)-specific antibodies. Homo- or heterogeneous staining and muEGFR protein 

levels of these specimens were evaluated with AQUA system. 

Results: Concordance rate between genotypes and AQUA-based phenotypes 

(deletion and L858R), with cut-off values based on ROC curve, were 60% and 

82%. Low sensitivity of 6B6 was due to lucking of reactivity for other 

deletion variants. Alternatively, specificities of both antibodies were 96% and 

92%, indicating highly selectivity to muEGFR protein. The AQUA score of 28 

pts treated with EGFR-TKIs were varied (5.4 – 798.5) but the falls plot 

analysis indicated that pts with high AQUA score showed better objective 

response. Specimens of partial response (PR) had significantly higher AQUA 

score than those of progression disease (67.4 vs 9.6, p = 0.025). However, 

there were no differences of AQUA score between specimens of PR and stable 

disease. When divided pts into two groups based on median AQUA score, 

the pts with high AQUA score showed a tendency of longer treatment 

duration (24 mo vs 15 mo, p = 0.210). Especially, the high AQUA score with 

low intratumoral deviation pts showed longer treatment duration in compared 

to others. These results indicate that AQUA-based analysis can classify pts 

carrying genotyped muEGFR into susceptible and less susceptible ones to 

EGFR-TKIs. 

Conclusions: We observed that pts with high AQUA score were more sensitive 

to EGFR-TKIs. It is important for predicting sensitivity to EGFR-TKIs to 

examine not only genotyping but also muEGFR protein levels by using AQUA 

system. 


1667P INFLUENCE OF DRUG EXPOSURE AND GENETIC VARIATION 

ON PACLITAXEL–INDUCED NEUROTOXICITY 

A.M. De Graan 1 , L. Elens 2 , A. Sparreboom 3 , L.E. Friberg 4 , B. van der Holt 5 , 

P.J. De Raaf 1 , E.A.C. Wiemer 1 , J. Verweij 1 , R.H. van Schaik 2 , R.H.J. Mathijssen 1 

1 Medical Oncology, Erasmus MC, Rotterdam, NETHERLANDS, 2 Clinical 

Chemistry, Erasmus MC, Rotterdam, NETHERLANDS, 3 Pharmaceutical 

Sciences, St. Jude Children’s Research Hospital, Memphis, TN, UNITED 

STATES OF AMERICA, 4 Pharmaceutical Biosciences, Uppsala University, 

Uppsala, SWEDEN, 5 Trials and Statistics, Erasmus MC, Rotterdam, 

NETHERLANDS 

Objectives: Paclitaxel is used for the treatment of several solid tumors and displays a 

high inter-individual variation in exposure and toxicity. Neurotoxicity is a frequent 

and sometimes serious adverse event frequently of paclitaxel treatment. This study 

aims to find predictive pharmacokinetic (PK) and pharmacogenetic determinants for 

the development of neurotoxicity. 

Methods: In 261 patients treated with paclitaxel, incidence of neurotoxicity during 

all courses (according to CTC 4.0 criteria) and PK parameters were determined. PK 

samples were measured by HPLC or LC-MS/MS, and individual PK parameters were 

estimated from previously developed population PK models by non-linear mixed 

effects modeling in the software NONMEM. Univariate and multivariate stepwise 

regression analysis were used to study the influence of co-variables on the 

development of neurotoxicity. Variables tested were age, dose, tumor type, ethnicity, 

co-medication, smoking status, and genetic variants in the PK-pathway of paclitaxel 

(CYP3A4*22, CYP3A5*3, CYP2C8*3, CYP2C8 rs1058932, and ABCB1 3435 C > T, 

determined by TaqMan genotyping assays on the ABI PRISM 7500 Fast real-time 

PCR System). 

Results: Exposure to paclitaxel (logAUC) was predictive for the development 

(P


1668P SYSTEMS BIOLOGY IN TRANSLATIONAL ONCOLOGY: 

COMPUTATIONAL AND EXPERIMENTAL STUDY OF EGFR 

AND IGF1R PATHWAYS IN NSCLC CELL LINES 

F. Bianconi 1 , K. Perruccio 2 , V. Ludovini 3 , E. Baldelli 3 , G. Bellezza 4 , A. Flacco 2 , 

P. Valigi 5 , L. Crinò 3 

1 Department of Surgical and Medical Specialties, and Public Health, University of 

Perugia, Perugia, ITALY, 2 Medical Oncology Division, S. Maria della Misericordia 

Hospital, Perugia, ITALY, 3 Medical Oncology, S. Maria della Misericordia 

Hospital, Perugia, ITALY, 4 University of Perugia, Institute of Pathological Anatomy 

and Histology, University of Perugia, Perugia, Italy, Perugia, ITALY, 5 Department 

of Electronic and Information Engineering, University of Perugia, Perugia, ITALY 

Background: The epidermal growth factor receptor (EGFR) and type 1 

insulin-like growth factor receptor (IGF1R) pathways are complex networks 

involving interactions between membrane-bound receptors, ligands, binding 

proteins, downstream effectors and mutual interactions. In this study we 

have designed a computational model of EGFR and IGF1R pathways in 

NSCLC and we validated their dynamic responses in several tumor cell 

lines. 

Materials and methods: EGFR and IGF1R pathways and the downstream MAPK 

and PIK3 networks have been modeled by means a mathematical model based on 

ODE. A549, H1299, H1675 and H1650 tumor cell lines were stimulated by EGF, 

IGF-I, EGF/IGF-I and without ligands. For these induction conditions we quantified 

at 0, 2, 5, 10, 20, 30, 40, 50, 60 minutes by western blotting the following proteins: 

phospho-AKT, AKT, phospho-EGFR, EGFR, phospho-p44/42 MAPK(ERK 1/2), p44/ 

42 MAPK(ERK1/2), phospho-IGF1R and IGF1R. Model simulations and experiment 

data have been combined together. 

Results: The time series performed in all cell lines under the four induction 

conditions allowed us to characterize the signal transduction through EGFR and 

IGF1R pathways. Our model has reproduced proteins behavior of A549, H1299, 

H1675 and H1650 cell lines and also the robustness of the network has been 

confirmed. 

Conclusions: We propose a Systems Biology approach, combined with Translational 

Oncology tolls, to understand the interaction between EGFR and IGF1R pathways in 

NSCLC cell lines and validate model predictions. Future work will investigate the 

effect of drugs action on cell lines. 


1669P ONCO-I2B2 PROJECT: A BIOINFORMATICS TOOL 

INTEGRATING –OMICS AND CLINICAL DATA TO SUPPORT 

TRANSLATIONAL RESEARCH 

A. Zambelli 1 , D. Segagni 2 , V. Tibollo 2 , A. Dagliati 2 , A. Malovini 2 , V. Fotia 1 , 

S. Manera 1 , R. Bellazzi 3 

1 Oncology, Fondazione Salvatore Maugeri, Pavia, ITALY, 2 Information 

Technology, Fondazione Salvatore Maugeri, Pavia, ITALY, 3 Industrial and 

Information Engineering, University of Pavia, Pavia, ITALY 

The ONCO-i2b2 project, supported by the University of Pavia and the Fondazione 

Salvatore Maugeri (FSM), aims at supporting translational research in oncology and 

exploits the software solutions implemented by the Informatics for Integrating 

Biology and the Bedside (i2b2) research centre, an initiative funded by the NIH 

Roadmap National Centres for Biomedical Computing. The ONCO-i2b2 software is 

designed to integrate the i2b2 infrastructure with the FSM hospital information 

system and the Bruno Boerci Biobank, in order to provide well-characterized cancer 

specimens along with an accurate patients clinical data-base. The i2b2 infrastructure 

provides a web-based access to all the electronic medical records of cancer patients, 

and allow researchers analyzing the vast amount of biological and clinical 

information, relying on a user-friendly interface. Data coming from multiple sources 

are integrated and jointly queried. 

In 2011 at AIOM Meeting we reported the preliminary experience of the 

ONCO-i2b2 project, now we’re able to present the up and running platform and the 

Table: 1670P 

extended data set. Currently, more than 4400 specimens are stored and more than 

600 of breast cancer patients give the consent for the use of specimens in the context 

of clinical research, in addition, more than 5000 histological reports are stored in 

order to integrate clinical data. 

Within the ONCO-i2b2 project is possible to query and merge data regarding: 

• Anonymous patient personal data; 

• Diagnosis and therapy ICD9-CM subset from the hospital information system; 

• Histological data (tumour SNOMED and TNM codes) and receptor profile testing 

(Her2, Ki67) from anatomic pathology database; 

• Specimen molecular characteristics (DNA, RNA, blood, plasma and cancer tissues) 

from the Bruno Boerci biobank management system. 

The research infrastructure will be completed by the development of new set of 

components designed to enhance the ability of an i2b2 hive to utilize data generated 

by NGS technology, providing a mechanism to apply custom genomic annotations. 

The translational tool created at FSM is a concrete example regarding how the 

integration of different information from heterogeneous sources could bring scientific 

research closer to understand the nature of disease itself and to create novel 

diagnostics through handy interfaces. 


1670P EVALUATION OF ALTERNATE TUMOR METRICS AND 

CUT-POINTS FOR RESPONSE CATEGORIZATION USING THE 

RECIST 1.1 DATA WAREHOUSE 

S.J. Mandrekar 1 ,M.An 2 , J. Meyers 1 , A. Grothey 3 , J. Bogaerts 4 , D.J. Sargent 1 

1 Health Sciences Research, Mayo Clinic, Rochester, MN, UNITED STATES OF 

AMERICA, 2 Mathematics, Vassar College, Poughkeepsie, UNITED STATES OF 

AMERICA, 3 Medical Oncology, Mayo Clinic, Rochester, MN, UNITED STATES 

OF AMERICA, 4 Statistics Dept, EORTC, Brussels, BELGIUM 

Purpose: We previously showed that the trichotomized response metric (TriTR: 

Complete or Partial Response (CR or PR) vs. Stable (SD) vs. Progression (PD)) had 

better predictive ability than the Response Evaluation Criteria in Solid Tumors 

(RECIST) best response (BR) metrics (CR/PR vs. others) (An et al., 2011). We 

sought to test and validate TriTR, disease control rate (DCR: CR/PR/SD vs. PD) and 

BR metrics utilizing alternate cut-points for PR and PD using the RECIST data 

warehouse. 

Methods: Data from 13 trials (5994 patients with breast, lung or colorectal 

cancer) were randomly split (60:40) into training and test sets stratified by 

tumor type, survival and progression status. 21 pairs of cut points for (PR, 

PD) were considered: PR (20-50% decrease, by 5% increments) and PD 

(10-20% increase, by 5% increments), where the pair (30%, 20%), 

corresponds to the RECIST categorization. Cox proportional hazards models 

with a flexible landmark analysis at 12- and 24-weeks post-baseline, adjusted 

for baseline tumor burden, were used to assess the impact of the metrics 

(using alternate cutoffs) on overall survival (OS). Model discrimination was 

assessed using the concordance (c-) index [c = 0.5: no association; c = 1.0: 

perfect association]. 

Results: Standard RECIST cutoffs demonstrated similar predictive ability as the 

alternate (PR, PD) cutoffs for all metrics at both time points. Regardless of 

tumor type, the last TriTR and DCR metrics (assessed at the landmark time 

point) had higher (or similar) c-indices to BR, and best TriTR and DCR metrics 

(assessed any time before the landmark time point). The 24-week metrics were 

no better than those at 12-weeks. None of the metrics did particularly well for 

breast cancer. 

Conclusions: Alternative cut-points to RECIST standards provided no 

meaningful improvement in OS prediction. TriTr and DCR metrics assessed after 

12-weeks have good predictive performance. These results are currently being 

validated. 


C-Index at 12 and 24 weeks (Training Set) 

Breast Colon Lung 

Metric (based on RECIST cutoffs) 12 wks (N = 1048) 24 wks (N = 1060) 12 wks (N = 710) 24 wks (N = 727) 12 wks (N = 1816) 24 wks (N = 1819) 

BR 0.57 0.58 0.61 0.64 0.62 0.62 

Last TriTR 0.58 0.59 0.63 0.66 0.64 0.63 

Best TriTR 0.58 0.58 0.62 0.64 0.63 0.62 

Last DCR 0.58 0.58 0.62 0.65 0.61 0.61 

Best DCR 0.57 0.56 0.59 0.59 0.62 0.59 


1671P PHASE I CLINICAL TRIAL OF CANCER VACCINE COMBINED 

WITH CHEMOTHERAPY TARGETING BOTH TUMOR 

ANTIGEN AND IMMUNE TOLERANCE AGAINST ADVANCED 

SOLID TUMORS 

M. Murahashi 1 , Y. Hijikata 1 , Y. Tanaka 2 , H. Inoue 2 , T. Marumoto 2 , Y. Nakanishi 3 , 

K. Yoshida 4 , T. Tsunoda 4 , Y. Nakamura 5 , K. Tani 2 

1 Department of Advanced Cell and Molecular Therapy, Kyushu University 

Hospital, Fukuoka, JAPAN, 2 Medical Institute of Bioregulation, Kyushu University, 

Fukuoka, JAPAN, 3 Research Institute for Diseases of the Chest, Kyushu 

University Hospital, Fukuoka, JAPAN, 4 Cancer Immunology, OncoTherapy 

Science, Inc., Tokyo, JAPAN, 5 Institute of Medical Science, University of Tokyo, 

Tokyo, JAPAN 

Background: Antitumor immunotherapy to target tumor antigens and evade 

immune tolerance is considered reasonable and promising. However, no combined 

immunotherapy has been established. We designed a phase I trial of cancer vaccine 

combined with chemotherapy to investigate safety as the primary endpoint, and 

immune responses and clinical benefits as secondary endpoints. 

Methods: Patients positive for HLA-A2402 who showed locally advanced, 

metastatic, and/or recurrent gastrointestinal, lung or cervical cancer were 

evaluated in a phase I clinical trial of cancer vaccine and chemotherapy. 

Cyclophosphamide (CPM) was administered 4 days before vaccination to 

eliminate regulatory T cells (Treg). 18 patients were treated in cohorts of six 

patients, each with escalating CPM dose (150, 300 and 600 mg/m2). Five 

HLA-A2402-restricted tumor-associated antigen (TAA) epitope peptides from 

KOC1, TTK, URLC10, DEPDC1, and MPHOSPH1 were injected once a week 

for 4 weeks. Patients without gastrointestinal bleeding, pleural effusion or ascites 

also received low dose IL-2 every after vaccination. 

Results: The treatment was tolerated well without any associated adverse events 

above grade 3. The study included primary disease with 9 cases of colorectal 

cancer, 3 cholangiocellular carcinoma, 3 lung cancer, and one each of esophageal, 

gastric and cervical cancer. Nine of 13 patients (69%) assessed by Elispot assay 

showed cytotoxic T lymphocytes (CTL) specific for TAA to more than one of five 

antigens after vaccination. Log-rank test among these demonstrated that CTL 

responses induced by vaccine contributed significantly to overall survival (MST: 

9.2 vs 3.9 months, P = 0.003). In addition, a significantly broader antigenic 

repertoire was found in longer survivors (p = 0.033). Treg number dropped from 

baseline with dose just after CPM administration. This seems to reflect direct 

inhibition of CPM on Treg. Interestingly, reduced Treg correlated significantly 

with longer overall survival (P = 0.024), suggesting CPM augmented, 

vaccine-induced CTL responses through Treg reduction. 

Conclusion: This phase I clinical study demonstrated promising survival associated 

with Treg inhibition, as well as CTL responses that warrants further clinical studies. 

Disclosure: K. Yoshida: I am a research staff of the company, OncoTherapy 

Science Inc. providing the peptide vaccines used in this study. T. Tsunoda: I am 

the President and CEO of the company, OncoTherapy Science, Inc. providing 

the peptide vaccines used in this study. Y. Nakamura: I am one of the major 

stock holders of the company, OncoTherapy Science, Inc. K. Tani: Our 

department obtained the partial research funding in 2007 from the comapany, 

OncoTherapy Science, Inc. All other authors have declared no conflicts of 

interest. 

1672P NOVEL STRATEGY FOR DESIGNING AND OPTIMIZING OF 

DENDRITIC – CELL – BASED ANTICANCER VACCINE 

N. Khranovska 1 , G.P. Potebnia 2 , O.V. Skachkova 1 , O.A. Tanasienko 2 , 

N.M. Svergun 1 , V.V. Sitko 1 , O.G. Fedorchuk 3 , V.V. Niculina 1 

1 Experimental Oncology, National Cancer Institute of the MPH Ukraine, Kiev, 

UKRAINE, 2 Department of Biotherapy Means Construction, R.E.Kavetsky 

Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, 

Kiev, UKRAINE, 3 Department of Medical Correction of Oncogenesis, R.E. 

Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS 

of Ukraine, Kiev, UKRAINE 

Background: Despite widely explore of DC based immunotherapy in cancer, 

optimal conditions for the generation of phenotypically and functionally 

mature DCs remain to be established. Maturation of DC can be achieved by 

several stimuli: pathogen-associated triggers or endogenous danger signals. In 

this study, we diversely explore the new approach for creating effective 

DC-vaccine employing the exogenous cytotoxic lectins (CLs) from Bacillus 

subtilis. 

Methods: To study the effect of CLs on degree of DCs maturity and ability to 

produce IL-12 DCs of 10 healthy donors were used. DCs were generated from 

peripheral blood monocytes ex vivo in the presence of GM-CSF and IL-4 

during 8 days. CLs from Bacillus subtilis (18,5 and 79 kDa) were added to 

immature DCs on day 6. Maturation state and functional activity of DCs were 

evaluated by the expression of cell surface markers CD83, CD86, HLA-DR 

and IL-10, 12 p35, p40 mRNA levels. For clinical trial DCs loaded with lysate 

of tumor cells (LTC) and treated with CLs were used. DC-vaccine has been 


tested in adjuvant regimen in 73 stage III-IV ovarian cancer (OC) patients. 

Patients of control group received the same treatment, except the 

DC-immunotherapy. 

Results: IL-12 p40, p35 and IL-10 mRNA levels were strongly up-regulated by CLs. 

Exposure DCs to CLs caused 2-10 - fold increase in mRNA cytokine level expression 

in comparison with control DC incubated in the presence of grows factors only. The 

effect of CLs was dose dependent and was not due to a block of DCs maturation as 

determined by analysis of DC surface markers. CLs contributed to a simultaneously 

significant increasing in CD86/HLA-DR expression (up to 89,44 ±5.26 vs 55,94 ± 

12,0 %) and slightly augmented CD83 expression. The most prominent changes in 

the expression of maturation-associated molecules was observed in DCs treated with 

CLs in the concentrations 0,04-0,1 mg/ml and thus appear to be the most suitable 

CLs concentrations for use in the DC-immunotherapy clinical trial. Kaplan-Meier 

analysis revealed prolonged 4 - year overall survival of OC patients treated with 

elaborated DC – vaccine compared with the control group (50 vs 39 %; F Cox test: 

P = 0,034). 

Conclusion: Manipulation of DCs with CLs from B.subtilis may prove to be a 

particularly effective way to stimulate antitumor immunity in cancer patients which 

leads to a clinical benefit. 


1673P INTEGRATED GENOMIC APPROACHES TO THERAPEUTIC 

TARGET IDENTIFICATION FOR HEPATOCELLULAR 

CARCINOMA 

T. Yamada, R. Satow, M. Masuda, K. Honda 

Division of Chemotherapy and Clinical Research, National Cancer Center 

Research Institute, Tokyo, JAPAN 

Purpose: Recently, a multi-kinase inhibitor, sorafenib, has been approved as a 

systemic chemotherapeutic drug for advanced hepatocellular carcinoma (HCC), but 

further improvement seems to be necessary. To identify an “Achilles heel” of HCC 

cells, we performed an unbiased survey of the whole genome. 

Methods: To develop new therapeutic agents that act specifically on HCC but 

interfere only minimally with residual liver function, we adopted a combined 

functional approach. We first searched for genes that were up-regulated in 

HCC in comparison with the background non-tumorous liver tissue. This was 

followed by siRNA-based screening of genes required for HCC cell 

proliferation. 

Results: We searched for genes that were upregulated in 20 cases of HCC in 

comparison with corresponding non-tumorous liver and a panel representing 

normal organs using high-density microarrays capable of detecting all exons in 

the human genome. Eleven transcripts whose expression was significantly 

increased in HCC were subjected to small-interfering RNA (siRNA)-based 

secondary screening of genes required for HCC cell proliferation as well as 

quantitative RT-PCR analysis [Validation Sets 1 (n = 20) and 2 (n = 44)] and 

immunohistochemistry (n = 19). We finally extracted 4 genes, AKR1B10, 

HCAP-G, RRM2, and TPX2, as candidate therapeutic targets for HCC. 

siRNA-mediated knockdown of these candidate genes inhibited the proliferation 

of HCC cells and the growth of HCC xenografts transplanted into 

immunodeficient mice. 

Conclusions: The 4 genes we identified were highly expressed in HCC, and HCC 

cells are highly dependent on these genes for proliferation. Technologies such as 

microarray, high-speed sequencing, and mass spectrometry have advanced rapidly in 

recent years, allowing genome-wide-scale examination of alterations in chromosomal 

gains and losses, the structure, epigenetic modification, and expression of genes, the 

expression and post-translational modification of proteins, and cell signaling 

pathways. I would like to discuss the possible combination of these technologies for 

therapeutic target identification. 


1674P IDENTIFICATION OF PHOSPHORYLATED RIBOSOMAL 

PROTEIN S6 AS A POTENTIAL PREDICTOR OF 

HEPATOCELLULAR CARCINOMA RESPONSE TO SORAFENIB 

BY PATHWAY-BASED PHOSPHOPROTEIN PROFILING 

M. Masuda, K. Honda, T. Yamada 

Division of Chemotherapy and Clinical Research, National Cancer Center 

Research Institute, Tokyo, JAPAN 

Backgroud: Sorafenib is a multi-kinase inhibitor that has been proved to be effective 

for the treatment of advanced hepatocellular carcinoma (HCC). However, only a 

small proportion of patients receiving sorafenib obtain the anticipated therapeutic 

benefits. It would therefore be desirable to clarify the precise molecular mechanisms 

that confer resistance to sorafenib and identify a predictive biomarker for 

unresponsiveness to sorafenib. 

Methods: We constructed reverse-phase protein microarrays (RPPAs) onto which 

whole lysates of 95 cell lines derived from various tumors, including 23 HCCs, were 



plotted and examined for phosphorylation expression of 183 proteins serving as 

nodes in 120 signaling pathways registered in the NCI-Nature curated pathway 

(NCI-Nature_Curated.bp2.owl 2011.12.19). The sensitivity (IC50 value) of the 23 

HCC cell lines to sofafenib was quantified using the CellTiter-Glo Luminescent Cell 

Viability Assay kit. 

Results: Use of fluorescence dye significantly expanded the sensitivity and dynamic 

range of the RPPAs. We found that the relative level of phosphorylation of ribosomal 

protein S6 (p-rpS6) at the Ser235/236 residues showed the highest correlation with 

sensitivity to sorafenib among the 183 signaling nodes (P = 0.0044, Spearman 

correlation analysis), followed by phosphorylation of the same protein at the Ser240/ 

244 residues (P = 0.0070). Immunoblot analysis confirmed that the sorafenib-resistant 

cell lines had the highest level of rpS6 phosphorylation. We found that in some HCC 

cell lines the mitogen-activated protein kinase (MAPK) pathway was activated 

downstream of RAF kinase and showed sensitivity to MEK (CI-1040) and RSK 

(SL0101) inhibitors. 

Conclusions: To achieve personalization of molecular therapies, precise mapping of 

activated signaling pathways in individual patients is essential. RPPA requires only a 

small amount of protein and is ideal for application to clinical settings. We are 

collecting tumor biopsy samples from HCC patients to verify the present findings, 

and plan to present the data at the meeting. 


1675P PRECLINICAL AND PRELIMINARY CLINICAL ACTIVITY OF 

NVP-BKM120, AN ORAL PAN-CLASS I PI3K INHIBITOR, IN 

THE BRAIN 

M. Maira 1 , C. Schnell 1 , P. Lollini 2 , C. Chouaid 3 , P. Schmid 4 , P. Nanni 5 , D. Lam 6 , 

E. Di Tomaso 7 , C. Massacesi 8 , J. Rodon 9 

1 Oncology, Novatis Institute for Biomedical Research, Basel, SWITZERLAND, 

2 Department of Hematology and Oncological Sciences, University of Bologna, 

Bologna, ITALY, 3 Pulmonology, Hopital Saint-Antoine, Paris, FRANCE, 4 Clinical 

Investigation and Research Unit, Brighton and Sussex Medical School, Brighton, 

UNITED KINGDOM, 5 Department of Experimental Pathology, University of 

Bologna, Bologna, ITALY, 6 Oncology, Novartis, Florham Park, NJ, UNITED 

STATES OF AMERICA, 7 Institutes for Biomedical Research, Novartis, 

Cambridge, MA, UNITED STATES OF AMERICA, 8 Oncology, Novartis, Paris, 

FRANCE, 9 Medical Oncology, Vall d’Hebron University Hospital, Barcelona, 

SPAIN 

Background: New therapies that penetrate the blood–brain barrier (BBB) are needed 

to combat brain metastases (BM). Activity of BKM120, an oral pan-class I PI3K 

inhibitor, in the brain was assessed in vivo, with additional evidence collected from 

Ph I/II clinical trials. 

Methods: The ability of BKM120 to penetrate the BBB and inhibit PI3K signaling 

was determined by: (1) comparison of IHC staining of insulin-induced S473P-AKT 

levels in the brains of untreated/BKM120-treated (5 mg/kg, po, once) rats; and (2) 

regular monitoring of drug concentrations and S473P-AKT levels over 24 hrs upon 

BKM120 (50 mg/kg, po, once) or pan-PI3K inhibitor GDC0941 (150 mg/kg, po, 

once) treatment in plasma, tumor and brain tissue of Rat1-myr-p110 tumor-bearing 

(subcutaneous) mice. Activity of BKM120 against BM was also assessed in 1 

preclinical model of HER2+ breast cancer (BC) BM and in 2 clinical trials of pts 

with advanced solid tumors (CBKM120X2101) and metastatic NSCLC 

(CBKM120D2201). 

Results: BKM120 strongly reduced insulin-induced S473P-AKT in the brain vs. 

untreated controls, with the most notable effects observed in the cerebellum. 

Uptake of BKM120 in Rat1-myr-p110 tumor-bearing mice over 24 hrs was 

similar across plasma, tumor and brain tissues, with the highest concentration of 

BKM120 at 1 hr post-administration. At this time point, BKM120 completely 

reduced S473P-AKT in both tumor and brain samples. In contrast, uptake of 

GDC0941 was undetectable in the brain and had no effect on S473P-AKT levels 

in this tissue. Uptake of GDC0941 and inhibition of S473P-AKT was similar to 

BKM120 in plasma and tumor. In addition, BKM120 strongly inhibited growth 

of BM by human HER2+ BC cells MDA-MB-453 in immunodeficient Rag2 −/- / 

Il2rg −/- mice. In 2 clinical trials, 4 pts with BM have been treated with 

single-agent BKM120 to date: 1 pt with metastatic BC had a 29% reduction in a 

brain lesion, while disappearance of a non-target brain lesion was seen in 1 pt 

with squamous NSCLC. 

Conclusions: Preclinical data suggest that BKM120 penetrates the BBB and inhibits 

PI3K signaling in the brain. This unique property of BKM120 is not a class effect. 

Preliminary clinical evidence supports these findings. Clinical trials of BKM120 in 

pts with BM are planned. 

Disclosure: M. Maira: Stock ownership and employee of Novartis. C. Schnell: 

Stockholder and employee of Novartis. C. Chouaid: Member of the advisory boards 

for Lilly, Amgen, Roche and has undertaken research sponsored by Lilly, Amgen, 

Roche, Novartis and AstraZeneca. D. Lam: Employee of Novartis. E. Di Tomaso: 

Employee of Novartis. C. Massacesi: Employee of Novartis. All other authors have 


1676P GEMCITABINE, PI3KINASE-AKT PATHWAY INHIBITION AND 

RADIATION IN HUMAN GLIOMA CELL LINES 

M.S. Elnaggar 1 , P. Sminia 2 , S. Shehata 3 , C. Fedrigo 4 , G. Peters 1 

1 Medical Oncology Department, VUMC, Amsterdam, NETHERLANDS, 

2 Radiation Oncology, VUMC, Amsterdam, NETHERLANDS, 3 Clinical Oncology 

Department, Assiut University Hospital, Assiut, EGYPT, 4 Medicina e Ciências da 

Saúde, 2Pontifícia Universidade Católica do Rio Grande do Sul, Rio Grande do 

Sul, BRAZIL 

Introduction: Glioblastoma multiforme (GBM) is the most common primary brain 

tumor. Standard treatment is surgery and Radiotherapy (RT) with temozolomide. 

The median survival is ranging from 12-14 months. However, patients with an 

unmethylated MGMT gene promoter do not show a survival advantage for 

temozolomide, and might be eligible for alternative treatment. Gemcitabine is an 

excellent radiosensitizer and is investigated as an alternative for temozolomide in 

GBM patients. Activation of the PI3Kinase-Akt pathway may preclude effective RT; 

therefore we investigated the radiosensitizing effect of gemcitabine in combination 

with the Akt inhibitor MK-2206. 

Materials and methods: Three malignant glioma cell lines (U87, U251, and D384) 

were tested on cell proliferation (SRB assay) cell survival (clonogenic assay) and 

spheroid growth following treatment by the allosteric Akt-inhibitor MK-2206 (1 uM, 

10 uM), gemcitabine and γ-irradiation (4 Gy single dose or 5 fractions of 2 Gy). 

Expression of Akt and pAkt was assessed by Western blot. 

Results: The U87 cell line was most sensitive and D384 was the most resistant one. 

MK-2206 decreased the IC50 of gemcitabine in all cell lines from 86, 237, 903 nM 

for gemcitabine alone to 57, 93, 860 nM, respectively. MK-2206 down regulated pAkt 

expression in a concentration and time dependent manner; at 0.1 µM pAkt was 

partly inhibited at 30 min and completely at 1, 2, 4 and 24 h, but started to recover 

at 48 h. At 1 µM pAkt inhibition was immediate and lasted longer. Since 25 nM 

gemcitabine and 4 GY RT alone stimulated pAKT expression, cells were preincubated 

with MK-2206 (1 µM for 1h). MK-2206 was additive to Gemcitabine and RT in 

reducing clonogenic cell survival, but MK-2206 was synergistic with gemcitabine 

alone and with RT in inhibition of spheroid growth The effect was more pronounced 

with RT. 

Conclusion: Addition of MK-2206 to gemcitabine significantly enhanced inhibition 

of cell proliferation and spheroid growth and inhibited the gemcitabine and RT 

mediated pAkt stimulation. The use of gemcitabine in combination with 

PI3kinase-Akt pathway inhibitors is a promising tool in GBM therapy and might be 

an alternative for patients resistant to temozolomide. 


1677P COMBINING EXTERNAL BEAM RADIOTHERAPY WITH 

MEASLES-VIRUS ONCOLYTIC THERAPY AND SAR-020106, 

A NOVEL RADIOSENSITIZER, IN HEAD AND NECK CANCER 

MODELS 

Y. Touchefeu 1 , A. Khan 2 , V. Roulstone 2 , K.J. Harrington 2 

1 Institut des Maladies de ’Appareil Digestif, University Hospital, Nantes, 

FRANCE, 2 Targeted Therapy Laboratory, Institute of Cancer Reserach, London, 


We have previously demonstrated the antitumour activity of a treatment combining a 

replication-defective adenovirus encoding the sodium iodide symporter (NIS), 

external beam radiotherapy (EBRT) and DNA repair inhibitors. Engineered Measles 

viruses (MeV) expressing NIS are replication-competent, oncolytic viruses, currently 

being tested in phase 1 trials. The aim of this study was to evaluate the therapeutic 

efficacy of a combination of MeV-NIS, EBRT, and a novel checkpoint-1 inhibitor, 

SAR-020106. This approach was investigated in HN-3, HN-5 and PJ-41 head and 

neck cancer models. In vitro toxicity was assessed by MTS and clonogenic assays. 

CD46 (cell receptor for MeV) expression on head and neck cell lines was evaluated by 

flow cytometry. NIS viral transgene expression was assessed by 125I uptake assays. 

Apoptosis was evaluated by Caspase Glo® and western blot assays. In vivo therapy 

experiments were performed in CD1 nude mice with subcutaneous tumour 

xenografts. In this study, we have demonstrated that EBRT and MeV-NIS had in vitro 

synergistic antitumour effects in head and neck cancer cell lines. EBRT did increase 

neither CD46 expression nor viral replication, but significantly increased viral gene 

expression in infected cells. In vitro, SAR-020106 had synergistic antitumour effect 

with EBRT. This effect was related to increased apoptosis. In vitro, the combination of 

MeV-NIS and SAR-020106 was associated with a significantly increased antitumour 

effect, as compared with control, MeV-NIS alone or SAR-020106 alone (P < 0.05). In 

the HN5 in vivo model, we observed significant differences in overall survival. In the 

control and EBRT groups, we observed a median survival of 32.5 and 35 days, 

respectively. In the MeV-NIS, MeV-NIS with EBRT and the MeV-NIS combined with 

EBRT and SAR-020106 groups we observed significantly improved overall survival 

(Log-rank (Mantel-Cox) Χ2 = 12.8; df = 5; p = 0.025) with fewer than 50% of animals 

in each group achieving humane end point. Our study strongly supports further 

translational and clinical research on MeV in combination with radiation therapy and 

radiosensitising agents in head and neck cancers. 



1678P PREDICTIVE VALUE OF TWO PHENOTYPING PROBES FOR 

THE PHARMACOKINETICS OF SUNITINIB IN CANCER 

PATIENTS 

J.S.L. Kloth 1 , H.J. Klumpen 2 , C.F. Samer 3 , K. Eechoute 1 , N.A.G. Lankheet 4 , 

B.L. Kam 5 , M. Wong 6 , J.H.M. Schellens 7 , R.H.J. Mathijssen 8 , H. Gurney 9 

1 Medical Oncology, Erasmus Medical Center, Rotterdam, NETHERLANDS, 

2 Medical Oncology, Academic Medical Center (AMC), Amsterdam, 

NETHERLANDS, 3 Swiss Center for Applied Human Toxicities (SCAHT), Geneva 

University, Geneve, SWITZERLAND, 4 Department of Pharmacy and 

Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, 

Amsterdam, NETHERLANDS, 5 Department of Nuclear Medicine, Erasmus 

Medical Center, Rotterdam, NETHERLANDS, 6 Department of Nuclear Medicine, 

Westmead institute for Cancer Research, Sydney, NSW, AUSTRALIA, 

7 Department of Clinical Pharmacology, The Netherlands Cancer Institute, 

Amsterdam, NETHERLANDS, 8 Department of Medical Oncology, Erasmus 

University Medical Center, Rotterdam, NETHERLANDS, 9 Medical Oncology, 

Westmead Hospital, Sydney, NSW, AUSTRALIA 

Background: Cancer patients treated with sunitinib show a wide inter-patient 

variability in drug exposure. This may at least partly explain the variation in toxicity 

and efficacy related to sunitinib treatment. The primary aim of this study was to 

investigate whether the clearance of 2 phenotyping probes are related to the 

pharmacokinetics (PK) of sunitinib. 

Patients and methods: A prospective multi-center study was performed in cancer 

patients treated with single agent sunitinib. PK of sunitinib and its active metabolite 

N-desethyl-sunitinib were measured at start of sunitinib intake and within 4 weeks of 

continuous daily dosing. A correlation analysis was performed between these PK data 

and midazolam clearance (as a CYP3A phenotyping probe) and hepatic 99m Tc-MIBI 

scans (as a probe for ABCB1 [P-glycoprotein] activity). 

Results: A total of 52 GIST and renal cell cancer patients were included in this study, 

of whom 46 were evaluable for analysis of sunitinib PK. Mean trough level of 

sunitinib, adjusted for dose, at day 1 of a new course was 14.7 ng/mL (range 7.2-28.9 

ng/mL), and 56.2 ng/mL (range 19.1-151.1 ng/mL) in the 4 th week of a treatment 

cycle. A significant correlation between N-desethyl-sunitinib trough levels and 

plasma clearance of midazolam (r = 0.58, P = 0.006) within 24 hours after the first 

intake of sunitinib was found. In addition, a trend was seen for the correlation 

between midazolam clearance and sunitinib trough levels at steady state (r = 0.26, P 

= 0.09). No correlation between sunitinib trough levels and hepatic 99m Tc-MIBI 

clearance was seen in an interim analysis after 27 patients. 

Conclusions: These observations show a correlation between the midazolam 

clearance test that serves as a probe for CYP3A and the exposure to sunitinib. 

Meanwhile, a lack of correlation was seen between sunitinib PK and the studied 

ABCB1 probe. These data could ultimately lead to a further personalization of 

sunitinib dosing. Additional investigations are in progress, including population PK 

modeling of sunitinib, and incorporation of pharmacogenetic parameters to further 

unravel the mechanisms behind these findings. 


1679P HEAT SHOCK PROTEIN 90 INHIBITION DOWNREGULATES 

C-KIT EXPRESSION IN GIST CELLS THROUGH DIMINISHING 

TRANSCRIPTION AND ENHANCING PROTEIN DEGRADATION 

VIA BOTH AUTOPHAGY AND PROTEASOME PATHWAYS 

Y. Hsueh 1 ,C.Yen 2 , N. Shih 1 , N. Chiang 1 ,C.Li 3 , L. Chen 1 


Tainan, TAIWAN, 2 Hematology/Oncology, Taipei Veteran General Hospital, Taipei, 

TAIWAN, 3 Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, 

TAIWAN 

Background: Gastrointestinal stromal tumor (GIST) is a mutant oncoprotein c-Kit 

droved cancer. Patients suffered drug resistance after prolonged standard treatment of 

tyrosine kinase inhibitor (TKI), imatinib mesylate (IM). Inhibition of heat-shock 

protein 90 (Hsp90), a chaperone responsible for protein maturation and stability, 

causing its client proteins degradation, as c-Kit, is a developing therapy for cancer. 

However, the mechanisms of Hsp90 inhibition-induced c-Kit downregulation in 

post-translational and transcriptional levels have rarely been investigated. 

Methods and results: Our data showed that NVP-AUY922 (AUY922), a new 

class of Hsp90 inhibitor, inhibited the growth of GIST882 and GIST48 cells with 

mutant c-Kit protein expression that was accompanied with reduction of both 

total and phosphor-c-Kit protein and induction of apoptosis. Pharmacological 

inhibition on either autophagy or proteasome degradation pathway could 

partially reverse endogenous c-Kit turnover and AUY922-induced c-Kit 

reduction. These findings were further confirmed by the co-localization of c-Kit 

with either LC-3B or acridine orange-labeled autophagosome in confocal 

microscopy, and delay of c-Kit degradation by silencing autophagosome essential 

Beclin-1 protein. In addition, AUY922 could also reduce c-Kit mRNA without 

affecting its degradation. Our preliminary data showed that activities and nuclear 

levels of several transcription factors in GIST cells were diminished after 

AUY922 treatment. DNA affinity precipitation assay and chromatin 

immunoprecipitation (ChIP) will be performed to validate the binding of the 

candidate transcript factors on the c-Kit promoter. 


Conclusions: This is the first report showing the involvement of autophagy in 

endogenous as well as Hsp90 inhibitor-induced c-Kit degradation. Moreover, 

AUY922 treatment resulted in downregulation of c-Kit through protein degradation 

and transcriptional mRNA regulation in GIST cells. These findings address the 

mechanisms of AUY922 on c-Kit protein downregulation and highlight the potential 

use of AUY922 in TKI-refractory, c-Kit-expressing GIST. 


1680P MOLECULAR PROFILING OF HIGH-RISK LOCALIZED 

PROSTATE CANCER (HRLPC) TREATED WITH DOCETAXEL 

(D) AND COMPLETE ANDROGEN BLOCKADE (CAB) PRIOR 

TO RADICAL PROSTATECTOMY 

M. Marín-Aguilera 1 , A. Font 2 , E. Gallardo 3 , A. Alcaraz 4 , V. Pereira 5 , M.J. Ribal 4 , 

J. Areal 6 , N. Hannaoui 7 , P. Gascon 8 , B. Mellado 5 

1 Translational Oncology Laboratory, Fundacio Clínic per a la Recerca Biomèdica, 

Barcelona, SPAIN, 2 Medical Oncology, Institut Català d’Oncologia-Badalona, 

Badalona, SPAIN, 3 Oncologia Medica, Hospital de Sabadell Corporacis Parc 

Tauli, Sabadell, SPAIN, 4 Urology, Hospital Clínic, Barcelona, SPAIN, 5 Medica 

Oncology, Hospital Clínic, Barcelona, SPAIN, 6 Urology, Hospital Germans Trias i 

Pujol, Badalona, SPAIN, 7 Urology, Hospital Parc Tauli, Sabadell, SPAIN, 

8 Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona, SPAIN 

Background: HRLPC has an increased risk of positive margins and recurrence after 

local treatment. Neoadjuvant docetaxel has not shown to increase the percentage of 

pathological complete responses (pRCs) respect to hormone-therapy alone. In a 

previous phase II trial of neoadjuvant D plus CAB in patients with HRLPC we 

reported a 6% pRCs. (Mellado B, Br J Cancer 2009). We proposed that the molecular 

analysis of residual tumor cells after D + CAB may help to identify molecular 

mechanisms of treatment resistance. 

Methods: 93 genes potentially involved in D resistance were selected from a previous 

molecular study of our group (Marin-Aguilera M, Mol Cancer Ther 2012). Gene 

transcriptional levels were analyzed by using Taqman low density arrays in 28 

formalin-fixed paraffin-embedded (FFPE) tumors from HRLPC patients treated with 

D + CAG prior radical prostatectomy, and in 36 HRLPC patients who underwent 

radical prostatectomy without neoadjuvant therapy. GUSB housekeeping gene was 

the reference for normalization. Gene expression determination was performed with 

RQ Manager Software for manual data analysis. 

Results: Differential gene expression of 67.7% (63 of 93 analyzed genes) was found 

in neoadjuvant treated tumors versus samples without neoadjuvant treatment (P < 

0.05). Among them, there were found differences in the expression of genes related 

with androgen receptor signalling, NFkB transcription factor and 

epithelial-mesenquimal transition processes. Data on gene expression and its 

correlation with clinical outcome will be presented at the meeting. 

Conclusions: Residual tumor cells in prostatectomy specimens after neoadjuvant 

hormone- and chemotherapy treatment already exhibits a gene expression profile 

that may be involved in hormone/chemo resistant phenotype. 


1681P THE ROLE OF MACROPHAGES POLARIZATION IN 

PREDICTING PROGNOSIS IN RADICALLY RESECTED 


F. Pantano 1 , P. Berti 1 , F.M. Guida 1 , S. Intagliata 1 , F. Graziano 2 , G. Perrone 3 , 

A. Onetti Muda 3 , B. Vincenzi 1 , G. Tonini 1 , D. Santini 1 

1 Medical Oncology, University Campus Bio-Medico, Rome, ITALY, 2 Medical 

Oncology, Ospedale di Urbino, Urbino, ITALY, 3 Department of Pathology, 

University Campus Bio-Medico, Rome, ITALY 

Introduction: Macrophages are one of the major populations of tumor-infiltrating 

immune cells. Tumor associated Macrophages (TAM) present two different phenotypes 

or polarizations: classical (M1) characterized by immunostimulation activity and tumor 

suppression; alternative (M2) characterized by angiogenesis, tumor promotion, and 

immune suppression. Despite these opposite properties, most of the previous studies 

focused merely on evaluating absolute TAM count. In this work, for the first time in 

literature, we evaluated the correlation between the two forms of TAM with survival 

time in patients affected by gastric cancer after radical surgery. 

Methods: 52 chemo- and radio-naïve gastric cancer patients undergone to resection for 

curative intent were included in this retrospective study. Two slides were prepared for 

each patients and double-stained for CD68/NOS2 (M1) or CD68/CD163 (M2) and five 

representative high-power fields (×400 magnification) per slide were evaluated for TAM 

count. The median value of the two macrophage populations density (M1 = 7.0; M2 = 

6.4) and the median value of M1/M2 ratio (1.16) was used as cut-off. 

Results: 27 patients with M1 density above the median had a significantly higher 

survival compared to those below the median (median OS of 25.6 months, 

CI95%:22.33-44.85 vs 17.1 months, CI95%:13.66-27.98; P = 0.041). 26 patients with 

M1/M2 ratio above the median showed median OS of 27.2 months 

(CI95%:25.45-47.51) compared to 15.5 months (CI95%:11.36-25.50) of the patients 

below the median (P = 0.001). No statistically significant difference in terms of M1/ 

M2 ratio was observed between intestinal vs diffuse histological type. No association 



between M2 macrophage density and patients outcome (P= 0.724) was found. In 

multivariate analysis M1/M2 was a positive independent predictor of survival (P= 

0.001; HR 0.420, CI95%: 0.22-0.78) whereas grading, histotype and TNM stage were 

not statistically significant. 

Conclusion: The M1 macrophage density and in particular M1/M2 ratio, as 

confirmed in multivariate analysis, is an independent factor that can predict patients 

survival time in gastric cancer after radical surgery. The role of macrophage 

phenotype in influencing the gastric cancer prognosis warrant further investigation. 


1682P ANTHRACYCLINE-INDUCED CARDIOTOXICITY IN MICE IS 

PREVENTED BY LATE INA INHIBITION WITH RANOLAZINE, 

WITH IMPROVEMENT IN HEART FUNCTION, FIBROSIS AND 

APOPTOSIS 

N. Maurea 1 , C. Coppola 1 , C. Quintavalle 2 ,D.Rea 3 , A. Barbieri 3 , G. Piscopo 4 , 

R.V. Iaffaioli 4 , G. Condorelli 2 , C. Arra 3 , C.G. Tocchetti 1 

1 Cardiology, National Cancer Institute, Pascale Foundation, Naples, ITALY, 

2 Biology and Cellular and Molecular Pathology, Federico II University, Naples, 

ITALY, 3 Animal Experimental Research, National Cancer Institute, Pascale 

Foundation, Naples, ITALY, 4 Colorectal Oncology, National Cancer Institute, 

Pascale Foundation, Naples, ITALY 

Background: Doxorubicin (DOX) produces a well-known cardiomyopathy through 

multiple mechanisms, which include, among many, Ca2+ overload due to reduced 

SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial 

energetics. DOX generates Reactive Oxygen and Nitrogen Species (ROS and RNS), 

posing the heart at increased demand for oxygen, setting the stage for metabolic 

ischemia that also activates late INa, target of ranolazine (RAN). Here, we aim at 

assessing whether RAN, diminishing intracellular Ca2+ through inhibition of late 

I Na, and enhancing myocardial glucose utilization (and/or reverting impairment of 

glucose utilization caused by chemotherapy) prevents DOX cardiotoxicity. 

Methods: We measured left ventricular (LV) function with fractional shortening (FS) 

by echocardiography in C57BL6 mice, 2-4 mo old, pretreated with RAN (370mg/kg/ 

day, a dose comparable to the one used in humans) per os for 3 days. RAN was then 

administered for additional 7 days, alone and together with DOX (2.17mg/kg/day ip), 

according to our well established protocol. Hearts were then excised, mRNA 

expression was analyzed by qRT- PCR, interstitial fibrosis with picrosirius red 

staining. By Western blotting, we measured the activation of the apoptotic pathway. 

Results: After 7 days with DOX, FS decreased to 50 ± 2%, p = .002 vs 60 ± 1% 

(sham). RAN alone did not change FS (59 ± 2%). Interestingly, in mice treated with 

RAN + DOX, the reduction in FS was milder: 57 ± 1%, p = 0.01 vs DOX alone. 

DOX-cardiotoxicity was accompanied by significant elevations in ANP (1000 folds), 

BNP (500 folds), CTGF (26 folds) and MMP2 (81 folds) mRNAs, while co-treatment 

with RAN significantly lowered these same genes compared to DOX. The alterations 

in extracellular matrix remodeling were confirmed by an increase of interstitial 

collagen with DOX (3.66%), p = .004 vs 2.19% (sham), which was normal in hearts 

co-treated with RAN (2.02%, p = .0002 vs DOX). Finally, the levels of PARP and 

pro-Caspase 3 were significantly decreased in DOX (indicating activation of 

apoptosis) but not in RAN + DOX. 

Conclusions: In mice, RAN prevents DOX cardiotoxic effects. We plan to test RAN 

as a cardioprotective agent with other antineoplastic cardiotoxic drugs in mice, and 

to better characterize the cardioprotective mechanisms of RAN in these settings. 


1683P CATUMAXOMAB VERSUS CATUMAXOMAB PLUS 

PREDNISOLONE IN PATIENTS WITH MALIGNANT ASCITES 

DUE TO EPITHELIAL CANCER: RESULTS FROM THE 

CASIMAS STUDY 

J. Sehouli 1 , P. Wimberger 2 , I.B. Vergote 3 , P. Rosenberg 4 , A. Schneeweiss 5 , 

C. Bokemeyer 6 , C. Salat 7 , G. Scambia 8 , D. Berton-Rigaud 9 , F. Lordick 10 

1 Department of Gynecology, Charite Medical University, Berlin, GERMANY, 

2 University of Duisburg-essen, AGO and Department of Gynecology and 

Obstetrics, Essen, GERMANY, 3 Obstetrics & Gynaecology, University Hospital 

Gasthuisberg, Leuven, BELGIUM, 4 Onkologiska Kliniken Universitetssjukhuset, 

University Hospital Linköping, Linköping, SWEDEN, 5 Heidelberg, National Center 

for Tumor Diseases, Heidelberg, GERMANY, 6 Head of The Department for 

Oncology, Haematology and Bone Marrow Transplantation, UKE II. Medizinische 

Klinik und PoliklinikMedizinische Klinik II., Hamburg-Eppendorf, GERMANY, 

7 Munich, Hematology Oncology Clinic, Munich, GERMANY, 8 Department of 

Gynecologic Oncology, Catholic University, Rome, ITALY, 9 Oncology, Centre 

René Gaducheau, Nantes, FRANCE, 10 Medizinische Klinik III, Staedtisches 

Klinikum Braunschweig, Braunschweig, GERMANY 

Purpose: This phase III b study compared catumaxomab with prednisolone (CP) to 

catumaxomab without prednisolone (C) as 3-hour intraperitoneal (i.p.) infusion in 

patients with malignant ascites from epithelial cancers. 

Patients and methods: We randomised 219 patients to receive catumaxomab plus 

25 mg prednisolone as premedication (111 pts) or catumaxomab alone (108 pts). 

Primary endpoint of the study was the composite safety score (CSS) summarizing the 

worst CTCAE grades for the main TEAEs (pyrexia, nausea, vomiting, and abdominal 

pain). A potential impact of prednisolone on efficacy was assessed by the co-primary 

endpoint puncture-free survival (PuFS). Further parameters included overall survival 

(OS) and time to next therapeutic puncture (TTPu). 

Results: The primary objective, to demonstrate superiority for safety of the CP arm 

was not met as the mean CSS was comparable for the two groups (CP: 4.1; C: 3.8 

for; p= 0.383). The median PuFS was slightly lower in CP (30 days) compared to C 

(37 days). However the hazard ratio (HR) for PuFS (HR: 1.130, p = 0.402) as well as 

the 75% quartiles (CP: 155 days, C: 92 days) were in favour of CP compared to 

C. The median TTPu was similar in both groups (CP: 78 days; C: 102 days, p= 

0.599). The majority of patients (123 pts) had no therapeutic paracentesis prior to 

death (CP: 54.8%; C; 61.7%, p = 0.297). Median OS was longer for CP (CP: 124 days; 

C: 86 days, p= 0.186), but lacking statistical significance. 

Conclusions: The administration of 25mg prednisolone as premedication prior to 

catumaxomab infusion did not change the safety profile and did not negatively impact 

the efficacy of catumaxomab. The efficacy results of the CASIMAS study are in 

concordance with the data of the pivotal study and thus confirm the robustness of the 

treatment effect of catumaxomab in malignant ascites. The composite safety score after 

3-hour infusion time was comparable to that seen in the pivotal study using 6 hours. 

Disclosure: J. Sehouli: consultant for Fresenius Biotech GmbH. P. Wimberger: 

consultant for Fresenius Biotech GmbH. I.B. Vergote: consultant for Fresenius 

Biotech GmbH. P. Rosenberg: financial support for clinical studies from Fresenius 

Biotech GmbH. A. Schneeweiss: financial support for clinical studies from Fresenius 

Biotech GmbH. C. Bokemeyer: consultant for Fresenius Biotech GmbH. C. Salat: 

financial support for clinical studies from Fresenius Biotech GmbH. G. Scambia: 

financial support for clinical studies from Fresenius Biotech GmbH. 

D. Berton-Rigaud: financial support for clinical studies from Fresenius Biotech 

GmbH. F. Lordick: consultant for Fresenius Biotech GmbH 

1684P CHARACTERISATION OF A NOVEL ROLE OF MST2 IN 

CANCER CELL MIGRATION IN THE CONTEXT OF HEAD AND 

NECK CANCER 

C. Escriu, F. Watt 

Medical Oncology, Li Ka Shing Centre, Cancer Research UK, Cambridge 

Research Institute Addenbrooke’s Hospital, Cambridge, UNITED KINGDOM 

MST2 has so far been considered a tumour suppressor, however, its expression 

correlates with poor prognosis in several cancer types. We aimed to understand the 

unknown mechanism by which these tumours appear more aggressive in the context of 

head and neck cancers, where MST2 is highly expressed. We tested the role of MST2 in 

cell migration in automated boyden chambers and scratch wound assays in several early 

passage oral squamous cell cancer cell lines. Interestingly, cancer cell migration was 

significantly reduced in knock down cells using short hairpin and short interfering RNA 

knock down systems. Furthermore, overexpression of wild type MST2 promoted cell 

migration, whereas overexpression of kinase dead MST2 had a dominant negative effect. 

In 3D confocal microscopy quantification of inverted matrigel invasion assays MST2 

knock down also showed reduced invasion. Trying to characterise this effect further we 

quantified cell attachment using confocal microscopy and image analysis in different 

laminin substrate concentrations. MST2 knock down cells showed a reduced cell 

number attachement and impaired cell spreading ability. Further image analysis of 

migrating cells revealed, in keeping with the attachment defect, that MST2 knock down 

cells had larger focal adhesions with lower proportional surface of paxillin 

phosphorylation than control cells. MST2 knock down cells also required a longer time 

for actin cytoskeleton recovery after cytochalasin D treatment, suggesting a role in actin 

polymerisation that could explain the cell-spreading defect. Furthermore, using 

automated boyden chamber assays, Akt inhibition reduced cell migration over time in a 

directly proportional manner to cell MST2 expression levels. We are currently testing 

the effect of MST2 modulation in time to metastasis and survival using a tongue 

injection xenograft model. We describe here a novel role for MST2 in cell migration, 

explained by focal adhesion architecture and activity change, and by modulating actin 

polymerisation. Akt inhibirors can reverse this migration effect, which may lead to 

MST2 potentially becoming a predictor marker of response to biological therapies in 

head and neck cancers. 


1685P PROSTATE CANCER STEM CELLS DISPLAY LOWERED 

ACTIVITY OF THE MTOR PATHWAY AND RESISTANCE 

AGAINST MTOR INHIBITION CAUSED BY ELEVATED 

HYPOXIC SIGNALING 

M. Marhold 1 , E. Tomasich 1 , A. Haschemi 2 , G. Hofbauer 3 , A. Spittler 3 , 

M. Krainer 1 , P. Horak 1 

1 Department of Internal Medicine I, Medical University of Vienna, Vienna, 

AUSTRIA, 2 Department of Laboratory Medicine, Medical University of Vienna, 

Vienna, AUSTRIA, 3 ASCTR Core Facility Flow Cytometry, Medical University of 

Vienna, Vienna, AUSTRIA 

Tumor-initiating subpopulations of cancer cells, also known as cancer stem cells 

(CSCs), were recently identified and characterized in Prostate cancer (PCa). We 


theorized that the PI3K/AKT pathway and mTOR, one of its main effectors, play a role 

in CSC maintenance. Moreover, hypoxia was known to be involved in CSC 

maintenance and to have a regulating effect on mTOR signaling. 

In our study, we therefore evaluated the effects of mTOR inhibitors on proliferation, 

assessed the activity of the mTOR pathway and measured the mitochondrial activity 

as well as levels of radical oxygen species (ROS) of human as well as murine CSCs 

in vitro. Further, we examined basal levels of mediators of hypoxic signaling such 

as HIF1α and its effectors.We isolated CSC like cells from the human PCa cell line 

DU145 and the murine PCa cell line TRAMPC1 using FACS according to their 

expression of the stem cell markers CD44, CD49f and Sca-1. We used sphere 

formation assays to confirm stem and progenitor cell properties. Next, we treated 

the CSC and non-CSC cell populations with mTOR inhibitors under normoxic and 

hypoxic conditions in order to determine their cell viability at time points up to 

72h. Mitochondrial activity was measured using extracellular flux (XF) analysis and 

levels of ROS were obtained using ROS-specific fluorescent dyes and flow cytometry. 

Our results suggest that CSC like PCa cells are more resistant to mTOR inhibitors 

when compared to their non-CSC counterparts. Most interestingly, while the 

non-CSC population displays higher sensitivity to mTOR inhibitors under hypoxic 

conditions, the viability of CSCs remains unaffected. Immunoblotting uncovers 

generally lower mTOR activity in CSCs compared to non-CSCs. Hypoxia leads to a 

decrease in mTOR activity in both subpopulations, though this effect is stronger in 

CSC like subpopulations through higher HIF1α-mediated negative feedback in both 

cell lines studied. At the same time we do not observe alterations in signaling 

through AR or PI3K downstream effectors besides mTOR, such as AKT. We 

propose that prostate CSCs might be resistant against mTOR inhibition and that 

inhibitors targeting multiple kinases along the PI3K/AKT/mTOR axis would be 

more effective. Our findings could be helpful to assess the impact of mTOR 

targeted therapy in prostate cancer in light of ongoing clinical trials. 


1686P SRC INHIBITION AS A METHOD TO OVERCOME 

TEMOZOLOMIDE RESISTANCE IN MELANOMA 

E.J. Jordan 1 , A. Eustace 2 , D.M. Collins 2 , N. O Donovan 2 , J.P. Crown 3 

1 Medical Oncology, Mater University Hospital, Dublin, IRELAND, 2 Dublin City 

University, N.I.C.B, Dublin, IRELAND, 3 Medical Oncology, St Vincents University 

Hospital, Dublin, IRELAND 

Background: Malignant melanoma is resistant to chemotherapeutic agents. Src 

signalling plays a role in many malignancies including melanoma. Src is important in 

cell adhesion regulation, invasiveness and activating other downstream cellular 

pathways. Src activity is elevated in melanoma and has potential to provide a 

treatment target for melanoma. Temozolomide is an oral alkylating prodrug. 

Dasatinib is a dual Src/Abl kinase inhibitor with antiproliferative activity. AZD0530 

is a selective oral Src kinase inhibitor. 

Methods: We examined the anti-proliferative effects of dasatinib and AZD0530 alone 

and in combination with temozolomide (TMZ) in melanoma cell lines - MALME, 

HT144 parent and temozolomide resistant cell lines MALME-TMZ and 

HT144-TMZ. MALME-TMZ and HT144-TMZ were produced by the pulse method. 

IC50 and combination proliferation assays were performed using an acid 

phosphatase-based colourimetric assay. 

Results: IC50 (50% inhibitory concentrations ± SD) values for TMZ were 338 ±25 

µM in HTI44 and 490 ±19 µM in HT144-TMZ. IC50 values for TMZ were 306 ±29 

µM in MALME and 515 ±45 µM in MALME-TMZ. Dasatinib was more effective as 

a single agent in HT144-TMZ (71 ± 8% growth inhibition at 1 µM) and 


MALME-TMZ (60 ± 6% growth inhibition at 1 µM) as compared to MALME (14 ± 

10% inhibition at 1 µM) and HTI44 (0 ± 3% inhibition at 1 µM). The combination of 

dasatinib/TMZ was more effective than TMZ alone in HT144 and HT144-TMZ. 

AZD0530 increased proliferation in HT144 (25 ± 8% at 1 µM) and HT144-TMZ 

(35 ± 9% at 1 µM) as a single agent. AZD0530 caused growth inhibition as a single 

agent in MALME-TMZ (18 ± 6% inhibition at 1 µM) and MALME (4 ± 2% at 1 µM). 

The combination of AZD0530 and TMZ had no effect in HT144 or HT144-TMZ 

while AZD0530 combined with TMZ was more effective than TMZ alone in 

MALME and MALME-TMZ. 

Conclusion: Dasatinib improved response to TMZ in both the chemotherapy naive 

and resistant cell line models tested (HT144, HT144-TMZ, MALME, 

MALME-TMZ). AZD0530 improved response to TMZ in one of the models only– 

MALME and MALME-TMZ. These in vitro results support further preclinical 

evaluation of Src Kinase inhibitors in combination with TMZ, and other 

DNA-targeting agents, particularly in TMZ-refractory melanoma. 


1687 VEGF AND VEGF RECEPTORS IN THYMIC EPITHELIAL 

TUMORS (TET): PATHOLOGICAL FEATURES AND CLINICAL 

IMPLICATIONS 

L. Nappi 1 , V. Damiano 1 , M. Marino 2 , T. Gelardi 1 , L. Formisano 1 , P. Federico 1 , 

E. Matano 1 , L. Puglia 1 , S. De Placido 1 , G. Palmieri 1 

1 Medical Oncology, University Federico II, Naples, ITALY, 2 Department of 

Pathology, National Cancer Institute “Regina Elena”, Rome, ITALY 

Background: Thymic Epithelial Tumors (TET) are very rare cancers. They derives 

from Thymic gland and are associated with different clinical syndromes, such as 

miastenic and Good syndrome and other immunological and paraneoplastic 

disorders. The principal treatment of these patients is chemotherapy with 

schedule containing cisplatin characterized by high response rates (60%). 

Unfortunately some patients do not respond at all and most patients do not 

achieve long-lasting remission. For these patients have not other therapeutic 

chances at the moment. There are few data of the efficacy of anti-angiogenetic 

drugs in TET but new knowledges are emerging on the potential use of this class 

of drugs in patients with TET on the basis of laboratory and preclinical 

translational findings. 

Materials and methods: we investigated the expression of Vascular Endothelial 

Growth Factor (VEGF) and its receptors (VEGFR1, 2 and 3) in 200 TET arranged in 

Tissue Micro Array (TMA). We observed both histotype distribution and modulation 

of angiogenetic factors (both VEGFRs and VEGFs) in TET. 

Results: we observed that, when compared with the low-grade counterpart, high 

grade TET (B2, B3 and Carcinomas) contained significantly higher numbers of 

VEGFA, VEGFC, VEGFD, VEGFR1 and VEGFR2 expressing tumor cells. In 

addition, in high grade TET, strong positive correlations between staining for 

VEGFA and those for all other markers were found. In the same tumors, VEGFC 

staining was not associated with VEGFR1, VEGFR3 and PDGFRB staining and no 

correlation was obtained between VEGFD and VEGFR1 or VEGFR3 staining. The 

co-expression in epithelial cells of growth factors and their receptors suggests the 

presence of autocrine mechanisms in TET. 

Conclusions: according to our data VEGFs and VEGFRs in TET are potential targets 

of anti-angiogenesis drugs. Further studies are needed to investigate the potential role 

of anti-angiogenetic agents. 



tumor biology and pathology 

1688PD THE COMBINED EXPRESSION OF CXCR7 AND ITS LIGAND 

CXCL12 IS A MARKER FOR UNFAVORABLE PROGNOSIS IN 


H.J. Lee 1 , K.S. Lee 1 , H. Ryu 2 , I.C. Song 2 , S.M. Huang 3 , H.J. Yun 2 , J. Kim 3 , 

D.Y. Jo 2 and S. Kim 2 

1 Intenal Medicine, Chungnam National University, Daejeon, KOREA, 2 Internal 

Medicine, Chungnam National University Hospital, Daejeon, KOREA, 3 Pathology, 

Chungnam National University Hospital, Daejeon, KOREA 

Background: Chemokines and their receptors have been shown to play a critical role 

in cancer growth and metastasis. In particular, recent data have suggested that the 

chemokine CXCL12 and its receptor CXCR7 (also known as RDC1), which has been 

recently identified as a chemokine receptor, have key functions in promoting tumor 

development and progression. However, there is little information regarding their 

expression and clinical relevance in gastric cancer. Here we investigated for the first 

time the effects of combined CXCR7 and CXCL12 expression on the prognosis of 

patients with gastric cancer. 

Methods: We studied CXCL12 and CXCR7 protein expression in 221 specimens of 

primary gastric cancer using immunohistochemistry, and investigated the 

relationaship between CXCL12/CXCR7 expression and clinicopathological features 

and clinical outcomes. 

Results: Patients were categorized into four groups according to CXCR7 and 

CXCL12 expression: low CXCR7/low CXCL12, high CXCR7/low CXCL12, low 

CXCR7/high CXCL12, and high CXCR7/high CXCL12. No significant differences 

existed in age, gender, histology, tumor location, lymphovascular invasion among the 

four groups. However, high CXCR7/high CXCL12 expression in tumor cells was 

significantly associated with invasion depth of the tumor (T status; P < 0.001), lymph 

node involvement (N status; P = 0.002), higher tumor stage (P = 0.002), and 

proportion of tumor size >5 cm (P = 0.006) compared to tumors with low CXCR7/ 

low CXCL12 expression or high CXCR7/low CXCL12–low CXCR7/high CXCL12 

expression. Furthermore, patients with high CXCR7/high CXCL12 expression had 

the worst prognosis (5-year survival rate 30.6%; median, 2.3 years; range, 0.1 - 5.7 

years) compared to those of other patient groups (5-year survival rate, 52.4%; 

median, not reached; log-rank test, P = 0.008) . 

Conclusions: CXCR7 and CXCL12 are useful prognostic factors in gastric cancer, 

and the combination of high CXCR7 protein expression with high CXCL12 

expression suggests a dismal prognosis. 


1689P CACHEXIA IN PANCREATIC CANCERS. COMPARISON OF 

ADENOCARCINOMA AND NEUROENDOCRINE TUMORS 

M.K. Mallath, A. Yelsengekar, S.A. Mehta and P.S. Patil 

Digestive Diseases, Tata Memorial Hospital Centre, Mumbai, INDIA 

Background: Patients with pancreatic adenocarcinoma (pCA) have high propensity 

for weight loss and cachexia. Patients with pancreatic neuroendocrine tumors 

(pNET) maintain their muscle mass for long period of time. Aims: We undertook a 

study to quantify the magnitude of cachexia in patients with pNET and compare it 

with pCA. 

Methods: An audit of the nutrition clinic database from 2000 to 2011 was reviewed 

and identified patients with pNET or pCA who had full nutritional work up 

including subjective global assessment scores (SGA) and body mass index (BMI). 

Cachexia was defined as a SGC score = C or BMI

Material and methods: 101 patients who underwent surgical resection due to lung 

cancer were participated in this study. None of them received any kind of treatment 

prior to surgery. 86 were men and 15 women with a mean age of 62 years old. The 

tumors were classified histologically as adenocarcinoma in 48, squamous cell 

carcinoma in 33, large cell carcinoma in 11 and small cell carcinoma in 9 cases. 

Using tissue microarray technology, 101 paraffin-embedded tissue samples were 

cored, re-embedded to the final recipient block and used for EphA4 protein 

immunohistochemical expression. All analyses were performed by SPSS for Windows 

Software (SPSS Inc, Chicago, IL, USA) and a p value less than 0.05 was considered 

the limit of statistical significance. 

Results: EphA4 positivity was noted in 36 out of 101 (36%) cases. EphA4 staining 

intensity was classified as mild in 11 (31%), moderate in 23 (64%) and intense in 2 

(5%) out of 36 positive cases. Increased EphA4 positivity and moderate/intense 

EphA4 staining intensity were noted in adenocarcinoma and squamous cell lung 

carcinoma cases compared to large cell and neuroendocrine carcinoma ones (p = 

0.0049 and p = 0.0170, respectively). EphA4 positivity and staining intensity were 

associated with the presence of lymph node metastases (p = 0.0349 and p = 0.0404, 

respectively). EphA4 staining intensity was also correlated with tumor 

histopathological stage (p = 0.0145). No association of EphA4 positivity nor staining 

intensity were noted with tumor histopathological grade, size and organ metastasis. 

Conclusions: The current study supports evidence for possible EphA4 participation 

in lung cancer biological behaviour, implying also its potent role as a therapeutic 

target. However, further molecular and clinical studies are required in order to define 

the significance of Ephs and their ligands (ephs) in lung cancer prognosis and 

management. 


1692P CORRELATION OF WTEGFR ACTIVATION ASSESSED BY 

MAB806 BINDING AND EGFR KINASE MUTATIONS IN STAGE 

IIIA N2 NSCLC 

M.S. Liew 1 , C. Murone 2 , M. Walkiewicz 2 , P. Mitchell 1 , H. Gan 1 , S. Barnett 3 , 

P. Russell 4 , G. Wright 5 , A. Scott 2 and T. John 1 

1 Joint Austin-ludwig Oncology Unit, Austin Health, Heidelberg, VIC, AUSTRALIA, 

2 Ludwig Institute for Cancer Research (licr), Austin Health, Heidelberg, VIC, 

AUSTRALIA, 3 Department of Thoracic Surgery, Austin Health, Heidelberg, VIC, 

AUSTRALIA, 4 Department of Pathology, St Vincent’s Health, Fitzroy, SA, 

AUSTRALIA, 5 Department Thoracic Surgery, St Vincent’s Health, Fitzroy, VIC, 

AUSTRALIA 

The epidermal growth factor receptor (EGFR) pathway is a regulator of cellular 

proliferation and tumour progression. EGFR overexpression occurs with gene 

amplification and activating EGFR kinase mutations (EGFRmt). Monoclonal 

antibody 806 (mAb806) is an anti-EGFR antibody which targets tumours with EGFR 

mutation variant III and overexpression but not cells with low EGFR expression 

(wild type EGFR, wtEGFR) and normal tissues. To characterise mAb806 binding, we 

correlated mAb806 expression with EGFRmt, EGFR immunohistochemical (IHC) 

expression and overall survival (OS). Formalin fixed paraffin embedded tissues were 

stained using the mAb806 (Ludwig Institute for Cancer Research) and EGFR (Dako, 

PharmDx kit). A H-score was obtained based on staining intensity and percentage of 

cells stained. mAb806 H-scores 0-50 were classified as negative (mAb806-) and ≥50 

as positive expression (mAb806+). EGFR H-scores were calculated to stratify patients 

into low (Dako score


expression, but not in Gli3-undetectable HCT116 or DLD-1 cells. Silencing of 

endogenous Gli3 down-regulated colony formation and proliferation in HT29 and 

SW480 cells. However, truncated Gli3 (Gli3-R; repressor isoform) transduction had 

no effect on these phenotypes although Gli1 expression was inhibited. After 

implantation of Gli3- or mock-transfected DLD-1 cells into immunedeficient SCID 

mice, tumor formation was observed in only Gli3-transfectant DLD-1 group but not 

in mock control. In surgically resected colorectal cancer specimen, Gli3 expression 

was heterogeneously detected and Shh expression was highly observed. 

Conclusions: Gli3-FL and Shh signals induce tumorigenicity in Gli1 independent 

manner, and Gli3-FL may be molecular targets for refractory colorectal cancer. 


1695P FIBROBLAST INDUCED EPITHELIAL TO MESENCHYMAL 

TRANSITION (EMT) IN A NOVEL NON-SMALL CELL LUNG 

CANCER (NSCLC) MODEL 

A. Amann 1 , M. Zwierzina 2 , M. Bitsche 2 , G. Gamerith 3 , J. Huber 1 , S. Koeck 1 , 

J. Kelm 4 , W. Hilbe 3 and H. Zwierzina 1 

1 Internal Medicine 1, Medical University Innsbruck, Innsbruck, AUSTRIA, 

2 Anatomy, Histology and Embryology, Medical University Innsbruck, Innsbruck, 

AUSTRIA, 3 Internal Medicine 5, Medical University Innsbruck, Innsbruck, 

AUSTRIA, 4 Insphero AG, Zürich, SWITZERLAND 

Introduction: Different molecular processes lead to metastatic spread and the 

occurrence of tumour cell resistance to therapeutic interventions. Among them, the 

epithelial to mesenchymal transition (EMT) process plays a key role. During EMT, 

epithelial tumour cells lose the expression of specific proteins and adopt the 

phenotype of mesenchymal cells. These structural conversions are substantially 

dependent on the tumour microenvironment. EMT of tumour cells can induce drug 

resistance and metastasis. Thus, EMT inhibition may offer a new strategy for 

overcoming tumour progression. 

Methods: To evaluate EMT in a non-small cell lung cancer (NSCLC) model a 2D 

and a 3D- cell culture system was applied using both the human lung cancer cell line 

(A549) and the human lung fibroblast cell line (SV-80). For generating 3D cell 

spheroids, a novel system was established consisting of 96-well hanging drop 

microtiter plates (InSphero AG, Zürich, Switzerland). 2D co-culture assays were 

performed in transwell filter inserts (Costar). EMT was induced with transforming 

growth factor-β (TGF-β) or co-cultivation with fibroblasts in 2D/3D. The switch 

from epithelial to mesenchymal cells was monitored by Western Blot (WB) analyses 

of e-cadherin, vimentin and n-cadherin. Furthermore, immunohistochemical 

analyses of e-cadherin, vimentin, α-smooth muscle actin, fibronectin, KI-67 and 

CA-IX were done on paraffin embedded spheroids. 

Results: EMT could be induced in the 2D not only by incubating tumour cells with 

TGF-β but also by co-culturing them with fibroblasts in transwell filter inserts. In 

A549 cells a change in morphology as well as in protein expression defined by WB 

analysis (down regulation: E-cadherin; up regulation; Vimentin, n-cadherin) could be 

detected. When cultivated in the 3D system, A549 cells showed an up regulation of 

the mesenchymal protein vimentin without TGF-ß stimulation. Furthermore, a 

significant up regulation of vimentin, KI-67, CA-IX, and a slight down regulation of 

e-cadherin could be measured compared to monocultures. 

Conclusion: 3D culture represents a model to study EMT in tumour cell lines 

without addition of growth factors and thus reflects in vivo conditions closer than 

2D culture. 


1696P CANCER STEM CELL MARKERS IN CLINICAL PANCREATIC 

CANCER: IMPACT OF CD44 + /CD24 + /EPCAM+ 

EXPRESSION ON HISTOLOGY AND PROGNOSIS 

Y. Ohara, T. Oda, Y. Akashi, R. Miyamoto, K. Yamada, S. Hashimoto and 

N. Ohkohchi 

Surgery, University of Tsukuba, Tsukuba, JAPAN 

Purpose: Emerging evidence suggests that the capability of a tumor to grow and 

propagate is dependent on a small subset of cells within it, termed cancer stem cells 

(CSCs). In pancreatic cancer, CD44 + /CD24 + /EpCAM+ cells have been reported to 

be CSCs; however, the histological and clinical importance of these cells has not yet 

been investigated. Here we clarified the characteristics of CD44 + /CD24 + /EpCAM+ 

cells in clinical specimens of pancreatic cancer using immunohistochemical assay. 

Materials and methods: We used surgical specimens of pancreatic ductal 

adenocarcinoma from 30 patients. In view of tumor heterogeneity, we randomly 

selected 10 high-power fields per case, and triple-positive CD44 + /CD24 + /EpCAM+ 

expression was identified using our scoring system. The distribution, histological 

characteristics, and prognostic importance of CD44 + /CD24 + /EpCAM+ cells were 

then analyzed. 

Results: Among a total of 300 assessed fields, 41 (14%) were evaluated as 

triple-positive. The distribution of CD44 + /CD24 + /EpCAM+ cells varied widely 

among the 30 cases examined, and CD44 + /CD24 + /EpCAM+ expression was 

correlated with poor glandular differentiation and high proliferation (high Ki-67 

labeling). Analysis of the three markers individually showed that CD44 and CD24 

were also correlated with poor differentiation and high proliferation, while EpCAM 

was not. Survival analysis showed that CD44 + /CD24 + /EpCAM+ expression was 

not correlated with patient outcome; however, CD44 and CD24 each appeared to be 

correlated with poor prognosis. 

Conclusion: In pancreatic cancer, CD44 + /CD24 + /EpCAM+ cells overlapped with 

poorly differentiated cells and possess high proliferative potential. In particular, 

double-positive CD44 + /CD24+ cells seem to have relevance when considering 

clinical aspects. 


1697P SEMULOPARIN EFFICIENTLY INHIBITS THROMBIN 

GENERATION TRIGGERED BY PANCREAS 

ADENOCARCINOMA CELLS BXPC3. DISTINCT ROLES OF 

ANTI-XA AND ANTI-IIA ACTIVITY 

G. Gerotziafas 1 , M.P. Roman 1 , E. Mdemba 1 , M. Hatmi 1 , J. Fareed 2 ,J. 

F. Bernaudin 1 and I. Elalamy 1 

1 ER2UPMC, Faculty of Medicin, Université Pierre et Marie Curie (Paris VI), Paris, 

FRANCE, 2 Pathology, Loyola University Medical Center, Maywood, IL, UNITED 


Background: Venous thromboembolism (VTE) is a common complication in 

patients with cancer receiving chemotherapy. Currently no anticoagulant is approved 

for VTE prophylaxis in this setting. Semuloparin is an ultra-LMWH generated 

through a highly selective depolymerization of heparin which protects the 

antithrombin (AT) binding site in order to improve the benefit/risk ratio compared 

to existing anitcoagulants. 

Aims: We studied in vitro the mechanism of action of semuloparin on the inhibition 

of thrombin generation (TG) of human platelet poor plasma (PPP) triggered by 

human pancreatic cancer cells BXPC3. We compared the antithrombotic efficiency of 

semuloparin to that of enoxaparin and the specific AT-dependent factor Xa inhibitor 

fondaparinux. 

Materials and methods: BXPC3 cells were suspended in PPP spiked with clinically 

relevant concentrations of semuloparin, enoxaparin and fondaparinux. The 

endogenous thrombin potential (ETP) and the mean rate index (MRI) of the 

propagation phase of TG were monitored with the CAT assay (Stago France) as 

described previously (Gerotziafas et al Thromb Res 2011). Anti-Xa and anti-IIa 

specific activities were assessed assays obtained from Diagnostica Stago. 

Results: Both semuloparin and enoxaparin, at the concentration of 0.4 anti-Xa IU/ 

ml, completely abrogated TG. Total inhibition of TG occured in the presence of 

0.002 anti-IIa IU/ml of semuloparin and 0.05 anti-IIa IU/ml of enoxaparin. 

Fondaparinux, even at concentrations higher than 2 µg/ml, reduced the MRI but did 

not significantly affect the ETP and did not completely inhibited TG,. The IC50 for 

the ETP of the anti-IIa activity of enoxaparin was 37-fold higher as compared to that 

of semuloparin. 

Conclusion: In a cancer cell model of hypercoagulability, semuloparin reduced 

efficiently thrombin generation. The unique anticoagulant profile of semuloparin 

based on its high AT-affinity differentiates it from enoxaparin and fondaparinux. The 

residual anti-IIa activity of semuloparin amplifies its antithrombotic efficacy. This 

profile is expected to translate into an improved benefit/risk ratio. 


1698P DO THE WELL-KNOWN RISK FACTORS OF BREAST CANCER 

HAVE THE SAME IMPACT ON DEVELOPMENT OF 

MOLECULAR SUBTYPES? 

F. Paksoy Türköz 1 , M. Solak 1 , O. Keskin 2 ,Z.Arık 1 , F.S. Sarıcı 1 ,I_.H. Petekkaya 1 , 

T. Babacan 2 and K.M. Altundag 2 

1 Medical Oncology, Abdurrahman Yurtaslan Ankara Oncology Research and 

Education Hospital, Ankara, TURKEY, 2 Medical Oncology, Hacettepe University 

Oncology Institute, Ankara, TURKEY 

Background: Altough clinical differences between breast cancer (BC) subtypes have 

been well-described, etiologic heterogeneity have not been fully studied. The aim of 

this study was to assess the associations between risk factors and molecular subtypes 

of BC. 

Methods: 1884 invasive BC cases were retrospectively analyzed. The odds ratios (OR) 

and 95% confidence intervals (CI) were estimated using multiple logistic regression 

analysis. 

Results: 1249 patients had luminal A, 234 had luminal B, 169 had HER-2 


overexpressing and 232 had triple negative BC. The age of ≥40 years was found to be 

a risk factor for luminal A (OR 1.41 95% CI 1.15-1.74; p = 0.001) and HER-2 

overexpressing subtype (OR:1.51, 95% CI:1.01-2.25; p = 0.04). Women who were 

nulliparous (OR 1.48, 95% CI 1,03-2,13; p = 0.03) or who had their first full-term 

pregnancy ≥30 years (OR 1.25 95% CI 0.83-1.88; p = 0.04) were at increased risk of 

luminal BC, whereas women with >2 children had a decreased risk (OR 0.68, 95% CI 

0.47-0.97; p = 0.03). Breast-feeding was a protective factor for luminal BC (OR 0.74, 

95% CI 0.53-1.04; p = 0.04). We found increased risks for postmenopausal women 

with HER-2 overexpressing (OR 2.20, 95% CI 0.93-5.17; p = 0.04) and luminal A 

(OR 1.87, 95% CI 0.93-3.90, p = 0.02) BC, who used hormone replacement therapy 

for ≥5 years. Overweight and obesity increased the risk of triple negative BC (OR 

1.89 95% CI 1.06-3.37; p = 0.04 and OR 1.90 95% CI 1.00-3.61; p = 0.03), on the 

contrary, decreased the risk of luminal BC (OR 0.63 95% CI 0.43-0.95; p = 0.02 and 

OR 0.50 95% CI 0.32-0.76; p = 0.002, respectively) in premenopausal women. There 

were no significant differences between risk of BC subtypes and early menarche, late 

menopause, family history, postmenopausal obesity, oral contraseptive use, smoking, 

in vitro fertilization and blood groups. 

Conclusions: Reproductive and hormonal characteristics were associated with luminal 

BC. Obesity and overweight increased the risk of triple negative subtype, particularly 

in premenopausal women. Older age and use of hormone replacement therapy were 

related to the risk of HER-2 overexpressing BC. Our data suggest a significant 

heterogeneity in association of traditional BC risk factors and tumor subtypes. 


1699P IDENTIFYING TRANS-ACTING COPY-NUMBER 

ALTERATIONS IN LUNG ADENOCARCINOMAS 

S. Camilleri-Broet 

Department of Pathology, HEGP, Paris, FRANCE 

Background: One of the main challenges in genomic oncology is to identify somatic 

copy-number alterations (CNAs) that include critical genes driving either the 

initiation or the progression of cancer disease. Most integrated genomic/ 

transcriptomic analyses have primarily focused on identifying cis-acting CNAs, 

whose copy gains or losses are significantly associated with gene expression changes 

for the genes they regulate. In this work, we do not restrict our analysis to cis-acting 

CNAs but focus on CNAs whose changes are associated with large number of 

significant transcriptomic changes distributed over the entire genome. We 

hypothesize that CNAs influencing a large number of transcripts either by direct or 

indirect effect are likely to harbor candidate targetable genes. 

Material and methods: A homogeneous series of 129 early stage lung 

adenocarcinomas, profiled using both high-resolution array-based genotyping 

(SNP-array) and gene expression, was analyzed. After classical preprocessing, we 

selected recurrent CNAs that were exclusively amplified or deleted using a previously 

published latent class model analysis (BMC Med Genomics. 2009 Jul 14;2:43). For 

each genomic area, we computed genome-wide statistics measuring the relationship 

between transcriptomic changes over the different levels of copy number changes 

(copy loss/modal/copy gain). Then, we reported the number of significant 

associations taking into account multiple testing. We finally focused on “trans-acting 

CNAs” defined as those having extreme values. 

Results: Main trans-acting CNAs were found on 1q, 4q, 5q, 9p, 14q, harboring 

several known oncogenes/tumor suppressor genes. In contrast, other classical 

recurrent CNAs (such as 5p amplification) were not selected, suggesting they were 

not associated with significant phenotype changes, as defined by transcriptomic 

analysis. The relationship between each “trans-acting CNAs” and clinico-pathological 

variables, as well as outcome is discussed. 

Conclusion: Using an integrative high-throughput microarray analysis in a series of lung 

adenocarcinomas, we identify “trans-acting CNAs”. We show the interest of focusing on 

these CNAs which are likely to harbor potentially targetable candidate genes. 


1700 WNT-2, BUT NOT WNT-1 EXPRESSION INCREASES DURING 

TUMORGENESIS IN BREAST, PROSTATE, LUNG CANCER 

AND MELANOMA 

A. Stanczak 1 , A. Brozyna 2 , H. Wisniewska 2 , W. Jozwicki 2 , L. Bodnar 3 , 

M. Lamparska-Przybysz 1 and M. Wieczorek 4 

1 Research and Development, Celon Pharma, Lomianki, POLAND, 2 Department 

of Tumor Pathology and Pathomorphology of The Franciszek Lukaszczyk 

Oncology Center, The Ludwik Rydygier Collegium Medicum, Nicolaus 

Copernicus University, Bydgoszcz, POLAND, 3 Department of Oncology, Military 

Institute of Medicine, Warsaw, POLAND, 4 Celon Pharma, Lomianki, POLAND 

WNT/β-catenin pathway regulates cell cycle and proliferation. It is triggered by WNT 

ligands, and drives β-catenin regulated expression of cyclin D1, c-Myc, MMP7. 

Moreover β-catenin, along with E-cadherin, forms adherent junctions mediating cell 

adhesion. WNT-1 is a known oncogene and its expression occurs in several 

malignancies such as breast, prostate and lung cancers, while WNT-2 is less known 

member of WNT ligands family. The aim of our study was to investigate the 

expression of WNT-1, WNT-2, β-catenin, E-cadherin and cyclin D1 in melanoma, 

breast, lung, prostate cancer in comparison to adjacent normal tissue and to further 

understand WNT ligands significance as a potential biomarker. Formalin-fixed, 

paraffin-embedded samples were obtained from tumors and adjacent-normal tissues 

from 26 breast cancer patients, 22 non small cell lung cancers patients, 23 prostate 

cancers patients, 24 melanomas patients in I-III stage of the disease. Expression of 

WNT-1, WNT-2, β-catenin, E-cadherin and cyclin D1 was assessed by 

immunohistochemistry and analyzed by two independent histopathologists. Changes 

of studied proteins expression profiles between normal and malignant tissues were 

measured with Wilcoxon test, while comparison of expression of analyzed proteins 

between tumors was performed with Kruskall-Wallis and post hoc test. A value of p 

< 0,05 was considered significant. The study received approval by the Local Bioethics 

Committee. In our study, WNT-1 cytoplasmic expression was increased in breast 

cancer (p = 0,003) and melanoma (p = 0,0001), while in lung cancer it was decreased 

(p = 0,002). WNT-2 cytoplasmic expression was increased in breast (p < 0,0001), 

prostate cancer (p = 0,0002), melanoma (p = 0,0007), while in lung cancer WNT-2 

increased expression showed a trend towards significance (p = 0,06). Moreover 

WNT-2 ligand was found in cell nuclei in all tumors and its expression level was 

increased in breast cancer (p = 0,007) and decreased in melanoma (p = 0,042). Our 

study revealed that WNT-2, but not WNT-1 expression was increased in all analyzed 

tumors. Moreover WNT-2 ligand was detected in cell nuclei, what could implicated 

its yet undiscovered role in gene expression regulation. 

Disclosure: M. Wieczorek: Maciej Wieczorek is Chief Executive Officer of Celon 

Pharma Ltd.All other authors have declared no conflicts of interest. 

1701 PROTEOMIC ANALYSIS OF HUMAN LUNG CANCER 

CELL LINES 


M. Nomura 1 , J. Mobley 2 , D. Chen 3 , T. Ohira 1 , N. Gotoh 4 , A.F. Gazdar 5 and 

N. Ikeda 1 

1 1st Department of Surgery, Tokyo Medical University Hospital, Tokyo, JAPAN, 

2 Division of Urology, University of Alabama at Birmingham, Birmingham, AL, 

UNITED STATES OF AMERICA, 3 Division of Preventive Medicine, University of 

Alabama at Birmingham, Birmingham, AL, UNITED STATES OF AMERICA, 

4 Division of Systems Biomedical Technology, The University of Tokyo, The 

Institute of Medical Science, Tokyo, JAPAN, 5 Hamon Center for Therapeutic 

Cancer Research, UT Southwestern Medical Center, Dallas, TX, UNITED 


The causes and morphological appearances of human lung cancers are variable. We 

analyzed thirty seven lung cancer cell lines including thirty adenocarcnima (ADC), 

three small cell carcinoma (SCLC), one large cell carcinoma (LCC) and one 

adenosquamous carcinoma (AdSq) with LC/MS and identified less than 500 proteins of 

each cell line. We compared proteomic profiles between EGFR mutations and K-Ras 

mutations, smokers and non/less-smokers, and non-small cell carcinoma (NSCLC) and 

small cell carcinoma (SCLC). Eleven proteins, CALR, KYNU, SLC3A2, ALDH2, PGD, 

LAP3, DLC1, KIAA0664, ILKAP, ABCA13 and PTGR1 are related to the relationship 

between cell lines with EGFR mutations and K-Ras mutations and some of them are 

associated to the signal network of cell cycle. Twelve proteins, PPP2R1B, RAP1A, RPS3, 

RNF113, TGM2, KIF22, UBA6, IFT122, IFI16, AKR1C1/AKR1C2, RPS5 and AKR1C3 

are related to the relationship between cell lines in from non/less-smokers and those 

from smokers and all proteins are associated to the signal network of cell morphology. 

Fifteen proteins, ANXA2, P4HB, ACTN4, MSN, ANXA5, IDH2, DPYSL2, DPYSL3, 

DPYSL5, CKB, IPO8, MAP1B, ETFA, TRIM28 and USP5, are related to the 

relationship between cell lines of NSCLC and SCLC, and some of them are associated 

to many signal pathways including cancer. Principle Component Analaysis could 

separate NSCLC from SCLC distinctly. We also detected common proteins among each 

group as candidate markers of cancer stem cells. AKR1C1/AKR1C2 was detected as 

common proteins between EGFR mutations vs K-ras mutations and smokers vs non/ 

less smokers and has been reported as one of cancer stem cell markers. These results 

suggested that this methodology was very useful to detect not only specific proteins of 

each group but also protein-related signal pathways. 


1702 HISTOLOGY OF SYNCHRONOUS AND METACHRONOUS 

CONTRA-LATERAL BREAST CARCINOMA 

Z. Tomasevic 1 , Z. Tomasevic 2 , D. Kolarevic 1 and Z. Milovanovic 3 

1 Daily Chmotherapy Hospital, Institute for Oncology and Radiology, Belgrade, 

SERBIA, 2 Medical Oncology, Institute for Oncology and Radiology, Belgrade, 

SERBIA, 3 Pathology, Institute for Oncology and Radiology, Belgrade, SERBIA 

Background: Contra-lateral breast cancer (CBC) is considered to be the most 

frequent new malignancy after primary breast cancer (PBC). However, there are few 

reports about concordance of the histology and other major molecular characteristics 

between PBC and CBC. Also, to the best of our knowledge, there is no report about 

CBC histology according to the time of development from PBC. 

Aim: To evaluate and compare PBC/CBC histology type according to time of CBC 

development. Age at CBC and other major molecular characteristics (tumor grade, 

estrogen/progesterone receptors, HER2) have also been analyzed. Patients and 



method A cohort of 113 CBC patients, without distant metastases, has been 

prospectively registered during 28 months. Patients are divided in 2 groups according 

to the time of CBC diagnose: 1. Synchronous, if the CBC (S-CBC) was diagnosed 

either simultaneously or within 6 months after PBC; 2. Metachronous (M-CBC) if 

CBC was diagnosed > 6 months after PBC. (Table 1) 

Pts N = 113 

Synchronous 

CBC N = 49 

Metachronous 

CBC N = 64 P 

Median age at CBC diagnose (yrs) 57 (33-74) 50 (25-75) 0.007 

Median time to CBC (months) 0 (0-≤ 6) 60,5 (0-408) / 

PBC-CBC Histology identical (%) 76% 52% 0.006 

Lobular/Ductal (%) 41%/59% 41%/59% / 

Results: Patient with S-CBC are median 7 years older than patients with M- CBC 

(p-0.007). S-CBC is more likely to be of the same histological type (76%) than 

M-CBC (56%) (P- 0.006) In the whole analyzed group, and each subgroup 

separately, lobular carcinoma is registered in higher percentage (41%) than expected. 

For all other characteristics (tumor grade, estrogen/progesterone receptors and HER2 

status) there was no statistical difference. 

Conclusion: According to these results, it seems that patients destined to develop 

S-CBC or M-CBC, as a first recurrence site, have a greater susceptibility to lobular 

carcinoma, because this histology type was confirmed in significantly higher 

percentage than expected. Whether this reflects different genetic susceptibility for 

S-CBC and M-CBC, and what could be implications on further prognosis, is yet to 

be analyzed. 


1704P PROSPECTIVE FEASIBLE STUDY TO EVALUATE 

NEOADJUVANT-SYNCHRONUS S-1 + RT FOR LOCALLY 

ADVANCED RECTAL CANCER: A MULTICENTER PHASE-II 

TRIAL (UMIN ID03396) 

M. Inomata 

Department of Gastroenterological Surgery, Oita University Faculty of Medicine, 

Oita, JAPAN 

Background: Fluorouracil-based chemoradiotherapy (CRT) is regarded as a standard 

perioperative treatment in locally advanced rectal cancer. We investigated the efficacy 

and safety of substituting fluorouracil with the oral prodrug TS-1. 

Methods: A multi-institutional (17 specialized centers), interventional phase II trial, 

was conducted from April 2009 to August 2011.This study is registered with 

UMIN-CTR, number C003396. For inclusion, patients must fulfill the following 

requirements before neoadjuvant CRT: (i) histologically proven rectal carcinoma; (ii) 

tumor located in the rectum (upper,lower); (iii) cancer classified as T3-4, N0–3 and 

M0; Two cycles of neoadjuvant CRT with TS-1 (100 mg/m2 on days 1-5, 8-12, 

22-26, and 29-33) is administered, and irradiation (total 45Gy/25fr, 1.8Gy/day, on 

days 1-5, 8-12, 15-19, 22-26, and 29-33) is performed. Total mesorectal excision with 

D3 lymphadenectomy is performed during the 4th and 8th week after the end of the 

neoadjuvant CRT. The primary end-point is rate of complete treatment of 

neoadjuvant CRT. Secondary endpoints are response rate of neoadjuvant CRT, 

short-term clinical outcomes, rate of curative resection, and pathological response 

(grade2/3). 

Results: This trial included 37 patients. A complete treatment of neoadjuvant CRT 

was found in 83.3% of patients (95%CI;71.2 ∼ 95.5%), and an adverse event (grade 3/ 

4) occurred in 4 patients (11.1%). A rate of an overall downstaging (PR/CR;RECIST 

1.0) was 83.3% (95%CI; 71.2 ∼ 95.5%), and a pathologic response rate was 50.0% 

(95%CI; 33.7 ∼ 66.3%). 

Conclusion: Our prospective phase-II study demonstrated that a 

neoadjuvant-synchronus TS-1 + RT for locally advanced rectal cancer was feasible in 

terms of pathological response and adverse events. 



author 

index 

author index 

A 

Aamdal S. ix32 (27IN) 

Aapro M.S. ix502 (1555P), ix507 (1571P) 

Aarntzen E. ix363 (1114PD) 

Aarts M.J. ix501 (1553P) 

Aasebø U. ix392 (1200P) 

Abbadessa G. ix225 (669PD), ix244 (738P), 

ix245 (739P) 

Abd Elwahab A.A. ix111 (304) 

Abdalaziz K.K. ix98 (256P) 

Abdel Azim H. ix288 (874) 

Abdel Halim I. ix341 (1039P), ix398 (1221) 

Abdel Karim K. ix150 (432) 

Abdel Latif H.A. ix93 (239) 

Abdel Latif R. ix341 (1039P) 

Abdel Metaal G. ix288 (874) 

Abdel-Rahman S. ix487 (1505P) 

Abdelhafez M.N. ix111 (304) 

Abdelrhman O. ix253 (770) 

Abdelwahab M. ix253 (770) 

Abdelwahab S. ix253 (770) 

Abdiganieva S.R. ix71 (162P) 

Abdul Rahman R. ix248 (750) 

Abdulkhalek H. ix337 (1028P) 

Abdullah H. ix337 (1028P) 

Abdurakhmanov D.A. ix71 (162P) 

Abe K. ix467 (1443) 

Abella L.E. ix291 (886) 

Abotouk N. ix114 (314) 

Abouelnaga S. ix448 (1374P) 

Abraham I. ix502 (1555P) 

Abraira V. ix205 (604P) 

Abreu M.H. ix132 (371P), ix222 (661) 

Abrial C. ix102 (270P) 

Abu Zeinah G.F. ix468 (1445) 

Abul Khair K. ix341 (1039P) 

Achilles K. ix255 (778TiP) 

Acikgoz O. ix110 (300) 

Ackerl M. ix145 (415PD), ix147 (421P) 

Acosta F. ix314 (952) 

Adachi S. ix227 (677P) 

Adam K. ix485 (1499P) 

Adam R. ix243 (733P) 

Adam Z. ix348 (1064O) 

Adamo B. ix104 (276P) 

Adamo V. ix104 (276P) 

Adamopoulos C. ix92 (236) 

Adams L. ix153 (442O) 

Adamson A. ix149 (431) 

Adaway G. ix199 (582P) 

Adenis A. ix206 (607P) 

Adetchessi T. ix150 (434) 

Adewole I. ix65 (135IN) 

Adhoute X. ix181 (529PD) 

Adjei A.A. ix155 (447PD), ix158 (456P) 

Adu-Aryee N.A. ix257 (782TiP) 

Advani R. ix348 (1063O) 

Aebi S. ix462 (1423O) 

Afc G. ix241 (727P) 

Afchain P. ix234 (703P) 

Afonso F.J. ix436 (1333), ix273 (826P) 

Afonso N. ix132 (371P) 

Afzal P. ix298 (904P) 

Agarwal N. ix153 (442O) 

Agarwal S. ix391 (1198P), ix154 (443PD) 

Agarwala S.S. ix371 (1137P), ix258 (783O) 

Agati R. ix147 (424P) 

Agbaje O. ix133 (372P) 

Agbor-Tarh D. ix95 (247O) 

Agelaki S. ix436 (1335) 

Agelidou M. ix436 (1335) 

Aghajanian C. ix319 (967O) 

Aglietta M. ix369 (1131P), ix205 (605P), 

ix270 (818P) 

Agostara B. ix463 (1425P) 

Agrawal R.K. ix97 (253PD) 

Agrawal S. ix502 (1557P) 

Aguas L. ix525 (1639) 

Aguila C. ix126 (349P) 

Aguilar A. ix136 (386) 

Aguirre I. ix418 (1273P) 

Agus D.B. ix302 (918P) 

Aherne S. ix528 (1645PD) 

Ahluwalia A. ix337 (1028P) 

Ahmad A. ix69 (154P) 

Ahmadizar F. ix122 (335P) 

Ahmed S. ix182 (531P) 

Ahmed S.A. ix145 (413PD) 

Ahmedov O.M. ix325 (985P) 

Ahn H. ix276 (834P), ix287 (872) 

Ahn J-H. ix108 (291P) 

Ahn J. ix276 (834P), ix287 (872) 

Ahn J.B. ix185 (543P) 

Ahn J.S. ix424 (1292P), ix97 (254PD) 

Ahn M. ix402 (1230PD) 

Ahn M.A. ix424 (1292P), ix430 (1311P) 

Ahn S-H. ix108 (291P) 

Ahn S. ix492 (1520PD) 

Ahn Y. ix276 (834P) 

Ährlund-Richter L. ix299 (906P) 

Aiello R.A. ix104 (275P) 

Aieta M. ix370 (1135P), ix280 (846P) 

Aikawa K. ix69 (153P) 

Airoldi M. ix343 (1047P), ix346 (1058), 

ix523 (1628) 

Aissa F. ix350 (1070PD) 

Aissat N. ix334 (1017O) 

Ait El Haj M. ix476 (1470P) 

Aitelhaj M. ix476 (1472P) 

Aitini E. ix280 (846P) 

Aizawa M. ix234 (702P) 

Ajani J.A. ix224 (668PD), ix232 (695P) 

Akahane M. ix441 (1351) 

Akamaru S. ix230 (688P) 

Akamatsu H. ix430 (1310P) 

Akasbi Y. ix137 (389) 

Akashi Y. ix543 (1696P) 

Akatsuka S. ix514 (1597P), ix203 (598P) 

Akbulut H. ix469 (1448PD) 

Akel S.Y. ix134 (376) 

Akgün Cetinkaya Z. ix394 (1207P) 

Akimoto T. ix396 (1215) 

Akimov M. ix152 (438O) 

Akita H. ix434 (1326), ix512 (1590P) 

Akiyoshi K. ix203 (598P) 

Akman L. ix173 (508) 

Akman T. ix173 (508), ix234 (701P) 

Akram M. ix98 (257P) 

Aksu G. ix110 (300) 

Aktas B. ix118 (323PD), ix186 (547P), ix217 (645) 

Akyurek S. ix525 (1636) 

Al Buali A. ix337 (1028P) 

Al Jamali M. ix72 (164) 

Alì M. ix104 (275P) 

Al-Batran S. ix459 (1413TiP), ix231 (691P) 

Al-Hajeili M. ix342 (1043P) 

Al-Kindi S.G. ix468 (1445) 

Al-Sakaff N. ix103 (273P) 

Álvarez Suárez S. ix198 (579P) 

Álvarez-Ossorio J.L. ix266 (805P) 

Alabiso O. ix123 (340P) 

Alagizy H.A. ix352 (1078P) 

Alba-Conejo E. ix101 (268P), ix128 (356P), 

ix140 (400) 

Albaghdadi J. ix327 (996P) 

Published by Oxford University Press on behalf of the European Society for Medical Oncology. 



Albanell J. ix97 (252PD) 

Albano A. ix370 (1135P) 

Alberola V. ix505 (1564P), ix523 (1629) 

Albert S. ix340 (1036P) 

Alberts D. ix324 (982P) 

Albiges L. ix277 (837P), ix278 (841P), 

ix304 (924P), ix313 (951) 

Albrand H. ix504 (1563P), ix506 (1568P), 

ix506 (1569P) 

Alcaraz A. ix538 (1680P), ix266 (805P) 

Alcindor T. ix200 (586P) 

Aledavood S.A. ix248 (749) 

Alekseev B. ix258 (783O), ix267 (809P) 

Alemany I. ix276 (835P) 

Alessandra P. ix164 (476P) 

Alexander H.R.Jr. ix371 (1141P), ix246 (743P) 

Alexandre J. ix170 (498P), ix327 (993P) 

Alexandre M.T.A. ix176 (514P) 

Alfaar A.S. ix448 (1374P), ix449 (1376P) 

Alface M. ix458 (1409) 

Alfaraj A.A. ix337 (1028P) 

Alfonsi S. ix86 (214P) 

Alfonso S. ix406 (1238PD) 

Algaba F. ix275 (832P) 

Ali G.T. ix134 (376) 

Alibay A.T. ix503 (1559P), ix517 (1607P) 

Aliberti C. ix371 (1140P) 

Aliberti G. ix344 (1050P) 

Alibhai S. ix464 (1432P) 

Alkis N. ix332 (1015) 

Allani B. ix254 (774) 

Allard A. ix410 (1250P) 

Allard M. ix243 (733P) 

Allegra C. ix198 (581P), ix214 (633) 

Allegrini G. ix528 (1646PD), ix94 (243), 

ix127 (354P), ix176 (515P) 

Allen A. ix236 (709P) 

Alloul K. ix205 (602P) 

Almagro Casado E. ix459 (1410), ix494 (1527P), 

ix112 (307) 

Almagro-Casado E. ix492 (1521PD) 

Almeida A. ix357 (1096) 

Almeida D. ix147 (423P) 

Almeida M. ix357 (1095), ix357 (1097) 

Almici C. ix338 (1029P) 

Almotlak H. ix128 (357P) 

Aloj L. ix193 (567P) 

Alonso-Jara J. ix380 (1165P) 

Alonso-Orduna V. ix195 (571P) 

Alonso I. ix135 (380) 

Alonso L. ix374 (1150) 

Alonso M. ix436 (1333) 

Alonso V. ix380 (1165P) 

Aloui A. ix254 (774) 

Alousi A. ix342 (1043P) 

Alsan Cetin I. ix394 (1207P) 

Alsner J. ix96 (249PD) 

Altaei T.S. ix163 (473P) 

Altomonte M. ix364 (1117PD), ix367 (1128P), 

ix373 (1148) 

Altug S. ix400 (1225O) 

Altun A. ix220 (654) 

Altundağ K.M. ix543 (1698P) 

Altundag M.K. ix104 (278P) 

Alumkal J. ix303 (920P), ix317 (964TiP) 

Alvarado-Zermeño A. ix329 (1003P) 

Alvarez Fernandez C. ix218 (647) 

Alvarez E. ix440 (1349) 

Alvarez I. ix82 (200P) 

Alvarez L. ix330 (1005P) 

Alvarez R.H. ix160 (461P) 

Alves F. ix331 (1010) 

Amadori A. ix91 (230P)

Annals of Oncology author index 

Amadori D. ix119 (327PD), ix285 (863P) 

Amanam I. ix460 (1416PD) 

Amann A. ix543 (1695P) 

Amano M. ix518 (1610P), ix526 (1643) 

Amano T. ix512 (1590P), ix220 (653) 

Amato R.J. ix300 (911P) 

Ambavane A. ix283 (856P) 

Amendolara A. ix472 (1456P) 

Ameye L. ix408 (1243P), ix199 (584P) 

Amiel C. ix337 (1025P) 

Amin A. ix368 (1129P) 

Amin H.M. ix154 (444PD) 

Amir E. ix91 (231P), ix158 (455P) 

Amitay Y. ix164 (477P) 

Amler L.C. ix89 (226P) 

Amling C. ix310 (939P) 

Amorim J. ix357 (1097) 

Ampollini L. ix496 (1536P) 

An A. ix465 (1433P) 

An A.R. ix465 (1434P) 

An H.J. ix108 (291P) 

An H.J. ix250 (757) 

An M. ix535 (1670P) 

Anak Ö. ix258 (783O) 

Anand A. ix89 (223P) 

Anand A.S. ix356 (1092P), ix134 (377) 

Anand B. ix317 (963TiP) 

Ananda S. ix321 (975PD) 

Anderes K. ix300 (911P) 

Anderhuber W. ix340 (1038P) 

Andersen R. ix530 (1654P), ix73 (168O) 

Anderson P. ix460 (1417PD), ix488 (1508P) 

Anderson S. ix327 (996P) 

Andersson M. ix142 (408TiP) 

Ando M. ix427 (1301P) 

Ando Y. ix220 (655) 

András C. ix223 (665TiP) 

André F. ix29 (18IN), ix122 (336P) 

André T. ix180 (525PD), ix190 (559P), 

ix195 (571P), ix206 (607P), ix218 (648) 

Andrade E.M.P.D. ix331 (1009) 

Andre F. ix84 (206P), ix116 (319O), ix125 (346P) 

Andreo Garcia F. ix431 (1315) 

Andreopoulos D. ix337 (1026P) 

Andreozzi M. ix77 (181P) 

Andresen C. ix269 (814P) 

Andrews E. ix207 (610P) 

Andric Z.G. ix428 (1304P), ix436 (1332) 

Andrikopoulos E. ix474 (1465P) 

Ang J.E. ix161 (464P), ix162 (469P) 

Ang M.K. ix412 (1257P) 

Ang S.F. ix245 (741P) 

Angevin E. ix170 (498P) 

Anghel R. ix116 (317O) 

Angouridakis N. ix338 (1030P), ix338 (1031P) 

Anguera G. ix292 (888) 

Anicic M. ix359 (1104) 

Anido U. ix273 (826P), ix312 (945) 

Annunziata M.A. ix474 (1462PD) 

Anota A. ix109 (296P) 

Ansari F.A. ix149 (430P) 

Ansell P.J. ix83 (203P), ix173 (505) 

Anserini P. ix521 (1621) 

Antón A. ix82 (200P), ix118 (323PD) 

Anter A.H. ix129 (360P) 

Anthoney A. ix500 (1549PD), ix129 (358P) 

Anthony S. ix170 (496P) 

Antoine E. ix128 (355P) 

Anton Aparicio L.M. ix306 (931P), ix314 (953) 

Anton-Aparicio L. ix380 (1165P), ix440 (1349), 

ix273 (826P) 

Antonarakis E.S. ix303 (920P), ix317 (964TiP) 

Antonello J. ix91 (230P) 

Antoni G. ix462 (1422O), ix463 (1427P), 

ix466 (1438P), ix164 (476P) 

Antonia S.J. ix405 (1237PD) 

Antonietti M. ix252 (767) 

Antoun S. ix511 (1587P), ix168 (491P) 

Anvari K. ix248 (749) 

Aoki Y. ix226 (672P) 

Aomatsu N. ix84 (205P) 

Aoyagi K. ix248 (751) 

Aoyama I. ix226 (673P) 

Aparicio A.M. ix261 (790O) 

Aparicio J. ix181 (527PD) 

Aparicio T. ix181 (529PD), ix234 (703P), 

ix237 (710P) 

Appaji L. ix358 (1102) 

Aquino L.C.M. ix215 (637) 

Arıcan A. ix312 (947) 

Arık Z. ix543 (1698P) 

Arab A. ix344 (1051) 

Arafat W. ix265 (801P), ix265 (803P) 

Aragane N. ix438 (1340) 

Arai J. ix71 (161P) 

Arai R. ix450 (1380P) 

Arai Y. ix243 (732P) 

Aramaki T. ix243 (732P) 

Aramendia J.M. ix149 (429P) 

Arance A. ix366 (1124P), ix135 (380) 

Aranda Aguilar E. ix529 (1648P), ix530 (1652P), 

ix131 (365P), ix186 (546P) 

Araujo A.M.F. ix78 (184P) 

Arbayo C. ix309 (938P) 

Arbea L. ix239 (718P) 

Arcana C. ix140 (399) 

Archer V. ix405 (1236PD), ix406 (1239P) 

Ardeleanu C. ix67 (146P) 

Ardigo M.L. ix406 (1238PD) 

Ardizzone A. ix95 (248O) 

Ardizzoni A. ix442 (1355), ix174 (509TiP), 

ix175 (513PD), ix216 (642) 

Areal J. ix538 (1680P), ix265 (802P) 

Arena V. ix433 (1322) 

Ares L. ix166 (484P) 

Areses C. ix436 (1333) 

Aretini P. ix176 (515P) 

Arevalo E. ix508 (1577P), ix239 (718P), 

ix291 (886), ix305 (927P) 

Argal csov S. ix81 (196P) 

Argiris A. ix424 (1291P), ix498 (1543TiP) 

Ariad S. ix373 (1147) 

Arias Santos I. ix92 (234) 

Aricò D. ix137 (388) 

Arifi S. ix137 (389) 

Armengol-Alonso A. ix135 (380) 

Armstrong A. ix303 (919P) 

Armstrong A.J. ix297 (899PD) 

Armstrong A.J. ix297 (901PD), ix311 (943P) 

Armstrong G. ix378 (1161P) 

Arnold D. ix35 (40IN), ix178 (518O), 

ix190 (559P), ix193 (565P), ix228 (680P) 

Arnould L. ix125 (346P) 

Arpaci F. ix286 (866P) 

Arpin D. ix391 (1199P) 

Arpino G. ix142 (407TiP) 

Arqueros C. ix292 (888) 

Arra C. ix539 (1682P) 

Arranz Arija J.A. ix264 (799P) 

Arruti M. ix212 (627) 

Artal-Cortes A. ix414 (1264P) 

Artale S. ix205 (605P) 

Artru P. ix85 (210P), ix237 (710P) 

Arts J. ix222 (663TiP) 

Arya D. ix356 (1092P), ix134 (377) 

Arzoz M. ix265 (802P) 

Asahara T. ix200 (585P) 

Asahina H. ix497 (1538P), ix159 (459P), 

ix164 (475P) 

Asai K. ix412 (1258P) 

Asaka M. ix202 (592P) 

Asami K. ix439 (1344) 

Asamura H. ix383 (1174P), ix387 (1186P) 

Ascierto P.A. ix361 (1110O), ix364 (1118PD), 

ix366 (1124P), ix367 (1128P), ix369 (1131P), 

ix369 (1133P), ix373 (1148), ix375 (1152) 

Ashabe Yamin R. ix107 (287P) 

Asselain B. ix218 (648) 

Asser T. ix146 (418PD), ix149 (431) 

Assi H. ix316 (960) 

Assikis V. ix303 (919P) 

Astone A. ix84 (207P) 

Ata A. ix312 (947) 

Ataergin A.S. ix286 (866P) 

Atagi S. ix393 (1204P), ix511 (1586P), ix91 (232) 

Ataman O. ix207 (609P) 

Atanackovic D. ix228 (680P) 

Ataseven B. ix114 (315TiP), ix117 (321PD) 

Ataseven H. ix220 (654) 

Atasoy B.M. ix394 (1207P), ix186 (547P) 

Atchison C. ix449 (1377P) 

Atif E. ix216 (639) 

Atil B. ix72 (165) 

Atilli S. ix174 (510TiP) 

Atkins M.B. ix258 (784O) 

Atsushi N. ix234 (702P) 

Attali C. ix460 (1419PD) 

Attard G. ix298 (903P), ix301 (913P), ix304 (924P) 

Atz J. ix163 (472P) 

Atzori F. ix276 (836P) 

Aubele P.O. ix487 (1505P) 

Aucoin N. ix202 (594P), ix316 (960) 

Augusto I. ix525 (1639) 

Augusto J.S. ix357 (1096) 

Aung K. ix87 (219P) 

Aung T. ix199 (583P) 

Aura C.M. ix531 (1656P), ix84 (204P), 

ix98 (255PD) 

Aust D. ix211 (622) 

Avallone A. ix193 (567P) 

Avci N. ix129 (359P) 

Avila D. ix470 (1450P) 

Avsar E. ix152 (438O) 

Awad I. ix353 (1081P), ix114 (314) 

Awada A. ix33 (32IN), ix125 (347P), ix157 (454P), 

ix23 (6IN) 

Awan U.E.K. ix358 (1100) 

Axtner J. ix453 (1389P), ix466 (1437P) 

Ayadi M. ix254 (774) 

Ayala F. ix364 (1118PD) 

Ayers S. ix319 (969PD), ix324 (983P) 

Azad A.K. ix78 (186P) 

Azanza J.R. ix508 (1577P) 

Azevedo S. ix255 (776TiP) 

Azim H.A. ix355 (1088P), ix114 (315TiP) 

Azim H.A.Jr ix58 (103IN), ix95 (247O), 

ix98 (255PD) 

Azkona E. ix212 (627) 

Aznar I. ix106 (284P) 

Azzarà M. ix138 (391) 

Azzarello D. ix505 (1565P), ix137 (388) 

Azzarello G. ix335 (1020PD) 

B 

Baas P. ix385 (1179O), ix392 (1203P) 

Baba H. ix188 (552P), ix217 (646) 

Baba T. ix436 (1334) 

Babacan N.A. ix220 (654) 

Babacan T. ix543 (1698P) 

Babaee N. ix346 (1059) 

Babaev A. ix229 (684P) 

Babakulov S. ix290 (882) 

Babalioglu I. ix525 (1636) 

Bachellier P. ix241 (727P) 

Bachelot T. ix62 (121IN), ix142 (409TiP) 

Bachet J. ix180 (525PD), ix238 (716P) 

Bachleitner-Hofmann T. ix179 (522PD) 

Bachour M. ix72 (164) 

Backen A. ix207 (609P) 

Bacon L. ix126 (349P) 

Badalamenti G. ix478 (1478O) 

Badar F. ix327 (994P) 

Badescu C. ix356 (1094) 

Badescu M. ix356 (1094) 

Volume 23 | Supplement 9 | June 2012 doi:10.1093/annonc/mds466 | ix547

author index 

Badran A. ix288 (874) 

Badulescu O.V. ix356 (1094) 

Bae W.K. ix467 (1441), ix468 (1446) 

Baertschi D. ix302 (917P) 

Bafaloukos D. ix373 (1146), ix85 (211P), 

ix94 (242) 

Bagalà C. ix84 (207P) 

Bagal B. ix350 (1069PD), ix351 (1074P) 

Bagayatkar P. ix350 (1069PD) 

Bago-Horvath Z. ix145 (414PD) 

Bagriacik Ü.E. ix277 (838P) 

Bahary N. ix224 (666O) 

Bahl A. ix449 (1377P), ix242 (729P), ix306 (931P) 

Bahleda R. ix496 (1534P), ix116 (319O), 

ix155 (446PD) 

Bai L. ix349 (1066PD) 

Bai M. ix213 (630) 

Bai Y. ix231 (690P) 

Baiget M. ix408 (1244P), ix183 (536P), 

ix185 (544P), ix216 (641) 

Bailey S. ix152 (438O) 

Bailly C. ix286 (864P) 

Bair A. ix268 (811P) 

Baird A. ix68 (150P), ix495 (1532P) 

Baitar A. ix452 (1386P) 

Bajetta E. ix373 (1148), ix288 (873) 

Bakalian S. ix519 (1614P) 

Baker-Neblett K.L. ix275 (833P) 

Bakhouche H. ix81 (196P) 

Bakhshi R. ix349 (1067PD) 

Bakhshi S. ix349 (1067PD), ix358 (1103) 

Bal O. ix105 (279P) 

Balakumaran A. ix360 (1108TiP) 

Baldelli E. ix535 (1668P) 

Baldini C. ix101 (266P) 

Baldini E. ix123 (340P) 

Baldo X. ix388 (1189P) 

Balke P. ix523 (1628) 

Ballas M. ix422 (1287P) 

Ballesteros A. ix374 (1150) 

Ballesteros P. ix254 (773) 

Balogh A. ix368 (1129P) 

Balvan O. ix497 (1540) 

Bambury R. ix248 (750) 

Bamias A. ix278 (841P) 

Ban H. ix492 (1520PD) 

Banal A. ix340 (1036P) 

Banani A. ix137 (389) 

Bandai Y. ix211 (625) 

Bandieri E. ix516 (1601P), ix516 (1602P), 

ix520 (1617), ix524 (1631) 

Bando H. ix164 (474P), ix196 (574P) 

Banerjee S. ix455 (1399P), ix320 (972PD) 

Banerji U. ix162 (469P) 

Bang Y. ix376 (1155O) 

Bannink M. ix109 (295P) 

Bapsy P.P. ix174 (510TiP) 

Barón F. ix395 (1212), ix505 (1564P), ix523 (1629) 

Bara I. ix411 (1254P), ix417 (1271P) 

Baracos V. ix168 (491P) 

Baranda J.C. ix223 (664TiP) 

Baranowski W. ix323 (979P) 

Barbare J. ix464 (1430P) 

Barbareschi M. ix99 (259P) 

Barber B. ix192 (564P) 

Barbero S. ix247 (747P) 

Barbi S. ix226 (675P) 

Barbieri A. ix539 (1682P) 

Barboriak D.P. ix146 (417PD) 

Baretti M. ix238 (714P) 

Bargallo-Rocha J.E. ix107 (289P), ix126 (349P) 

Bariani G.M. ix450 (1380P), ix486 (1503P) 

Barinov K. ix470 (1451P) 

Barista I. ix286 (866P) 

Barker H. ix502 (1557P) 

Barlesi F. ix403 (1232PD), ix426 (1299P), 

ix152 (438O) 

Barletta G. ix79 (187P) 

Barlier A. ix146 (419PD) 

Barnadas A. ix408 (1244P), ix183 (536P), 

ix185 (544P), ix216 (641) 

Barnett S. ix542 (1692P) 

Barney B. ix329 (1002P) 

Barni S. ix435 (1328), ix463 (1425P), ix467 (1440), 

ix515 (1599P), ix519 (1615P), ix131 (368P), 

ix192 (563P), ix229 (685P) 

Barone C. ix433 (1322), ix84 (207P) 

Barr M. ix68 (148P), ix68 (149P), ix495 (1531P), 

ix69 (154P) 

Barret M. ix511 (1587P) 

Barriga S. ix395 (1211) 

Barrios C. ix403 (1233PD), ix115 (316TiP), 

ix258 (783O) 

Barriuso J. ix165 (480P) 

Barron N. ix528 (1645PD) 

Barroso-Sousa R. ix331 (1009), ix455 (1397P), 

ix308 (935P) 

Barroso S. ix357 (1096) 

Barsoum E. ix288 (874) 

Bartfai Z. ix493 (1523P) 

Bartlett C.H. ix415 (1267P), ix416 (1268P) 

Bartlett N.L. ix348 (1063O) 

Bartoli C. ix343 (1047P) 

Bartolini S. ix145 (416PD) 

Bartolotti M. ix147 (424P) 

Bartosiewicz M. ix236 (709P) 

Bartsch R. ix145 (414PD) 

Baryshnikov K. ix371 (1138P) 

Basak J. ix355 (1090P), ix356 (1093P), 

ix359 (1105), ix359 (1106), ix448 (1375P), 

ix472 (1457P), ix135 (381) 

Basaran M. ix306 (931P) 

Basch E. ix295 (895O), ix295 (896O) 

Bascoul-Mollevi C. ix109 (296P) 

Basdra E.K. ix92 (236) 

Baselga J. ix27 (16IN), ix84 (204P), ix95 (247O), 

ix118 (324PD), ix121 (334P), ix124 (344P), 

ix126 (350P), ix126 (351P), ix154 (443PD), 

ix158 (457P) 

Basile P. ix252 (767) 

Bassett R. ix366 (1126P) 

Basso M. ix84 (207P) 

Basso S.M.M. ix287 (868) 

Basso U. ix91 (230P) 

Basté N. ix388 (1189P) 

Bastiaannet E. ix100 (263P) 

Bastie A. ix85 (210P) 

Bastit L. ix511 (1584P) 

Bastuji-Garin S. ix452 (1387P), ix460 (1419PD) 

Bastus R. ix136 (386) 

Basu S. ix301 (912P) 

Batagelj E.J. ix448 (1373P) 

Batinic D. ix359 (1104) 

Batist G. ix200 (586P) 

Batista N. ix314 (953) 

Batra K.K. ix470 (1450P) 

Battley J.E. ix248 (750) 

Batty A. ix370 (1134P), ix372 (1143P) 

Batus M. ix467 (1442) 

Baudelet C. ix319 (966O) 

Baudin E. ix378 (1160P), ix85 (209P) 

Baudrin L. ix419 (1276P) 

Bauduceau O. ix150 (433), ix285 (862P) 

Bauer S. ix481 (1486PD) 

Baumann S. ix507 (1574P) 

Baumann W. ix457 (1403) 

Baumert B. ix425 (1296P) 

Baurain J. ix321 (975PD) 

Bavington M. ix98 (255PD) 

Bay J. ix260 (789O) 

Baykara M. ix227 (678P) 

Bazan F. ix332 (1014), ix128 (357P) 

Bazhenova L. ix493 (1522PD), ix152 (439O) 

Bazin H. ix84 (206P) 

Beale P. ix499 (1544O) 

Beare S. ix206 (608P) 


Bearzi I. ix533 (1663P), ix86 (214P), ix86 (215P), 

ix239 (720P), ix243 (734P), ix250 (756) 

Beau-Faller M. ix388 (1190P), ix403 (1232PD) 

Beauchemin C. ix350 (1070PD), ix119 (328PD) 

Beaumont H. ix534 (1665P) 

Beaumont J. ix261 (792PD) 

Bebb D.G. ix440 (1350) 

Beccari S. ix166 (483P) 

Beck J.T. ix121 (334P) 

Beckman R. ix222 (662TiP) 

Bedard P. ix155 (448PD), ix156 (450PD), 

ix158 (455P) 

Bedenne L. ix181 (529PD), ix242 (730P) 

Bedikian A. ix363 (1115PD), ix366 (1126P), 

ix454 (1392P) 

Bedini N. ix315 (959) 

Bedognetti D. ix215 (636) 

Beebe-Dimmer J. ix244 (735P) 

Beech J. ix199 (582P) 

Beecham K. ix257 (782TiP) 

Beeram M. ix165 (481P), ix169 (492P) 

Beghelli S. ix226 (675P) 

Behlendorf T. ix357 (1098) 

Bekaii-Saab T. ix191 (560P) 

Belan E.V. ix470 (1451P) 

Belani C.P. ix421 (1281P) 

Belathur K.V. ix358 (1102) 

Belbaraka R. ix476 (1471P) 

Belderbos J. ix392 (1203P), ix396 (1213), 

ix396 (1216) 

Bell R. ix115 (316TiP) 

Bella M.A. ix175 (513PD) 

Bellardita L. ix315 (959) 

Bellazzi R. ix535 (1669P) 

Bellezza G. ix387 (1185P), ix535 (1668P) 

Belli C. ix240 (724P) 

Belli R. ix439 (1346) 

Belli S. ix379 (1164P) 

Bellido-Ribes C. ix136 (386) 

Bellmunt J. ix39 (53IN), ix260 (787O), 

ix265 (804P), ix266 (805P), ix266 (806P), 

ix267 (809P), ix278 (840P), ix312 (945) 

Bello P. ix106 (284P) 

Belloc J. ix340 (1036P) 

Belton L. ix523 (1628) 

Ben Ahmed S ix332 (1013) 

Ben Fatma L. ix332 (1013) 

Ben Itzhak O. ix498 (1541) 

Ben-Horin I. ix72 (163P) 

Benaim E. ix160 (461P), ix303 (921P) 

Benard M. ix339 (1033P) 

Benbrahim Z. ix137 (389) 

Bendahmane B. ix193 (565P) 

Bendell J. ix498 (1543TiP), ix158 (457P), 

ix159 (458P), ix191 (560P) 

Benedetti A. ix243 (734P) 

Benedetto L. ix375 (1152) 

Benedict A. ix279 (843P) 

Benekli M. ix227 (678P), ix277 (838P) 

Benelli G. ix122 (336P) 

Bengrine-Lefevre L. ix378 (1160P), ix85 (209P) 

Benhamouda N. ix75 (174O) 

Benitez J. ix281 (850P) 

Benjaafar N. ix328 (999P) 

Benkovičová J. ix503 (1560P) 

Benlloch S. ix86 (213P) 

Bennati C. ix387 (1185P), ix423 (1288P), 

ix427 (1302P) 

Bennett B. ix476 (1473P), ix298 (902P) 

Bennett K. ix368 (1129P) 

Bennett L. ix121 (334P), ix191 (560P) 

Bennett M.W. ix248 (750) 

Bennouna J. ix409 (1247P), ix410 (1250P), 

ix160 (461P), ix165 (478P), ix169 (494P), 

ix190 (559P), ix193 (565P), ix218 (648) 

Bensouda Y. ix432 (1318) 

Bento S. ix176 (514P) 

Benusiglio P.R. ix175 (511PD) 

ix548 | author index Volume 23 | Supplement 9 | September 2012


Benzidane B. ix249 (753) 

Bepler G. ix67 (144PD), ix49 (77IN) 

Berard H. ix406 (1240P) 

Berardi R. ix387 (1184P), ix533 (1663P), 

ix148 (425P) 

Bercier S. ix460 (1419PD) 

Bercovich D. ix109 (294P) 

Berdel W.E. ix284 (858P) 

Berenato F. ix140 (399) 

Berg E. ix390 (1195P) 

Bergamini C. ix335 (1019O), ix341 (1040P) 

Bergamo F. ix209 (618), ix240 (724P) 

Bergan E.Q. ix271 (819P) 

Berghian A. ix339 (1033P) 

Berghmans T. ix408 (1243P) 

Berghoff A.S. ix145 (414PD), ix148 (426P) 

Berghold A. ix340 (1038P) 

Bergmann L. ix274 (828P), ix278 (841P), 

ix288 (875) 

Berkenblit A. ix263 (796PD), ix293 (892TiP) 

Berman D.M. ix260 (788O) 

Berman R. ix363 (1113PD), ix464 (1431P) 

Bernardez Ferran B. ix92 (234) 

Bernardo A. ix123 (339P), ix138 (391) 

Bernardo G. ix463 (1425P), ix123 (339P), 

ix138 (391) 

Bernards R. ix32 (30IN) 

Bernaudin J.F. ix543 (1697P) 

Bernengo M.G. ix367 (1128P), ix369 (1131P) 

Berney D. ix172 (501) 

Bernhard S. ix332 (1014), ix128 (357P) 

Berrino L. ix67 (143PD) 

Berrocal A. ix374 (1150), ix374 (1151) 

Berry S. ix316 (960) 

Berry W. ix303 (920P) 

Bersani S. ix226 (675P) 

Bertarelli G. ix212 (628) 

Bertelli G. ix113 (311) 

Berthou C. ix522 (1624) 

Berti P. ix500 (1550PD), ix538 (1681P) 

Bertocci E. ix364 (1117PD) 

Berton-Rigaud D. ix514 (1596P), ix539 (1683P) 

Bertorelle R. ix144 (411O) 

Bertulli R. ix483 (1491P) 

Bertuzzi A.F. ix483 (1494P), ix487 (1506P) 

Bertwistle D. ix460 (1417PD), ix122 (337P) 

Bes¸irog˘lu M. ix186 (547P) 

Beslija S. ix116 (317O) 

Besova N. ix250 (760) 

Besse B. ix403 (1232PD), ix406 (1240P), 

ix415 (1267P), ix416 (1268P), ix421 (1284P), 

ix426 (1299P), ix496 (1534P), ix94 (244), 

ix152 (438O) 

Bestani C. ix379 (1164P) 

Besterman J. ix163 (471P), ix169 (492P), 

ix169 (493P) 

Bethune A. ix499 (1547PD) 

Betsuyaku T. ix422 (1285P) 

Betta P.G. ix247 (747P) 

Betticher D. ix396 (1214) 

Betticher D.C. ix462 (1423O) 

Beuzeboc P. ix125 (346P), ix259 (786O), 

ix294 (893O) 

Beveridge R. ix425 (1297P) 

Bhalla K. ix223 (664TiP) 

Bhat K. ix343 (1049P) 

Bhatt M. ix339 (1034P) 

Bhattacharjee S. ix471 (1453P) 

Bhattacharya(Majumdar) D. ix355 (1090P) 

Bhattacharya(majumder) D. ix472 (1457P) 

Bhattacharyya D. ix359 (1106), ix135 (381) 

Bhattacharyya G.S. ix301 (912P) 

Biagetti S. ix86 (214P) 

Biaggi C. ix480 (1482PD) 

Biagioli M. ix364 (1117PD) 

Biagioni F. ix183 (535P) 

Bianchini D. ix298 (903P), ix301 (913P), 

ix304 (924P) 

Bianchini G. ix74 (172O) 

Bianco R. ix530 (1651P), ix532 (1659P), 

ix287 (869) 

Bianconi F. ix387 (1185P), ix535 (1668P) 

Bianconi M. ix86 (214P), ix86 (215P), ix219 (652), 

ix239 (720P), ix243 (734P), ix250 (756), 

ix274 (829P) 

Bianconi M.I. ix330 (1005P) 

Bias P. ix500 (1548PD) 

Biasco E. ix290 (881) 

Biasoni D. ix285 (861P) 

Bidoli P. ix418 (1275P) 

Biedrzycka S. ix475 (1466P) 

Bier A. ix409 (1249P) 

Biggs H. ix74 (171O) 

Bighin C. ix454 (1393P), ix501 (1551PD), 

ix521 (1621), ix123 (340P) 

Biglia N. ix123 (340P) 

Bikov K. ix205 (603P), ix214 (634) 

Bilic E. ix359 (1104) 

Billiot F. ix94 (244) 

Binder C. ix284 (858P) 

Bines J. ix128 (356P) 

Binkhorst L. ix109 (295P) 

Bins S.B. ix111 (301) 

Biondani P. ix212 (628) 

Bíró K. ix281 (849P), ix286 (867P) 

Biron P. ix481 (1487P), ix260 (789O) 

Birrer M.J. ix81 (198P) 

Birtle A.J. ix284 (859P), ix292 (887) 

Bisagni G. ix101 (267P) 

Biscotti T. ix533 (1663P) 

Bisogno G. ix483 (1494P) 

Biswas B. ix264 (800P) 

Biswas J. ix301 (912P) 

Bitsche M. ix543 (1695P) 

Bittoni A. ix86 (215P), ix148 (425P), ix219 (652), 

ix239 (720P), ix250 (756), ix274 (829P) 

Biville-Hedouin F. ix409 (1247P) 

Bjarnason G.A. ix259 (785O), ix271 (820P) 

Blackhall F. ix73 (167O) 

Blackhall F.H. ix403 (1231PD), ix80 (193P), 

ix86 (213P) 

Blackstein M. ix478 (1478O) 

Blake-Cerda M. ix329 (1003P) 

Blanc J.F. ix238 (716P) 

Blanchet B. ix91 (229P) 

Blanchon F. ix455 (1396P) 

Blanckmeister C. ix415 (1266P) 

Blanco Campanario E. ix510 (1582P) 

Blanco Codesido M. ix520 (1619), ix198 (579P) 

Blanco Villalba M. ix448 (1373P), ix477 (1475) 

Blanco-Prieto S. ix92 (234) 

Blanco G. ix505 (1565P), ix104 (276P) 

Blandino G. ix183 (535P) 

Blank C. ix366 (1124P) 

Blank S.V. ix319 (967O) 

Blasi L. ix104 (276P) 

Blay J-Y. ix478 (1477O), ix54 (92IN) 

Blay J-Y ix21 (1IN) 

Blay J. ix470 (1452P), ix472 (1460), ix478 (1478O), 

ix479 (1480PD), ix481 (1487P), ix482 (1488P), 

ix482 (1489P), ix483 (1493P), ix488 (1511P), 

ix236 (708P) 

Blayau M. ix175 (511PD) 

Blidaru A. ix67 (146P) 

Block A. ix514 (1596P) 

Blohmer J.U. ix117 (321PD) 

Blons H. ix77 (180P) 

Blough D. ix203 (596P) 

Blum D. ix462 (1423O) 

Blumenstein B.A. ix313 (949) 

Boér K. ix504 (1562P) 

Bobos M. ix337 (1026P), ix430 (1312), 

ix213 (630) 

Boccadoro M. ix502 (1555P) 

Boccardo F. ix276 (836P), ix301 (914P) 

Boccardo S. ix301 (914P) 

Bocci G. ix127 (354P) 

Bodei L. ix47 (75IN) 

Bodnar L. ix544 (1700), ix268 (812P), 

ix320 (971PD), ix323 (979P) 

Bodoky G. ix224 (668PD), ix232 (695P), 

ix255 (777TiP) 

Bodrogi I. ix286 (867P), ix307 (933P) 

Body J. ix447 (1372P) 

Boeckenhoff A. ix270 (817P), ix279 (844P) 

Boehm A. ix336 (1023PD) 

Boelle E. ix198 (581P) 

Boerman O. ix192 (562P) 

Boeru S.E. ix398 (1222) 

Bogaerts J. ix60 (111IN), ix535 (1670P) 

Boggi U. ix241 (726P) 

Boguradzki P. ix504 (1562P) 

Boher J.M. ix241 (727P) 

Boichuk I. ix69 (151P) 

Boige V. ix194 (568P), ix198 (580P) 

Bokemeyer C. ix502 (1555P), ix539 (1683P), 

ix228 (680P), ix284 (858P) 

Boku N. ix200 (587P), ix231 (689P), ix233 (697P) 

Bol K. ix363 (1114PD) 

Boland W. ix440 (1350) 

Boldini S. ix516 (1601P), ix516 (1602P), 

ix520 (1617), ix524 (1631) 

Boleti E. ix272 (822P) 

Bollag D. ix322 (978P) 

Bolzoni-Villaret A. ix338 (1029P) 

Bona E. ix94 (243), ix127 (354P), ix176 (515P) 

Bonanni B. ix83 (201P) 

Bonanno L. ix533 (1661P) 

Bonardi C. ix355 (1089P) 

Bonastre J. ix397 (1217) 

Bondarenko I. ix367 (1127P) 

Bondarenko I.M. ix500 (1548PD) 

Bonfils C. ix163 (471P) 

Boni C. ix463 (1425P), ix280 (846P) 

Boni L. ix528 (1646PD) 

Boni V. ix166 (484P) 

Bonizzoni E. ix507 (1571P), ix515 (1599P) 

Bonnetain F. ix464 (1430P), ix109 (296P), 

ix120 (331P), ix237 (710P) 

Bonneterre J. ix101 (266P), ix106 (285P), 

ix113 (309) 

Bonnin N. ix286 (864P) 

Bono P. ix261 (792PD) 

Bonomi M. ix117 (322PD), ix273 (825P) 

Bonomi P. ix408 (1245P), ix467 (1442) 

Bonvalot S. ix482 (1488P), ix486 (1502P) 

Booth C.M. ix260 (788O) 

Bootsma G. ix396 (1213), ix425 (1296P) 

Borad M. ix156 (449PD), ix222 (662TiP), 

ix224 (666O) 

Boral A.L. ix153 (440O) 

Borbath I. ix376 (1155O), ix225 (669PD) 

Bordi P. ix442 (1355) 

Bordignon C. ix410 (1251P), ix167 (487P), 

ix167 (488P), ix172 (502) 

Bordonaro R. ix104 (276P) 

Borg C. ix332 (1014), ix193 (565P), ix204 (600P), 

ix206 (607P), ix249 (753) 

Borg J. ix184 (539P) 

Borgato L. ix326 (991P) 

Borget I. ix397 (1219) 

Borgonovo K.F. ix435 (1328), ix463 (1425P), 

ix467 (1440), ix519 (1615P), ix131 (368P), 

ix192 (563P) 

Borreani C. ix474 (1462PD) 

Borrego M. ix208 (614P) 

Borresen-Dale A. ix96 (249PD) 

Børresen-Dale A. ix25 (9IN) 

Borsellino N. ix104 (276P) 

Bortesi B. ix175 (513PD) 

Bosch-Barrera J. ix388 (1189P) 

Bosch A. ix111 (301) 

Bosdet I. ix412 (1255P) 

Bose C.K. ix359 (1105), ix448 (1375P), 

ix471 (1453P), ix471 (1454P), ix471 (1455P), 

ix135 (381) 

Boshoff C. ix421 (1282P) 


author index 

Bösmüller H. ix209 (616) 

Bosomworth M. ix171 (500P) 

Bosset J. ix475 (1468P), ix206 (607P) 

Bossi L.S. ix133 (374P) 

Bossi P. ix335 (1019O), ix341 (1040P), 

ix342 (1045P), ix344 (1050P) 

Boterberg T. ix341 (1042P) 

Botta M. ix247 (747P) 

Botteri E. ix83 (201P) 

Botti C. ix142 (406TiP) 

Bottini A. ix101 (267P) 

Bottomley A. ix483 (1493P) 

Bouattour M. ix379 (1163P), ix167 (485P) 

Bouché O. ix464 (1430P), ix482 (1489P), 

ix180 (525PD), ix236 (708P) 

Bouchahda M. ix194 (568P) 

Bouche O. ix190 (559P) 

Boucher E. ix482 (1489P), ix196 (572P), 

ix198 (580P) 

Boucher K.M. ix260 (787O) 

Boucher T. ix205 (602P) 

Bouda D. ix421 (1284P) 

Boudagga M. ix332 (1013) 

Boudghène F. ix206 (607P) 

Boudou-Rouquette P. ix91 (229P) 

Bouhlel A. ix103 (272P) 

Boukir A. ix432 (1318) 

Boukovinas I. ix139 (395), ix236 (707P) 

Boulanger V. ix499 (1547PD) 

Bourgeois H. ix456 (1401P) 

Bourlaud I. ix455 (1396P) 

Bourré L. ix312 (946) 

Boussen H. ix332 (1013) 

Bouzid K. ix344 (1051), ix221 (658) 

Bowden S.J. ix97 (253PD) 

Bowen Jones S.C. ix381 (1168P) 

Bowman A. ix119 (325PD) 

Bowman L. ix421 (1281P) 

Boye M. ix421 (1281P) 

Boyko I.N. ix311 (944P) 

Boyle H. ix286 (864P) 

Boyle T. ix469 (1449PD) 

Bozón V. ix158 (456P) 

Bozionelou V. ix139 (395) 

Bozzetti C. ix216 (642) 

Bozzi F. ix483 (1491P) 

Brédart A. ix475 (1468P) 

Brümmendorf T.H. ix342 (1044P) 

Bracarda S. ix264 (798PD), ix267 (809P), 

ix271 (820P), ix273 (825P), ix278 (840P), 

ix278 (842P), ix307 (932P), ix315 (958) 

Brada M. ix31 (26IN) 

Bradbury I. ix95 (247O) 

Brade A. ix148 (428P) 

Bradley R. ix436 (1332), ix125 (347P) 

Brady G. ix87 (219P) 

Bragagni M. ix285 (863P) 

Brahmadhi A. ix88 (221P) 

Brahmer J.R. ix405 (1237PD), ix157 (453P) 

Braiteh F. ix170 (496P) 

Bramajo M.P. ix448 (1373P), ix477 (1475) 

Bramati A. ix511 (1585P) 

Bramley S. ix90 (227P) 

Bramley T. ix122 (338P) 

Brammer M. ix122 (338P) 

Brana Garcia I. ix156 (450PD), ix158 (455P) 

Brandes A. ix145 (416PD), ix147 (424P) 

Braun A. ix509 (1580P), ix115 (316TiP) 

Braun E.R. ix381 (1170P) 

Braun M. ix199 (582P) 

Braun S. ix190 (558P), ix192 (564P) 

ix194 (570P) 

Bravo Marques J. ix141 (404) 

Breathnach O.S. ix468 (1444), ix494 (1526P), 

ix513 (1592P) 

Brechenmacher T. ix272 (823P) 

Brega N. ix424 (1291P) 

Breitenbuecher F. ix437 (1339) 

Breitkreuz T. ix466 (1437P) 

Bremnes R. ix392 (1200P) 

Brenner A.J. ix150 (435TiP) 

Brhane Y. ix78 (186P) 

Bria E. ix442 (1355), ix458 (1408), ix117 (322PD), 

ix226 (675P), ix237 (713P), ix240 (721P), 

ix273 (825P) 

Brichard V. ix361 (1110O), ix386 (1182P) 

Bridgewater J.A. ix178 (520O) 

Bridgewater J.A. ix242 (731P) 

Brighenti M. ix232 (693P) 

Brindel I. ix260 (789O) 

Brito M. ix141 (404) 

Brixi Z. ix460 (1419PD) 

Broadbridge V.T. ix208 (612P) 

Brocia C. ix363 (1113PD) 

Brodowicz T. ix116 (317O) 

Brogi E. ix98 (257P) 

Bronowicki J. ix225 (670PD) 

Brookes C. ix97 (253PD) 

Brose M. ix154 (445PD) 

Brossard J. ix350 (1071P) 

Broszeit-Luft S. ix523 (1627) 

Brouchet L. ix388 (1190P) 

Brown C. ix414 (1263P), ix151 (437TiP) 

Brown J.E. ix309 (937P) 

Brown M. ix366 (1124P) 

Browne B.C. ix528 (1645PD) 

Brozos E. ix92 (234) 

Brozyna A. ix544 (1700) 

Bruce J. ix317 (963TiP) 

Bruera E. ix466 (1439), ix517 (1605P) 

Bruera G. ix524 (1633), ix213 (629) 

Bruey J. ix101 (267P) 

Brugger W. ix417 (1271P) 

Brugiati C. ix431 (1313) 

Brugnatelli S. ix507 (1571P) 

Bruix J. ix63 (125IN) 

Brundel D.H.S. ix456 (1402P) 

Brunelli A. ix387 (1184P), ix533 (1663P) 

Brunello A. ix131 (367P) 

Brunner A. ix100 (261P) 

Brunt A.M. ix97 (253PD) 

Brusa F. ix291 (884) 

Bruzgin V. ix382 (1172) 

Bruzzi P. ix501 (1551PD), ix119 (327PD) 

Bruzzone A. ix80 (192P) 

Brzeska B. ix354 (1084P) 

B S A.K. ix358 (1102) 

Bu Y-Z. ix126 (348P) 

Bubendorf L. ix385 (1179O), ix73 (167O), 

ix80 (193P) 

Büchler M. ix228 (680P) 

Buchner A. ix500 (1548PD) 

Buckley A. ix505 (1566P) 

Budakoglu B. ix473 (1461), ix105 (279P) 

Budakoglu I.I. ix473 (1461) 

Buder R. ix255 (778TiP) 

Budillon A. ix193 (567P) 

Budisin E. ix428 (1304P) 

Buecher B. ix175 (511PD) 

Buettner R. ix481 (1486PD) 

Buges Sanchez C. ix431 (1315) 

Buges C. ix265 (802P) 

Buglione M. ix338 (1029P) 

Bui B. ix482 (1488P), ix236 (708P) 

ix260 (789O) 

Bullinger L. ix349 (1068PD) 

Bulotta A. ix410 (1251P), ix167 (487P), 

ix172 (502) 

Buonaccorso L. ix516 (1601P), ix516 (1602P), 

ix520 (1617), ix524 (1631) 

Buonerba C. ix316 (962TiP) 

Buosi R. ix496 (1536P) 

Buque A. ix212 (627) 

Burattini L. ix148 (425P), ix274 (829P) 

Burcoveanu D. ix260 (789O) 

Burdaeva O. ix406 (1239P) 


Burger D.M. ix456 (1402P) 

Burger R.A. ix81 (198P) 

Burggraaf K. ix103 (274P) 

Burgio M.A. ix496 (1536P) 

Burian M. ix340 (1038P) 

Burke E. ix107 (289P) 

Burkholder T. ix336 (1022PD) 

Burlaka D. ix69 (151P) 

Burrill W. ix93 (240) 

Burris H. ix121 (334P) 

Burtness B. ix42 (59IN) 

Burton L. ix519 (1613P) 

Burudpakdee C. ix122 (337P) 

Buschke S. ix162 (468P) 

Buschmann-Maiworm R.E. ix457 (1403) 

Bushmakin A. ix269 (815P) 

Bussink J. ix192 (562P) 

Busson P. ix337 (1025P) 

Buti S. ix442 (1355) 

Büttner R. ix394 (1208) 

Butts C. ix395 (1210) 

Buxó M. ix388 (1189P) 

Buyse M. ix91 (229P) 

Büyükafs¸ar K. ix312 (947) 

Buyukberber S. ix227 (678P), ix277 (838P) 

Buzyn A. ix66 (140IN) 

Buzzoni R. ix288 (873) 

Bycott P. ix409 (1246P), ix453 (1391P) 

C 

Caballero M. ix343 (1046P) 

Cabanne A. ix379 (1164P) 

Cabiddu M. ix435 (1328), ix467 (1440), 

ix519 (1615P), ix131 (368P), ix192 (563P) 

Cabrera P. ix308 (934P) 

Cabuk D. ix110 (300) 

Caccialanza R. ix355 (1089P) 

Cadeddu C. ix164 (476P) 

Cadiot G. ix378 (1160P) 

Cadoo K. ix176 (516P) 

Caeiro C. ix147 (423P) 

Cagnazzo C. ix205 (605P) 

Cagossi K. ix101 (267P) 

Cai J. ix495 (1530P), ix217 (643) 

Cai K. ix77 (182P) 

Cai L. ix421 (1283P) 

Cai S. ix216 (640), ix217 (643) 

Cai W. ix81 (195P) 

Caillet P. ix452 (1387P) 

Caires I.Q.S. ix331 (1009) 

Cairns D. ix500 (1549PD) 

Cakar M. ix286 (866P) 

Cakir Gokce S. ix525 (1636) 

Calabek B. ix145 (415PD) 

Calabrò L. ix364 (1117PD), ix369 (1131P) 

Calazan C. ix331 (1010) 

Calcagnile S. ix508 (1575P) 

Caldara A. ix99 (259P) 

Caldas C. ix74 (171O) 

Calderero V. ix275 (832P) 

Calderon M. ix281 (850P) 

Caldes T. ix183 (537P) 

Calegari A. ix84 (207P) 

Calhoun R. ix49 (77IN) 

Califano R. ix386 (1183P), ix493 (1525P), 

ix90 (227P) 

Caligo M.A. ix176 (515P) 

Caliskan D. ix469 (1448PD) 

Call J.A. ix329 (1002P) 

Callari M. ix74 (172O) 

Cals L. ix522 (1624), ix128 (357P) 

Calvo E. ix166 (484P), ix272 (823P) 

Camaño S. ix520 (1619) 

Cámara J.C. ix113 (310) 

Camargo V.P. ix486 (1503P) 

Camboni M.G. ix116 (319O) 

Camerini A. ix528 (1646PD), ix127 (354P) 

Cameron D. ix125 (347P) 



Camidge D.R. ix389 (1191PD), ix401 (1227O), 

ix408 (1245P), ix422 (1287P), ix423 (1290P), 

ix152 (439O), ix153 (440O) 

Camilleri-Broet S. ix544 (1699P) 

Caminal J.M. ix370 (1136P) 

Caminiti C. ix474 (1462PD) 

Camisa R. ix442 (1355), ix175 (513PD) 

Campana L.G. ix371 (1140P), ix486 (1504P), 

ix131 (367P) 

Campanero M.A. ix508 (1577P) 

Campayo M. ix135 (380), ix282 (853P) 

Campbell A. ix524 (1634) 

Campbell P. ix57 (99IN) 

Campennì G. ix488 (1509P) 

Campone M. ix62 (121IN), ix118 (324PD) 

Campos-Gomez S. ix184 (541P) 

Campos A. ix187 (549P) 

Campos B. ix374 (1151), ix436 (1333), 

ix440 (1349) 

Camps C. ix531 (1655P) 

Cañadas C. ix187 (549P) 

Cañamares I. ix281 (850P) 

Cañas A. ix530 (1652P) 

Candamio Folgar S. ix328 (1000P) 

Candido Reis D.G. ix524 (1632) 

Canela M. ix385 (1179O) 

Canhoroz M. ix497 (1540) 

Cannita K. ix524 (1633), ix213 (629) 

Cano Osuna M.T. ix131 (365P), ix186 (546P) 

Canon J. ix197 (578P) 

Canonici A.M. ix108 (292P) 

Canouï-Poitrine F. ix452 (1387P) 

Cantley L.C. ix21 (2IN) 

Cantos B. ix459 (1410), ix494 (1527P), ix112 (307) 

Canturk Z. ix110 (300) 

Cao Q. ix108 (290P) 

Caparello C. ix238 (714P), ix251 (761), ix251 (762) 

Caparros X. ix135 (380) 

Capasso A. ix67 (143PD) 

Capdevila Riera L. ix431 (1315) 

Capdevila J. ix377 (1156O), ix377 (1157O), 

ix380 (1165P), ix529 (1648P), ix157 (452P) 

Capdevila L. ix533 (1662P), ix266 (806P) 

Capelletto E. ix444 (1360) 

Caplin M. ix378 (1161P) 

Caponi S. ix238 (714P), ix241 (726P), ix251 (761), 

ix251 (762) 

Cappelleri J.C. ix269 (815P) 

Cappelli C. ix241 (726P) 

Cappetta A. ix283 (854P) 

Cappuzzo F. ix417 (1271P), ix423 (1288P), 

ix77 (181P), ix183 (535P) 

Caracò C. ix375 (1152) 

Caramanti M. ix387 (1184P), ix533 (1663P) 

Caramella C. ix198 (580P) 

Carames C. ix187 (549P) 

Carapezza M. ix123 (340P) 

Caratú G. ix531 (1656P) 

Carbognin L. ix117 (322PD) 

Carcas A. ix165 (480P) 

Carcereny E. ix418 (1273P), ix531 (1655P), 

ix152 (438O) 

Cardiga R. ix458 (1409) 

Cardoso-Filho C. ix133 (374P) 

Carducci M. ix268 (811P), ix303 (919P), 

ix309 (937P) 

Carles J. ix266 (806P), ix302 (916P) 

Carli M. ix483 (1494P) 

Carlomagno C. ix530 (1651P) 

Carlson D.M. ix83 (203P), ix173 (505), ix173 (507) 

Carlton R. ix122 (338P) 

Carneiro A.F. ix201 (591P) 

Carneiro F. ix210 (620), ix221 (657) 

Carnell D. ix347 (1061TiP) 

Carney D.N. ix525 (1635) 

Carnio S. ix343 (1047P), ix346 (1058) 

Carola E. ix501 (1554P) 

Caron O. ix175 (511PD) 

Carothers T. ix244 (738P) 

Carpino A. ix142 (406TiP) 

Carranza Rua O.E. ix149 (429P), ix239 (718P) 

Carranza A.C. ix183 (534P) 

Carranza O.E. ix291 (886), ix305 (927P) 

Carrasco E. ix118 (323PD) 

Carrasco J. ix197 (578P), ix211 (622) 

Carrato A. ix377 (1157O), ix457 (1404), 

ix459 (1412), ix472 (1456P), ix205 (604P), 

ix232 (695P), ix255 (776TiP) 

Carrera C. ix343 (1046P) 

Carrera S. ix212 (627) 

Carroll P. ix310 (939P) 

Carteni G. ix523 (1628) 

Carthon B. ix302 (918P) 

Caruso M. ix104 (275P), ix104 (276P) 

Carvajal R. ix361 (1109O), ix363 (1115PD) 

Carvalho-Verlinde M. ix452 (1387P) 

Carvalho B. ix339 (1032P) 

Carvalho C. ix194 (568P) 

Carvalho C.T. ix458 (1409) 

Casadei V. ix127 (354P) 

Casado A. ix321 (975PD) 

Casado V. ix80 (194P) 

Casal Rubio J. ix395 (1212) 

Casal J. ix436 (1333) 

Casali P.G. ix478 (1478O), ix483 (1491P), 

ix484 (1496P), ix485 (1500P) 

Casalta-Lopes J. ix208 (614P) 

Casanova C. ix335 (1020PD) 

Casanovas O. ix377 (1157O) 

Casas A. ix505 (1564P), ix523 (1629) 

Casbard A. ix498 (1542TiP) 

Casciano R. ix272 (823P) 

Cascinu S. ix387 (1184P), ix431 (1313), 

ix533 (1663P), ix86 (214P), ix86 (215P), 

ix148 (425P), ix37 (43IN), ix205 (605P), 

ix219 (652), ix239 (720P), ix243 (734P), 

ix250 (756), ix274 (829P) 

Casinello J. ix125 (345P) 

Cassano A. ix433 (1322), ix84 (207P) 

Cassier P. ix482 (1489P) 

Cassoni P. ix140 (402) 

Castañeda C. ix96 (250PD) 

Castaing D. ix243 (733P) 

Castanon Alvarez E. ix365 (1123P), ix149 (429P), 

ix239 (718P), ix291 (886), ix305 (927P) 

Castella Fernandez E. ix431 (1315) 

Castellano D. ix377 (1157O) 

Castellano D.E. ix266 (806P), ix314 (953) 

Castellano D.E. ix276 (835P), ix281 (850P) 

Castillo A. ix291 (886), ix305 (927P) 

Castonguay V. ix155 (448PD) 

Castro J.E. ix395 (1212) 

Castro L. ix147 (423P) 

Catalán G. ix125 (345P) 

Catane R. ix463 (1426P), ix34 (37IN) 

Catanzaro M. ix285 (861P) 

Catarino R. ix78 (184P) 

Cathomas R. ix283 (857P), ix302 (917P) 

Caty A. ix260 (789O) 

Catzeddu T. ix113 (311) 

Cau M.C. ix462 (1422O), ix463 (1427P), 

ix466 (1438P) 

Causeret S. ix109 (296P), ix120 (331P) 

Cauvin C. ix150 (434) 

Cavaliere C. ix316 (962TiP) 

Cavalli F. ix65 (137IN) 

Cavanagh M. ix176 (517P) 

Cavanna L. ix466 (1436P), ix216 (642) 

Cavicchioli F. ix532 (1660P), ix73 (169O) 

Cazap E.L. ix65 (132IN) 

Cazes A. ix77 (180P) 

Cazzaniga M.E. ix127 (354P) 

Ceccaldi B. ix477 (1476), ix150 (433), ix285 (862P) 

Cecere F.L. ix528 (1646PD) 

Cedres S. ix496 (1533P) 

Ceia F. ix458 (1409) 

Cejas P. ix181 (527PD) 

Celik I. ix334 (1018O), ix417 (1272P) 

Celio L. ix507 (1571P) 

Celiz P. ix265 (802P), ix266 (807P) 

Cella D. ix261 (792PD), ix269 (815P) 

Cellerino R. ix431 (1313) 

Cellier D. ix478 (1477O), ix481 (1487P) 

Cerbone L. ix270 (818P), ix278 (840P) 

Cereda E. ix355 (1089P) 

Cereda R. ix116 (319O) 

Cereda S. ix240 (724P) 

Ceric T. ix436 (1332) 

Cervantes Ruiperez A. ix381 (1170P), ix159 (458P) 

Cesic D. ix293 (892TiP) 

Cetintas S. ix291 (885) 

Cetto G.L. ix166 (483P) 

Chabaud S. ix391 (1199P), ix397 (1219) 

Chabolle F. ix340 (1036P) 

Chabowski M. ix395 (1211) 

Chachaty E. ix503 (1559P) 

Chacon Lopez-Muniz J.I. ix125 (345P) 

Chacon M. ix496 (1535P) 

Chacon R. ix496 (1535P) 

Chadjaa M. ix410 (1250P) 

Chae Y.S. ix208 (613P) 

Chahine G. ix288 (874) 

Chai F. ix244 (738P), ix245 (739P) 

Chaib I. ix266 (807P) 

Chaiet N. ix254 (774) 

Chaigneau L. ix128 (357P), ix236 (708P) 

Chairion Sileni V. ix369 (1133P) 

Chakrabandhu S. ix339 (1035P) 

Chakrabarty B. ix381 (1168P) 

Chakraborty A. ix359 (1106), ix472 (1457P), 

ix135 (381) 

Chakravartty A. ix83 (203P) 

Challacombe B. ix275 (831P) 

Chami S. ix344 (1051) 

Chamming’S F. ix99 (258P) 

Chan A. ix531 (1657P) 

Chan B. ix179 (522PD) 

Chan C.H.T. ix70 (157P) 

Chan J. ix515 (1600P) 

Chan J.K. ix460 (1416PD) 

Chan K. ix200 (586P) 

Chan K.S. ix412 (1257P) 

Chan P. ix244 (736P) 

Chan S. ix116 (318O), ix173 (505), ix310 (939P) 

Chand V. ix174 (509TiP) 

Chandra A. ix475 (1467P), ix275 (831P) 

Chandran R.K. ix173 (505) 

Chang A.L.S. ix362 (1111PD) 

Chang H. ix69 (152P) 

Chang S. ix336 (1022PD), ix522 (1626) 

Chang T. ix107 (286P) 

Chang W. ix375 (1153), ix430 (1311P), 

ix450 (1381P) 

Chang Y. ix345 (1052), ix253 (769) 

Chang Y.H. ix69 (152P) 

Chao C. ix107 (289P) 

Chao R. ix376 (1155O) 

Chaput-Gras N. ix169 (495P) 

Chargari C. ix477 (1476), ix150 (433), 

ix285 (862P) 

Charpentier J. ix312 (946) 

Chasalow S.D. ix75 (175PD) 

Chaslerie A. ix456 (1401P) 

Chatterjee B. ix452 (1388P) 

Chatterjee K. ix452 (1388P) 

Chatziioannou M. ix136 (385) 

Chau I. ix199 (582P), ix213 (632), ix224 (667PD) 

Chau N.M. ix412 (1257P) 

Chaubet Houdu M. ix421 (1284P) 

Chauffert B. ix242 (730P) 

Chaves A.C.R. ix308 (935P) 

Chawla S. ix479 (1480PD), ix480 (1483PD) 

Chawla S.P. ix483 (1493P), ix166 (482P) 

Chemin C. ix482 (1488P) 


author index 

Chen A. ix319 (966O) 

Chen B. ix432 (1319) 

Chen C. ix453 (1391P), ix130 (361P), ix279 (843P) 

Chen D. ix376 (1154O), ix544 (1701), 

ix278 (842P) 

Chen D.M. ix362 (1111PD), ix477 (1474) 

Chen E.X. ix155 (448PD), ix156 (450PD) 

Chen G. ix443 (1359), ix444 (1362TiP), 

ix180 (524PD), ix189 (556P) 

Chen G.Y. ix438 (1341) 

Chen H. ix345 (1052), ix437 (1336), 

ix155 (448PD) 

Chen I. ix522 (1626) 

Chen J. ix415 (1266P), ix501 (1552P), 

ix227 (676P), ix246 (744P), ix247 (746P) 

Chen L. ix351 (1075P), ix482 (1490P), 

ix538 (1679P), ix77 (182P), ix247 (746P), 

ix281 (847P), ix292 (889TiP) 

Chen P. ix355 (1087P) 

Chen S. ix103 (272P), ix103 (273P) 

Chen W. ix108 (290P) 

Chen X. ix81 (195P), ix117 (320PD) 

Chen Y. ix345 (1052), ix93 (238), ix245 (739P), 

ix268 (811P) 

Chen Z. ix78 (186P) 

Cheng A. ix351 (1075P), ix246 (744P), ix253 (769) 

Cheng D. ix78 (186P) 

Cheng L. ix107 (286P) 

Cheng Q. ix495 (1530P) 

Cheng Y. ix415 (1266P), ix444 (1362TiP), 

ix253 (769) 

Chenoufi S. ix446 (1367TiP) 

Cher L. ix151 (437TiP) 

Cherny N. ix456 (1707) 

Cherny N.I. ix64 (128IN) 

Chester J. ix292 (887) 

Cheung M. ix377 (1158P), ix380 (1167P) 

Cheung W. ix188 (551P), ix204 (601P), 

ix231 (691P) 

Cheung W.Y. ix215 (635) 

Chevreau C. ix263 (797PD) 

Chi K. ix295 (896O), ix297 (899PD), 

ix297 (900PD), ix304 (922P), ix305 (925P) 

Chi P. ix217 (643) 

Chia S. ix83 (202P) 

Chiang N. ix538 (1679P) 

Chiannilkulchai N. ix327 (993P) 

Chiappino I. ix291 (884) 

Chiara G.B. ix287 (868) 

Chiarenza M. ix104 (275P) 

Chiari R. ix387 (1185P), ix423 (1288P), 

ix427 (1302P) 

Chiarion Sileni V. ix367 (1128P), ix368 (1130P), 

ix371 (1140P), ix373 (1148) 

Chiba T. ix226 (673P) 

Chiba Y. ix393 (1204P) 

Chibaudel B. ix334 (1017O), ix340 (1036P), 

ix180 (525PD) 

Chien S. ix522 (1626) 

Chiesi F. ix516 (1602P) 

Chikamori K. ix413 (1260P), ix527 (1705) 

Chin F. ix485 (1499P), ix485 (1501P) 

Chin K. ix363 (1116PD), ix367 (1127P) 

Chin S. ix74 (171O) 

Chinot O. ix146 (419PD) 

Chiritescu G. ix222 (663TiP) 

Chirivella Gonzalez I. ix266 (805P) 

Chitapanarux I. ix339 (1035P) 

Chiu C. ix349 (1066PD) 

Chiu J. ix244 (736P) 

Chiu Y. ix173 (507) 

Chkadua G.Z. ix371 (1138P) 

Chkhikvadze N. ix130 (364P) 

Chmielowska E. ix409 (1246P), ix322 (978P) 

Chmielowski B. ix158 (456P) 

Cho B. ix424 (1292P) 

Cho G.J. ix172 (503) 

Cho H.J. ix72 (166) 

Cho J.Y. ix240 (722P) 

Cho S. ix467 (1441), ix468 (1446) 

Chodak G. ix310 (940P) 

Choi C.W. ix352 (1077P) 

Choi D.R. ix193 (566P) 

Choi E.J. ix512 (1589P) 

Choi H. ix253 (771) 

Choi H.J. ix276 (834P) 

Choi M. ix72 (166), ix244 (735P) 

Choi M.K. ix375 (1153), ix430 (1311P) 

Choi Y.J. ix454 (1394P), ix172 (503) 

Choi Y.N. ix512 (1589P) 

Chollet P. ix102 (270P) 

Cholujova D. ix286 (865P) 

Chone C.T. ix339 (1032P) 

Chong D. ix182 (533P), ix199 (583P) 

Choo S. ix182 (533P), ix245 (741P), ix247 (746P) 

Chou C. ix69 (152P) 

Chou Y. ix355 (1087P) 

Chouahnia K. ix414 (1265P) 

Chouaid C. ix397 (1219), ix446 (1367TiP), 

ix537 (1675P) 

Chouaki N. ix395 (1211), ix418 (1275P) 

Choueiri T.K. ix258 (784O), ix260 (787O), 

ix265 (804P), ix278 (840P) 

Choussy O. ix339 (1033P) 

Chow-Maneval E. ix303 (920P), ix317 (964TiP) 

Chow S. ix324 (983P) 

Chowdhury S. ix271 (821P), ix272 (822P), 

ix275 (831P) 

Choy E. ix479 (1480PD) 

Chren M. ix477 (1474) 

Christensen T.B. ix507 (1573P) 

Christofilakis C. ix435 (1329) 

Christophylakis C. ix436 (1335), ix139 (395) 

Chrysafi S. ix337 (1026P) 

Chu L. ix171 (499P) 

Chua C. ix199 (583P) 

Chua V.S. ix480 (1483PD), ix166 (482P) 

Chubenko V.A. ix139 (397) 

Chumsri S. ix108 (290P) 

Chung C. ix425 (1295P), ix428 (1305P), 

ix144 (410O) 

Chung I.J. ix467 (1441), ix468 (1446), ix193 (566P) 

Chung J.S. ix172 (503) 

Churn M. ix97 (253PD) 

Chwieduk A. ix353 (1082P) 

Cianci C. ix290 (881) 

Ciaparrone M. ix466 (1436P) 

Ciardiello F. ix430 (1309P), ix451 (1382P), 

ix67 (143PD), ix75 (173O) 

Cichowicz M. ix268 (812P), ix323 (979P) 

Cierniak S. ix268 (812P) 

Cilingir F. ix221 (660) 

Cinefra M. ix95 (248O) 

Cinieri S. ix95 (248O) 

Cintra M.L. ix365 (1122P) 

Cioè A. ix80 (192P) 

Ciocoiu M. ix356 (1094) 

Cioffi A. ix486 (1502P), ix489 (1514) 

Cipková A. ix504 (1562P) 

Cirera L. ix136 (386) 

Cirri L. ix124 (342P) 

Ciruelos E. ix96 (250PD), ix96 (251PD), 

ix134 (378), ix142 (409TiP), ix325 (986P) 

Cislo P. ix283 (856P) 

Ciuffreda L. ix140 (402), ix291 (884) 

Ciuffrida L. ix75 (173O) 

Ciuleanu E. ix337 (1026P) 

Civelli E. ix344 (1050P) 

Clack G. ix87 (219P), ix90 (227P) 

Clackson T. ix152 (439O) 

Claes K. ix34 (33IN) 

Clamp A. ix319 (969PD), ix324 (983P), 

ix326 (992P) 

Clara A. ix141 (404), ix175 (512PD) 

Claringbold P. ix379 (1162P) 

Clark-Langone K.M. ix179 (523PD) 


Clark J. ix389 (1191PD) 

Clark W.R. ix302 (918P) 

Clarke R. ix469 (1449PD) 

Clarke S. ix499 (1544O) 

Clatot F. ix339 (1033P) 

Clayton M. ix425 (1297P) 

Cleeland C. ix509 (1580P), ix295 (895O) 

Clemente C. ix78 (183P) 

Clementi S. ix104 (275P) 

Climent M. ix266 (805P), ix276 (835P), 

ix293 (891TiP), ix307 (932P) 

Climentzos P. ix477 (1475) 

Clince J. ix468 (1444), ix494 (1526P) 

Clottens N. ix287 (870) 

Cobo M. ix441 (1352) 

Coccia-Portugal M.A. ix103 (272P) 

Cocciolone V. ix524 (1633) 

Coebergh J.W. ix53 (89IN) 

Coeffic D. ix125 (346P) 

Coelho A. ix78 (184P) 

Coens C. ix483 (1493P) 

Coffey J.C. ix114 (312) 

Cognetti F. ix367 (1128P), ix463 (1425P), 

ix237 (713P), ix240 (721P), ix273 (825P), 

ix280 (846P) 

Cogoni A.A. ix35 (41IN) 

Cohen A.T. ix447 (1369P) 

Cohen D.P. ix259 (785O) 

Cohen E.E.W. ix154 (445PD) 

Cohn Cedermark G. ix299 (906P) 

Cohn A.L. ix224 (666O) 

Coindre J. ix482 (1488P) 

Cojocarasu O. ix196 (572P) 

Colacchi A.M. ix439 (1346) 

Colas C. ix175 (511PD) 

Colbeck M. ix208 (612P) 

Colby T. ix464 (1431P) 

Colecchia M. ix285 (861P) 

Coleman N. ix468 (1444) 

Coleman N.J. ix494 (1526P) 

Coleman R.E. ix115 (316TiP), ix296 (898PD), 

ix308 (936P) 

Collard O. ix488 (1511P) 

Collins D.M. ix540 (1686P) 

Collinson F. ix171 (500P) 

Collon T. ix455 (1396P) 

Colombino M. ix364 (1118PD) 

Colombo N. ix322 (978P), ix324 (982P) 

Colomer D. ix44 (66IN) 

Colucci G. ix370 (1135P), ix463 (1425P), 

ix229 (685P) 

Colussi O. ix75 (174O) 

Colwell H. ix477 (1474) 

Comandone A. ix483 (1494P) 

Comber H. ix315 (957) 

Comino A. ix73 (169O) 

Commenges B. ix446 (1367TiP), ix218 (648) 

Comolli G. ix529 (1650P) 

Comte A. ix282 (852P) 

Conca E. ix483 (1491P) 

Condò S. ix439 (1346) 

Conde M.C. ix183 (534P) 

Condorelli G. ix539 (1682P) 

Condori D. ix292 (888) 

Condrea I. ix67 (146P) 

Conen K. ix372 (1144) 

Cong N. ix161 (466P) 

Cong Z. ix509 (1580P) 

Conkling P. ix170 (496P) 

Connell L.C. ix525 (1635) 

Connolly E. ix469 (1449PD) 

Conroy T. ix109 (296P), ix120 (331P) 

Consoli F. ix338 (1029P) 

Conte P.F. ix101 (267P), ix119 (327PD), 

ix278 (842P), ix290 (879) 

Conter D. ix451 (1383P) 

Conter H.J. ix451 (1383P), ix517 (1605P) 

Contreras Martínez J. ix510 (1582P) 



Conway A. ix326 (992P) 

Coombs J. ix235 (704P), ix272 (823P) 

Cooper D. ix119 (328PD) 

Coppola C. ix539 (1682P) 

Coriat R. ix167 (485P), ix238 (716P) 

Corman J. ix310 (939P), ix311 (943P) 

Corn P.G. ix296 (897O) 

Cornic M. ix339 (1033P) 

Corona G. ix144 (411O) 

Coronado M. ix165 (480P) 

Corral J. ix418 (1275P) 

Correale P. ix530 (1653P) 

Corrie P. ix374 (1149), ix378 (1161P), 

ix242 (731P) 

Cortes-Funes H. ix96 (250PD), ix134 (378), 

ix281 (850P), ix325 (986P) 

Cortes J. ix370 (1136P), ix531 (1656P), 

ix83 (202P), ix29 (21IN), ix120 (330P), 

ix124 (344P), ix140 (400) 

Cortes P.A. ix128 (356P) 

Cortesi E. ix440 (1348), ix488 (1509P) 

Corti L. ix131 (367P) 

Cortot A. ix403 (1232PD), ix408 (1243P) 

Coscas Y. ix470 (1452P), ix472 (1460) 

Coskun U. ix227 (678P), ix277 (838P) 

Cossu Rocca M. ix335 (1020PD) 

Cossu A. ix364 (1118PD) 

Costa-Gurgel M.S. ix133 (374P) 

Costa A.S.A. ix147 (423P) 

Costa C. ix531 (1655P), ix533 (1661P), 

ix533 (1662P), ix229 (686P) 

Costa E.F.D. ix364 (1119P), ix365 (1121P) 

Costa F.F. ix339 (1032P) 

Costa L. ix289 (878) 

Costantini A. ix458 (1408) 

Costantini C. ix231 (691P) 

Costantini S. ix75 (173O) 

Cotreau M. ix263 (796PD) 

Counsell N. ix324 (982P) 

Cousin P. ix481 (1487P) 

Cousin S. ix168 (491P) 

Cousin T. ix165 (481P), ix167 (486P) 

Couto E. ix357 (1097) 

Coventry B.J. ix371 (1137P) 

Cowens J.W. ix75 (176PD) 

Cox M. ix304 (922P) 

Crabb S. ix272 (822P) 

Crafa P. ix216 (642) 

Cragg M.S. ix70 (157P) 

Craig J. ix377 (1158P), ix380 (1167P) 

Cramarossa A. ix370 (1135P) 

Cramer J. ix476 (1473P) 

Crea F. ix85 (208P) 

Credi M. ix391 (1198P), ix154 (443PD) 

Cremonesi M. ix435 (1328), ix467 (1440), 

ix519 (1615P), ix131 (368P), ix192 (563P), 

ix47 (75IN) 

Crespo C. ix118 (323PD) 

Cresti N. ix129 (358P) 

Crevenna R. ix145 (415PD) 

Crinò L. ix387 (1185P), ix402 (1230PD), 

ix423 (1288P), ix427 (1302P), ix535 (1668P), 

ix183 (535P) 

Crino L. ix403 (1231PD), ix403 (1233PD), 

ix419 (1278P), ix271 (820P) 

Criscitiello C. ix95 (247O) 

Critchfield J.J. ix244 (735P) 

Croce M.V. ix210 (619) 

Croitoru A. ix255 (777TiP) 

Crook T. ix532 (1660P), ix73 (169O) 

Cropet C. ix62 (121IN), ix478 (1477O), 

ix481 (1487P) 

Cros S. ix533 (1662P) 

Cross A. ix308 (936P) 

Crowe S. ix302 (917P) 

Crown J.P. ix528 (1645PD), ix540 (1686P), 

ix108 (292P) 

Cruz Jurado J. ix490 (1517TiP) 

Cruz Mora M.A. ix351 (1073P) 

Csoszi T. ix503 (1560P) 

Cstoth I. ix408 (1243P) 

Cuadra Urteaga J.L. ix265 (802P), ix266 (807P) 

Cubedo R. ix490 (1517TiP) 

Cubillo A. ix166 (484P) 

Cubukcu E. ix129 (359P) 

Cucala M. ix505 (1564P), ix523 (1629) 

Cueff A. ix238 (716P) 

Cueva J.F. ix328 (1000P) 

Cufer T. ix65 (136IN), ix522 (1625), ix523 (1630) 

Cuffe S. ix78 (186P) 

Cuisnier J. ix120 (331P) 

Culic S. ix359 (1104) 

Culine S. ix452 (1387P), ix259 (786O) 

Cumplido D. ix374 (1151) 

Cunningham D. ix378 (1161P), ix224 (667PD), 

ix242 (731P) 

Curé H. ix501 (1554P) 

Curca R. ix458 (1407) 

Curiel M.T. ix328 (1000P) 

Curigliano G. ix29 (22IN) 

Currà F. ix423 (1288P) 

Currà M.F. ix427 (1302P) 

Curran D. ix191 (561P) 

Curran V. ix207 (610P) 

Curran W.J. ix148 (428P) 

Curti E. ix204 (600P) 

Custodio Cabello S. ix176 (517P) 

Custodio A. ix472 (1456P), ix181 (527PD) 

Cusumano P. ix96 (251PD) 

Cuttone F. ix140 (399) 

Cuzick J. ix75 (176PD), ix53 (86IN) 

Cvancarova M. ix188 (553P) 

Cykowski L. ix363 (1116PD) 

Cynober L. ix91 (229P) 

Czaykowski P. ix316 (960) 

Czerw T. ix353 (1082P) 

Czibere A. ix321 (974PD) 

D 

Dąbek A. ix323 (979P) 

Dabakuyo T.S. ix109 (296P), ix120 (331P) 

Dabrowska Z. ix320 (971PD) 

Dacosta Byfield S. ix451 (1384P) 

D’Addario G. ix458 (1407) 

Dafni O. ix385 (1179O), ix73 (167O) 

D’Aiuto E. ix75 (173O) 

Daga H. ix432 (1320), ix433 (1321), 

ix492 (1519PD) 

Dagliati A. ix535 (1669P) 

Dahan L. ix464 (1430P) 

Dai D. ix153 (440O) 

Dai W.S. ix447 (1369P) 

Daidone M.G. ix88 (222P) 

Daiko H. ix89 (224P) 

Daisne J. ix334 (1016O) 

Daisuke A. ix422 (1285P) 

Dal Bello M.G. ix79 (187P) 

Dal Mas A. ix213 (629) 

Dalagiorgou G. ix92 (236) 

Dalal D. ix419 (1278P), ix420 (1279P), 

ix191 (560P) 

Dalal N. ix267 (808P) 

Dalban C. ix511 (1587P) 

Dalenc F. ix62 (121IN) 

Dall’Occa P. ix147 (424P) 

Dalla Palma M. ix326 (991P) 

D’Alonzo A. ix454 (1393P), ix501 (1551PD), 

ix521 (1621) 

Dalton J.T. ix304 (923P) 

Damasceno M. ix525 (1639), ix147 (423P) 

Damato A. ix288 (873) 

D’Amato C. ix530 (1651P), ix532 (1659P) 

D’Amato V. ix532 (1659P) 

D’Ambrosio C. ix335 (1020PD) 

Damian S. ix102 (269P) 

Damiano M.A. ix496 (1535P) 

Damiano V. ix530 (1651P), ix532 (1659P), 

ix540 (1687), ix287 (869) 

D’Amico R. ix101 (267P) 

Dane F. ix394 (1207P), ix186 (547P), ix217 (645) 

Daneshmand S. ix261 (790O) 

Danesi R. ix85 (208P) 

Daniele B. ix225 (669PD), ix255 (777TiP) 

Danielli R. ix364 (1117PD) 

D’Aniello C. ix316 (962TiP) 

Daniels I. ix215 (638) 

Danila D. ix89 (223P) 

Dank M. ix102 (271P), ix116 (317O) 

Danova M. ix529 (1650P) 

Dansin E. ix406 (1240P), ix409 (1247P), 

ix419 (1278P), ix426 (1299P) 

Danson S. ix374 (1149) 

Daprada G. ix99 (260P) 

Da Prat V. ix238 (714P) 

Darai E. ix322 (977P) 

D’Arcangelo M. ix423 (1288P), ix77 (181P) 

Darwish A. ix265 (801P), ix265 (803P) 

Darwish A.D. ix111 (304) 

Das A. ix171 (499P) 

Das K. ix358 (1100), ix497 (1539P), ix285 (860P) 

Das M. ix396 (1216) 

Das P. ix448 (1375P) 

Dasgupta S. ix355 (1090P), ix356 (1093P), 

ix359 (1105), ix359 (1106), ix472 (1457P), 

ix133 (375P) 

Dass R.N. ix314 (954) 

Datwyler S. ix83 (203P) 

Dauba J. ix419 (1276P) 

Daud A. ix153 (442O) 

Daugaard G. ix507 (1573P) 

D’Auria G. ix105 (280P) 

Davidenko I. ix230 (687P), ix322 (978P) 

Davidson C. ix107 (288P) 

Davies A. ix348 (1063O), ix69 (154P), 

ix518 (1612P), ix78 (185P) 

Davies F. ix44 (67IN) 

Davis D.W. ix300 (911P) 

Davis G. ix173 (505) 

Davis M.P. ix259 (785O) 

Davison C. ix190 (558P) 

Dawood T. ix114 (314) 

Dawson N. ix311 (943P) 

Dawson S. ix74 (171O) 

Day F. ix383 (1173P) 

Dazzani M.C. ix511 (1585P), ix102 (269P) 

De Aguirre I. ix533 (1662P) 

De Angelis V. ix427 (1302P), ix315 (958) 

De Azambuja E. ix95 (247O), ix98 (255PD) 

De Baere T. ix198 (580P) 

De Benedetto A. ix440 (1348) 

De Benedictis E. ix102 (269P) 

De Besi P. ix409 (1246P) 

De Blas B. ix334 (1018O) 

de Bono J.S. ix119 (325PD), ix161 (464P), 

ix162 (469P), ix38 (48IN), ix294 (894O), 

ix295 (896O), ix296 (897O), ix297 (899PD), 

ix298 (903P), ix301 (913P), ix304 (924P), 

ix307 (933P) 

De Bont E.S.J.M. ix484 (1497P) 

De Both A. ix287 (870) 

De Braud F. ix187 (550P) 

De Braud F.G.M. ix507 (1571P), ix88 (222P), 

ix102 (269P), ix116 (319O), ix212 (628), 

ix288 (873), ix305 (926P) 

De Braud F.G.M. ix272 (824P) 

De Bree R. ix450 (1379P) 

De Bruin D.M. ix330 (1006P) 

De Camargo Cancela M. ix315 (957) 

De Castro G.Jr. ix486 (1503P), ix308 (935P) 

De Castro J. ix414 (1264P), ix441 (1352), 

ix505 (1564P), ix523 (1629) 

De Censi A. ix83 (201P) 

De Cock E. ix103 (274P) 

De Coene E. ix287 (870) 


author index 

De Droogh E. ix452 (1386P) 

De Fiore L. ix458 (1408) 

De Fromont M. ix263 (797PD) 

De Galitiis F. ix367 (1128P), ix368 (1130P), 

ix369 (1131P), ix369 (1132P), ix369 (1133P) 

De Geus-Oei L. ix160 (462P), ix192 (562P) 

De Giorgi U. ix285 (863P) 

De Giorgi V. ix364 (1118PD) 

De Graan A.M. ix534 (1667P) 

De Gregorio N. ix322 (976P) 

De Gregorio V. ix85 (208P) 

De Gruijl T. ix301 (915P) 

De Haan T. ix179 (521O) 

De Haas S. ix81 (198P) 

De Herder W.W. ix377 (1156O) 

de Jong J. ix73 (167O) 

De Jong J. ix80 (193P) 

De Jong R.S. ix124 (342P) 

De Jonge M. ix319 (966O) 

De Jonge M.J.A. ix158 (457P) 

De Kam M. ix103 (274P) 

De Koning H. ix53 (87IN) 

De La Cruz L. ix351 (1073P) 

De La Cueva H. ix106 (284P) 

De La Haba Rodriguez J. ix530 (1652P) 

De La Haba Rodriguez J. ix140 (400), ix186 (546P) 

De La Haba J. ix131 (365P) 

De La Haba J.R. ix118 (323PD), ix142 (407TiP) 

De La Motte Rouge T. ix125 (346P), ix313 (951) 

De La Piedra C. ix266 (805P), ix312 (945) 

De Laroche G. ix481 (1487P) 

De Las Penas R. ix490 (1517TiP) 

De Lio N. ix241 (726P) 

De Maglio G. ix78 (183P) 

De Maio A.P. ix532 (1659P) 

De Manzoni G. ix226 (675P) 

De Maria A. ix454 (1393P) 

De Marinis F. ix404 (1235PD), ix439 (1346) 

De Mattos-Arruda L. ix531 (1656P), ix159 (458P) 

De Meerleer G. ix330 (1007), ix325 (987P) 

De Minicis S. ix243 (734P) 

De Mont-Serrat H. ix165 (478P), ix169 (494P) 

De Never G. ix325 (987P) 

De Pas T. ix386 (1182P), ix402 (1230PD), 

ix410 (1251P) 

De Pas T. ix153 (440O) 

De Pasquale M. ix95 (248O) 

De Paula Costa R. ix455 (1397P) 

De Pauw A. ix175 (511PD) 

De Placido S. ix530 (1651P), ix540 (1687), 

ix280 (846P), ix316 (962TiP) 

De Raaf P.J. ix534 (1667P) 

de Revel T. ix260 (789O) 

De Roock W. ix213 (630) 

De Rooij S. ix100 (263P) 

De Roos W. ix111 (301) 

De Rosa F. ix369 (1132P) 

De Ruysscher D. ix392 (1201P), ix396 (1213), 

ix396 (1216), ix397 (1217), ix425 (1296P), 

ix212 (626), ix49 (80IN) 

De Sanctis R. ix483 (1494P), ix487 (1506P) 

De Santis S. ix439 (1346) 

de Schultz W. ix306 (931P) 

De Souza P. ix100 (262P), ix294 (894O) 

De Torres I. ix302 (916P) 

de Velasco G. ix377 (1157O) 

De Velasco G.A. ix96 (250PD) 

De Vincenzo F. ix167 (488P) 

De Visser I. ix103 (274P) 

De Vita F. ix229 (685P) 

De Vivo R. ix285 (863P) 

De Vriendt V. ix75 (173O) 

De Vries A. ix340 (1038P) 

De Vries E.G.E. ix40 (57IN) 

De Vries J. ix363 (1114PD) 

Dean E. ix326 (992P) 

Dearnaley D. ix301 (913P) 

Deb R. ix83 (202P) 

Debieuvre D. ix419 (1276P), ix455 (1396P) 

Debois M. ix386 (1182P) 

Debruyne P.R. ix341 (1042P) 

Debucquoy A. ix222 (663TiP) 

Debus M. ix453 (1389P) 

Decensi A. ix119 (327PD) 

Decillis A. ix174 (1708PD) 

Dediu M. ix418 (1275P) 

Dees E.C. ix153 (442O) 

Defilles C. ix146 (419PD) 

Degardin M. ix160 (461P) 

Degiovanni D. ix247 (747P) 

Degli Esposti R. ix145 (416PD) 

Deguiral P. ix196 (572P) 

Degun R. ix122 (336P) 

Dei Tos A.P. ix485 (1500P) 

Del Barrio A. ix508 (1577P) 

Del Buono S. ix315 (958) 

Del Mastro L. ix454 (1393P), ix501 (1551PD), 

ix521 (1621), ix142 (408TiP) 

Del Prete M. ix219 (652), ix239 (720P), 

ix250 (756), ix274 (829P) 

Del Rio E. ix408 (1244P) 

Del Signore E. ix439 (1346) 

Del Valle E. ix233 (699P) 

Del Vecchio M. ix366 (1124P), ix367 (1128P), 

ix368 (1130P), ix369 (1131P) 

Delabaye I. ix510 (1583P) 

Delaloge S. ix110 (297P), ix175 (511PD) 

Delaney G. ix100 (262P) 

Delaunoit T. ix194 (569P) 

Delaurentiis M. ix114 (315TiP) 

Delcorso L. ix80 (192P) 

Deleporte A. ix194 (569P), ix199 (584P) 

Delforge M. ix510 (1583P) 

Delgado J.R. ix351 (1073P), ix254 (773) 

Della Corte C.M. ix430 (1309P) 

Della Puppa A. ix144 (411O) 

Delmonte A. ix116 (319O) 

Delord J. ix165 (478P), ix169 (494P) 

Delord J.P. ix334 (1017O), ix342 (1044P) 

Delpero J. ix184 (539P), ix241 (727P) 

Delrio P. ix193 (567P) 

Delrue L. ix330 (1007), ix325 (987P) 

Delva R. ix260 (789O), ix294 (893O) 

Demarchi M. ix332 (1014) 

Demetri G. ix482 (1490P) 

Demetri G.D. ix478 (1478O) 

Demichellis S. ix210 (619) 

Demidkina A. ix70 (156P) 

Demidov L.V. ix371 (1138P) 

Demir G. ix217 (645) 

Demirag G. ix221 (660) 

Demirci U. ix227 (678P), ix277 (838P) 

Demura Y. ix420 (1280P) 

Denda T. ix449 (1378P), ix217 (646) 

Deng H. ix437 (1337) 

Deng J. ix501 (1552P) 

Deng Q. ix389 (1193P) 

Denhaerynck K. ix502 (1555P) 

Denis L.J. ix401 (1227O) 

Denkert C. ix117 (321PD) 

Dennis M. ix349 (1068PD) 

Deo S.V.S. ix455 (1398P), ix110 (298P) 

Deonarain M. ix160 (463P) 

Deplanque G. ix259 (786O), ix294 (893O) 

Deptala A. ix230 (687P) 

Derbel O. ix478 (1477O) 

Dercksen M.W. ix501 (1553P) 

Derosa L. ix290 (881) 

Des Guetz G. ix414 (1265P) 

Desai B. ix148 (428P) 

Desai J. ix383 (1173P), ix220 (656) 

Desar I.M.E. ix160 (462P) 

Desauw C. ix241 (725P) 

Descallar J. ix100 (262P) 

Deshmukh S.P. ix101 (265P) 

Desjardins A. ix146 (417PD) 

Desjardins L. ix519 (1614P) 

Dessi’ A. ix516 (1604P) 


Dessi’ M. ix462 (1422O), ix516 (1604P), 

ix164 (476P) 

Destro A. ix77 (181P) 

Deutsch E. ix155 (446PD) 

Deutschbauer S. ix209 (616) 

Devanarayan V. ix173 (505) 

Devesa M. ix205 (604P) 

Devi B.C. ix136 (383) 

Devries T. ix310 (941P) 

Dhadda A.S. ix106 (283P) 

D’Hoore A. ix222 (663TiP) 

Di Bartolomeo M. ix212 (628) 

Di Battista M. ix145 (416PD), ix147 (424P) 

Di Benedetto A. ix142 (406TiP) 

Di Cosimo S. ix95 (247O), ix98 (255PD) 

Di Costanzo F. ix463 (1425P), ix528 (1646PD) 

Di Fiore F. ix339 (1033P), ix234 (703P), 

ix252 (767) 

Di Gennaro E. ix193 (567P) 

Di Giacomo A.M. ix364 (1117PD), ix369 (1132P), 

ix373 (1148) 

Di Giacomo D. ix213 (629) 

Di Guardo L. ix369 (1132P), ix369 (1133P) 

Di Hariry I. ix436 (1332) 

Di Lauro L. ix142 (406TiP) 

Di Leo A. ix27 (13IN) 

Di Lorenzo G. ix270 (818P), ix280 (846P), 

ix290 (879), ix306 (931P), ix316 (962TiP) 

Di Lucca G. ix240 (724P) 

Di Maio M. ix458 (1408), ix78 (183P) 

Di Monta G. ix375 (1152) 

Di Noia V.P. ix433 (1322) 

Di Palma M. ix517 (1607P) 

Di Palma T. ix229 (685P) 

Di Pasquale M.C. ix99 (259P) 

Di Rocco R. ix330 (1004P) 

Di Rocco Z.C. ix466 (1436P) 

Di Salvatore M. ix84 (207P) 

Di Tomaso E. ix537 (1675P), ix158 (457P) 

Diéras V. ix62 (121IN), ix519 (1614P), 

ix120 (329P), ix128 (355P) 

Diamand F. ix214 (633) 

Diaz-Padilla I. ix156 (450PD) 

Diaz-Rubio E. ix438 (1342), ix183 (537P) 

Diaz A. ix325 (986P) 

Diaz C. ix251 (763) 

Diaz G. ix494 (1527P) 

Diaz J. ix261 (792PD) 

Dicato M.A. ix186 (548P), ix209 (615), ix56 (98IN) 

Dickman E. ix223 (664TiP) 

Diebold M.D. ix180 (525PD) 

Dieckmann K. ix147 (421P) 

Diederich C.J. ix130 (363P) 

Diehl S. ix480 (1484PD) 

Dienstmann R. ix116 (319O) 

Dierickx D. ix518 (1609P) 

Dietel M. ix390 (1195P), ix394 (1208), ix86 (213P) 

Dieterle N. ix487 (1505P) 

Dietrich D. ix480 (1482PD) 

Dietz A. ix336 (1022PD) 

Díez J.J. ix377 (1157O) 

Digumarti R. ix400 (1225O) 

Dilsizian V. ix108 (290P) 

Dimaiuta M. ix511 (1585P) 

Dimitroulis J. ix493 (1524P) 

Dimopoulos M. ix95 (246O) 

Dimoudis S.T. ix239 (717P) 

D’Incecco A. ix77 (181P) 

Ding K.F. ix202 (595P) 

Ding X.Y. ix140 (401) 

Dingemans A-M. ix385 (1179O) 

Dingemans A.C. ix392 (1201P), ix396 (1213), 

ix396 (1216), ix425 (1296P), ix212 (626) 

Dini G. ix80 (192P) 

Dinter D. ix480 (1484PD) 

Diodati F. ix474 (1462PD) 

Dionysopoulos D. ix338 (1031P) 

Diouf M. ix464 (1430P) 

Dipalma M. ix503 (1559P) 



Dirix L. ix362 (1112PD), ix157 (454P) 

Dittrich C. ix100 (261P), ix32 (28IN) 

Dive C. ix87 (219P), ix90 (227P), ix199 (582P), 

ix207 (609P) 

Dixit S. ix298 (904P) 

Diz M. ix331 (1009) 

Djedi H. ix221 (658) 

Djuraev M. ix229 (684P), ix254 (772) 

Dobbs N. ix119 (325PD) 

Dobi E. ix128 (357P), ix204 (600P) 

Dobon F. ix106 (284P) 

Dockry É. ix68 (150P) 

Doebele R. ix408 (1245P) 

Doebele R.C. ix422 (1287P) 

Doger de Speville B.G. ix494 (1527P) 

Doherty M. ix300 (909P) 

Doi T. ix164 (474P) 

Doihara H. ix74 (172O) 

Doki Y. ix481 (1485PD), ix227 (677P) 

Dolcimascolo S. ix215 (636) 

Domanska-Czyz K. ix354 (1084P) 

Dombret H. ix349 (1068PD) 

Dome B. ix493 (1523P) 

Domenech M. ix265 (802P), ix275 (832P) 

Domerg C. ix74 (170O) 

Domine M. ix414 (1264P), ix441 (1352), 

ix80 (194P) 

Domingues N. ix357 (1095) 

Dominguez-Tinajero S. ix378 (1160P) 

Dominichini E. ix379 (1164P) 

Domont J. ix480 (1482PD), ix486 (1502P) 

Donadio M. ix123 (340P), ix140 (402) 

Donat D.A. ix137 (390) 

Donati G. ix474 (1462PD) 

Donegani S. ix315 (959) 

Donehower R.C. ix230 (687P) 

Dong Q. ix454 (1395P) 

Dong W. ix416 (1269P) 

Donnadieu A. ix101 (266P) 

Donnini A. ix93 (240) 

Donny P. ix456 (1401P) 

Donovan J. ix292 (887) 

Donskov F. ix259 (785O), ix271 (819P) 

Dooms C. ix73 (167O) 

Dorer D.J. ix152 (439O) 

Dorff T.B. ix261 (790O), ix314 (952) 

ix316 (961) 

Doroumian S. ix170 (497P) 

Dosaka-Akita H. ix443 (1358), 

ix497 (1538P) 

Douillard J-Y. ix194 (570P) 

Douillard J. ix389 (1192PD), ix417 (1272P), 

ix456 (1401P), ix190 (558P), ix192 (564P), 

ix196 (572P) 

Doval D.C. ix128 (356P) 

Dowler Nygaard A. ix73 (168O) 

Dowsett M. ix75 (176PD), ix119 (325PD) 

Doyen C. ix510 (1583P) 

Dražd ˇ áková M. ix81 (196P) 

Drake C.G. ix258 (784O) 

Dreslerova J. ix474 (1464P) 

Dreyer C. ix334 (1017O), ix379 (1163P), 

ix167 (485P) 

Dreyling M.H. ix354 (1084P), ix359 (1107TiP), 

ix44 (65IN) 

Droege C. ix396 (1214) 

Dromain C. ix378 (1159P) 

Drouin M. ix169 (493P) 

Droz J. ix286 (864P), ix308 (934P) 

D’Souza A. ix122 (338P) 

Du Bois A. ix322 (976P), ix323 (980P) 

Du Y. ix110 (299), ix130 (361P) 

Dua D. ix503 (1558P) 

Dubey S. ix230 (687P) 

Dubot C. ix260 (789O) 

Dubray-Longeras P. ix102 (270P) 

Ducimetiere F. ix488 (1511P) 

Duck L. ix510 (1583P) 

Ducreux M. ix456 (1400P), ix85 (209P), 

ix85 (210P), ix194 (568P), ix198 (580P), 

ix218 (648) 

Ducreux M.P. ix378 (1159P), ix378 (1160P) 

Duffaud F. ix482 (1489P) 

Duffy S.W. ix470 (1451P) 

Dufour H. ix146 (419PD) 

Duhamel A. ix241 (725P) 

Duignan E. ix524 (1634) 

Duin S. ix88 (221P) 

Duman B.B. ix326 (990P) 

Dumas L.E. ix139 (398) 

Dummer R. ix366 (1125P) 

Dumon K. ix222 (663TiP) 

Dunant A. ix389 (1192PD) 

Dünne A. ix142 (409TiP) 

Dupont-Gossard A.C. ix237 (710P) 

Duprez F. ix341 (1042P) 

Dupuis O. ix196 (572P) 

Duque C.G. ix215 (637) 

Durán I. ix377 (1157O) 

Duran I. ix449 (1377P), ix277 (839P) 

Durand J. ix91 (229P) 

Durando X. ix102 (270P) 

Durante M. ix153 (442O) 

Duranti S. ix427 (1302P) 

Durie B.G. ix360 (1108TiP) 

Durnali A. ix332 (1015) 

Durusoy R. ix274 (830P) 

Duus E. ix512 (1588P), ix161 (465P) 

Duvillard P. ix322 (977P) 

Dy G.K. ix155 (447PD) 

Dy G.K. ix158 (456P) 

Dykstra K. ix263 (796PD) 

Dyson G. ix244 (735P) 

Dyszkiewicz W. ix395 (1211) 

Dzik C. ix308 (935P) 

E 

Eaddy M. ix428 (1303P) 

Earl J. ix377 (1157O) 

Easaw J. ix202 (594P) 

Easty D. ix495 (1532P) 

Eatock M.M. ix249 (754) 

Eaton K. ix424 (1291P) 

Eberhardt W. ix407 (1241P), ix437 (1339) 

Ebert M. ix37 (44IN) 

Eccher C. ix99 (259P) 

Echeveste J.I. ix365 (1123P), ix432 (1316) 

Eckert L. ix447 (1369P) 

Eckert R. ix440 (1347), ix458 (1407), 

ix494 (1529P) 

Eckhardt S.G. ix155 (447PD), ix156 (449PD) 

Edeline J. ix105 (281P) 

Edenfield W. ix170 (496P) 

Edmonds K. ix273 (827P) 

Edwards J. ix495 (1531P) 

Eechoute K. ix538 (1678P) 

Efstathiou E. ix308 (934P) 

Egamberdiev D. ix229 (684P), ix254 (772) 

Egawa S. ix211 (624) 

Eggert J. ix505 (1567P) 

Eggmann N. ix366 (1125P) 

Eguchi K. ix442 (1354), ix469 (1447PD), 

ix511 (1586P) 

Eidtmann H. ix95 (247O) 

Eiermann W. ix97 (252PD) 

Eigl B.J. ix304 (922P) 

Eisen T.Q.G. ix407 (1241P), ix262 (795PD) 

Eisenberger M. ix317 (963TiP) 

Eisenhauer E.A. ix40 (54IN), ix304 (922P) 

Eisinger F. ix470 (1452P), ix472 (1460) 

Eisterer W. ix249 (755) 

Ekici F. ix137 (387) 

Ekinci O. ix227 (678P), ix277 (838P) 

El Hajbi F. ix241 (725P) 

El Hariry I. ix529 (1647PD), ix533 (1664P) 

El Hawwari B. ix462 (1424P) 

El Hussiny G. ix265 (801P) 

El Kouri C. ix456 (1401P), ix511 (1584P) 

El Mansy H. ix199 (584P) 

El Mesbahi O. ix137 (389) 

El Ouagari K. ix235 (704P) 

El Shehaby A. ix150 (432) 

El-Ashry M. ix398 (1221) 

El-Hadaad H. ix353 (1081P), ix93 (239) 

El-Sadda W. ix341 (1039P), ix398 (1221) 

Elaidi R.T. ix499 (1545O), ix280 (845P), 

ix282 (852P) 

Elalamy I. ix543 (1697P) 

Elbassiouny M. ix253 (770) 

Eldebaway E. ix145 (413PD) 

Eleftheraki A. ix95 (246O) 

Elens L. ix534 (1667P) 

Elez E. ix154 (443PD) 

Elfakir S. ix137 (389) 

Elghissassi I. ix432 (1318) 

Elhussiny G. ix265 (803P) 

Elias D. ix35 (38IN) 

Elisei R. ix154 (445PD) 

Elkabets M. ix126 (350P) 

Elkhateeb N. ix145 (413PD) 

Elkhouly E.A. ix98 (256P) 

Ellard S. ix297 (900PD), ix305 (925P) 

Ellis-Pegler R.B. ix162 (470P) 

Ellis M.J. ix57 (102IN), ix27 (15IN) 

Ellis P.M. ix395 (1210) 

Ellis S. ix374 (1149), ix283 (857P) 

Ellithy M. ix253 (770) 

Elmajjaoui S. ix328 (999P) 

Elmashad N.M. ix150 (432) 

Elnaggar M.S. ix537 (1676P) 

Elsaesser R. ix500 (1548PD) 

Elyan F. ix109 (294P) 

Elzawahrey H.M. ix111 (304) 

Emelianova G. ix382 (1172) 

Emi M. ix226 (672P) 

Emiliani A. ix105 (282P), ix111 (303) 

Emmanouilides C. ix289 (876) 

Emori Y. ix384 (1177P) 

Emoto S. ix233 (698P) 

Enatsu S. ix393 (1206P), ix397 (1218) 

Endo K. ix518 (1611P) 

Endo M. ix430 (1310P), ix492 (1519PD) 

Eng C. ix150 (435TiP), ix224 (666O) 

Engelman J. ix389 (1191PD) 

English P.A. ix262 (794PD) 

Eniu A. ix116 (317O) 

Enjalbert A. ix146 (419PD) 

Enokida T. ix518 (1611P) 

Enomoto T. ix436 (1334) 

Enserink J. ix111 (301) 

Enting D. ix161 (464P) 

Eom H. ix353 (1080P) 

Epenetos A.A. ix160 (463P) 

Erbas O. ix173 (508) 

Erdel M. ix209 (616) 

Erdem D. ix221 (660) 

Erdem G. ix286 (866P) 

Ermani M. ix145 (416PD), ix147 (424P), 

ix287 (868) 

Errihani H. ix432 (1318), ix476 (1470P), 

ix476 (1472P), ix477 (1476) 

Esaki M. ix225 (671P) 

Esaki T. ix512 (1590P) 

Esbah O. ix105 (279P) 

Escrig V. ix374 (1150) 

Escriu C. ix539 (1684P) 

Escudero P. ix377 (1157O) 

Escudier B. ix261 (792PD), ix262 (793PD), 

ix263 (797PD), ix264 (798PD), ix270 (817P), 

ix277 (837P), ix278 (842P), ix279 (844P), 

ix293 (892TiP) 

Eser E.P. ix227 (678P) 

Eskens F. ix158 (457P) 

Esmaeili J. ix184 (538P) 

Espírito-Santo A. ix357 (1095) 

Espinos Jimenez J. ix149 (429P) 


author index 

Esposito G. ix209 (618) 

Ess S.M. ix132 (370P) 

Essa E. ix352 (1078P) 

Esteban E. ix266 (805P), ix273 (826P), 

ix275 (832P), ix276 (835P), ix277 (839P), 

ix312 (945), ix314 (953) 

Esterni B. ix150 (434), ix294 (893O) 

Esteves B. ix262 (795PD), ix263 (796PD) 

Esteves S. ix141 (404) 

Etchberger J. ix122 (336P) 

Eto T. ix348 (1062O) 

Etxaniz O. ix266 (806P) 

Eustace A. ix528 (1645PD), ix540 (1686P) 

Evans D.G.R. ix34 (35IN), ix319 (969PD) 

Evans T.L. ix403 (1231PD) 

Evans T.R.J. ix129 (358P) 

Evers D. ix532 (1658P) 

Ewald-Riegler N. ix322 (976P) 

Eymard J. ix278 (841P), ix314 (955) 

Ezoe Y. ix226 (673P) 

Ezz Alarab M. ix352 (1079P) 

Ezz Elarab L. ix352 (1079P) 

Ezzat S. ix448 (1374P) 

F 

Fabbri F. ix285 (863P) 

Fabbri M.A. ix105 (280P) 

Fabbro M. ix327 (993P) 

Faber D.J. ix330 (1006P) 

Fabre E. ix499 (1545O), ix77 (180P) 

Fabrini M.G. ix251 (761), ix251 (762) 

Facchinetti A. ix91 (230P) 

Fadoukhair Z. ix110 (297P) 

Faehling M. ix440 (1347), ix494 (1529P) 

Faez L. ix218 (647) 

Faggioni G. ix124 (343P) 

Fagnani D. ix474 (1462PD) 

Faivre S. ix334 (1017O), ix376 (1155O), 

ix379 (1163P), ix167 (485P) 

Falagán S. ix113 (310) 

Falandry C. ix501 (1554P) 

Falchook G.S. ix153 (442O) 

Falchook G.S. ix154 (444PD), ix168 (489P) 

Falci C. ix486 (1504P), ix131 (367P) 

Falco A. ix496 (1535P) 

Falcon S. ix103 (273P), ix224 (668PD) 

Falcone A. ix85 (208P), ix94 (243), ix127 (354P), 

ix176 (515P), ix206 (606P), ix238 (714P), 

ix241 (726P), ix251 (761), ix251 (762), 

ix290 (881) 

Falk M. ix395 (1210) 

Falk S. ix421 (1282P) 

Falkowski S. ix484 (1495P) 

Fallai C. ix341 (1040P), ix342 (1045P) 

Fallowfield L. ix509 (1580P) 

Faloppi L. ix86 (214P), ix86 (215P), ix219 (652), 

ix239 (720P), ix243 (734P), ix250 (756), 

ix274 (829P) 

Fan J. ix146 (417PD) 

Fan N. ix231 (690P) 

Fan S.T. ix244 (736P) 

Fan Y. ix140 (401) 

Fanale M. ix348 (1063O), ix353 (1083P) 

Fang H. ix248 (748) 

Fang I. ix345 (1052) 

Fang L. ix120 (329P) 

Fang W. ix256 (779TiP) 

Fani Pakdel A. ix459 (1411) 

Fanti S. ix60 (114IN), ix130 (362P), ix148 (425P) 

Farace F. ix406 (1240P), ix94 (244) 

Farace F.F. ix85 (209P) 

Faratian D. ix96 (249PD) 

Fareed J. ix543 (1697P) 

Farfan C. ix281 (850P) 

Fargues G. ix280 (845P) 

Farid M. ix485 (1501P) 

Farina G. ix466 (1436P), ix511 (1585P) 

Farina P. ix144 (411O) 

Farnesi A. ix290 (881) 

Faron M. ix198 (580P) 

Farrell M. ix469 (1449PD) 

Farrus B. ix135 (380) 

Farsi F. ix481 (1487P) 

Fasola G. ix457 (1405) 

Fatato P. ix493 (1522PD) 

Fatigoni S. ix485 (1500P) 

Faustino C. ix201 (591P), ix210 (620), ix221 (657), 

ix222 (661) 

Fauvet R. ix322 (977P) 

Favaretto A. ix533 (1661P) 

Faviana P. ix85 (208P) 

Favilla B. ix113 (311) 

Fayard F. ix486 (1502P) 

Fayette J. ix334 (1017O) 

Fedele P. ix95 (248O) 

Federico P. ix540 (1687), ix316 (962TiP) 

Fedorchuk O.G. ix536 (1672P) 

Fedorenko D.A. ix141 (403) 

Fedrigo C. ix537 (1676P) 

Fehr M. ix283 (857P) 

Fei F. ix130 (361P) 

Fekih M. ix340 (1037P) 

Felici A. ix280 (846P) 

Felip E. ix414 (1264P), ix496 (1533P), ix73 (167O), 

ix152 (438O), ix153 (440O), ix174 (509TiP) 

Feliu J. ix457 (1404), ix165 (480P), ix181 (527PD) 

Fellous M. ix125 (346P) 

Femenic R. ix359 (1104) 

Feng A. ix509 (1580P) 

Feng S. ix362 (1111PD) 

Fennell D. ix495 (1532P), ix529 (1647PD), 

ix533 (1664P) 

Fennell D.A. ix68 (149P), ix498 (1542TiP) 

Fenner M. ix299 (908P) 

Ferec M. ix196 (572P) 

Ferland E. ix200 (586P) 

Fernández Martos C. ix181 (527PD) 

Fernández-Parra E. ix275 (832P) 

Fernández J. ix136 (386) 

Fernández M. ix101 (268P), ix101 (268P) 

Fernández P.L. ix135 (380) 

Fernandes A.C. ix525 (1639) 

Fernandes I. ix289 (878) 

Fernandez Aceñero M. ix80 (194P) 

Fernandez-Cruz L. ix67 (145P) 

Fernandez O. ix436 (1333), ix273 (826P) 

Fernando I.N. ix97 (253PD) 

Ferrand F.R. ix337 (1025P), ix340 (1037P), 

ix341 (1041P), ix345 (1053) 

Ferrandez D. ix183 (537P) 

Ferrara R. ix229 (685P) 

Ferraresi V. ix369 (1132P) 

Ferrari A. ix483 (1494P), ix311 (943P) 

Ferrari A.C.R. ix486 (1503P) 

Ferrari A.C.R.C. ix450 (1380P) 

Ferrari D. ix335 (1020PD), ix245 (739P) 

Ferrari J.-. ix521 (1622) 

Ferrari L. ix240 (724P) 

Ferrari S. ix479 (1480PD) 

Ferrari V.D. ix338 (1029P) 

Ferrarini I. ix94 (243), ix176 (515P) 

Ferrario C. ix285 (863P) 

Ferraris E. ix99 (260P) 

Ferraro L. ix342 (1045P) 

Ferrat E. ix460 (1419PD) 

Ferree S. ix75 (176PD) 

Ferreira M. ix345 (1056) 

Ferreira P. ix201 (591P), ix210 (620), ix221 (657), 

ix222 (661) 

Ferreira R. ix458 (1409) 

Ferrero J. ix125 (346P), ix142 (407TiP) 

Ferrero J.M. ix294 (893O) 

Ferro A. ix99 (259P), ix127 (354P) 

Ferron G. ix327 (993P) 

Ferrucci P.F. ix369 (1131P) 

Ferry D. ix198 (581P) 


Ferry D.R. ix178 (519O), ix181 (530PD) 

Fetterly G. ix155 (447PD) 

Fiala O. ix474 (1464P) 

Ficorella C. ix524 (1633), ix213 (629) 

Fidler M. ix467 (1442) 

Fiduccia P. ix144 (411O), ix326 (991P) 

Fiegl M. ix494 (1528P), ix76 (178P) 

Field K. ix151 (437TiP) 

Figarella-Branger D. ix146 (419PD) 

Figdor C. ix363 (1114PD) 

Figg W. ix246 (743P) 

Figlin R.A. ix262 (794PD) 

Figueras J. ix219 (651) 

Figueredo M.A. ix165 (480P) 

Filatova L.V. ix139 (397) 

Filiberti S. ix474 (1462PD) 

Filimonov A.V. ix470 (1451P) 

Filipits M. ix389 (1192PD), ix86 (213P) 

Filleron T. ix464 (1430P) 

Fillitz M. ix348 (1064O) 

Findlay A. ix483 (1492P) 

Finek J. ix447 (1372P), ix474 (1464P) 

Fink M. ix449 (1377P) 

Finkelstein D.M. ix115 (316TiP) 

Fiore M. ix483 (1491P) 

Firat U. ix137 (387) 

Firvida J.L. ix436 (1333) 

Firvida X.L. ix395 (1212) 

Fischbach W. ix252 (766) 

Fischer von Weikersthal L. ix180 (526PD), 

ix204 (599P) 

Fischer G. ix278 (841P) 

Fischer J.R. ix390 (1194P) 

Fischer N. ix372 (1144) 

Fish S. ix420 (1279P) 

Fishman M.N. ix268 (811P) 

Fiteni F. ix249 (753) 

Fitzpatrick J.M. ix315 (957) 

Fizazi K. ix260 (789O), ix277 (837P), ix285 (862P), 

ix294 (893O), ix295 (895O), ix295 (896O), 

ix297 (899PD), ix304 (924P), ix309 (937P), 

ix313 (951) 

Flacco A. ix535 (1668P) 

Flaherty K.T. ix46 (70IN) 

Flamen P. ix194 (569P), ix199 (584P) 

Flament C. ix169 (495P) 

Flamm-Horak A. ix521 (1622) 

Flechl B. ix145 (415PD), ix147 (421P) 

Flechon A. ix260 (789O), ix286 (864P) 

Flechter E. ix498 (1541) 

Fleisher M. ix89 (223P) 

Fleury J. ix128 (355P) 

Flick E.D. ix420 (1279P) 

Flieser-Hartl M. ix465 (1435P) 

Floquet A. ix327 (993P) 

Flor M.J. ix235 (705P) 

Flores Arredondo J.H. ix184 (541P) 

Flores-Balcázar C. ix329 (1003P) 

Floriani I.C. ix335 (1020PD) 

Floyd J.R. ix150 (435TiP) 

Flucke U.E. ix484 (1497P) 

Fly K. ix482 (1490P), ix271 (820P) 

Focan C. ix194 (568P) 

Focaraccio L. ix444 (1360) 

Fode K. ix271 (819P) 

Fojo T. ix198 (579P) 

Follador A. ix457 (1405) 

Folprecht G. ix178 (520O), ix191 (561P), 

ix211 (622) 

Fong L. ix310 (939P) 

Fonsatti E. ix364 (1117PD) 

Fonseca C. ix458 (1409) 

Fonseca L.G. ix455 (1397P), ix308 (935P) 

Font A. ix538 (1680P), ix265 (802P), ix266 (806P), 

ix266 (807P) 

Fontana A. ix94 (243), ix127 (354P), ix176 (515P), 

ix290 (881) 

Fontanini G. ix85 (208P), ix183 (535P) 



Fonteyne V. ix325 (987P), ix330 (1007) 

Foo Siang Sheng L. ix485 (1499P), ix485 (1501P) 

Fora G. ix343 (1047P), ix346 (1058) 

Formenti S.C. ix130 (363P) 

Formisano L. ix530 (1651P), ix532 (1659P), 

ix540 (1687), ix287 (869) 

Fornaro L. ix85 (208P) 

Forsberg G. ix303 (919P) 

Forshew T. ix74 (171O) 

Forssman U. ix342 (1044P) 

Forster M. ix347 (1061TiP) 

Fosko S.W. ix477 (1474) 

Fossa S. ix307 (932P) 

Foster L. ix381 (1168P) 

Foster M. ix166 (484P) 

Fotia V. ix535 (1669P) 

Fotopoulou C. ix322 (976P) 

Fougeray R. ix260 (787O), ix265 (804P) 

Fountzilas E. ix338 (1030P), ix338 (1031P) 

Fountzilas G. ix337 (1026P), ix338 (1030P), 

ix338 (1031P), ix430 (1312), ix95 (246O), 

ix213 (630), ix239 (717P) 

Fouque J. ix280 (845P), ix282 (852P) 

Fourcade A. ix456 (1400P) 

Fouret P. ix388 (1190P) 

Fournel M. ix163 (471P), ix169 (492P) 

Fournel P. ix391 (1199P), ix416 (1270P) 

Fournier C. ix113 (309) 

Fournier M. ix178 (519O) 

Fourrier-Réglat A. ix219 (649) 

Fox G. ix507 (1573P) 

Fragoso M. ix210 (620), ix221 (657) 

Fragoso R. ix201 (591P), ix222 (661) 

Fragoso S. ix175 (512PD), ix176 (514P) 

Franceschi E. ix145 (416PD), ix147 (424P) 

Franciosi V. ix466 (1436P) 

Francis S. ix367 (1127P) 

Francois E. ix219 (649), ix238 (716P) 

Franke F.A. ix403 (1233PD) 

Franzese E. ix105 (282P), ix111 (303) 

Frasci G. ix102 (271P) 

Frassoldati A. ix101 (267P) 

Frati L. ix105 (282P), ix111 (303) 

Fratte S. ix204 (600P) 

Freas E. ix157 (452P) 

Frebourg T. ix213 (629) 

Fregoni V. ix99 (260P) 

Freire J. ix141 (404) 

Fresno J.A. ix96 (250PD) 

Freudensprung U. ix128 (356P) 

Freyer G. ix499 (1547PD), ix501 (1554P), 

ix299 (907P) 

Frezza A.M. ix489 (1512), ix500 (1550PD) 

Frias J. ix165 (480P) 

Friberg L.E. ix534 (1667P) 

Fridrik M.A. ix352 (1076P) 

Fridrik M.A. ix249 (755) 

Friend J. ix512 (1588P) 

Frittelli P. ix105 (280P) 

Frizziero M. ix226 (675P) 

Frohlich M.W. ix310 (941P) 

Frosch A. ix417 (1271P) 

Fruehauf S. ix522 (1624) 

Frye J. ix174 (1708PD) 

Frye S. ix170 (496P) 

Fu C. ix453 (1390P) 

Fu S. ix154 (444PD) 

Fu Y. ix401 (1227O) 

Fuchs B.C. ix542 (1693P), ix246 (742P) 

Fuchs C. ix255 (776TiP) 

Fuchs H. ix162 (468P) 

Fuchs M. ix211 (622) 

Fucikova T. ix81 (197P) 

Fuentes S. ix150 (434) 

Fujii H. ix449 (1378P) 

Fujii S. ix344 (1706P), ix196 (574P) 

Fujii T. ix433 (1323), ix542 (1693P), ix220 (655), 

ix246 (742P) 

Fujimoto-Ouchi K. ix390 (1197P), ix534 (1666P) 

Fujimura Y. ix383 (1175P) 

Fujisaka Y. ix393 (1204P), ix424 (1293P), 

ix167 (486P) 

Fujita J. ix227 (677P) 

Fujita S. ix422 (1286P), ix423 (1289P) 

Fujita T. ix139 (396) 

Fujita Y. ix434 (1326), ix443 (1358), ix497 (1538P) 

Fujiuchi S. ix434 (1326) 

Fujiwara K. ix163 (472P) 

Fujiwara T. ix250 (758) 

Fujiwara Y. ix510 (1581P), ix90 (228P), 

ix250 (758) 

Fukma E. ix87 (216P) 

Fukuda T. ix200 (588P), ix320 (973PD) 

Fukui M. ix467 (1443) 

Fukuoka M. ix426 (1298P), ix91 (232) 

Fukushima N. ix228 (682P) 

Fukutomi A. ix241 (728P) 

Fulvi A. ix439 (1346) 

Fumagalli D. ix57 (100IN) 

Fumagalli E. ix483 (1491P) 

Funahashi Y. ix517 (1608P) 

Funakoshi A. ix241 (728P) 

Funk C. ix520 (1618) 

Füreder T. ix253 (768) 

Furini L. ix326 (991P) 

Furlanetto J. ix117 (322PD) 

Furugaki K. ix390 (1197P) 

Furukawa H. ix196 (573P) 

Furukawa T. ix385 (1180PD) 

Furumoto H. ix326 (989P) 

Furuse J. ix63 (124IN) 

Furuta K. ix89 (224P) 

Fusco J.P. ix149 (429P), ix239 (718P), ix291 (886), 

ix305 (927P) 

Fuse N. ix164 (474P), ix231 (689P) 

Fushida S. ix228 (682P) 

Fust G. ix493 (1523P) 

Fuster J. ix377 (1157O) 

Futamura Y. ix439 (1343) 

G 

Gaba Garcia L. ix300 (910P) 

Gabizon A.A. ix519 (1616P), ix164 (477P) 

Gachet J. ix499 (1545O) 

Gachot B. ix503 (1559P) 

Gadgeel S. ix174 (509TiP) 

Gagliardini D. ix431 (1313) 

Gagua R. ix460 (1414TiP) 

Gaiardo M. ix457 (1405) 

Galdermans D. ix452 (1386P) 

Gale D. ix74 (171O) 

Galetta D. ix423 (1288P) 

Galffy G. ix493 (1523P) 

Galicia I. ix165 (480P) 

Galizia E. ix431 (1313) 

Gallagher D. ix469 (1449PD) 

Gallagher M. ix192 (564P) 

Gallardo E. ix538 (1680P) 

Galle P. ix255 (778TiP) 

Gallego Plazas J. ix181 (527PD) 

Galli L. ix290 (881) 

Galligioni E. ix99 (259P) 

Gallizzi G. ix99 (260P) 

Galsky M.D. ix297 (901PD) 

Galun D. ix237 (712P) 

Galuppo S. ix131 (367P) 

Galve Calvo E. ix125 (345P) 

Galvis V. ix267 (808P) 

Gambardella V. ix430 (1309P) 

Gamerith G. ix543 (1695P) 

Gamez A. ix96 (250PD) 

Gamez C. ix370 (1136P) 

Gamucci T. ix229 (685P) 

Gan H. ix542 (1692P) 

Gandara D. ix445 (1365TiP), ix49 (77IN) 

Gandhi J.G. ix302 (918P) 

Gandhi L. ix405 (1237PD), ix152 (438O) 

Gangolli E. ix158 (456P) 

Gangopadhyay S. ix455 (1399P), ix133 (375P) 

Ganjoo K.N. ix480 (1483PD) 

Ganser A. ix299 (908P) 

Gansert J. ix255 (776TiP) 

Ganten T. ix255 (778TiP) 

Garanzini E. ix272 (824P) 

Garbe C. ix367 (1127P) 

García Alfonso P. ix380 (1165P), ix198 (579P) 

García Bueno J.M. ix510 (1582P) 

García Palomo A. ix125 (345P) 

García Sanz R. ix360 (1108TiP) 

García-Campelo R. ix414 (1264P) 

García-Carbonero R. ix377 (1157O) 

García-Herrera A. ix135 (380) 

Garcia Arroyo F.R. ix351 (1073P) 

Garcia Castaño A. ix374 (1150) 

Garcia Del Muro X. ix490 (1517TiP), ix235 (705P) 

Garcia Foncillas J. ix187 (549P) 

Garcia Martinez A. ix106 (284P) 

Garcia-Bueno J.M. ix441 (1352) 

Garcia-Campelo R. ix440 (1349), ix533 (1662P) 

Garcia-Carbonero R. ix183 (534P) 

Garcia-Donas J. ix113 (310), ix276 (835P), 

ix293 (891TiP) 

Garcia-Foncillas J. ix80 (194P), ix82 (200P), 

ix183 (537P) 

Garcia-Gomez R. ix441 (1352) 

Garcia-Vargas J.E. ix308 (936P) 

Garcia A. ix136 (386) 

Garcia C. ix199 (584P) 

Garcia E. ix416 (1270P) 

Garcia J.M. ix512 (1588P) 

Garcia P.E. ix183 (534P) 

Gardiman M.P. ix144 (411O) 

Gardini G. ix216 (642) 

Gardner E. ix246 (743P) 

Garey J. ix425 (1297P) 

Gargalionis A.N. ix92 (236) 

Gargot D. ix181 (529PD) 

Garmo H. ix133 (372P) 

Garnero P. ix84 (206P) 

Garon E.B. ix152 (438O) 

Garralda E. ix233 (699P) 

Garrido Lopez P. ix414 (1264P), ix419 (1278P) 

Garrone O. ix113 (311), ix123 (340P) 

Garzaro M. ix343 (1047P), ix346 (1058) 

Gascón P. ix523 (1629), ix300 (910P) 

Gasco A. ix531 (1655P) 

Gasco M. ix483 (1494P), ix487 (1506P) 

Gascon P. ix343 (1046P), ix502 (1555P), 

ix502 (1557P), ix505 (1564P), ix538 (1680P) 

Gasmi M. ix181 (529PD), ix242 (730P) 

Gasparini G. ix515 (1599P) 

Gąsowska- Bodnar A. ix323 (979P) 

Gately K.A. ix68 (148P), ix495 (1531P), 

ix69 (154P), ix78 (185P) 

Gatineau M. ix334 (1017O) 

Gau J. ix355 (1087P) 

Gauler T.C. ix336 (1022PD), ix336 (1023PD), 

ix437 (1339), ix284 (858P) 

Gauler T.C. ix288 (875) 

Gaulet M. ix260 (789O) 

Gauthier M. ix237 (710P) 

Gautschi O. ix403 (1232PD), ix49 (78IN) 

Gavelli G. ix496 (1536P) 

Gawel S. ix173 (505) 

Gazdar A.F. ix544 (1701) 

Gazzah A. ix474 (1463P) 

Geater S.L. ix391 (1198P), ix393 (1205P) 

Gebbia V. ix140 (399) 

Gebski V. ix414 (1263P), ix178 (519O) 

Géczi L. ix281 (849P), ix286 (867P) 

Gedamke M. ix299 (905P), ix306 (930P) 

Gedouin D. ix105 (281P) 

Gee A.S. ix215 (638) 

Geertsen P.F. ix271 (819P) 


author index 

Geiges G. ix306 (930P) 

Geitona M. ix236 (707P) 

Gelardi T. ix532 (1659P), ix540 (1687) 

Geldart T. ix283 (857P) 

Gelderblom H. ix478 (1478O), ix184 (540P) 

Gelibter A. ix237 (713P), ix240 (721P) 

Gemma A. ix383 (1174P), ix404 (1234PD), 

ix412 (1256P), ix427 (1301P), ix200 (587P) 

Generali D.G. ix96 (251PD) 

Genestreti G. ix496 (1536P) 

Gennari A. ix119 (327PD) 

Gennma A. ix387 (1186P) 

Genova C. ix79 (187P) 

Gentilcore G. ix375 (1152) 

Gentile A.L. ix285 (863P) 

George A. ix320 (972PD) 

George D.J. ix292 (889TiP), ix310 (941P) 

Georgoulias V. ix381 (1170P), ix429 (1308P), 

ix431 (1314), ix435 (1329), ix436 (1335), 

ix139 (395), ix174 (509TiP), ix213 (631) 

Geraedts W. ix425 (1296P) 

Gerber B. ix117 (321PD) 

Gereke U. ix409 (1249P) 

Gerevini F. ix232 (693P) 

Gerken G. ix255 (778TiP) 

Gerletti P. ix292 (889TiP) 

Gerotziafas G. ix543 (1697P) 

Gerritsen W. ix307 (932P) 

Gerritsen W.R. ix363 (1114PD), ix301 (915P) 

Gerritsen W.R. ix306 (931P) 

Gershanovich M.L. ix139 (397) 

Gervais R. ix397 (1219), ix409 (1247P), 

ix446 (1367TiP) 

Gervasi M.T. ix326 (991P) 

Gettinger S. ix401 (1227O), ix403 (1231PD), 

ix405 (1237PD), ix415 (1267P), ix152 (439O), 

ix157 (453P) 

Getzenberg R.H. ix304 (923P) 

Ghanem I. ix96 (250PD), ix96 (251PD), 

ix134 (378), ix325 (986P) 

Ghanouni P. ix463 (1426P) 

Gharami F.H. ix355 (1090P) 

Gharami F.H. ix359 (1105) 

Gharbi O. ix332 (1013) 

Ghate S.W. ix343 (1049P) 

Ghazal H. ix449 (1377P) 

Ghi M.G. ix335 (1020PD) 

Ghielmini M. ix452 (1385P), ix45 (68IN) 

Ghilardi M. ix435 (1328), ix467 (1440), 

ix519 (1615P), ix131 (368P), ix192 (563P) 

Ghiotto C. ix124 (343P), ix131 (367P) 

Giaccone G. ix423 (1290P) 

Giaginis C. ix541 (1691P) 

Giagkas G. ix429 (1308P) 

Giaj Levra M. ix444 (1360) 

Giampieri R. ix431 (1313), ix86 (214P), 

ix86 (215P), ix219 (652), ix239 (720P), 

ix250 (756), ix274 (829P) 

Gianatti A. ix365 (1120P) 

Gianfelice D. ix463 (1426P) 

Giannarelli D. ix364 (1117PD), ix427 (1302P), 

ix117 (322PD), ix273 (825P) 

Giannatempo P. ix88 (222P), ix285 (861P) 

Gianni A.M. ix88 (222P), ix285 (861P) 

Gianni L. ix531 (1657P), ix74 (172O), ix89 (226P) 

Giantonio B.J. ix189 (555P) 

Giassas S. ix139 (395) 

Gibbs P. ix383 (1173P), ix220 (656) 

Giebel S. ix353 (1082P) 

Giessen C. ix180 (526PD), ix204 (599P) 

Giganti M.O. ix270 (818P) 

Gigot J. ix197 (578P) 

Gil-Aldea I. ix305 (927P) 

Gil-Bazo I. ix149 (429P), ix291 (886) 

ix305 (927P) 

Gil R.D.A. ix215 (637) 

Gilabert M. ix241 (727P) 

Gillessen S. ix302 (917P) 

Gillet M. ix361 (1110O) 

Gillmore R. ix242 (731P) 

Gilly F-N. ix478 (1477O) 

Gimbergues P. ix102 (270P) 

Gimenez-Capitan A. ix531 (1655P), ix533 (1661P), 

ix229 (686P) 

Gingerich J.R. ix297 (900PD) 

Gingrich J.R. ix303 (919P) 

Ginocchi L. ix238 (714P), ix241 (726P), 

ix251 (761), ix251 (762) 

Giordano C. ix343 (1047P), ix346 (1058) 

Giordano L. ix487 (1506P) 

Giovannetti E. ix240 (724P) 

Giovannini M. ix410 (1251P) 

Giralt J. ix334 (1016O) 

Giranda V.L. ix148 (428P) 

Girard M. ix315 (956) 

Girardi F. ix145 (416PD), ix147 (424P) 

Giraudi S. ix454 (1393P), ix501 (1551PD), 

ix521 (1621) 

Girelli S. ix511 (1585P) 

Gissmann L. ix22 (4IN) 

Giuffrida D. ix505 (1565P), ix137 (388) 

Giuliani C. ix528 (1646PD) 

Giuliano C. ix507 (1574P), ix508 (1575P), 

ix520 (1618) 

Gizzi M. ix197 (578P) 

Gläser U. ix357 (1098) 

Gladkov O.A. ix500 (1548PD) 

Glas A. ix179 (522PD) 

Glassock R.J. ix171 (499P) 

Glaudemans A.W.J.M. ix40 (57IN) 

Gleave M.E. ix297 (900PD) 

Glennie M.J. ix70 (157P) 

Gligorov J. ix97 (252PD), ix114 (315TiP), 

ix128 (356P), ix260 (789O) 

Glimelius B. ix188 (553P) 

Glitza I.C. ix517 (1605P) 

Glowala-Kosinska M. ix353 (1082P) 

Gnant M. ix126 (351P) 

Gnocchi C. ix483 (1494P) 

Goéré D. ix169 (495P), ix198 (580P) 

Gocze P. ix322 (978P) 

Goda F. ix93 (237) 

Goddemeier T. ix342 (1044P) 

Godinho Bexiga J. ix201 (591P), ix210 (620), 

ix221 (657) 

Godwin A. ix223 (664TiP) 

Godwin P. ix68 (148P), ix495 (1531P) 

Goessl C. ix309 (937P) 

Goethals L. ix341 (1042P) 

Goff B. ix319 (967O) 

Gogas H. ix95 (246O) 

Gogia A. ix358 (1101), ix455 (1398P), 

ix110 (298P) 

Gogov S. ix278 (842P) 

Göhler T. ix255 (778TiP) 

Goh B.C. ix70 (155P), ix83 (203P) 

Gokgoz S. ix129 (359P) 

Gökmen E. ix274 (830P) 

Gold A. ix269 (814P) 

Goldberg Y. ix109 (294P) 

Goldberg Z. ix401 (1228O), ix423 (1290P) 

Goldinger S. ix366 (1125P) 

Goldkorn A. ix316 (961) 

Goldman J. ix157 (452P), ix168 (489P) 

Goldman J.W. ix156 (449PD) 

Göldner R. ix162 (468P) 

Goldwasser F. ix91 (229P), ix167 (485P), 

ix259 (786O) 

Goldwasser M. ix153 (440O) 

Gollins S. ix199 (582P), ix206 (608P) 

Gomella L.G. ix310 (941P) 

Gomes M. ix78 (184P) 

Gómez Caamaño A. ix312 (945) 

Gomez Codina J. ix351 (1073P) 

Gomez Dorronsoro M. ix219 (651) 

Gómez García J. ix324 (984P) 


Gomez-Martin C. ix233 (699P) 

Gómez A. ix529 (1648P), ix186 (546P) 

Gómez N. ix365 (1123P) 

Gómez R.E. ix406 (1238PD) 

Gomez M.L. ix457 (1404) 

Gonçalves A. ix150 (434), ix184 (539P) 

Goncalves M.S. ix486 (1503P) 

Gong G. ix108 (291P) 

Gong Y. ix247 (745P) 

Gonullu I. ix469 (1448PD) 

Gonullu U. ix469 (1448PD) 

González Beca R. ix264 (799P) 

González-Farré X. ix135 (380) 

González-Lois C. ix112 (307) 

González-Piñeiro A. ix92 (234) 

González-Rivas C. ix254 (773) 

González-Vicente A. ix254 (773) 

González B. ix266 (805P) 

Gonzalez Cao M. ix374 (1151) 

Gonzalez Costas S. ix92 (234) 

Gonzalez Del Alba A. ix276 (835P) 

Gonzalez Garcia C. ix472 (1456P) 

Gonzalez Gordaliza C. ix472 (1456P) 

Gonzalez Martin A. ix140 (400), ix324 (982P) 

Gonzalez Patiño E. ix328 (1000P) 

Gonzalez-Angulo A.M. ix57 (101IN), ix96 (249PD) 

Gonzalez-Astorga B. ix254 (773) 

Gonzalez-De-Castro D. ix224 (667PD) 

Gonzalez-Larriba J.L. ix438 (1342) 

Gonzalez A. ix216 (641) 

Gonzalez A.A. ix183 (534P) 

Gonzalez J.A. ix239 (718P) 

Gonzalez S. ix136 (386) 

Good J. ix304 (922P) 

Goonetilleke D. ix326 (992P) 

Gopalakrishna P. ix393 (1205P) 

Gorana A. ix378 (1159P) 

Gorbounova V.A. ix382 (1172), ix410 (1250P), 

ix435 (1330) 

Gorbunova V.A. ix405 (1236PD), ix224 (668PD), 

ix250 (760) 

Gorbunova V.A. ix255 (777TiP) 

Gordon D. ix503 (1558P) 

Gordon M. ix363 (1115PD) 

Gore M.E. ix262 (793PD), ix267 (809P), 

ix271 (820P), ix273 (827P), ix320 (972PD) 

Gori B. ix439 (1346) 

Gorican K. ix513 (1593P) 

Gornadha Y. ix499 (1545O) 

Gornet J. ix234 (703P) 

Gosain P. ix470 (1450P) 

Goss G. ix395 (1210), ix529 (1647PD), 

ix174 (509TiP) 

Goss P.E. ix115 (316TiP) 

Gosselink R. ix518 (1609P) 

Goswami J. ix452 (1388P) 

Goto K. ix413 (1260P), ix515 (1598P), 

ix534 (1666P) 

Goto S. ix463 (1428P) 

Goto Y. ix429 (1306P) 

Gotoh N. ix544 (1701) 

Gouerant S. ix339 (1033P) 

Gough N. ix485 (1498P) 

Gourzones C. ix337 (1025P) 

Gousia A. ix213 (630) 

Gouy S. ix322 (977P) 

Govindan R. ix424 (1291P), ix445 (1365TiP) 

Grávalos C. ix529 (1648P), ix125 (345P) 

Grünwald V. ix336 (1023PD), ix264 (798PD), 

ix268 (811P), ix268 (813P), ix278 (842P), 

ix288 (875), ix299 (908P) 

Graf L. ix493 (1523P) 

Graff J. ix303 (921P) 

Grah C. ix466 (1437P) 

Graham D.M. ix524 (1634) 

Graillon T. ix146 (419PD) 

Gralla R. ix414 (1263P) 

Grana C.M. ix47 (75IN) 



Granata R. ix335 (1019O), ix341 (1040P), 

ix342 (1045P), ix344 (1050P) 

Grande E. ix377 (1157O), ix380 (1165P), 

ix206 (606P) 

Grandjouan S. ix175 (511PD) 

Graser A. ix60 (113IN), ix188 (554P) 

Grasic Kuhar C. ix112 (308) 

Grau J.J. ix343 (1046P) 

Gravis-Mescam G. ix150 (434), ix259 (786O), 

ix260 (789O) 

Gravis G. ix263 (797PD), ix294 (893O), 

ix307 (933P) 

Gray L. ix235 (706P) 

Gray S.G. ix68 (149P), ix68 (150P), ix495 (1531P), 

ix495 (1532P) 

Grazi G. ix237 (713P) 

Graziano F. ix538 (1681P) 

Graziano P. ix78 (183P) 

Graziano S. ix389 (1192PD) 

Greco C. ix241 (726P) 

Green M. ix428 (1303P) 

Greenberg J. ix222 (662TiP) 

Greggi S. ix323 (980P) 

Gregorc V. ix410 (1251P), ix167 (487P), 

ix172 (502) 

Gregori J. ix531 (1656P) 

Gregory W. ix171 (500P) 

Greijer A.E. ix88 (221P) 

Greil R. ix340 (1038P), ix348 (1064O), 

ix352 (1076P), ix531 (1657P), ix116 (317O), 

ix193 (565P), ix195 (571P), ix249 (755) 

Greillier L. ix391 (1199P), ix397 (1219) 

Greiner R. ix148 (427P) 

Greshock J. ix153 (442O) 

Gridelli C. ix404 (1235PD), ix418 (1275P) 

Griebsch I. ix191 (561P) 

Griesinger F. ix419 (1278P) 

Griffin M. ix153 (442O) 

Griffin T. ix294 (894O), ix295 (895O) 

Griffiths G. ix498 (1542TiP) 

Grigorescu A. ix398 (1222) 

Griguolo G. ix209 (618) 

Gril B. ix61 (120IN) 

Grimaldi A.M. ix375 (1152) 

Grimer R.J. ix479 (1480PD) 

Grincuka E. ix124 (344P) 

Grinsted L. ix403 (1233PD) 

Grisanti S. ix338 (1029P) 

Grivaux M. ix455 (1396P) 

Groen H.J.M. ix401 (1227O), ix152 (438O) 

Grogan L. ix468 (1444) 

Grogan T. ix383 (1173P) 

Grogan W.M. ix494 (1526P) 

Gromut I. ix470 (1451P) 

Gronchi A. ix484 (1496P) 

Gronesova P. ix286 (865P) 

Gronowitz S.J. ix88 (220P) 

Groshen S. ix261 (790O), ix316 (961) 

Grosman G. ix210 (619) 

Gross Goupil M. ix313 (951) 

Grossi F. ix410 (1250P), ix410 (1251P), 

ix79 (187P) 

Grosso F. ix247 (747P) 

Grothey A. ix329 (1002P), ix535 (1670P), 

ix191 (560P), ix222 (662TiP) 

Grover K. ix106 (283P) 

Grude F. ix456 (1401P), ix196 (572P) 

Gruenberger B. ix249 (755) 

Grumett S. ix181 (530PD) 

Grunberg S. ix64 (129IN), ix507 (1572P) 

Gruschkus S. ix428 (1303P) 

Grutters J.P. ix397 (1217), ix501 (1553P), 

ix212 (626) 

Guérif S. ix511 (1584P) 

Guérin O. ix501 (1554P) 

Gu A. ix454 (1395P) 

Gu W. ix217 (643) 

Gu X. ix389 (1193P), ix130 (361P) 

Gu Y. ix174 (509TiP) 

Guan Q. ix437 (1337) 

Guan Z. ix189 (555P), ix217 (643) 

Guardino E. ix89 (226P), ix120 (329P) 

Guarducci C. ix27 (13IN) 

Guarin M.J. ix106 (284P) 

Guarneri V. ix101 (267P) 

Gucalp A. ix98 (257P) 

Guderian G. ix278 (841P) 

Guerra P.P. ix406 (1238PD) 

Guerrieri Gonzaga A. ix83 (201P) 

Guettier C. ix243 (733P) 

Gui L. ix394 (1209) 

Guida F.M. ix500 (1550PD), ix516 (1603P), 

ix538 (1681P), ix206 (606P) 

Guida M. ix369 (1132P), ix369 (1133P), 

ix370 (1135P) 

Guidon M. ix513 (1592P) 

Guigay J. ix337 (1025P), ix340 (1037P), 

ix341 (1041P), ix345 (1053) 

Guild R. ix498 (1543TiP) 

Guillemin F. ix109 (296P), ix120 (331P) 

Guillen-Ponce C. ix459 (1412), ix472 (1456P) 

Guillot A. ix289 (876), ix313 (951) 

Guimbaud R. ix194 (568P) 

Guirado Rueño M. ix140 (400) 

Guiterrez M.E. ix498 (1543TiP) 

Guiu M. ix85 (210P) 

Gujral S. ix351 (1074P) 

Guler O.C. ix425 (1294P), ix526 (1641), 

ix237 (711P), ix238 (715P) 

Gullo G. ix108 (292P) 

Guma J. ix351 (1073P) 

Gumurdulu D. ix326 (990P) 

Gumus M. ix497 (1540) 

Gunsilius E. ix76 (178P) 

Günther O. ix298 (902P) 

Gunther O. ix447 (1372P) 

Guntinas-Lichius O. ix336 (1023PD) 

Güntsch F. ix357 (1098) 

Guo J. ix453 (1390P), ix279 (844P), ix282 (851P) 

Guo W. ix436 (1332), ix216 (640) 

Guo X. ix346 (1057) 

Gupta A. ix361 (1109O), ix405 (1237PD), 

ix157 (453P), ix258 (784O) 

Gupta G. ix98 (257P) 

Gupta P. ix356 (1091P), ix328 (997P) 

Gupta R. ix349 (1067PD), ix358 (1101), 

ix242 (729P) 

Gupta R.K. ix114 (312) 

Gupta S. ix470 (1450P), ix224 (667PD), 

ix320 (972PD) 

Gurney H. ix538 (1678P) 

Gurpide A. ix365 (1123P), ix432 (1316), 

ix508 (1577P) 

Gurrieri L. ix457 (1405) 

Gut P.A. ix148 (427P) 

Gutiérrez Damian E.I. ix212 (627) 

Gutierrez M. ix424 (1291P) 

Gutsch J. ix453 (1389P), ix466 (1437P) 

Gutzmer R. ix361 (1110O) 

Gyergyay F. ix281 (849P) 

H 

Habibian M. ix294 (893O) 

Hackshaw A. ix421 (1282P) 

Haddock M.G. ix329 (1002P) 

Haga N. ix69 (153P) 

Hager H. ix73 (167O) 

Häggman M. ix303 (919P) 

Hagiwara E. ix436 (1334) 

Hagiwara K. ix412 (1256P), ix413 (1259P) 

Hahn H. ix236 (709P) 

Hahn N.M. ix303 (921P) 

Haibo M. ix256 (779TiP) 

Haid V. ix490 (1516) 

Haider K. ix182 (531P) 

Haigentz M. ix422 (1287P) 

Hainaut P. ix389 (1192PD), ix74 (170O) 

Hainsworth J.D. ix362 (1111PD), ix362 (1112PD) 

Halabi A. ix162 (468P) 

Halawani H. ix337 (1028P) 

Haley V. ix532 (1660P), ix73 (169O) 

Hall E. ix292 (887) 

Hall G. ix329 (1001P), ix500 (1549PD), 

ix171 (500P) 

Hall P. ix483 (1492P) 

Hall S. ix311 (943P) 

Haller D. ix187 (550P) 

Haluska F. ix152 (439O) 

Hamada C. ix449 (1378P) 

Hamaguchi T. ix514 (1597P), ix529 (1649P), 

ix200 (587P), ix202 (593P), ix203 (598P), 

ix251 (764) 

Hamai Y. ix226 (672P) 

Hamajima N. ix518 (1610P), ix526 (1643), 

ix527 (1705) 

Hamaker M. ix100 (263P) 

Hamamoto Y. ix241 (728P) 

Hamberg P. ix314 (954) 

Hamburger T. ix109 (294P) 

Hamdan D. ix340 (1037P) 

Hamed A. ix323 (981P) 

Hamed R.H. ix129 (360P) 

Hamid O. ix336 (1022PD), ix362 (1111PD), 

ix368 (1129P), ix124 (342P), ix261 (790O) 

Hamidou Z. ix120 (331P) 

Hammel P. ix379 (1163P) 

Hammerschmid N. ix100 (261P) 

Hammon R. ix136 (385) 

Hamoir M. ix336 (1021PD) 

Hamzaj A. ix315 (958) 

Han B. ix400 (1225O), ix413 (1261P), 

ix454 (1395P), ix193 (566P) 

Han H.S. ix116 (318O) 

Han J. ix403 (1231PD) 

Han K. ix253 (771) 

Han M. ix391 (1198P), ix154 (443PD) 

Han M.H. ix353 (1080P) 

Han X. ix390 (1196P), ix394 (1209), ix435 (1331), 

ix111 (302) 

Hanada S. ix348 (1062O), ix433 (1323) 

Hanahan D. ix23 (5IN) 

Hanazaki K. ix250 (758) 

Hancock M. ix304 (923P) 

Handforth C. ix171 (500P) 

Hanin F. ix336 (1021PD) 

Hann C.L. ix498 (1543TiP) 

Hanna G.G. ix107 (288P) 

Hanna N. ix205 (603P), ix214 (634) 

Hannan A. ix327 (994P) 

Hannaoui N. ix538 (1680P) 

Hansen S. ix307 (933P) 

Hao D. ix440 (1350) 

Hao X. ix435 (1331) 

Hao Y. ix295 (895O) 

Haouas S. ix99 (258P) 

Happe A. ix453 (1389P), ix466 (1437P) 

Harada M. ix413 (1259P), ix420 (1280P), 

ix434 (1326), ix153 (441O) 

Harada T. ix427 (1301P), ix434 (1326), 

ix443 (1358), ix497 (1538P) 

ix511 (1586P) 

Harano K. ix320 (973PD) 

Harding T. ix301 (915P) 

Hardingham J. ix182 (532P), ix208 (612P) 

Hariharan S. ix262 (793PD) 

Harita S. ix434 (1327) 

Harlin O. ix523 (1627) 

Harmankaya K. ix363 (1116PD) 

Harmenberg U. ix281 (848P), ix299 (906P) 

Harries M. ix133 (372P) 

Harrington K.J. ix537 (1677P), ix42 (61IN) 

Harrison D. ix93 (240) 

Harrison M. ix242 (731P) 

Hart C. ix150 (435TiP) 

Harter P. ix323 (980P) 

Hartford A. ix317 (963TiP) 

Hartmann J.T. ix284 (858P) 


author index 

Hartono S. ix70 (155P) 

Hartwigsen D. ix409 (1249P) 

Harunal Rashid M.F. ix485 (1499P) 

Haryana S.M. ix88 (221P) 

Harza M. ix262 (795PD) 

Harzstark A.L. ix296 (897O) 

Hasan J. ix199 (582P), ix319 (969PD), 

ix324 (983P), ix326 (992P) 

Haschemi A. ix539 (1685P) 

Hase T. ix445 (1366TiP) 

Hasegawa H. ix230 (688P) 

Hasegawa K. ix163 (472P), ix211 (625) 

Hasegawa Y. ix434 (1325), ix439 (1343), 

ix445 (1366TiP), ix144 (412O) 

Hashem T.A. ix98 (256P) 

Hashiguchi Y. ix506 (1570P) 

Hashimoto H. ix514 (1597P) 

Hashimoto K. ix248 (751) 

Hashimoto S. ix407 (1242P), ix543 (1696P) 

Haslbauer F. ix523 (1628) 

Hassan A.A. ix468 (1445) 

Hassan E.A. ix337 (1028P) 

Hassan R. ix493 (1522PD) 

Hassanain O. ix448 (1374P) 

Hassouni K. ix328 (999P) 

Hata A. ix423 (1289P), ix437 (1338) 

Hatake K. ix87 (218P) 

Hatanaka K. ix202 (592P) 

Hatmi M. ix543 (1697P) 

Hato S. ix250 (758) 

Hatoum G. ix334 (1016O) 

Hatsuse K. ix211 (625) 

Hattori M. ix139 (396) 

Hattori Y. ix422 (1286P) 

Hauke R. ix317 (964TiP) 

Hauptmann S. ix322 (976P) 

Hauschild A. ix362 (1112PD), ix366 (1124P) 

Hauschild M. ix124 (344P) 

Hauser S. ix268 (813P) 

Hausheer F.H. ix512 (1590P) 

Haustermans K. ix222 (663TiP) 

Havel L. ix409 (1246P), ix409 (1247P), 

ix436 (1332) 

Hawes D. ix316 (961) 

Hawkins R. ix267 (808P) 

Hayashi H. ix424 (1293P), ix167 (486P) 

Hayashi N. ix82 (199P), ix100 (264P), 

ix133 (373P), ix220 (655) 

Hayashi R. ix344 (1706P) 

Hayashi T. ix71 (161P) 

Haynes H. ix311 (942P) 

Hayoz S. ix462 (1423O) 

Hazama S. ix93 (237), ix159 (460P), ix200 (588P), 

ix240 (723P) 

Hazra P. ix472 (1458P) 

He A. ix398 (1220), ix119 (326PD) 

He J. ix389 (1193P) 

He M. ix501 (1552P) 

He P. ix389 (1193P) 

Heath E.I. ix302 (918P) 

Heath G. ix500 (1549PD) 

Heavey S. ix68 (148P), ix495 (1531P), ix69 (154P), 

ix78 (185P) 

Hebbar M. ix194 (568P) 

Hebert G. ix456 (1400P) 

Hechmati G. ix447 (1372P), ix449 (1377P) 

Heerschap A. ix192 (562P) 

Hege K. ix301 (915P) 

Hegg R. ix83 (202P), ix103 (273P) 

Heidegger I.M. ix76 (178P) 

Heideman D.A.M. ix179 (521O) 

Heidenreich A. ix306 (931P), ix307 (932P), 

ix308 (934P) 

Heigener D. ix407 (1241P) 

Heijmen L. ix192 (562P) 

Heil J. ix117 (321PD) 

Heilbrun L. ix342 (1043P) 

Heinemann V. ix180 (526PD), ix188 (554P), 

ix204 (599P) 

Heinz M. ix504 (1561P) 

Heinzmann D. ix102 (271P), ix103 (273P), 

ix162 (470P) 

Hejna M. ix249 (755) 

Hela R. ix254 (774) 

Helbekkmo N. ix392 (1200P) 

Held C.P. ix409 (1249P) 

Helissey C. ix150 (433), ix285 (862P) 

Hellebrand E. ix505 (1567P) 

Heller G. ix89 (223P) 

Hellerstedt B. ix170 (496P) 

Hellmich M. ix504 (1561P) 

Helvaci K. ix105 (279P) 

Hembry N. ix136 (385) 

Hendifar A. ix480 (1483PD), ix166 (482P) 

Hendlisz A. ix63 (127IN), ix194 (569P), 

ix199 (584P) 

Hendriks B. ix532 (1658P) 

Henin E. ix299 (907P) 

Hennemann B. ix336 (1023PD) 

Hennessy B. ix96 (249PD) 

Henrique R. ix132 (371P) 

Henry D.H. ix509 (1580P) 

Henschel V. ix81 (198P) 

Hense J. ix437 (1339) 

Hentic O. ix379 (1163P) 

Heo D. ix465 (1433P) 

Heo D.S. ix465 (1434P), ix283 (855P) 

Hera M. ix474 (1465P) 

Heras P. ix474 (1465P) 

Herbst F. ix114 (315TiP) 

Herbstreit C. ix453 (1389P) 

Herchenhorn D. ix524 (1632), ix215 (637), 

ix289 (877) 

Hermann G.G. ix271 (819P) 

Hermine O. ix354 (1084P) 

Hernández Nieto V. ix530 (1652P) 

Hernández E. ix395 (1212) 

Hernandez-Guerrero T. ix187 (549P) 

Hernandez I. ix219 (651) 

Hernandez S. ix438 (1342) 

Hernando B. ix82 (200P) 

Hernando S. ix113 (310), ix293 (891TiP) 

Herráez-Baranda L.A. ix162 (470P) 

Herrera L. ix126 (349P) 

Herrera M.D.P. ix183 (534P) 

Herrstedt J. ix507 (1573P) 

Herzberg C. ix359 (1107TiP) 

Hess D. ix157 (454P) 

Hess G. ix359 (1107TiP) 

Heudel P. ix481 (1487P) 

Heyburn J.W. ix493 (1522PD) 

Heyd B. ix204 (600P), ix249 (753) 

Heymach J.V. ix261 (791PD) 

ix275 (833P) 

Hibshoosh H. ix84 (204P) 

Hida T. ix393 (1204P), ix413 (1260P), 

ix433 (1324), ix153 (441O) 

Hidalgo M. ix374 (1151), ix156 (449PD) 

Higano C. ix303 (920P), ix303 (921P), 

ix311 (942P) 

Higashi T. ix384 (1177P) 

Higashi Y. ix467 (1443) 

Hihara J. ix226 (672P) 

Hijikata Y. ix536 (1671P) 

Hijri F.Z. ix137 (389) 

Hilal A.M. ix111 (304) 

Hilbe W. ix494 (1528P), ix543 (1695P), 

ix76 (178P) 

Hilfiker P.R. ix366 (1125P) 

Hill M. ix187 (550P) 

Hinoda Y. ix93 (237) 

Hipp M. ix459 (1413TiP) 


Hirabayashi M. ix442 (1356) 

Hirabayashi N. ix228 (681P) 

Hirai F. ix387 (1187P) 

Hirai S. ix514 (1597P), ix203 (598P) 

Hirai T. ix250 (758) 

Hirakawa K. ix84 (205P) 

Hirami Y. ix541 (1690P) 

Hirano H. ix220 (653) 

Hirashima T. ix424 (1293P), ix432 (1320), 

ix433 (1321), ix439 (1344) 

Hirata K. ix412 (1258P), ix79 (189P), ix79 (190P), 

ix92 (235) 

Hirmand M. ix295 (896O), ix297 (899PD) 

Hironaka S. ix233 (697P) 

Hiroyuki B. ix527 (1705) 

Hirsch F.R. ix445 (1365TiP) 

Hirsh V. ix402 (1229PD), ix410 (1252P), 

ix414 (1263P), ix509 (1580P) 

Hirte H.W. ix155 (448PD), ix156 (450PD) 

Hitier S. ix306 (931P), ix307 (932P) 

Hitij N.T. ix522 (1625), ix523 (1630) 

Hitre E. ix191 (561P) 

Hjelm-Eriksson M. ix299 (906P) 

Ho-Pun-Cheung A. ix84 (206P) 

Ho A. ix98 (257P) 

Ho C. ix412 (1255P), ix493 (1525P) 

Ho J.C.M. ix383 (1176P) 

Hochlef M. ix332 (1013) 

Hocke J. ix245 (740P), ix246 (744P) 

Hodge L. ix263 (796PD) 

Hodi F.S. ix361 (1109O), ix368 (1129P), 

ix157 (453P) 

Hoefeler H. ix449 (1377P) 

Hoeffkes H. ix459 (1413TiP) 

Hoefliger M. ix132 (370P) 

Hoersch S. ix187 (550P) 

Hofbauer G. ix539 (1685P) 

Hofbauer G.F. ix372 (1144) 

Hofert K. ix110 (297P) 

Hoff P.M. ix331 (1009), ix450 (1380P), 

ix455 (1397P), ix486 (1503P), ix181 (528PD), 

ix308 (935P) 

Hoffman D. ix422 (1287P) 

Hoffmann A.C. ix68 (149P) 

Hofheinz R. ix459 (1413TiP) 

Hofman P. ix388 (1190P) 

Hohenberger P. ix478 (1478O), ix480 (1484PD), 

ix481 (1486PD) 

Hohenegger M. ix72 (165) 

Hoiczyk M. ix437 (1339) 

Hokka D. ix92 (233) 

Holbrechts S. ix194 (569P) 

Holcroft C. ix200 (586P) 

Holford C. ix101 (267P) 

Hollebecque A. ix474 (1463P), ix496 (1534P), 

ix94 (244), ix116 (319O), ix155 (446PD), 

ix159 (458P), ix168 (491P) 

Holmberg L. ix133 (372P) 

Holmskov K. ix507 (1573P) 

Holowiecki J. ix353 (1082P) 

Holt S. ix97 (252PD) 

Holubec L. ix474 (1464P) 

Homesley H. ix81 (198P) 

Honda-Okubo Y. ix503 (1558P) 

Honda K. ix383 (1174P), ix387 (1186P), 

ix518 (1610P), ix526 (1643), ix536 (1673P), 

ix536 (1674P), ix89 (224P), ix156 (451P), 

ix159 (459P), ix164 (475P) 

Hong D.S. ix154 (444PD) 

Hong J.H. ix276 (834P) 

Hong J.H. ix287 (872) 

Hong J.Y. ix375 (1153), ix430 (1311P) 

Hong M. ix522 (1626) 

Hong S.H. ix250 (757) 

Hong Y. ix355 (1087P) 

Hong Y.S. ix479 (1479PD), ix250 (757) 



Honma N. ix104 (277P) 

Honma Y. ix529 (1649P), ix202 (593P), 

ix251 (764) 

Hooftman L. ix103 (274P) 

Hooper B. ix208 (612P) 

Hopper C. ix347 (1061TiP) 

Hor P. ix356 (1091P) 

Horai T. ix418 (1274P), ix441 (1353) 

Horak P. ix539 (1685P) 

Horchani A. ix308 (934P) 

Hori K. ix517 (1608P) 

Horiike A. ix413 (1260P), ix418 (1274P), 

ix441 (1353) 

Horimatsu T. ix226 (673P) 

Horio A. ix139 (396) 

Horio Y. ix433 (1324) 

Horn E. ix260 (789O) 

Horn L. ix401 (1227O), ix405 (1237PD) 

Horsch D. ix377 (1156O) 

Hortobagyi G.N. ix118 (324PD), ix121 (334P), 

ix126 (351P) 

Hosokawa A. ix203 (598P) 

Hosomi Y. ix441 (1351), ix497 (1537P) 

Hospers G.A.P. ix40 (57IN) 

Hossain A.M. ix336 (1022PD) 

Hoth D. ix460 (1416PD) 

Hotta K. ix397 (1218), ix434 (1327) 

Hotte S.J. ix155 (448PD), ix156 (450PD), 

ix297 (900PD) 

Hou J. ix362 (1112PD) 

Hou M. ix443 (1359), ix247 (745P) 

Houben R. ix212 (626) 

Houbiers G. ix194 (569P) 

Houede N. ix314 (955) 

Houlgatte A. ix285 (862P) 

Hoverman J.R. ix425 (1297P) 

Hovey E. ix151 (437TiP) 

Howe K. ix528 (1645PD) 

Howlett M. ix123 (341P) 

Hoyos S. ix325 (986P) 

Hsiao L. ix355 (1087P) 

Hsiao S. ix425 (1295P), ix428 (1305P) 

Hsieh R. ix345 (1052) 

Hsu C. ix522 (1626), ix246 (744P), ix246 (744P), 

ix253 (769) 

Hsu P. ix351 (1075P) 

Hsueh Y. ix538 (1679P) 

Hu F. ix522 (1626) 

Hu J. ix261 (790O) 

Hu X. ix394 (1209), ix435 (1331) 

Hu Z. ix453 (1390P) 

Huang C. ix444 (1362TiP) 

Huang D.C. ix246 (744P) 

Huang S. ix501 (1552P), ix32 (30IN) 

Huang S.M. ix541 (1688PD) 

Huang X. ix376 (1155O), ix262 (794PD) 

Huang Y. ix346 (1057), ix453 (1390P), ix219 (650), 

ix282 (851P) 

Hubay S. ix316 (960) 

Hubbard J.M. ix157 (452P) 

Huber J. ix543 (1695P) 

Hubert A. ix255 (777TiP) 

Hubner R. ix381 (1168P) 

Hucke C. ix350 (1072P) 

Hudes G.R. ix262 (794PD) 

Hudis C.A. ix98 (257P) 

Huebner G. ix409 (1249P) 

Hughes A. ix87 (219P), ix90 (227P) 

Hui D. ix466 (1439) 

Huillard O. ix519 (1614P) 

Huitzil Melendez D. ix184 (541P) 

Humanes B. ix520 (1619) 

Hummel M. ix390 (1195P), ix394 (1208) 

Hummerlsberger M. ix499 (1547PD) 

Humphrey R.W. ix163 (471P), ix169 (492P) 

Hunt W. ix169 (493P) 

Huovinen R. ix384 (1178TiP) 

Hurtado A. ix113 (310) 

Hurvitz S. ix89 (226P), ix120 (329P) 

Hurwitz H.I. ix163 (471P), ix189 (555P), 

ix191 (560P) 

Husain A. ix319 (967O) 

Huss S. ix481 (1486PD) 

Hussain A. ix499 (1547PD), ix107 (288P) 

Hussain M. ix317 (965TiP) 

Hutajulu S.H. ix88 (221P) 

Hutchinson A. ix526 (1640) 

Hutson T.E. ix262 (794PD), ix263 (796PD), 

ix269 (814P), ix278 (840P) 

Huynh T. ix482 (1489P) 

Hwang J.E. ix467 (1441), ix468 (1446) 

Hwu P. ix366 (1126P), ix454 (1392P) 

Hwu W. ix366 (1126P), ix454 (1392P) 

Hyodo I. ix233 (697P) 

I 

Iacobelli S. ix523 (1628) 

Iacono C. ix104 (276P) 

Iacono G. ix454 (1393P), ix521 (1621) 

Iacovelli R. ix440 (1348), ix488 (1509P), 

ix270 (818P), ix272 (824P), ix276 (836P) 

Iaffaioli R.V. ix539 (1682P) 

Iaffaioli V.R. ix193 (567P) 

Iafrate A. ix389 (1191PD) 

Iannace A. ix105 (282P), ix111 (303) 

Iannessi A. ix534 (1665P) 

Ianotti N. ix393 (1205P) 

Ibba T. ix341 (1040P) 

Ibeas P. ix492 (1521PD), ix494 (1527P) 

Ibragimov J.M. ix71 (162P) 

Ibrahim N.H. ix134 (376) 

Ibuki Y. ix385 (1180PD) 

Ichiei N. ix509 (1579P) 

Ichikawa K. ix71 (159P) 

Ichinose Y. ix387 (1187P), ix438 (1340), 

ix492 (1519PD) 

Ichou M. ix477 (1476) 

Icli F. ix469 (1448PD) 

Idoate M.A. ix365 (1123P) 

Igaki H. ix89 (224P) 

Igarashi S. ix388 (1188P) 

Ignatiadis M. ix98 (255PD) 

Iguchi M. ix441 (1351), ix497 (1537P) 

Iida M. ix240 (723P) 

Iizasa T. ix144 (412O) 

Ikari Y. ix508 (1576P) 

Ikeda K. ix244 (737P) 

Ikeda M. ix241 (728P), ix244 (737P) 

Ikeda N. ix544 (1701) 

Ikeda Y. ix518 (1610P), ix526 (1643) 

Ikejiri K. ix217 (646) 

Ikemura S. ix422 (1285P) 

Ileana E. ix304 (924P) 

Ilhan-Mutlu A. ix148 (426P) 

Ilie S.M. ix341 (1041P), ix345 (1053) 

Illidge T. ix348 (1063O) 

Imai M. ix91 (232) 

Imamura F. ix411 (1253P), ix422 (1286P), 

ix437 (1338), ix511 (1586P) 

Imanaka K. ix243 (732P) 

Imbeaud S. ix180 (525PD) 

Imberti G. ix365 (1120P) 

Imbevaro S. ix439 (1345), ix447 (1370P), 

ix283 (854P) 

Imperatori M. ix500 (1550PD) 

Imtiaz S. ix497 (1539P) 

Inaba Y. ix243 (732P) 

Inagaki H. ix230 (688P) 

Inal A. ix137 (387) 

_Inanc M. ix332 (1015) 

Inauen R. ix480 (1482PD) 

Inbar M. ix116 (317O) 

Inbar Y. ix463 (1426P) 

Incarbone M. ix77 (181P) 

Indraccolo S. ix209 (618) 

Indrasari S.R. ix88 (221P) 

Indrawati L.P.L. ix88 (221P) 

Ingemi M.C. ix140 (399) 

Ingle J. ix28 (17IN) 

Ingles Garces A.H. ix331 (1010) 

Inno A. ix433 (1322) 

Inomata M. ix208 (1704P), ix545 (1704P) 

Inoue A. ix404 (1234PD), ix412 (1256P), 

ix413 (1259P), ix414 (1263P), ix427 (1301P), 

ix153 (441O) 

Inoue H. ix536 (1671P) 

Inoue Y. ix196 (574P), ix201 (590P), ix202 (592P), 

ix232 (692P), ix240 (723P), ix93 (237) 

Inrhaoun H. ix432 (1318) 

Insa Molla A. ix418 (1273P) 

Intagliata S. ix516 (1603P), ix538 (1681P) 

Ioannou E. ix136 (385) 

Ioka T. ix254 (775) 

Ionescu D. ix412 (1255P) 

Ionova T.I. ix141 (403) 

Iozeffi D. ix463 (1426P) 

Ip M.S. ix383 (1176P) 

Iqbal S. ix349 (1067PD), ix354 (1085P) 

Iqbal S.U. ix203 (597P), ix213 (632) 

Iqbal U. ix214 (633) 

Irelli A. ix524 (1633) 

Irwin M. ix453 (1390P) 

Isa L. ix474 (1462PD) 

Isaacson J. ix236 (709P) 

Isakoff S. ix159 (458P), ix321 (974PD) 

Isambert N. ix165 (478P), ix169 (494P), 

ix170 (498P) 

Isayama H. ix241 (728P) 

Ishfaq T. ix483 (1492P) 

Ishibashi K. ix69 (153P) 

Ishibashi M. ix433 (1323) 

Ishida T. ix517 (1606P) 

Ishida Y. ix100 (264P) 

Ishigami H. ix233 (698P) 

Ishigure K. ix220 (655) 

Ishiguro M. ix197 (576P), ix200 (588P) 

Ishii G. ix387 (1186P), ix534 (1666P) 

Ishii Y. ix413 (1259P), ix420 (1280P) 

Ishikawa T. ix84 (205P), ix197 (576P) 

Ishikawa Y. ix418 (1274P) 

Ishiki H. ix518 (1611P), ix344 (1706P) 

Ishimoto O. ix420 (1280P) 

Ishitani K. ix326 (989P) 

Ishitsuka K. ix348 (1062O), ix508 (1576P) 

Ishiyama A. ix220 (655) 

Isikdogan A. ix137 (387) 

Isla Casado D. ix414 (1264P), ix418 (1273P), 

ix510 (1582P) 

Ismael G. ix102 (271P), ix103 (273P) 

Ismaili N. ix328 (999P) 

Isobe H. ix404 (1234PD), ix413 (1259P), 

ix434 (1326), ix443 (1358), ix497 (1538P) 

Isobe T. ix248 (751) 

Issels R. ix487 (1505P) 

Itakura M. ix144 (412O) 

Italiano A. ix489 (1514) 

Ito M. ix210 (621) 

Ito S. ix385 (1181PD) 

Ito T. ix376 (1154O) 

Ito Y. ix396 (1215), ix126 (351P) 

Itoh K. ix131 (366P) 

Itri L. ix165 (481P) 

Iuchi T. ix144 (412O) 

Iuliani M. ix489 (1512), ix516 (1603P), 

ix530 (1653P) 

Ivanyi P. ix336 (1023PD) 

Iveson T. ix230 (687P), ix242 (731P) 

Ivy S.P. ix155 (448PD), ix156 (450PD) 

Iwai T. ix390 (1197P) 

Iwamoto S. ix93 (237), ix196 (573P) 

Iwamoto T. ix74 (172O), ix112 (305) 

Iwamoto Y. ix385 (1181PD) 

Iwanicki-Caron I. ix252 (767) 

Iwasa S. ix529 (1649P), ix202 (593P), ix251 (764) 


author index 

Iwasaki H. ix542 (1694P) 

Iwasaku M. ix422 (1286P), ix437 (1338) 

Iwase H. ix225 (671P) 

Iwata H. ix115 (316TiP), ix139 (396) 

Iyer S. ix403 (1231PD), ix416 (1268P) 

Izarzugaza Y. ix80 (194P) 

Izquierdo A. ix388 (1189P) 

Izumi K. ix518 (1611P) 

J 

Jaal J. ix146 (418PD), ix149 (431) 

Jackisch C. ix97 (254PD), ix102 (271P), 

ix103 (272P) 

Jackson A. ix207 (609P) 

Jacob A. ix220 (656) 

Jacob J. ix150 (433) 

Jacob U. ix136 (385) 

Jacobasch L. ix289 (876) 

Jacobs I. ix479 (1480PD) 

Jacobs J. ix342 (1043P), ix363 (1114PD) 

Jaeger E. ix459 (1413TiP) 

Jaén-Morago A. ix101 (268P) 

Jafarian A. ix107 (287P), ix184 (538P) 

Jäger D. ix270 (817P), ix279 (844P) 

Jahan T. ix422 (1287P), ix493 (1522PD) 

Jahanzeb M. ix420 (1279P) 

Jain A. ix412 (1257P) 

Jain K. ix503 (1558P) 

Jain M. ix174 (510TiP) 

Jain N. ix244 (735P) 

Jakic-Razumovic J. ix86 (212P) 

Jakobsen A. ix530 (1654P), ix73 (168O) 

Jakobsen J.N. ix443 (1357), ix80 (191P) 

Jakobsson M. ix281 (848P) 

Jakovljevic G. ix359 (1104) 

Jamal N. ix339 (1034P) 

Jambor I. ix384 (1178TiP) 

James C.R. ix107 (288P) 

Jamnig H. ix494 (1528P) 

Janciauskiene R. ix267 (809P) 

Jang R.W. ix464 (1432P) 

Janjigian Y.Y. ix401 (1227O) 

Jankilevich G. ix330 (1005P) 

Janne P.A. ix401 (1228O), ix403 (1233PD), 

ix423 (1290P), ix74 (170O), ix51 (84IN) 

Janot F. ix340 (1037P), ix341 (1041P), 

ix345 (1053) 

Jansen M. ix244 (738P) 

Jansman F.G.A. ix456 (1402P) 

Janssens A. ix518 (1609P) 

Jantus-Lewintre E. ix385 (1179O) 

Jara C. ix113 (310) 

Jardin F. ix339 (1033P) 

Jarosz J. ix518 (1612P) 

Jasas K. ix395 (1210) 

Jassem J. ix319 (966O) 

Jasso-Mosqueda J. ix203 (597P) 

Jayaram A. ix248 (750) 

Jayson G. ix326 (992P) 

Jayson G.C. ix207 (609P), ix324 (983P) 

Jayson G.C. ix319 (969PD) 

Jazeih A.R. ix288 (874) 

Jeannin G. ix403 (1233PD) 

Jebali M. ix280 (845P), ix282 (852P) 

Jego V. ix154 (444PD) 

Jelaca-Maxwell K. ix317 (963TiP) 

Jenkins J. ix108 (290P) 

Jennions E. ix495 (1531P) 

Jensen N.V. ix271 (819P) 

Jensen S.A. ix443 (1357) 

Jeon E. ix250 (757) 

Jerez, Y. ix176 (517P) 

Jerjes W. ix347 (1061TiP) 

Jerusalem G. ix96 (251PD), ix116 (318O), 

ix122 (336P) 

Jerzak M. ix323 (979P) 

Jeske W. ix481 (1486PD) 

Ji L. ix316 (961) 

Jia L.Q. ix438 (1341) 

Jiang H. ix144 (410O), ix256 (779TiP) 

Jiang J. ix389 (1193P) 

Jiang Y. ix226 (674P), ix230 (687P) 

Jiang Z. ix128 (356P) 

Jiang Z.F. ix58 (104IN) 

Jiao S. ix231 (690P) 

Jiménez J. ix131 (365P), ix186 (546P) 

Jimenez Fonseca P. ix380 (1165P), ix218 (647), 

ix233 (699P) 

Jimenez M. ix62 (121IN), ix263 (797PD) 

Jimeno A. ix43 (62IN) 

Jin B. ix437 (1337) 

Jin J. ix282 (851P) 

Jin L. ix233 (696P) 

Jin W. ix256 (780TiP) 

Jinga D.C. ix67 (146P) 

Jinga V. ix262 (795PD) 

Jiratrachu R. ix339 (1035P) 

Jirillo A. ix439 (1345), ix447 (1370P), ix283 (854P) 

Jitlal M. ix206 (608P) 

Jo D.Y. ix541 (1688PD) 

Jo J. ix479 (1479PD) 

Jochum W. ix394 (1208) 

Joensuu H. ix478 (1478O) 

Jofre-Bonet M. ix460 (1417PD) 

John T. ix542 (1692P) 

John W. ix404 (1235PD), ix421 (1281P) 

Johne A. ix154 (444PD) 

Johnson M. ix292 (887) 

Johnson P. ix44 (64IN) 

Johnston C. ix129 (358P) 

Johnston D.S. ix246 (743P) 

Johnston J.B. ix350 (1070PD) 

Johnston M. ix102 (271P), ix103 (272P) 

Johnston M.A. ix304 (923P) 

Johnston S.R.D. ix27 (14IN), ix119 (325PD) 

Jokhadze N. ix460 (1414TiP) 

Jolly D. ix109 (296P), ix120 (331P) 

Joly Lobbedez F. ix294 (893O), ix329 (1001P) 

Joly K. ix85 (209P) 

Jones A. ix119 (325PD) 

Jones E. ix292 (887) 

Jones L. ix108 (290P) 

Jones R.J. ix272 (822P), ix292 (887) 

Joore M.A. ix397 (1217) 

Jordan E.J. ix540 (1686P) 

Jordan K. ix357 (1098) 

Jordan W.O. ix523 (1627) 

Josephs D.H. ix139 (398) 

Joshua A.M. ix297 (900PD) 

Jouinot A. ix280 (845P) 

Joulain F. ix214 (633) 

Jouve J. ix181 (529PD), ix242 (730P) 

Jovanovic D. ix428 (1304P) 

Jove J. ix219 (649) 

Jovenin N. ix499 (1547PD) 

Jozwicki W. ix544 (1700) 

Ju L. ix76 (179P) 

Ju Z. ix96 (249PD) 

Juan O. ix441 (1352) 

Judde J-G. ix312 (946) 

Judson I. ix485 (1498P), ix54 (90IN) 

Juhasz E. ix405 (1236PD), ix406 (1239P) 

Julier P. ix181 (530PD) 

Julieron M. ix340 (1037P) 

Jung A. ix180 (526PD) 

Jung H.A. ix430 (1311P) 

Jung J. ix168 (489P) 

Jung K.H. ix108 (291P), ix114 (315TiP) 

Junqueira M. ix309 (938P) 

Juretic M. ix163 (471P), ix169 (493P) 

Jusko W.J. ix155 (447PD) 

Jyothi B.M. ix345 (1055) 

K 

Kabakov A. ix70 (156P) 

Kabbinavar F.F. ix189 (555P) 


Kabilan S. ix133 (372P) 

Kaburaki K. ix418 (1274P) 

Kacar-Kukric V. ix428 (1304P) 

Kadowaki S. ix196 (574P) 

Kaduri L. ix109 (294P) 

Kagamu H. ix509 (1579P), ix71 (159P) 

Kageyama H. ix144 (412O) 

Kageyama S. ix509 (1578P) 

Kahan Z. ix116 (317O) 

Kahl C. ix288 (875) 

Kaiser K. ix261 (792PD) 

Kaji R. ix423 (1289P) 

Kajiura S. ix196 (574P) 

Kajiura Y. ix82 (199P), ix100 (264P) 

Kakeji Y. ix188 (552P) 

Kalanovic D. ix359 (1107TiP), ix274 (828P) 

Kalbacher E. ix332 (1014) 

Kalbakis K. ix435 (1329) 

Kalogeras K.T. ix338 (1031P) 

Kalykaki A. ix139 (395) 

Kam B.L. ix538 (1678P) 

Kamal M. ix448 (1374P), ix449 (1376P) 

Kamata H. ix525 (1637) 

Kamijo A. ix185 (542P), ix197 (575P), 

ix207 (611P) 

Kamikawa H. ix513 (1591P) 

Kaminsky M.C. ix342 (1044P) 

Kamioner D. ix522 (1624) 

Kamiran J. ix327 (996P) 

Kammler R. ix80 (193P) 

Kamp T. ix440 (1347) 

Kampmann E. ix487 (1505P) 

Kamura T. ix326 (989P), ix327 (995P) 

Kanıtez M. ix186 (547P), ix217 (645) 

Kanai F. ix243 (732P) 

Kanaka G.B. ix301 (912P) 

Kanat O. ix129 (359P) 

Kane A. ix322 (977P) 

Kaneko M. ix469 (1447PD) 

Kaneko S. ix243 (732P) 

Kaneko Y. ix170 (498P) 

Kang B. ix332 (1012) 

Kang B.W. ix208 (613P) 

Kang H. ix492 (1520PD) 

Kang J.H. ix466 (1439) 

Kang S.Y. ix135 (382) 

Kang W.K. ix186 (545P), ix209 (617) 

Kang Y. ix478 (1478O), ix480 (1481PD), 

ix482 (1490P), ix227 (679P), ix234 (700P) 

Kannan K. ix331 (1011) 

Kantoff P. ix310 (940P) 

Kantoff P.W. ix38 (46IN) 

Kanyev S. ix463 (1426P) 

Kao H. ix522 (1626) 

Kaplan M.A. ix137 (387) 

Kapoor R. ix242 (729P) 

Kapp D.S. ix460 (1416PD) 

Kapp K. ix340 (1038P) 

Kaprin A. ix267 (809P) 

Karaüç G. ix394 (1207P) 

Karachaliou N. ix531 (1655P), ix229 (686P) 

Karadurmus N. ix286 (866P) 

Karam N. ix416 (1270P) 

Karameris A. ix541 (1691P) 

Karamouzis M.V. ix458 (1407) 

Karaoz E. ix110 (300) 

Karapetis C.S. ix503 (1558P), ix178 (519O) 

Karasmanis I. ix338 (1030P) 

ix338 (1031P) 

Karavasilis V. ix430 (1312), ix239 (717P) 

Karayannopoulou G. ix337 (1026P) 

Kargar-Samani K. ix341 (1042P) 

Karimi Shahri M. ix184 (538P) 

Karina M. ix519 (1613P) 

Karsan A. ix412 (1255P) 

Karsh L. ix309 (937P) 

Kase M. ix146 (418PD), ix149 (431) 

Kase S. ix146 (418PD), ix149 (431) 



Kasem I. ix72 (164) 

Kashiwagi N. ix197 (576P) 

Kashiwagi S. ix84 (205P) 

Kasparu H. ix348 (1064O) 

Kassem N.M. ix355 (1088P) 

Kastrissios H. ix244 (738P) 

Katakami N. ix413 (1260P), ix422 (1286P), 

ix423 (1289P), ix437 (1338), ix511 (1586P), 

ix91 (232) 

Katalinic D. ix86 (212P) 

Katano M. ix542 (1694P), ix79 (188P) 

Kataoka M. ix514 (1595P) 

Kataoka T. ix510 (1581P) 

Katayama N. ix509 (1578P) 

Katayose Y. ix211 (624) 

Kato B. ix225 (671P) 

Kato G. ix321 (974PD) 

Kato H. ix527 (1705) 

Kato K. ix529 (1649P), ix89 (224P), ix202 (593P), 

ix251 (764) 

Kato M. ix79 (188P) 

Kato T. ix436 (1334), ix196 (573P), ix202 (592P), 

ix217 (646) 

Katsumata K. ix188 (552P) 

Katsumata N. ix320 (973PD) 

Katsuya H. ix348 (1062O), ix508 (1576P) 

Katz A. ix112 (306) 

Kaufman B. ix116 (317O) 

Kavan P. ix200 (586P) 

Kawabata R. ix227 (677P) 

Kawachi Y. ix228 (682P) 

Kawada K. ix518 (1610P), ix526 (1643), 

ix527 (1705) 

Kawada S. ix197 (575P) 

Kawaguchi T. ix439 (1344) 

Kawahara M. ix439 (1344) 

Kawai H. ix231 (689P) 

Kawai Y. ix497 (1538P) 

Kawajiri H. ix84 (205P) 

Kawakami H. ix167 (486P) 

Kawakami S. ix438 (1340) 

Kawano J. ix133 (373P) 

Kawasaki K. ix144 (412O) 

Kawasaki M. ix463 (1426P) 

Kawazoe S. ix244 (737P) 

Kaya S. ix110 (300) 

Kaya T. ix220 (654) 

Kayal S. ix354 (1085P) 

Kaye S.B. ix162 (469P), ix40 (55IN), ix319 (966O), 

ix320 (972PD) 

Kayser J. ix186 (548P) 

Kazakin J. ix245 (739P) 

Kazancioglu R. ix473 (1461) 

Kazmi S.A. ix497 (1539P) 

Ke C. ix115 (316TiP) 

Keam B. ix465 (1433P) 

Kebdani T. ix328 (999P) 

Keefe D. ix64 (130IN) 

Kefeli U. ix497 (1540) 

Keil F. ix340 (1038P), ix523 (1628), ix249 (755) 

Keilholz U. ix336 (1023PD) 

Kell M. ix469 (1449PD) 

Keller U. ix342 (1044P) 

Kelly C.M. ix525 (1635), ix74 (172O) 

Kelly P.J. ix207 (610P) 

Kelly Z. ix68 (147P), ix325 (988P) 

Kelm J. ix543 (1695P) 

Kemal Y. ix221 (660) 

Keni M. ix519 (1613P) 

Kenmotsu H. ix430 (1310P) 

Kennecke H. ix188 (551P), ix204 (601P), 

ix215 (635) 

Kennedy D.A. ix348 (1063O), ix353 (1083P) 

Kennedy M.J. ix469 (1449PD), ix108 (292P), 

ix176 (516P) 

Kentepozidis N. ix435 (1329), ix436 (1335), 

ix139 (395) 

Keohan M.L. ix489 (1514) 

Kerboua E. ix344 (1051) 

Kerbrat P. ix105 (281P) 

Kern J. ix76 (178P) 

Kern N. ix467 (1442) 

Kernstine K. ix49 (77IN) 

Kerr D.J. ix181 (530PD), ix184 (540P) 

Kerr K. ix80 (193P), ix86 (213P) 

Kerr K.M. ix417 (1272P), ix73 (167O) 

Kertmen N. ix104 (278P) 

Keskin O. ix543 (1698P), ix104 (278P) 

Ketchens C. ix261 (790O) 

Keyser R. ix283 (856P) 

Khabra K. ix273 (827P) 

Khairi H. ix332 (1013) 

Khaled H.M. ix288 (874) 

Khalil J. ix260 (789O) 

Khalifa R.H. ix355 (1088P) 

Khan A. ix537 (1677P) 

Khanin R. ix89 (223P) 

Khater L. ix339 (1032P) 

Khattak M.A. ix273 (827P) 

Khattry N. ix350 (1069PD), ix351 (1074P) 

Khays S. ix197 (577P) 

Kheoh T. ix294 (894O), ix295 (895O) 

Khoja L.T. ix87 (219P), ix90 (227P) 

Khouchani M. ix476 (1471P) 

Khranovska N. ix536 (1672P) 

Khudayorov S. ix229 (684P), ix254 (772) 

Kichenadasse G. ix503 (1558P) 

Kida Y. ix225 (671P) 

Kiemle-Kallee J. ix390 (1194P) 

Kiermaier A. ix83 (202P) 

Kiesewetter B. ix352 (1076P) 

Kiessling R. ix541 (1690P) 

Kieszkowska-Grudny A. ix457 (1406), 

ix475 (1466P) 

Kiet T.K. ix460 (1416PD) 

Kigawa J. ix326 (989P) 

Kii T. ix232 (692P) 

Kijima T. ix411 (1253P) 

Kilickap S. ix220 (654) 

Kilmartin L. ix68 (150P) 

Kim B.S. ix352 (1077P), ix227 (679P) 

Kim C. ix287 (872), ix308 (934P) 

Kim C.H. ix414 (1262P), ix72 (166) 

Kim C.H.S. ix204 (600P), ix249 (753) 

Kim D-W. ix152 (438O) 

Kim D. ix401 (1228O), ix402 (1230PD), 

ix416 (1268P), ix465 (1433P), ix483 (1493P), 

ix153 (440O), ix283 (855P) 

Kim D.E. ix467 (1441), ix468 (1446) 

Kim D.S. ix352 (1077P) 

Kim D.W. ix415 (1267P) 

Kim G. ix222 (662TiP) 

Kim H-K. ix400 (1225O) 

Kim H. ix352 (1077P), ix353 (1080P), ix89 (225P) 

Kim H.J. ix172 (503), ix227 (679P) 

Kim H.S. ix193 (566P) 

Kim I. ix352 (1077P) 

Kim J. ix454 (1392P), ix541 (1688PD), 

ix283 (855P) 

Kim J.E. ix108 (291P) 

Kim J.G. ix208 (613P) 

Kim J.H. ix193 (566P), ix250 (757) 

Kim J.S. ix454 (1394P) 

Kim K-P. ix108 (291P) 

Kim K. ix366 (1126P), ix454 (1392P), 

ix479 (1479PD), ix492 (1520PD) 

Kim K.S. ix135 (382) 

Kim M. ix424 (1292P) 

Kim M.H. ix127 (353P) 

Kim N.K. ix185 (543P) 

Kim S-B. ix108 (291P) 

Kim S. ix349 (1065O), ix375 (1153), 

ix424 (1292P), ix450 (1381P), ix450 (1381P), 

ix541 (1688PD), ix249 (752), ix262 (793PD), 

ix268 (811P) 

Kim S.H. ix185 (543P) 

Kim S-W. ix400 (1225O), ix152 (438O), 

ix186 (545P) 

Kim S.Y. ix479 (1479PD) 

Kim T. ix465 (1433P) 

Kim T.I. ix185 (543P) 

Kim T.M. ix271 (820P), ix283 (855P) 

Kim T.W. ix479 (1479PD) 

Kim W. ix492 (1520PD) 

Kim Y. ix492 (1520PD), ix283 (855P) 

Kim Y.A. ix512 (1589P) 

Kim Y.H. ix442 (1356) 

Kim Y.S. ix375 (1153), ix430 (1311P) 

Kimura T. ix412 (1258P), ix434 (1325), 

ix79 (189P), ix79 (190P), ix92 (235) 

Kimura Y. ix227 (677P) 

Kindler H.L. ix493 (1522PD) 

Kindler M. ix505 (1567P) 

Kindyanova L.V. ix141 (403) 

King B. ix87 (217P) 

Kinoshita F. ix197 (576P) 

Kinoshita H. ix467 (1443) 

Kinoshita I. ix443 (1358) 

Kinugasa Y. ix200 (588P) 

Kira Y. ix79 (189P), ix92 (235) 

Kirches E. ix147 (420PD) 

Kirchhoff T. ix363 (1113PD) 

Kirchner T. ix180 (526PD) 

Kireeva L. ix134 (379) 

Kishi K. ix429 (1306P), ix433 (1323), ix442 (1354) 

Kishimoto J. ix438 (1340) 

Kitagawa C. ix517 (1608P) 

Kitagawa R. ix327 (995P) 

Kitayama J. ix233 (698P) 

Kiura K. ix397 (1218), ix434 (1327), ix153 (441O) 

Kiyohara Y. ix426 (1298P) 

Kiyota N. ix510 (1581P) 

Kizaki J. ix248 (751) 

Kjaer A. ix47 (74IN) 

Kjaer S.K. ix22 (3IN) 

Klaase J. ix96 (251PD) 

Klech J. ix253 (768) 

Kleeberg U.R. ix457 (1403), ix518 (1612P) 

Kleha J.F. ix153 (442O) 

Klein Gunnewiek J. ix111 (301) 

Kleinberg L. ix148 (428P) 

Kleinerman E. ix488 (1508P) 

Klement T. ix100 (261P) 

Klersy C. ix355 (1089P) 

Klevesath M.B. ix154 (444PD) 

Klimczak A. ix484 (1495P) 

Klimenko V.V. ix139 (397) 

Klingelschmitt G. ix417 (1271P) 

Kloecker G. ix76 (177PD), ix87 (217P) 

Kloth J.S.L. ix538 (1678P) 

Klughammer B. ix400 (1226O), ix411 (1254P), 

ix417 (1271P) 

Klumpen H.J. ix538 (1678P) 

Knackmuss S. ix350 (1072P) 

Knecht H. ix350 (1071P) 

Kneeshaw P. ix106 (283P) 

Knoblauch P. ix349 (1068PD) 

Knopf K. ix203 (597P) 

Knudsen S. ix349 (1068PD) 

Koçar M. ix186 (547P) 

Ko Y.H. ix490 (1516), ix250 (757) 

Kobayashi A. ix210 (621) 

Kobayashi D. ix200 (585P) 

Kobayashi K. ix404 (1234PD), ix412 (1256P), 

ix413 (1259P), ix420 (1280P) 

Kobayashi M. ix228 (681P) 

Kobayashi O. ix509 (1579P) 

Kobayashi S. ix518 (1611P) 

Kobayashi T. ix518 (1611P), ix344 (1706P) 

Kocak I. ix307 (933P) 

Kocik M. ix513 (1593P) 

Kockelbergh R. ix292 (887) 

Kocsis J. ix493 (1523P) 

Koczwara B. ix503 (1558P) 


author index 

Kodaira M. ix90 (228P), ix164 (474P) 

Kodaira S. ix188 (552P) 

Kodera Y. ix542 (1693P), ix220 (655), ix246 (742P) 

Kodytkova J. ix513 (1593P) 

Koeberle D. ix462 (1423O) 

Koeck S. ix543 (1695P) 

Koenen R. ix162 (468P) 

Koepl L. ix203 (596P) 

Kogure Y. ix517 (1608P) 

Koh T.S. ix70 (155P) 

Koh Y. ix383 (1175P) 

Köhler J. ix437 (1339) 

Köhne C. ix191 (561P) 

Koizumi F. ix383 (1175P), ix90 (228P) 

Koizumi W. ix231 (689P) 

Kojima E. ix434 (1325), ix445 (1366TiP) 

Kojima M. ix210 (621) 

Kojima T. ix497 (1538P), ix89 (224P) 

Kojima Y. ix69 (153P) 

Kokudo N. ix211 (625) 

Kolaitis G. ix103 (273P) 

Kolarevic D. ix544 (1702) 

Kollia G. ix361 (1109O), ix405 (1237PD), 

ix258 (784O) 

Kollmannsberger C.K. ix163 (471P) 

Kollmeier J. ix409 (1247P) 

Komatsu Y. ix512 (1590P), ix201 (590P), 

ix202 (592P) 

Kommoss F. ix322 (976P) 

Komori T. ix510 (1581P) 

Komuta K. ix411 (1253P) 

Kondo C. ix433 (1324), ix232 (692P) 

Kondo H. ix71 (161P) 

Kondo K. ix188 (552P) 

Kondo M. ix445 (1366TiP) 

Kondo N. ix139 (396) 

Kondratova T. ix134 (379) 

Koner S. ix355 (1090P), ix359 (1105), 

ix471 (1453P), ix471 (1454P), ix471 (1455P) 

Kong A. ix116 (318O) 

Kong S. ix353 (1080P) 

Kong W. ix260 (788O) 

Kongruttanachok N. ix350 (1071P) 

Kongsted P. ix444 (1361) 

Konja J. ix359 (1104) 

König D. ix132 (370P) 

Königsberg R. ix100 (261P) 

Kono T. ix514 (1595P) 

Konopasek B. ix81 (197P) 

Kontopodis E. ix435 (1329), ix436 (1335), 

ix139 (395) 

Koo D.H. ix234 (700P) 

Koo J.S. ix127 (353P) 

Koo S.L. ix412 (1257P), ix485 (1501P), 

ix182 (533P) 

Kooiman G. ix275 (831P) 

Koopman M. ix179 (521O) 

Kopetz S. ix220 (656) 

Kopf B. ix285 (863P) 

Kopic A. ix136 (385) 

Kopp M.V. ix398 (1223), ix521 (1623), 

ix97 (254PD) 

Korach J. ix322 (978P) 

Korbenfeld E. ix270 (817P), ix279 (844P) 

Korkmaz T. ix497 (1540), ix217 (645) 

Korkolopoulou P. ix92 (236) 

Korn C. ix261 (790O), ix314 (952) 

Kornek G.V. ix340 (1038P), ix253 (768) 

Koroleva I.A. ix398 (1223), ix521 (1623) 

Korotkova O.V. ix371 (1138P) 

Korse T. ix392 (1203P) 

Korytowsky B. ix269 (815P) 

Kosaka S. ix442 (1356) 

Koscielny S. ix168 (491P) 

Kosela H.M. ix484 (1495P), ix489 (1513) 

Koshio J. ix71 (159P) 

Kosmas C. ix493 (1524P) 

Kosmider S. ix220 (656) 

Kosmidis P. ix430 (1312), ix85 (211P) 

Kostakis I. ix541 (1691P) 

Kostopoulos I. ix338 (1030P) 

Kosty M.P. ix420 (1279P) 

Kota I. ix422 (1285P) 

Kotecki N. ix113 (309) 

Kotek A. ix526 (1642) 

Kotelnikov A. ix197 (577P) 

Kothbauer K.F. ix148 (427P) 

Kotlyarov E.V. ix470 (1451P) 

Kotoula V. ix338 (1030P), ix338 (1031P), 

ix430 (1312) 

Kotsakis A. ix431 (1314), ix435 (1329), 

ix436 (1335) 

Kouakam C. ix113 (309) 

Koufuji K. ix248 (751) 

Koulouridi A. ix429 (1308P) 

Kousparou C. ix160 (463P) 

Koutoulaki A. ix431 (1314) 

Koutras A. ix95 (246O) 

Kovac V. ix446 (1368TiP) 

Kovalenko N. ix103 (273P) 

Kovel S. ix313 (950) 

Kowalski D. ix410 (1250P) 

Kowalski J. ix281 (848P) 

Koyama A. ix210 (621) 

Koyama S. ix527 (1705) 

Kozłowski W. ix268 (812P), ix323 (979P) 

Kozlov S.V. ix398 (1223) 

Kozuki T. ix434 (1327) 

Krüger C. ix228 (680P) 

Kraemer S. ix378 (1160P) 

Krainer M. ix539 (1685P) 

Krakowski I. ix501 (1554P), ix294 (893O) 

Kramar A. ix101 (266P) 

Kranewitter W. ix209 (616) 

Kratzke R. ix74 (170O) 

Krebs M. ix199 (582P) 

Kreipe H. ix394 (1208) 

Krekeler G. ix359 (1107TiP), ix274 (828P) 

Kriegshäuser G. ix373 (1145) 

Krieken V.H. ix184 (540P) 

Krikelis D. ix337 (1026P) 

Kris M. ix401 (1228O) 

Kristeleit R. ix161 (464P) 

Krivorotko P.V. ix139 (397) 

Kroening H. ix178 (518O) 

Kroez M. ix453 (1389P), ix466 (1437P) 

Kruse V. ix287 (870) 

Kruzel T. ix353 (1082P) 

Krzakowski M.J. ix409 (1247P) 

Krzyzanowska M.K. ix464 (1432P) 

Ktiouet M. ix511 (1584P), ix278 (841P), 

ix289 (876) 

Kuan S. ix156 (449PD) 

Kube U. ix278 (841P), ix288 (875) 

ix288 (875) 

Kubicka S. ix193 (565P), ix195 (571P) 

Kubisa B. ix386 (1182P) 

Kuboki Y. ix87 (218P) 

Kubota K. ix396 (1215), ix397 (1218), 

ix404 (1234PD) 

Kucuk O. ix342 (1043P) 

Kucukoner M. ix332 (1015), ix137 (387) 

Kudaba I. ix124 (344P) 

Kudo K. ix418 (1274P), ix441 (1353) 

Kudo M. ix381 (1171P), ix202 (592P), 

ix225 (670PD), ix243 (732P), ix244 (737P) 

Kudoh S. ix393 (1204P), ix404 (1234PD), 

ix412 (1258P), ix79 (189P), ix79 (190P), 

ix92 (235) 

Kudoh T. ix167 (486P) 

Kudryavtsev V. ix70 (156P) 

Kueppers F. ix309 (937P) 

Kühn T. ix117 (321PD) 

Kuhn A. ix505 (1567P) 

Kuhr K. ix504 (1561P) 

Kührer I. ix253 (768) 


Kuisma A.K. ix384 (1178TiP) 

Kumada H. ix244 (737P) 

Kumagai S. ix69 (153P) 

Kumaki N. ix112 (305) 

Kumanogoh A. ix411 (1253P) 

Kumar A. ix188 (551P) 

Kumar C. ix174 (510TiP) 

Kumar D. ix339 (1034P) 

Kumar L. ix349 (1067PD), ix358 (1101), 

ix264 (800P) 

Kumar R. ix354 (1085P), ix358 (1101), 

ix503 (1558P) 

Kumar S. ix339 (1034P), ix358 (1100), 

ix374 (1149), ix497 (1539P), ix285 (860P) 

Kümmel S. ix117 (321PD) 

Kunimasa K. ix434 (1327) 

Kunitoh H. ix429 (1306P) 

Kunz G. ix97 (254PD) 

Kuo S. ix351 (1075P) 

Kuo Y. ix107 (286P) 

Kuom S. ix494 (1529P) 

Kurata T. ix167 (486P) 

Kurbatova K.A. ix141 (403) 

Kuriyama N. ix391 (1198P), ix154 (443PD) 

Kurkjian C. ix498 (1543TiP) 

Kuroi K. ix104 (277P) 

Kurokawa Y. ix481 (1485PD), ix227 (677P) 

Küronya Z. ix281 (849P), ix286 (867P) 

Kurt E. ix291 (885) 

Kurt H. ix312 (947) 

Kurt M. ix291 (885) 

Kurtz J.E. ix378 (1160P) 

Kurzrock R. ix153 (442O), ix154 (444PD), 

ix168 (489P) 

Kushihara H. ix518 (1610P), ix526 (1643), 

ix527 (1705) 

Kushihara T. ix518 (1610P), ix526 (1643) 

Kuss I. ix478 (1478O) 

Kusumoto M. ix469 (1447PD) 

Kusunoki Y. ix197 (576P) 

Kut E. ix221 (660) 

Kutarska E. ix329 (1001P) 

Kutyreva J.G. ix398 (1223) 

Kuwabara S. ix228 (682P) 

Kvist A. ix90 (227P) 

Kwon H. ix249 (752) 

Kwon J.H. ix466 (1439) 

Kwon S.Y. ix414 (1262P) 

L 

La Verde N.M. ix511 (1585P) 

Laack E. ix404 (1235PD) 

Labbe-Devilliers C. ix62 (121IN) 

Labianca R. ix365 (1120P), ix515 (1599P) 

Labiano T. ix365 (1123P), ix432 (1316) 

Lacas B. ix389 (1192PD) 

Lacau Saint Guily J. ix340 (1036P) 

Lacave R. ix340 (1036P) 

Lachaine J. ix350 (1070PD), ix119 (328PD) 

Lackey J. ix317 (963TiP) 

Ladarre N. ix488 (1511P) 

Ladrera G.E.I. ix400 (1226O) 

Lafayette R. ix171 (499P) 

Lafitte J. ix408 (1243P) 

Laforest A. ix234 (703P) 

Lagerwaard F.J. ix62 (123IN) 

Lagha N. ix344 (1051) 

Lagoudaki E. ix381 (1170P), ix429 (1308P) 

Laguerre B. ix294 (893O) 

Lai Y. ix515 (1600P) 

Lainez N. ix277 (839P) 

Lake J. ix451 (1382P) 

Lakis S. ix430 (1312) 

Lakkis Z. ix204 (600P), ix249 (753) 

Lakomy R. ix198 (581P), ix223 (665TiP) 

Lakshmaiah K.C. ix358 (1102) 

Laktionov P.P. ix109 (293P) 

Lalla D. ix120 (329P), ix122 (338P) 



Lam D. ix537 (1675P) 

Lam D.C. ix383 (1176P) 

Lamar M. ix245 (739P) 

Lambertini M. ix454 (1393P), ix501 (1551PD), 

ix521 (1621) 

Lambertz H. ix204 (599P) 

Lambiase A. ix410 (1251P), ix167 (487P), 

ix167 (488P), ix172 (502) 

Lambin P. ix392 (1201P), ix396 (1213), 

ix396 (1216), ix425 (1296P), ix212 (626) 

Lammering G. ix212 (626) 

Lamparska-Przybysz M. ix544 (1700) 

Lampron M.E. ix278 (840P) 

Lamy A. ix213 (629) 

Lamy R. ix391 (1199P) 

Lancashire M. ix87 (219P) 

Landi B. ix482 (1489P) 

Landi L. ix423 (1288P), ix77 (181P), ix183 (535P) 

Landsman-Blumberg P. ix267 (810P) 

ix269 (816P) 

Landucci E. ix176 (515P) 

Lanfiuti Baldi P. ix524 (1633) 

Láng I. ix191 (561P) 

Lang I. ix116 (317O), ix224 (668PD) 

Lang P. ix337 (1025P) 

Lange O. ix505 (1567P) 

Lankes H. ix81 (198P) 

Lankheet N.A.G. ix538 (1678P) 

Lannert H. ix317 (965TiP) 

Lannoy V. ix197 (578P) 

Lanoy E. ix421 (1284P), ix110 (297P) 

Lanza G. ix179 (522PD) 

Lanzalone S. ix402 (1230PD) 

Lanzetta G. ix458 (1407) 

Lao-Sirieix S. ix378 (1161P) 

Laperriere N. ix144 (410O) 

Lapierre M. ix350 (1070PD), ix119 (328PD) 

Lapinska-Szumczyk S. ix320 (970PD) 

Lapolla A.M. ix95 (248O) 

Laporta R. ix459 (1410) 

Laquente B. ix529 (1648P) 

Lara F. ix107 (289P), ix126 (349P) 

Lara P.C. ix266 (805P) 

Laramas M. ix488 (1511P) 

Larkin J. ix366 (1124P), ix374 (1149), 

ix269 (814P), ix271 (821P), ix273 (827P), 

ix279 (843P) 

Larocca L.M. ix433 (1322) 

Larson S. ix294 (894O) 

Lasan Trcic R. ix359 (1104) 

Laskar S. ix351 (1074P) 

Laskin J. ix412 (1255P), ix419 (1278P) 

Lastoria S. ix193 (567P) 

Lata S. ix261 (792PD) 

Lathia C. ix407 (1241P) 

Latipova D.H. ix139 (397) 

Latko E. ix511 (1587P) 

Latorzeff I. ix294 (893O) 

Lattanzio L. ix528 (1644PD) 

Laubender R. ix487 (1505P), ix180 (526PD), 

ix188 (554P), ix204 (599P) 

Laurent-Puig P. ix77 (180P), ix85 (210P), 

ix180 (525PD), ix234 (703P) 

Laurent D. ix478 (1478O) 

Laurent M. ix452 (1387P) 

Lavinski Y. ix480 (1483PD), ix166 (482P) 

Lavole A. ix397 (1219) 

Lavoué V. ix105 (281P) 

Law C. ix377 (1158P), ix380 (1167P), ix490 (1516) 

Lawrence D. ix368 (1129P), ix202 (594P) 

Lawrence D.P. ix361 (1109O) 

Lazarev A. ix197 (577P) 

Lazarev I. ix373 (1147) 

Lazarev S. ix197 (577P) 

Lázaro A. ix520 (1619) 

Lazaro M. ix395 (1212), ix273 (826P) 

Lazzarelli S. ix232 (693P) 

Lazzeroni M. ix83 (201P) 

Le Cesne A. ix478 (1478O), ix482 (1488P), 

ix482 (1489P), ix236 (708P) 

Le Frère Belda M. ix99 (258P) 

Le Maignan C. ix128 (355P) 

Le Moulec S. ix406 (1240P), ix426 (1299P), 

ix477 (1476), ix150 (433), ix277 (837P), 

ix313 (951) 

Le Moulec S. ix285 (862P) 

Le Pechoux C. ix397 (1217), ix421 (1284P), 

ix486 (1502P) 

Le Pimpec-Barthes F. ix77 (180P) 

Le Poulain-Doubliez M. ix455 (1396P) 

Le Rhun E. ix62 (121IN) 

Le Teuff G. ix496 (1534P), ix74 (170O), ix94 (244) 

Le Thuaut A. ix452 (1387P) 

Le Tourneau C. ix334 (1017O), ix519 (1614P) 

León L. ix275 (832P), ix277 (839P) 

Le I.P. ix244 (735P) 

Leahy, T. ix148 (428P) 

Leahy M. ix478 (1478O) 

Lebbe C. ix363 (1116PD) 

Lebmeier M. ix370 (1134P) 

Leboreiro Enriquez B. ix92 (234) 

Lebret T. ix474 (1463P), ix511 (1584P) 

Lebreton J. ix460 (1419PD) 

Lebrun F. ix121 (334P) 

Lecesne A. ix486 (1502P) 

Lechuga M. ix297 (901PD) 

Lecleire S. ix252 (767) 

Lecomte T. ix85 (209P), ix237 (710P) 

Lécuru F. ix99 (258P), ix323 (980P) 

Ledermann J.A. ix324 (982P) 

Lee C. ix182 (532P) 

Lee C.K. ix414 (1263P) 

Lee D. ix370 (1134P), ix372 (1143P) 

Lee D.H. ix400 (1225O), ix424 (1292P), 

ix287 (872) 

Lee D.K. ix240 (722P) 

Lee H-J. ix108 (291P) 

Lee H. ix353 (1080P) 

Lee H.J. ix541 (1688PD) 

Lee J. ix345 (1052), ix375 (1153), ix450 (1381P), 

ix479 (1479PD), ix479 (1479PD), ix250 (757), 

ix276 (834P), ix287 (872) 

Lee J.D. ix72 (166) 

Lee J.J. ix480 (1481PD) 

Lee J.K. ix465 (1433P), ix465 (1434P) 

Lee J.S. ix400 (1225O), ix400 (1226O) 

Lee K.H. ix193 (566P) 

Lee K.S. ix541 (1688PD) 

Lee K.Y. ix185 (543P) 

Lee L. ix199 (583P) 

Lee M. ix179 (523PD) 

Lee M.A. ix186 (545P), ix209 (617) 

Lee P. ix160 (461P) 

Lee S. ix332 (1012), ix352 (1077P), ix421 (1282P), 

ix465 (1433P), ix127 (353P), ix253 (771), 

ix271 (820P), ix283 (855P) 

Lee S.J. ix375 (1153), ix430 (1311P), 

ix450 (1381P), ix208 (613P), ix240 (722P) 

Lee S.R. ix352 (1077P) 

Lee V. ix393 (1205P) 

Lee Y. ix515 (1600P) 

Lee Y.J. ix208 (613P) 

Lefebvre-Kuntz D. ix488 (1510P) 

Lefesvre P. ix197 (578P) 

Lefeuvre-Plesse C. ix105 (281P) 

Lefeuvre D. ix110 (297P) 

Lefevre M. ix340 (1036P) 

Legrier M. ix312 (946) 

Lehle M. ix162 (470P) 

Lehr H. ix61 (117IN) 

Lei L. ix495 (1530P) 

Leibetseder A. ix147 (421P) 

Leighl N.B. ix493 (1525P) 

Leis A. ix182 (531P) 

Leitão A. ix458 (1409) 

Leitgeb C. ix348 (1064O) 

Lemare F. ix456 (1400P) 

Lemke M. ix490 (1516) 

Lencioni M. ix238 (714P), ix251 (761), ix251 (762) 

Lencioni R. ix225 (670PD) 

Lennon O. ix513 (1592P) 

Lenze D. ix390 (1195P) 

Leo F. ix463 (1427P) 

Leo S. ix229 (685P) 

Leon A. ix187 (549P), ix233 (699P) 

Leon L. ix419 (1277P), ix419 (1278P), 

ix420 (1279P) 

Leonard E.J. ix303 (921P) 

Leonard G. ix248 (750) 

Leonard J. ix68 (150P) 

Leonardi M.C. ix83 (201P) 

Leone F. ix205 (605P) 

Leong S. ix157 (452P) 

Leonhartsberger N. ix270 (817P), ix279 (844P) 

Lepère C. ix378 (1159P) 

Lepage B. ix388 (1190P) 

Lepage C. ix178 (520O) 

Lepretre S. ix522 (1624) 

Lerer I. ix109 (294P) 

Leridant A.M. ix340 (1037P) 

Leschke M. ix494 (1529P) 

Leseur J. ix105 (281P) 

Lester J. ix498 (1542TiP) 

Lesterhuis W.J. ix363 (1114PD) 

Leu Y. ix345 (1052) 

Leung R. ix244 (736P) 

Levaggi A. ix454 (1393P), ix501 (1551PD), 

ix521 (1621) 

Levchenko E. ix361 (1110O), ix386 (1182P) 

Levesque E. ix316 (960) 

Levi F. ix194 (568P) 

Levidou G. ix92 (236) 

Levitt D. ix480 (1483PD) 

Levva S. ix338 (1030P), ix430 (1312) 

Levy-Lahad E. ix34 (34IN) 

Levy A. ix277 (837P) 

Levy C. ix519 (1614P), ix128 (355P) 

Lewanski C. ix421 (1282P) 

Lewis I.J. ix490 (1518TiP) 

Lewis K. ix362 (1112PD), ix363 (1115PD) 

Lewis R. ix292 (887) 

Leyden J.C. ix380 (1166P) 

Leyvraz S. ix480 (1482PD) 

Lhomel C. ix470 (1452P), ix472 (1460) 

Lhomme C. ix322 (977P) 

Lhommel R. ix336 (1021PD) 

Lhoumeau A. ix184 (539P) 

Lièvre A. ix85 (210P) 

Li C. ix538 (1679P), ix162 (470P), ix247 (746P), 

ix299 (906P) 

Li D. ix390 (1196P), ix256 (780TiP) 

Li G. ix260 (788O) 

Li H. ix453 (1390P), ix245 (741P) 

Li J. ix394 (1209), ix435 (1331), ix97 (254PD), 

ix111 (302), ix202 (595P), ix216 (640), 

ix217 (646), ix294 (894O) 

Li N. ix77 (182P) 

Li N.F. ix171 (499P) 

Li P. ix180 (524PD) 

Li Q. ix343 (1048P), ix140 (401) 

Li R. ix413 (1261P), ix454 (1395P) 

Li S. ix295 (895O) 

Li W. ix216 (640), ix217 (643), ix218 (647) 

Li X. ix67 (144PD), ix81 (195P), ix93 (238), 

ix117 (320PD), ix173 (507), ix227 (676P) 

Li Y. ix179 (522PD) 

Li Z. ix337 (1027P), ix416 (1269P), ix416 (1269P), 

ix443 (1359), ix219 (650) 

Liao G. ix77 (182P) 

Liao W. ix515 (1600P) 

Liao Y. ix515 (1600P) 

Libener R. ix247 (747P) 

Libertini M. ix485 (1500P) 

Lichinitser M. ix224 (668PD) 


author index 

Lichtensztejn D. ix350 (1071P) 

Lichtensztejn Z. ix350 (1071P) 

Licitra L. ix334 (1018O), ix335 (1019O), 

ix336 (1022PD), ix341 (1040P), ix342 (1045P), 

ix344 (1050P) 

Licour M. ix416 (1270P) 

Liebaert F. ix180 (525PD) 

Liede A. ix298 (902P) 

Liefers G. ix100 (263P) 

Liew M.S. ix493 (1525P), ix542 (1692P) 

Lifrange E. ix96 (251PD) 

Ligier K. ix241 (725P) 

Liguigli W. ix232 (693P) 

Lilja H. ix89 (223P) 

Lim F.L. ix290 (880) 

Lim H. ix188 (551P), ix204 (601P), ix215 (635) 

Lim J.Y. ix240 (722P) 

Lim S. ix253 (771) 

Lim S.H. ix70 (157P), ix100 (262P) 

Lim W-T. ix393 (1205P) 

Lim W.T. ix412 (1257P) 

Lima Santos C. ix464 (1429P) 

Lima C.S.P. ix364 (1119P), ix365 (1121P), 

ix365 (1122P), ix133 (374P) 

Lima R.C.A.D. ix331 (1009) 

Limetti V. ix516 (1603P) 

Lin C. ix349 (1066PD), ix351 (1075P) 

Lin D. ix311 (942P) 

Lin F. ix398 (1220), ix119 (326PD) 

Lin H. ix342 (1043P) 

Lin J. ix302 (918P) 

Lin J.C. ix25 (11IN) 

Lin K. ix236 (709P) 

Lin L. ix69 (152P) 

Lin P. ix349 (1066PD) 

Lin S. ix425 (1295P) 

Lin W. ix157 (452P) 

Lin X. ix259 (785O) 

Lin Y. ix219 (650), ix247 (746P), ix253 (769), 

ix261 (791PD), ix275 (833P) 

Linardou H. ix373 (1146), ix85 (211P), ix94 (242) 

Lindner L. ix487 (1505P) 

Linhares P. ix147 (423P) 

Linkesch W. ix348 (1064O), ix352 (1076P) 

Lipman P. ix158 (456P) 

Lipton L. ix255 (776TiP) 

Liskova S. ix293 ( ) 

Liskovsky G. ix316 (961) 

Lissia A. ix364 (1118PD) 

Little M. ix350 (1072P) 

Liu B. ix229 (686P) 

Liu C. ix345 (1052), ix355 (1087P) 

Liu G. ix78 (186P), ix153 (440O), ix302 (918P), 

ix303 (920P) 

Liu H.E. ix428 (1305P) 

Liu J. ix355 (1087P), ix453 (1390P), ix226 (674P), 

ix321 (974PD) 

Liu L. ix141 (405TiP) 

Liu M. ix343 (1048P) 

Liu S.V. ix306 (928P) 

Liu T. ix231 (690P) 

Liu W. ix346 (1057), ix443 (1359), ix77 (182P), 

ix300 (911P) 

Liu X. ix402 (1230PD) 

Liu Y. ix390 (1196P), ix435 (1331), ix437 (1337), 

ix488 (1508P), ix490 (1518TiP), ix515 (1600P), 

ix93 (238), ix138 (394), ix202 (595P), 

ix231 (690P), ix247 (745P), ix261 (791PD), 

ix275 (833P) 

Liuu E. ix452 (1387P) 

Livingstone A. ix151 (437TiP) 

Ljungberg B. ix281 (848P) 

Lkhoyaali S. ix476 (1470P) 

Lkoyaali S. ix476 (1472P) 

Llacer C. ix101 (268P) 

Llanos M. ix351 (1073P) 

Llombart A. ix82 (200P), ix114 (315TiP) 

Llorca C. ix125 (345P) 

Llorente R.M. ix125 (345P) 

Lloyd A.J. ix476 (1473P), ix296 (898PD) 

Lluch-Hernandez A. ix96 (249PD) 

Lo Nigro C. ix528 (1644PD), ix532 (1660P), 

ix73 (169O) 

Lo Re G. ix280 (846P), ix287 (868) 

Lo A. ix345 (1052) 

Lo G. ix463 (1426P) 

Lobo F. ix457 (1404), ix80 (194P) 

Locati L. ix335 (1019O), ix341 (1040P), 

ix342 (1045P), ix344 (1050P) 

Locher C. ix416 (1270P), ix446 (1367TiP), 

ix455 (1396P) 

Loembé A.B. ix245 (740P) 

Loewy J. ix263 (796PD) 

Logothetis C.J. ix295 (895O) 

Loh E. ix230 (687P) 

Lohneis P. ix390 (1195P) 

Loi S. ix59 (108IN) 

Loibl S. ix117 (321PD), ix118 (323PD) 

Lolkema M.P. ix153 (442O) 

Lollini P. ix537 (1675P) 

Lomas-Garrido M. ix101 (268P) 

Lombard-Bohas C. ix85 (209P) 

Lombardi G. ix144 (411O) 

Lombardo L. ix145 (416PD) 

Lonardi S. ix209 (618) 

Longo F. ix377 (1157O), ix507 (1571P) 

Loos A.H. ix395 (1210) 

Lopatin M. ix179 (523PD) 

Lopes C. ix132 (371P) 

Lopez Ben S. ix219 (651) 

López Juarez E. ix264 (799P) 

Lopez Lopez M.C. ix264 (799P) 

López Martí M.P. ix264 (799P) 

López Mata M. ix510 (1582P) 

Lopez Martin J.A. ix374 (1151) 

Lopez Pedrera C. ix530 (1652P) 

Lopez Picazo J.M. ix508 (1577P) 

Lopez Pousa A. ix408 (1244P), ix235 (705P) 

López Calderero I. ix510 (1582P), ix166 (484P), 

ix183 (534P) 

Lopez-Crapez E. ix84 (206P) 

López-González A. ix492 (1521PD) 

Lopez-Picazo J.M. ix336 (1022PD) 

Lopez-Pousa A. ix490 (1517TiP) 

Lopez-Rios F. ix233 (699P) 

Lopez-Vega J.M. ix82 (200P), ix142 (408TiP) 

Lopez-Vivanco G. ix212 (627) 

López-Tarruella S. ix176 (517P) 

López-Trabada D. ix176 (517P) 

López C. ix529 (1648P) 

Lopez A. ix277 (839P) 

Lopez G. ix379 (1164P) 

Lopez R. ix328 (1000P) 

Lopez R.I. ix102 (271P) 

Lora D. ix134 (378) 

Lorch A. ix284 (858P) 

Lordick F. ix514 (1596P), ix539 (1683P) 

Lorente D. ix106 (284P) 

Lorenzetti I.T. ix99 (260P) 

Lorenzi E. ix167 (488P) 

Loretelli C. ix431 (1313), ix86 (214P), ix86 (215P), 

ix239 (720P), ix243 (734P), ix274 (829P) 

Lorigan P. ix87 (219P), ix90 (227P) 

Loriot Y. ix277 (837P), ix304 (924P), ix313 (951) 

Lortholary A. ix511 (1584P), ix125 (346P) 

Lorusso D. ix330 (1004P), ix458 (1408) 

LoRusso P.M. ix362 (1111PD), ix158 (456P), 

ix170 (497P), ix173 (507) 

Lorusso V. ix276 (836P) 

Lorvidhaya V. ix339 (1035P) 

Losanno T. ix105 (282P), ix111 (303) 

Losonczy G. ix429 (1307P) 

Lotz J.-P. ix260 (789O) 

Lotz J. ix502 (1556P) 

Lou C. ix69 (152P), ix495 (1530P) 

Lou H. ix256 (780TiP) 


Lou Y. ix413 (1261P), ix454 (1395P) 

Lourenço G.J. ix364 (1119P), ix365 (1121P), 

ix365 (1122P), ix133 (374P) 

Lourenco G.J. ix339 (1032P) 

Louveau A. ix258 (783O) 

Lovati E. ix520 (1618) 

Love S. ix181 (530PD) 

Löser H. ix481 (1486PD) 

Lowy I. ix301 (915P) 

Lozano J.J. ix300 (910P) 

Lozano M.D. ix365 (1123P), ix432 (1316) 

Luís A. ix175 (512PD), ix176 (514P) 

Lu H. ix495 (1530P) 

Lu J. ix110 (299) 

Lu K.H. ix438 (1341) 

Lu S. ix385 (1179O), ix438 (1341), ix174 (509TiP) 

Lu Y. ix172 (501), ix247 (745P) 

Lu Z. ix189 (556P) 

Lub-De Hooge M.N. ix40 (57IN) 

Lubel J. ix56 (96IN) 

Lucassen G. ix532 (1658P) 

Lucchesi M. ix238 (714P), ix251 (761), ix251 (762) 

Lucchesi S. ix94 (243) 

Lucchini E. ix117 (322PD), ix240 (721P) 

Lucey D.J. ix207 (610P) 

Lucisano G. ix365 (1120P) 

Ludovini V. ix387 (1185P), ix427 (1302P), 

ix535 (1668P), ix183 (535P) 

Ludwig H. ix348 (1064O), ix502 (1555P) 

Lueck H. ix322 (976P) 

Lueftner D. ix449 (1377P) 

Luelmo S. ix256 (781TiP) 

Lueza B. ix397 (1217) 

Lugatti E. ix457 (1405) 

Lui L. ix302 (917P) 

Lum B.L. ix162 (470P) 

Lumachi F. ix287 (868) 

Lumbroso L. ix519 (1614P) 

Lundstam S. ix281 (848P) 

Lung M.S. ix526 (1640) 

Lungershausen J. ix402 (1229PD) 

Luo Y. ix437 (1337), ix93 (238) 

Luporsi E. ix504 (1563P), ix506 (1568P), 

ix506 (1569P) 

Luppi G. ix231 (691P) 

Lutiger B. ix267 (809P) 

Lutke Holzik M. ix96 (251PD) 

Lutman R. ix487 (1506P) 

Lwin Z. ix144 (410O) 

Lycke M. ix341 (1042P) 

Lyman G.H. ix447 (1369P) 

Lymperatou D.V. ix136 (384) 

Lynch T.J. ix420 (1279P) 

M 

Ma F. ix140 (401) 

Ma J. ix453 (1390P), ix270 (817P) 

Ma L. ix390 (1196P), ix111 (302) 

Ma M. ix363 (1113PD) 

Ma W.W. ix155 (447PD) 

Ma X. ix389 (1192PD) 

Maass N. ix124 (342P) 

Macías A. ix406 (1238PD) 

Maccaroni E. ix219 (652) 

Macciò A. ix462 (1422O), ix466 (1438P) 

Maccio’ A. ix463 (1427P) 

Macdonald K. ix502 (1555P) 

Macedo D. ix289 (878) 

Macedo T. ix357 (1097) 

Machado D. ix141 (404) 

Machado M. ix201 (591P), ix210 (620), 

ix221 (657), ix222 (661) 

Machado P. ix175 (512PD), ix176 (514P) 

Machalova A.S. ix521 (1623) 

Machida N. ix201 (590P) 

Machiels J. ix157 (454P), ix307 (933P) 

Machiels J.P. ix336 (1021PD), ix342 (1044P), 

ix42 (58IN), ix259 (786O) 



Maci E. ix433 (1322) 

Mack P. ix49 (77IN) 

Mackay J. ix470 (1451P) 

Mackillop W.J. ix260 (788O) 

Macpherson I. ix119 (325PD) 

Madan R. ix223 (664TiP) 

Maddison C. ix526 (1640) 

Madeddu C. ix462 (1422O), ix463 (1427P), 

ix466 (1438P), ix164 (476P) 

Madero R. ix181 (527PD) 

Madhumathi D.S. ix358 (1102) 

Madhuri K. ix68 (147P) 

Madoz J. ix80 (194P), ix183 (537P) 

Madroszyk A. ix391 (1199P), ix406 (1240P), 

ix150 (434) 

Maeda A. ix541 (1690P) 

Maeda Y. ix381 (1171P), ix164 (474P), 

ix240 (723P) 

Maemondo M. ix412 (1256P), ix413 (1259P), 

ix413 (1260P), ix420 (1280P), ix427 (1301P), 

ix443 (1358), ix153 (441O) 

Maeng C.H. ix375 (1153) 

Maeng C.H. ix430 (1311P) 

Maetens M. ix98 (255PD) 

Maffi M. ix528 (1644PD) 

Mafodda A. ix505 (1565P), ix137 (388) 

Maglakelidze M. ix460 (1414TiP) 

Magnani T. ix315 (959) 

Magnoni P. ix487 (1506P) 

Magnusson A. ix236 (709P) 

Magremanne M. ix336 (1021PD) 

Magri V. ix440 (1348) 

Magrini S.M. ix338 (1029P) 

Mahalingam D. ix168 (489P) 

Mahfoudi A. ix476 (1471P) 

Mahmood A. ix449 (1377P), ix174 (510TiP) 

Mahner S. ix322 (976P) 

Maho S. ix442 (1354) 

Mahon G. ix186 (548P), ix209 (615) 

Mai S. ix350 (1071P) 

Maier G. ix298 (903P) 

Maier S. ix75 (175PD) 

Maillard E. ix181 (529PD) 

Maillet D. ix299 (907P) 

Mailliez A. ix106 (285P), ix113 (309) 

Maimon O. ix109 (294P) 

Maines F. ix273 (825P) 

Maingon P. ix206 (607P) 

Mainwaring P.N. ix295 (895O) 

Maio M. ix363 (1116PD), ix364 (1117PD), 

ix367 (1127P), ix368 (1130P), ix369 (1133P), 

ix373 (1148) 

Mair S. ix508 (1575P) 

Maira M. ix537 (1675P) 

Maisano R. ix505 (1565P), ix137 (388) 

Maitland-Vd Zee A. ix122 (335P) 

Majem Tarruella M. ix408 (1244P), 

ix414 (1264P) 

Majem M. ix533 (1661P), ix533 (1662P) 

Majumder R. ix328 (997P) 

Mak M.P. ix455 (1397P) 

Makar A.P. ix330 (1007), ix325 (987P) 

Maki R. ix478 (1478O) 

Maki R.G. ix489 (1514), ix54 (93IN) 

Makino M. ix509 (1579P) 

Maksymiuk A. ix395 (1210) 

Makuuchi M. ix211 (625) 

Makuuchi Y. ix89 (224P) 

Malassé S. ix409 (1247P) 

Malatesta S. ix385 (1179O) 

Maldonado-Martinez H. ix107 (289P) 

Maldonado X. ix302 (916P) 

Malejczyk J. ix320 (971PD) 

Malet J. ix265 (802P) 

Malfertheiner P. ix255 (778TiP) 

Malheiro Sarmento T. ix222 (661) 

Malhotra H. ix301 (912P) 

Malik Z.I. ix306 (931P) 

Malka D. ix511 (1587P), ix175 (511PD), 

ix198 (580P), ix237 (710P), ix238 (716P) 

Mallath M.K. ix350 (1069PD), ix541 (1689P) 

Malli T. ix209 (616) 

Maloisel F. ix522 (1624) 

Malorni L. ix27 (13IN) 

Malovini A. ix535 (1669P) 

Maltzman J.D. ix493 (1522PD) 

Malvehy J. ix343 (1046P) 

Mammucari M. ix463 (1425P) 

Mamontov K. ix197 (577P) 

Manceau G. ix180 (525PD) 

Mancini J. ix482 (1489P) 

Mancini M. ix330 (1004P) 

Mandala M. ix365 (1120P), ix369 (1131P), 

ix369 (1133P) 

Mandigers C.M. ix501 (1553P) 

Mandolesi A. ix86 (214P), ix86 (215P), 

ix239 (720P), ix243 (734P), ix250 (756) 

Mandrekar S.J. ix535 (1670P) 

Mane A.D. ix101 (265P) 

Manegold C. ix529 (1647PD) 

Manera S. ix535 (1669P) 

Mangat R. ix162 (470P) 

Mangia A. ix331 (1010) 

Maniadakis N. ix447 (1372P) 

Maniar T. ix115 (316TiP) 

Manihkas A. ix103 (272P) 

Manikhas A. ix114 (315TiP) 

Maniwa Y. ix92 (233) 

Manji A. ix158 (455P) 

Mann Hong T. ix485 (1499P), ix485 (1501P) 

Manna G. ix105 (282P), ix111 (303) 

Manneh R.A. ix134 (378), ix325 (986P) 

Mannel R. ix81 (198P) 

Mano M.S. ix455 (1397P), ix112 (306), 

ix125 (347P) 

Manoharan P. ix207 (609P) 

Mansi J.L. ix139 (398) 

Mansi L. ix332 (1014), ix128 (357P) 

Mansmann U. ix180 (526PD) 

Manso L. ix96 (251PD), ix125 (345P), ix134 (378), 

ix325 (986P) 

Manso R. ix183 (537P) 

Manson S. ix483 (1493P), ix488 (1511P) 

Mansoor W. ix381 (1168P) 

Mansour M. ix138 (392) 

Mansourbakht T. ix511 (1587P) 

Mansouri K. ix124 (342P) 

Mansueto G. ix507 (1571P) 

Mansutti M. ix531 (1657P) 

Mantion G. ix206 (607P) 

Mantovani G. ix462 (1422O), ix463 (1427P), 

ix466 (1438P), ix516 (1604P), ix164 (476P) 

Manzano A. ix438 (1342) 

Manzano J.L. ix380 (1165P), ix529 (1648P) 

Manzo A. ix430 (1309P) 

Mao C. ix256 (779TiP) 

Mao W. ix495 (1530P), ix226 (674P) 

Marín-Aguilera M. ix538 (1680P), ix300 (910P) 

Marais R. ix46 (69IN) 

Marasà S. ix215 (636) 

Marcenaro S. ix80 (192P) 

Marchal F. ix482 (1489P) 

Marchesi L. ix365 (1120P) 

Marcheteau E. ix75 (174O) 

Marchetti A. ix423 (1288P), ix73 (167O), 

ix78 (183P) 

Marchetti S. ix32 (29IN) 

Marciano R. ix530 (1651P), ix532 (1659P) 

Marconcini R. ix368 (1130P), ix369 (1132P), 

ix290 (881) 

Mardiak J. ix270 (817P), ix279 (844P), 

ix286 (865P), ix293 (890TiP) 

Mare M. ix505 (1565P), ix137 (388) 

Marechal R. ix194 (569P) 

Marelli L. ix452 (1385P) 

Mareschal S. ix339 (1033P) 

Margaret Sheehan M. ix248 (750) 

Margery J. ix496 (1534P), ix94 (244) 

Marhold M. ix539 (1685P) 

Mariani G. ix124 (342P) 

Mariani L. ix88 (222P), ix212 (628) 

Mariani P. ix102 (269P) 

Mariano C. ix412 (1255P) 

Marino A. ix95 (248O) 

Marino D. ix205 (605P) 

Marino M. ix540 (1687) 

Marinsek N. ix122 (336P) 

Mariz J. ix357 (1095) 

Markou K. ix338 (1030P), ix338 (1031P) 

Markovich A. ix382 (1172) 

Marlow S. ix126 (350P) 

Marmé F. ix163 (472P), ix172 (504) 

Marmissolle F. ix379 (1164P) 

Marmol E. ix388 (1189P) 

Marone U. ix375 (1152) 

Marosi C. ix145 (415PD), ix147 (421P), 

ix148 (426P) 

Maroto J.P. ix264 (798PD) 

Maroto P. ix266 (806P), ix275 (832P), 

ix277 (839P), ix292 (888) 

Maroun C. ix163 (471P), ix169 (492P), 

ix169 (493P) 

Maroun J.A. ix187 (550P), ix205 (602P) 

Marples M. ix483 (1492P) 

Márquez-Rodas I. ix176 (517P) 

Marques A. ix78 (184P) 

Marques A.D. ix357 (1097) 

Marques D.S. ix201 (591P), ix210 (620), 

ix221 (657) 

Marques H. ix357 (1097) 

Marques M.T. ix345 (1056) 

Marques R.J. ix112 (306) 

Marques T. ix141 (404) 

Marquez R. ix140 (400) 

Marreaud S. ix483 (1493P) 

Marrero J. ix225 (670PD) 

Marrocolo F. ix315 (958) 

Marrodan I. ix212 (627) 

Marroni P. ix80 (192P) 

Marschner N. ix459 (1413TiP) 

Marschon R. ix209 (616) 

Marsh B. ix525 (1635) 

Marshall E. ix374 (1149), ix421 (1282P) 

Marshall M. ix215 (638) 

Martín-Richard M. ix183 (536P), ix185 (544P), 

ix216 (641) 

Martín P. ix149 (429P), ix305 (927P) 

Martínez-Monge R. ix291 (886) 

Martínez-Villacampa M. ix529 (1648P) 

Martarello L. ix70 (155P) 

Martel-Lafay I. ix391 (1199P) 

Martella F. ix528 (1646PD) 

Marthey L. ix238 (716P) 

Marti Ciriquian J.L. ix510 (1582P) 

Marti Marti F.E. ix207 (609P) 

Martignoni G. ix287 (869) 

Martin Algarra S. ix365 (1123P), ix374 (1150), 

ix432 (1316), ix508 (1577P) 

ix239 (718P) 

Martin Broto J. ix490 (1517TiP) 

Martin Lorente C. ix266 (806P) 

Martin Martorell P. ix458 (1407) 

Martin-Valades J.I. ix187 (549P) 

Martin A.L. ix203 (597P) 

Martin C. ix496 (1535P) 

Martin F. ix455 (1396P) 

Martin J.P. ix475 (1467P) 

Martin M. ix115 (316TiP), ix118 (323PD) 

Martinelli E. ix430 (1309P), ix67 (143PD), 

ix75 (173O) 

Martinez Del Prado P. ix82 (200P) 

Martinez Lago N. ix328 (1000P) 

Martinez-Galan J. ix254 (773) 

Martinez-Trufero J. ix490 (1517TiP) 


author index 

Martinez A. ix496 (1533P) 

Martinez L.H. ix457 (1404) 

Martinez P. ix496 (1533P) 

Martini G. ix430 (1309P) 

Martini J. ix262 (794PD) 

Martini M. ix433 (1322) 

Martinius H. ix163 (472P) 

Martins A.M. ix458 (1409) 

Martins D.F. ix127 (352P) 

Martins I.S. ix524 (1632) 

Martins R. ix401 (1228O) 

Martoni A.A. ix466 (1436P), ix130 (362P), 

ix205 (605P) 

Martorell M. ix73 (167O), ix80 (193P) 

Marucci G. ix147 (424P) 

Maruelli A. ix516 (1601P), ix516 (1602P), 

ix520 (1617), ix524 (1631) 

Marumoto T. ix536 (1671P) 

Marzin K. ix155 (446PD) 

Masaki M. ix508 (1576P) 

Mascaux C. ix408 (1243P) 

Maschio M. ix202 (594P) 

Masi G. ix85 (208P) 

Masini C. ix270 (818P), ix290 (879) 

Mason M. ix307 (932P) 

Mason W. ix144 (410O) 

Maspero F. ix435 (1328), ix467 (1440), 

ix519 (1615P), ix131 (368P), ix192 (563P) 

Massa E. ix516 (1604P) 

Massacesi C. ix537 (1675P) 

Massard C. ix474 (1463P), ix496 (1534P), 

ix94 (244), ix155 (446PD), ix277 (837P), 

ix285 (862P), ix304 (924P), ix313 (951) 

Massari A. ix105 (280P) 

Massari F. ix117 (322PD), ix240 (721P), 

ix273 (825P), ix276 (836P), ix287 (869) 

Massey D. ix410 (1252P), ix424 (1292P) 

Massi D. ix364 (1118PD) 

Massopust K. ix261 (790O) 

Massuti Sureda B. ix531 (1655P), ix533 (1661P) 

Mastico R. ix498 (1543TiP) 

Mastromauro C. ix466 (1436P) 

Masuda M. ix383 (1174P), ix536 (1673P), 

ix536 (1674P) 

Masuda N. ix104 (277P), ix124 (344P) 

Masuda S. ix112 (305) 

Matache C. ix67 (146P) 

Matano E. ix540 (1687) 

Matas Ochoa A. ix198 (579P) 

Matczak E. ix269 (815P) 

Mateescu C. ix379 (1163P) 

Matejka V.M. ix474 (1464P) 

Mateo J. ix159 (458P), ix162 (469P) 

Matheny S. ix294 (894O) 

Mathias S.D. ix477 (1474) 

Mathieu M. ix84 (206P), ix110 (297P) 

Mathijssen R.H.J. ix456 (1402P), ix534 (1667P), 

ix538 (1678P), ix109 (295P) 

Mathis G. ix84 (206P) 

Mathurin P. ix255 (777TiP) 

Matos E. ix112 (308), ix132 (371P) 

Matoušková O. ix81 (196P) 

Matsko D.E. ix139 (397) 

Matsubara N. ix131 (366P) 

Matsubara Y. ix197 (576P) 

Matsuda C. ix514 (1595P) 

Matsuguma H. ix388 (1188P) 

Matsui S. ix91 (232) 

Matsuki A. ix234 (702P) 

Matsumoto H. ix250 (758) 

Matsumoto S. ix515 (1598P) 

Matsumoto Y. ix467 (1443) 

Matsumura Y. ix247 (746P) 

Matsuo K. ix232 (694P) 

Matsuoka J. ix74 (172O) 

Matsuoka M. ix196 (573P) 

Matsusaka S. ix87 (218P) 

Matsusaki K. ix463 (1428P) 

Matsuura K. ix412 (1258P), ix79 (189P), 

ix79 (190P), ix92 (235) 

Matsuura N. ix227 (677P) 

Matta-Castro T. ix215 (637) 

Matthes B. ix466 (1437P) 

Matthes H. ix453 (1389P), ix466 (1437P) 

Matulonis U. ix321 (974PD) 

Matveev V. ix267 (809P) 

Matzkowitz A.J. ix130 (363P) 

Maughan B. ix260 (787O) 

Maughan T.S. ix179 (521O) 

Mauguen A. ix397 (1217) 

Maur M. ix373 (1148) 

Maurea N. ix539 (1682P) 

Maurel J. ix67 (145P), ix490 (1517TiP), 

ix181 (527PD) 

Mauri D. ix458 (1407) 

Mauri S. ix462 (1423O) 

Maurina T. ix204 (600P) 

Maute L. ix288 (875) 

Mavroudis D. ix381 (1170P), ix431 (1314), 

ix435 (1329), ix139 (395) 

Mawrin C. ix147 (420PD) 

Maximiano C. ix459 (1410), ix492 (1521PD), 

ix494 (1527P), ix112 (307) 

May C. ix264 (798PD) 

Mayer A. ix175 (512PD) 

Mayer F. ix178 (518O) 

Mayordomo J. ix374 (1151) 

Mazdai G. ix346 (1059) 

Mazières J. ix417 (1271P) 

Mazieres J. ix388 (1190P), ix403 (1232PD), 

ix406 (1240P), ix426 (1299P) 

Mazouni C. ix110 (297P) 

Mazur G. ix503 (1560P) 

Mazzanti C. ix94 (243) 

Mazzanti P. ix387 (1184P), ix533 (1663P) 

Mazzara C. ix229 (685P) 

Mazzini G. ix529 (1650P) 

Mazzoni F. ix528 (1646PD) 

Mc Keegan E.M. ix83 (203P), ix173 (505) 

McCaffrey J.A. ix469 (1449PD), ix525 (1635) 

McCall B. ix171 (499P), ix195 (571P) 

McCann L. ix261 (792PD) 

McCarthy M.T. ix71 (160P) 

McCook J. ix166 (482P) 

McCourt M. ix207 (610P) 

McCroskery P. ix222 (662TiP) 

McDermott D.F. ix361 (1109O), ix368 (1129P), 

ix157 (453P), ix258 (784O) 

McDermott R. ix248 (750), ix300 (909P) 

McDonagh C. ix170 (496P) 

McDonnell F. ix300 (909P) 

McDunn S. ix470 (1450P) 

McGrane J. ix215 (638) 

McHenry M.B. ix363 (1116PD) 

McHugh E. ix513 (1592P) 

McIntosh A. ix70 (157P) 

McKee K. ix391 (1198P) 

McKee M.D. ix83 (203P), ix173 (505) 

McKendrick J. ix198 (581P) 

McKenna E. ix362 (1111PD) 

McLennan B. ix165 (479P) 

McManus P. ix106 (283P) 

McNally V. ix83 (202P), ix124 (344P) 

McNamara M. ix144 (410O) 

McNicholas N. ix176 (516P) 

McPartlin A.J. ix284 (859P) 

McQuillan R. ix468 (1444) 

Mdemba E. ix543 (1697P) 

Mead G. ix283 (857P) 

Mebis J. ix452 (1386P) 

Medeiros R. ix78 (184P) 

Medhat F. ix337 (1028P) 

Median D. ix67 (146P) 

Medina J. ix374 (1151) 


Medina M. ix186 (546P) 

Medioni J. ix499 (1545O), ix99 (258P), 

ix280 (845P), ix282 (852P), ix319 (966O) 

Meeus P. ix478 (1477O), ix482 (1488P) 

Mego M. ix286 (865P), ix293 (890TiP) 

Mehmud F. ix261 (792PD) 

Mehra R. ix153 (440O) 

Mehta J. ix213 (632), ix323 (981P) 

Mehta K. ix118 (323PD) 

Mehta M.P. ix148 (428P) 

Mehta S.A. ix541 (1689P) 

Meier W. ix323 (980P) 

Meireles S.R. ix525 (1639), ix147 (423P) 

Meister M. ix390 (1194P) 

Mekki F. ix344 (1051) 

Mel J.R. ix440 (1349) 

Meldgaard P. ix385 (1179O) 

Melhouf A. ix137 (389) 

Melichar B. ix329 (1001P), ix97 (254PD), 

ix116 (317O), ix160 (461P), ix258 (783O), 

ix267 (809P) 

Melisi D. ix117 (322PD) 

Mellado B. ix538 (1680P), ix266 (805P), 

ix282 (853P), ix300 (910P) 

Mellas N. ix137 (389) 

Mellemgaard A. ix444 (1361) 

Mellor S. ix492 (1521PD) 

Melnikova V. ix300 (911P) 

Melnychuk D. ix200 (586P) 

Melo A. ix331 (1010) 

Melosky B. ix412 (1255P) 

Melotti F. ix212 (628) 

Mencoboni M. ix80 (192P) 

Méndez García M. ix459 (1410), ix492 (1521PD), 

ix112 (307) 

Méndez-Vidal M.J. ix275 (832P) 

Mendez G. ix379 (1164P) 

Mendez P. ix266 (807P) 

Mendiola C. ix134 (378), ix322 (978P), 

ix325 (986P) 

Mendoza I. ix406 (1238PD) 

Meng R. ix159 (458P) 

Menichetti F. ix56 (97IN) 

Menis J. ix444 (1360), ix457 (1405) 

Menon H. ix350 (1069PD), ix351 (1074P) 

Menu Y. ix60 (112IN) 

Menzel A. ix209 (615) 

Meoni G. ix528 (1646PD) 

Merad M. ix503 (1559P), ix517 (1607P) 

Meran J. ix521 (1622) 

Mercadante S. ix518 (1612P) 

Mercier-Blas A. ix128 (355P) 

Mercier M. ix475 (1468P), ix109 (296P), 

ix120 (331P) 

Mercuro G. ix164 (476P) 

Merelli B. ix365 (1120P) 

Mergenthaler H. ix284 (858P) 

Merkelbach-Bruse S. ix481 (1486PD) 

Merlano M. ix528 (1644PD), ix113 (311), 

ix123 (340P) 

Merlin J. ix85 (210P) 

Merlini G. ix355 (1089P) 

Merlini L. ix523 (1628) 

Merlo F. ix79 (187P) 

Mesbah H. ix105 (281P) 

Mescallado N. ix319 (969PD) 

Mescoli C. ix209 (618) 

Mesker W. ix184 (540P) 

Mesnard N. ix128 (355P) 

Messa F. ix528 (1644PD) 

Messaritakis I. ix213 (631) 

Messersmith W.A. ix155 (447PD) 

Messina A. ix484 (1496P) 

Messina C. ix270 (818P) 

Messina M. ix215 (636) 

Messinger D. ix116 (317O) 

Mestek O. ix513 (1593P) 



Meszko E. ix457 (1406) 

Metges J. ix456 (1401P), ix196 (572P) 

Metro G. ix423 (1288P), ix427 (1302P) 

Metwally H.M. ix98 (256P) 

Metzer C. ix377 (1156O) 

Metzger B. ix186 (548P), ix209 (615) 

Metzner B. ix284 (858P) 

Meyboom R. ix122 (335P) 

Meyer A. ix409 (1249P) 

Meyer T. ix378 (1161P), ix245 (740P) 

Meyers J. ix535 (1670P) 

Meyers M. ix295 (895O) 

Meyers P. ix488 (1508P) 

Meynier J. ix464 (1430P) 

Mezi S. ix488 (1509P) 

Mezlini A. ix254 (774) 

Mezzetti M. ix496 (1536P) 

M-H T. ix258 (783O) 

Miccinesi G. ix516 (1601P), ix516 (1602P), 

ix520 (1617), ix524 (1631) 

Michael A. ix68 (147P), ix325 (988P) 

Michaelson M.D. ix259 (785O), ix269 (814P), 

ix297 (901PD) 

Michalarea V. ix139 (398) 

Michallet M. ix504 (1563P), ix506 (1568P), 

ix506 (1569P) 

Michel P. ix242 (730P), ix252 (767) 

Michelazzi L.A. ix80 (192P) 

Michiara M. ix175 (513PD) 

Michie C.O. ix162 (469P) 

Michielin O. ix366 (1125P) 

Michoux N. ix336 (1021PD) 

Mickisch G. ix267 (809P) 

Miclea J.M. ix260 (789O) 

Middel P. ix417 (1271P) 

Middeldorp J.M. ix88 (221P) 

Middleton G. ix224 (667PD) 

Midena E. ix371 (1140P) 

Midgley R.S. ix181 (530PD) 

Mielgo X. ix113 (310) 

Migden M.R. ix362 (1112PD) 

Migliorati C.A. ix56 (95IN) 

Migliorino M.R. ix439 (1346) 

Mihali D. ix511 (1585P) 

Mihaylov G. ix503 (1560P) 

Mikhaylova I.N. ix371 (1138P) 

Mikulski S. ix70 (155P) 

Milano G. ix528 (1644PD) 

Milch C. ix168 (489P) 

Milella M. ix237 (713P), ix240 (721P), 

ix273 (825P), ix280 (846P), ix290 (879) 

Miles D. ix59 (110IN), ix120 (329P), 

ix142 (409TiP) 

Miles D.R. ix154 (445PD) 

Milewski L. ix320 (971PD) 

Milia J. ix388 (1190P), ix403 (1232PD) 

Milićević M. ix237 (712P) 

Milione M. ix212 (628) 

Millar B. ix144 (410O) 

Miller K. ix295 (896O), ix317 (965TiP) 

Miller R. ix244 (738P) 

Miller V. ix401 (1227O) 

Milleron B. ix419 (1276P) 

Mills G.B. ix96 (249PD) 

Millward C. ix179 (523PD) 

Milner R. ix90 (227P) 

Milovanovic Z. ix544 (1702) 

Mimae T. ix385 (1180PD) 

Min D. ix119 (326PD) 

Min Y.H. ix240 (722P) 

Minajeva A. ix146 (418PD), ix149 (431) 

Minami H. ix510 (1581P) 

Minami M. ix161 (465P) 

Minato K. ix511 (1586P) 

Minear F.G. ix215 (638) 

Minegishi Y. ix412 (1256P) 

Mineta T. ix527 (1705) 

Mini E. ix178 (520O) 

Minichsdorfer C. ix72 (165) 

Mink J. ix146 (417PD) 

Mino E.A. ix470 (1450P) 

Minor D.R. ix371 (1137P) 

Minotti V. ix427 (1302P) 

Minvielle E. ix456 (1400P) 

Miolo G. ix287 (868) 

Mir O. ix91 (229P), ix167 (485P) 

Mir R. ix139 (398) 

Mirabelli D. ix247 (747P) 

Mirabile A. ix335 (1019O) 

Miraglio E. ix528 (1644PD), ix113 (311) 

Miron M.L.L. ix183 (534P) 

Mishima H. ix514 (1595P), ix93 (237) 

Mishima M. ix442 (1356) 

Miskovska’ V. ix286 (865P), ix293 (890TiP) 

Misra V. ix207 (609P) 

Misumi K. ix385 (1180PD) 

Mita A.C. ix422 (1287P), ix498 (1543TiP) 

Mitchell C.L. ix464 (1431P) 

Mitchell L. ix366 (1124P), ix366 (1125P), 

ix142 (407TiP), ix142 (408TiP), ix142 (409TiP), 

ix189 (555P) 

Mitchell P. ix542 (1692P) 

Mitry E. ix378 (1159P), ix378 (1160P), 

ix85 (209P), ix181 (529PD), ix219 (649), 

ix234 (703P) 

Mitsudomi T. ix433 (1324), ix51 (81IN) 

Mitsukawa Y. ix412 (1258P) 

Mitsuoka S. ix412 (1258P), ix79 (190P), ix92 (235) 

Mittermüller J. ix504 (1561P) 

Mittica G. ix140 (402) 

Miura E. ix517 (1606P) 

Miura K. ix211 (624) 

Miura N. ix387 (1186P) 

Miura S. ix509 (1579P), ix71 (159P) 

Miura T. ix467 (1443) 

Miyagawa S. ix211 (625) 

Miyagi M. ix248 (751) 

Miyagishima T. ix202 (592P) 

Miyake Y. ix93 (237), ix196 (573P) 

Miyamoto A. ix433 (1323) 

Miyamoto K. ix525 (1637) 

Miyamoto R. ix543 (1696P) 

Miyamoto S. ix226 (673P) 

Miyanaga A. ix383 (1174P) 

Miyashita I. ix170 (498P) 

Miyashita Y. ix228 (681P) 

Miyata H. ix481 (1485PD) 

Miyata Y. ix385 (1180PD) 

Miyazaki Y. ix481 (1485PD) 

Mizuno T. ix509 (1578P) 

Mizunuma N. ix87 (218P) 

Mizusawa J. ix231 (689P) 

Mobley J. ix544 (1701) 

Mocci E. ix472 (1456P) 

Mocciaro F. ix215 (636) 

Modest D.P. ix180 (526PD) 

Moecks J. ix411 (1254P) 

Moghaddamnia A. ix346 (1059) 

Mohajer R. ix467 (1442) 

Mohamed A. ix146 (419PD) 

Mohamed Z. ix381 (1169P) 

Mohammadian Roshan N. ix184 (538P) 

Mohanti B. ix149 (430P) 

Mohanti B.K. ix455 (1398P), ix110 (298P), 

ix264 (800P) 

Mohar-Betancourt A. ix107 (289P), ix251 (763) 

Mohd Noor A. ix165 (479P) 

Mohd Sharial M.S.N. ix300 (909P) 

Mohorcic K. ix522 (1625), ix523 (1630) 

Moiseyenko V. ix198 (581P), ix224 (668PD) 

Mok T.S.K. ix391 (1198P), ix393 (1205P), 

ix400 (1226O), ix401 (1228O), ix402 (1229PD), 

ix405 (1236PD), ix406 (1239P), ix410 (1252P), 

ix411 (1254P), ix51 (83IN) 

Molassiotis A. ix507 (1573P) 

Molero X. ix67 (145P) 

Molife L.R. ix159 (458P) 

Molife L.R. ix162 (469P) 

Molina, M.A. ix533 (1662P) 

Molina-Garido M. ix457 (1404), ix459 (1412) 

Molina-Pinelo S. ix183 (534P) 

Molina A. ix294 (894O), ix295 (895O) 

Molina A.M. ix269 (814P) 

Molina M.A. ix418 (1273P) 

Molinas E. ix448 (1373P) 

Molinier O. ix404 (1235PD) 

Moliterni A. ix102 (269P) 

Moller H. ix165 (479P) 

Molnár L. ix429 (1307P) 

Molnar E. ix223 (665TiP) 

Moncayo G.E. ix71 (160P) 

Mondal S.K. ix452 (1388P) 

Mondejar Solis R. ix264 (799P) 

Moneer M.M. ix111 (304) 

Monges G. ix184 (539P) 

Monk B.J. ix460 (1416PD) 

Monnereau A. ix219 (649) 

Monnier A. ix475 (1468P) 

Montañana M. ix365 (1123P), ix432 (1316) 

Montella T. ix289 (877) 

Montemurro G. ix212 (628) 

Montemurro M. ix480 (1482PD) 

Montero J.C.M. ix205 (604P) 

Montero M.A. ix496 (1533P) 

Monteverde M. ix528 (1644PD), ix113 (311) 

Monti M. ix496 (1536P) 

Montin E. ix344 (1050P) 

Montironi R. ix274 (829P) 

Moodley S.D. ix103 (272P) 

Moon J. ix49 (77IN) 

Moore M. ix255 (776TiP) 

Moore N. ix531 (1657P), ix219 (649) 

Morère J. ix414 (1265P), ix470 (1452P), 

ix472 (1460) 

Mora O. ix452 (1385P) 

Mora P. ix331 (1010) 

Moraes A.M. ix364 (1119P), ix365 (1121P), 

ix365 (1122P) 

Morales Juarez L. ix184 (541P) 

Morales-Barrera R. ix266 (806P), ix302 (916P) 

Morales C. ix186 (546P) 

Morales S. ix118 (323PD) 

Moran Bueno T. ix431 (1315) 

Moran S. ix302 (918P) 

Morano F. ix488 (1509P) 

Mordenti G. ix317 (965TiP) 

Moreau M. ix194 (569P) 

Moreira A. ix345 (1056), ix141 (404) 

Moreira I. ix357 (1095) 

Morelli D. ix335 (1019O) 

Morelli F. ix335 (1020PD) 

Moreno A. ix131 (365P) 

Moreno J. ix181 (527PD) 

Moreno V. ix165 (480P) 

Morente M. ix276 (835P) 

Moretti A. ix511 (1585P) 

Morgan G. ix44 (67IN) 

Morgan M.A. ix299 (908P) 

Morgan R. ix68 (147P), ix325 (988P) 

Morgan R.K. ix468 (1444) 

Morgillo F. ix430 (1309P), ix67 (143PD), 

ix75 (173O) 

Mori K. ix518 (1610P), ix526 (1643) 

ix112 (305) 

Mori M. ix411 (1253P), ix481 (1485PD), 

ix227 (677P) 

Mori S. ix375 (1152) 

Mori Y. ix427 (1301P) 

Morice P. ix322 (977P) 

Morikawa N. ix420 (1280P), ix427 (1301P) 

Morimoto C. ix170 (498P) 

Morin F. ix419 (1276P) 

Morinaga R. ix438 (1340) 

Morise M. ix439 (1343), ix445 (1366TiP) 


author index 

Morishita N. ix432 (1320), ix433 (1321) 

Morita S. ix411 (1253P), ix412 (1256P), 

ix422 (1286P), ix437 (1338), ix442 (1354), 

ix514 (1595P), ix226 (673P), ix228 (681P), 

ix230 (688P), ix233 (697P) 

Moriuchi Y. ix348 (1062O) 

Moriya Y. ix390 (1197P) 

Morley S. ix347 (1061TiP) 

Mornex F. ix206 (607P) 

Moro-Sibilot D. ix403 (1231PD), ix403 (1232PD), 

ix426 (1299P), ix446 (1367TiP) 

Moro C. ix466 (1436P) 

Morodomi Y. ix387 (1187P) 

Morokawa N. ix433 (1323) 

Morosi C. ix483 (1491P), ix484 (1496P), 

ix88 (222P) 

Moroso S. ix99 (259P) 

Morote J. ix302 (916P), ix312 (945) 

Morreau H. ix61 (116IN) 

Morris D. ix440 (1350) 

Morris K. ix199 (582P) 

Morris M. ix294 (894O), ix317 (963TiP) 

Morris S.R. ix153 (442O) 

Morse N. ix126 (350P) 

Morsli N. ix155 (446PD) 

Mortara V. ix80 (192P) 

Mosca F. ix241 (726P) 

Moscetti L. ix105 (280P) 

Moscheni O. ix330 (1005P) 

Mosconi S. ix365 (1120P) 

Mosillo C. ix440 (1348) 

Moslemi D. ix346 (1059) 

Mossman T. ix447 (1372P) 

Mostyn-Jones A. ix519 (1613P) 

Mota-García A. ix329 (1003P) 

Motizuki S. ix433 (1323) 

Motoi N. ix418 (1274P) 

Motoki T. ix74 (172O) 

Motonaga S. ix467 (1443) 

Mottolese M. ix78 (183P), ix142 (406TiP) 

Motzer R.J. ix259 (785O), ix269 (814P) 

Motzer R.J. ix262 (793PD), ix262 (794PD), 

ix262 (795PD), ix263 (796PD), ix278 (842P), 

ix292 (889TiP) 

Mougiakakos D. ix541 (1690P) 

Moukoko R. ix340 (1036P) 

Moulard O. ix213 (632), ix323 (981P) 

Moulton B. ix108 (292P) 

Mountzios G. ix338 (1030P) 

Moura J.F.P. ix464 (1429P) 

Mourad C. ix138 (392) 

Mouret-Reynier M. ix102 (270P) 

Mourey L. ix294 (893O) 

Moussaid Y. ix150 (433) 

Mouysset J. ix511 (1584P) 

Mouzount H. ix476 (1472P) 

Moya Ortega B. ix264 (799P) 

Moya A.C. ix183 (534P) 

Moya B. ix176 (517P) 

Moyo V. ix170 (496P), ix321 (974PD) 

Mozzillo N. ix375 (1152) 

Mpananis K. ix213 (631) 

Mrabti H. ix432 (1318), ix476 (1470P), 

ix476 (1472P) 

Muazzam I.A. ix358 (1100), ix497 (1539P), 

ix285 (860P) 

Muddapur M.V. ix343 (1049P), ix345 (1055) 

Muehlbauer S. ix97 (254PD) 

Mueller N. ix252 (766) 

Mueller U. ix274 (828P) 

Muenzberg M. ix502 (1555P), ix502 (1557P) 

Muggia F. ix130 (363P) 

Mukai H. ix131 (366P) 

Mukherji D. ix296 (897O), ix298 (903P), 

ix301 (913P) 

Mukhopadhyay A. ix355 (1090P), ix356 (1091P), 

ix356 (1093P), ix359 (1105), ix359 (1106), 

ix448 (1375P), ix455 (1399P), ix471 (1453P), 

ix471 (1454P), ix471 (1455P), ix472 (1457P), 

ix472 (1458P), ix133 (375P), ix135 (381), 

ix328 (997P) 

Mukhopadhyay S. ix355 (1090P), ix356 (1091P), 

ix356 (1093P), ix359 (1105), ix359 (1106), 

ix448 (1375P), ix455 (1399P), ix472 (1457P), 

ix472 (1458P), ix133 (375P), ix135 (381) 

Mukohara T. ix510 (1581P) 

Mulcahey S. ix436 (1332) 

Mulders P. ix295 (896O) 

Mulick Cassidy A. ix298 (903P), ix301 (913P) 

Müllauer L. ix352 (1076P) 

Müller S.P. ix154 (445PD) 

Müller U. ix132 (370P) 

Muller E. ix322 (977P) 

Mullins C.D. ix205 (603P), ix214 (634) 

Mullot H. ix285 (862P) 

Mummy D. ix203 (596P) 

Mun Y. ix191 (560P) 

Munemoto Y. ix514 (1595P) 

Munot K. ix358 (1103) 

Muñoz Beltran M. ix472 (1456P) 

Muñoz Martín A.J. ix198 (579P) 

Muñoz Sanchez M. ix457 (1404), ix459 (1412) 

Muñoz A. ix212 (627) 

Muñoz E. ix370 (1136P) 

Muñoz J. ix505 (1564P), ix523 (1629) 

Muñoz M. ix135 (380) 

Munroe C. ix182 (532P) 

Munster P. ix153 (442O) 

Muracciole X. ix511 (1584P) 

Murahashi M. ix536 (1671P) 

Murakami H. ix424 (1293P), ix430 (1310P), 

ix492 (1519PD) 

Murakami Y. ix517 (1608P) 

Muranyi A. ix383 (1173P) 

Murata E.P. ix216 (641) 

Murdock M.I. ix311 (943P) 

Muro K. ix139 (396), ix200 (587P), ix232 (692P), 

ix232 (694P) 

Murone C. ix542 (1692P) 

Murphy A. ix207 (610P) 

Murray N. ix412 (1255P) 

Murray R.N. ix395 (1210) 

Murray S. ix373 (1146), ix85 (211P), ix86 (213P), 

ix94 (242) 

Murtaza M. ix74 (171O) 

Murtezani Z. ix428 (1304P) 

Musante F. ix247 (747P) 

Musha N. ix228 (682P) 

Muskett D. ix284 (859P) 

Musolino A. ix175 (513PD) 

Mustacchi G. ix128 (356P) 

Musya H. ix211 (624) 

Mut P. ix374 (1150) 

Muto M. ix226 (673P) 

Mutti L. ix495 (1532P) 

Muylle K. ix33 (31IN) 

Muzaffar N. ix358 (1100), ix285 (860P) 

Muzzafar N. ix497 (1539P) 

Myerson R.J. ix130 (363P) 

Myhre S. ix96 (249PD) 

Myint A.S. ix206 (608P) 

Myleiko V.A. ix109 (293P) 

N 

Na’Amad M. ix519 (1616P) 

Na I.I. ix414 (1262P) 

Na K. ix492 (1520PD) 

Nabhan C. ix310 (941P), ix311 (943P) 

Nabholtz J. ix102 (270P) 

Nabiço R. ix357 (1097) 

Nacci A. ix95 (248O) 

Nachabé R. ix532 (1658P) 

Nadal E. ix418 (1273P) 

Nadig J. ix462 (1423O) 

Nagai H. ix442 (1356) 

Nagai K. ix387 (1186P), ix534 (1666P) 


Nagai Y. ix203 (598P) 

Nagaraj N. ix283 (857P) 

Nagase H. ix185 (542P) 

Nagase M. ix241 (728P) 

Nagata K. ix423 (1289P) 

Nagata M. ix79 (189P), ix79 (190P), ix92 (235) 

Nagata N. ix514 (1595P), ix228 (681P) 

Nagata S. ix438 (1340) 

Nagata Y. ix197 (576P) 

Nagayasu T. ix71 (161P) 

Naghiby Sustany M. ix459 (1411) 

Nagtegaal I.D. ix179 (521O) 

Nagy B. ix235 (706P) 

Nagyivanyi K. ix281 (849P) 

Naini V. ix294 (894O) 

Nair R. ix350 (1069PD), ix351 (1074P) 

Naito T. ix430 (1310P) 

Naito Y. ix429 (1306P), ix131 (366P) 

Najda J. ix353 (1082P) 

Nakagawa A. ix423 (1289P) 

Nakagawa K. ix385 (1181PD), ix393 (1204P), 

ix393 (1206P), ix397 (1218), ix424 (1293P), 

ix153 (441O), ix167 (486P), ix211 (624) 

Nakagawa Y. ix407 (1242P) 

Nakahara R. ix388 (1188P) 

Nakahara Y. ix441 (1351), ix497 (1537P) 

Nakai M. ix412 (1258P) 

Nakai T. ix79 (189P), ix79 (190P), ix92 (235) 

Nakajima K. ix481 (1485PD), ix225 (670PD) 

Nakamichi S. ix156 (451P), ix161 (467P), 

ix174 (1708PD) 

Nakamori S. ix241 (728P) 

Nakamura F. ix384 (1177P) 

Nakamura K. ix513 (1591P), ix79 (188P), 

ix231 (689P) 

Nakamura M. ix513 (1591P), ix196 (573P), 

ix200 (588P), ix202 (592P), ix232 (692P) 

Nakamura S. ix82 (199P) 

Nakamura Y. ix536 (1671P), ix159 (460P) 

Nakanishi Y. ix385 (1181PD), ix407 (1242P), 

ix438 (1340), ix536 (1671P) 

Nakano K. ix542 (1694P) 

Nakashima M. ix71 (161P) 

Nakasima Y. ix508 (1576P) 

Nakata M. ix541 (1690P) 

Nakayama G. ix542 (1693P), ix220 (655), 

ix246 (742P) 

Nakayama N. ix449 (1378P) 

Nakazawa Y. ix411 (1253P) 

Nalbantov G. ix396 (1216) 

Naldi N. ix175 (513PD) 

Namba Y. ix411 (1253P) 

Namikawa K. ix372 (1142P) 

Namikawa T. ix250 (758) 

Nandi A. ix356 (1091P) 

Nanni C. ix148 (425P) 

Nanni O. ix119 (327PD) 

Nanni P. ix537 (1675P) 

Naoki K. ix422 (1285P) 

Naomoto Y. ix250 (758) 

Naoshy S. ix213 (632) 

Napoli A. ix463 (1426P) 

Napolitano S. ix67 (143PD) 

Nappi A. ix67 (143PD) 

Nappi L. ix530 (1651P), ix532 (1659P), 

ix540 (1687), ix287 (869) 

Narain N. ix166 (482P) 

Naranjo Hans D. ix431 (1315) 

Narasimhan N.I. ix152 (439O) 

Narasimhan V. ix166 (482P) 

Narayanaswamy K. ix490 (1515) 

Nardelli G.B. ix326 (991P) 

Nardi M. ix505 (1565P), ix137 (388) 

Nardin M. ix209 (618) 

Narine N. ix93 (240) 

Narita I. ix71 (159P) 

Nascimento E.C. ix112 (306) 

Nashimoto A. ix228 (682P) 



Nasim M. ix129 (358P) 

Naskhletashvili D.R. ix435 (1330) 

Nasser N.J. ix519 (1616P) 

Nathan P. ix374 (1149), ix264 (798PD) 

Nathan S. ix467 (1442) 

Nava Garcia P. ix198 (579P) 

Navarro A. ix377 (1157O) 

Navez B. ix197 (578P) 

Navruzov S. ix331 (1008), ix254 (772), ix290 (882) 

Navruzova V. ix331 (1008), ix328 (998P) 

Nawrocki S. ix457 (1406), ix475 (1466P) 

Necchi A. ix88 (222P), ix285 (861P) 

Neef C. ix456 (1402P) 

Neeman M. ix59 (109IN) 

Negoro S. ix422 (1286P) 

Negre S. ix480 (1483PD) 

Negri F.M. ix232 (693P) 

Negri F.V. ix216 (642) 

Negri T. ix484 (1496P), ix485 (1500P) 

Negrier S. ix453 (1391P), ix262 (793PD), 

ix264 (798PD), ix279 (843P) 

Neibart S. ix312 (948) 

Neise M. ix504 (1561P) 

Nelli F. ix105 (280P) 

Nematov O. ix229 (684P), ix254 (772) 

Nemeth H. ix281 (849P), ix286 (867P) 

Nemoto N. ix407 (1242P) 

Nered S. ix252 (765) 

Neri T.M. ix175 (513PD) 

Nerich V. ix332 (1014), ix128 (357P), ix249 (753) 

Nesrine M. ix254 (774) 

Netto E. ix345 (1056) 

Netzer F. ix456 (1400P) 

Neubauer A. ix349 (1068PD) 

Neuzillet Y. ix474 (1463P) 

Neves J. ix289 (878) 

Neveux N. ix91 (229P) 

Nevinny M. ix494 (1528P) 

Neyns B. ix363 (1116PD) 

Nezu M. ix131 (366P) 

Nezu R. ix200 (588P) 

Ng C.H.M. ix119 (325PD) 

Ng Q.S. ix412 (1257P), ix70 (155P) 

Ng V. ix89 (226P) 

Ngai Y. ix421 (1282P) 

Nguyen H. ix319 (967O) 

Nguyen L.T. ix154 (445PD) 

Nguyen T. ix204 (600P), ix249 (753), ix289 (876) 

Nguyen T.V.F. ix475 (1468P) 

Niarou V. ix474 (1465P) 

Niazi T. ix200 (586P) 

Nibu K. ix510 (1581P) 

Nicacio L. ix312 (948) 

Niccoli P. ix376 (1155O) 

Nicodemo M. ix290 (879) 

Nicolai N. ix88 (222P), ix285 (861P), 

ix315 (959) 

Nicolai P. ix338 (1029P) 

Nicolas P. ix414 (1265P) 

Nicolau C. ix282 (853P) 

Nicoletti S.V.L. ix369 (1133P) 

Nicoletto M.O. ix326 (991P) 

Nicolle D. ix312 (946) 

Nicolson M. ix385 (1179O) 

Niculina V.V. ix536 (1672P) 

Niedersuess-Beke D. ix521 (1622) 

Niegisch G. ix260 (787O), ix265 (804P) 

Niethammer A. ix409 (1246P) 

Nigita G. ix111 (303) 

Nihei K. ix396 (1215) 

Niho S. ix396 (1215), ix515 (1598P), 

ix534 (1666P) 

Niikura N. ix112 (305) 

Niinepuu K. ix146 (418PD), ix149 (431) 

Nikaidoh J. ix442 (1356) 

Nikitina T.P. ix141 (403) 

Nikoglou T. ix370 (1134P), ix372 (1143P) 

Nikolaou A. ix338 (1030P), ix338 (1031P) 

Nilsson S. ix296 (898PD), ix299 (906P), 

ix308 (936P) 

Ninomiya M. ix250 (758) 

Nisbet I. ix508 (1575P) 

Nisenbaum B. ix116 (317O) 

Nishida T. ix478 (1478O), ix481 (1485PD) 

Nishikawa G. ix220 (653) 

Nishikawa K. ix227 (677P), ix230 (688P) 

Nishimoto H. ix384 (1177P) 

Nishimura G. ix188 (552P) 

Nishimura M. ix434 (1326), ix443 (1358), 

ix497 (1538P) 

Nishimura Y. ix393 (1204P) 

Nishina T. ix512 (1590P), ix196 (574P), 

ix233 (697P) 

Nishino K. ix437 (1338) 

Nishio M. ix404 (1234PD), ix413 (1260P), 

ix418 (1274P), ix441 (1353), ix153 (441O) 

Nishio S. ix326 (989P) 

Nishio W. ix92 (233) 

Nishiyama A. ix434 (1327), ix437 (1338) 

Nishizawa Y. ix210 (621) 

Nisman B. ix88 (220P) 

Nistér M. ix299 (906P) 

Nitsche D. ix178 (518O) 

Nixon L. ix498 (1542TiP) 

Nobes J. ix374 (1149) 

Nobre-Góis I. ix208 (614P) 

Nogami N. ix393 (1206P), ix434 (1327) 

Noguchi S. ix118 (324PD), ix126 (351P) 

Nogueira G.A.S. ix364 (1119P), ix365 (1121P) 

Noh S. ix332 (1012) 

Noize P. ix219 (649) 

Nokihara H. ix396 (1215), ix156 (451P), 

ix159 (459P), ix161 (467P), ix164 (475P), 

ix174 (1708PD) 

Nolan C. ix469 (1449PD) 

Nomoto K. ix200 (585P) 

Nomura F. ix518 (1610P), ix526 (1643), 

ix527 (1705) 

Nomura M. ix544 (1701) 

Nomura S. ix210 (621) 

Nonaka D. ix495 (1532P), ix80 (193P) 

Nong X. ix501 (1552P) 

Noonan K. ix305 (925P) 

Noonan S. ix176 (516P) 

Nordle Ö. ix303 (919P) 

Normanno N. ix78 (183P), ix86 (213P) 

Noro R. ix387 (1186P) 

North S. ix304 (922P) 

Northrup R. ix161 (465P) 

Nortier J.W. ix501 (1553P) 

Nosov D. ix263 (796PD) 

Nosrati F. ix248 (749) 

Nourani C.L. ix306 (929P) 

Novarino A. ix240 (724P) 

Novello S. ix442 (1355), ix444 (1360) 

Novy M. ix373 (1145) 

Nowak A.K. ix151 (437TiP) 

Nozaki K. ix71 (159P) 

Nukiwa T. ix412 (1256P), ix427 (1301P) 

Numico G. ix229 (685P) 

Nunez Hernandez I. ix302 (916P) 

Nuñez Viejo M.A. ix510 (1582P) 

Nuyts S. ix334 (1016O) 

Nuzzo C. ix368 (1130P) 

Nuzzo P.V. ix301 (914P) 

Nycum L.R. ix319 (967O) 

O 

Oaknin Benzaquen A. ix321 (975PD) 

Oba M. ix211 (625) 

Obadia V. ix136 (386) 

Obasaju C. ix421 (1281P) 

Oberaigner W. ix494 (1528P) 

Oberg K. ix377 (1156O) 

Oberkanins C. ix373 (1145) 

Oberndorfer S. ix145 (415PD) 

Obertin S. ix186 (548P) 

Obertova J. ix286 (865P), ix293 (890TiP) 

O’Brien J.P. ix146 (417PD), ix244 (737P) 

O’Brien T. ix518 (1612P), ix275 (831P) 

O’Bryan-Tear C.G. ix308 (936P) 

O’Byrne K. ix385 (1179O), ix524 (1634), 

ix73 (167O) 

O’Byrne K.J. ix402 (1229PD), ix410 (1252P), 

ix417 (1272P), ix68 (148P), ix68 (149P), 

ix68 (150P), ix495 (1531P), ix495 (1532P), 

ix69 (154P), ix78 (185P) 

O’Callaghan C. ix71 (160P) 

Ocana A. ix91 (231P) 

Occelli M. ix113 (311) 

Ochiai A. ix210 (621) 

Ochiai K. ix326 (989P), ix327 (995P) 

Ochoa de Olza M. ix370 (1136P) 

O’Connell J. ix401 (1228O) 

O’Connell M.J. ix179 (523PD) 

O’Connor B.M. ix130 (363P) 

Oconnor J.M. ix379 (1164P) 

Ocvirk J. ix504 (1562P) 

O Donovan N. ix540 (1686P) 

O’Donovan N. ix528 (1645PD), ix108 (292P) 

Oda H. ix509 (1578P) 

Oda T. ix436 (1334), ix543 (1696P) 

Odate S. ix79 (188P) 

O’Dwyer P. ix319 (966O) 

O’Dwyer P.J. ix169 (492P) 

Oeberg K. ix47 (1703IN) 

Oellers M. ix396 (1216) 

Ofosu-Appiah W. ix152 (438O) 

O Gorman P. ix525 (1635) 

Ogasawara M. ix239 (719P) 

Ogasawara T. ix434 (1325) 

Ogawa K. ix433 (1323), ix514 (1597P) 

Ogawa T. ix515 (1598P) 

Ogiwara A. ix91 (232) 

Ogura T. ix436 (1334) 

Oguro T. ix69 (153P) 

Oh H. ix193 (566P) 

Oh I. ix492 (1520PD) 

Oh S.T. ix186 (545P), ix209 (617), ix227 (679P) 

Oh W.K. ix302 (918P) 

O’Hanlon-Brown C. ix161 (464P) 

Ohara Y. ix543 (1696P) 

Ohashi Y. ix429 (1306P), ix511 (1586P), 

ix512 (1590P), ix220 (653), ix254 (775) 

Ohata K. ix220 (653) 

Ohba T. ix387 (1187P) 

Ohe Y. ix396 (1215), ix492 (1519PD), 

ix515 (1598P), ix534 (1666P) 

Ohgino K. ix422 (1285P) 

Ohigashi S. ix200 (585P) 

Ohira T. ix544 (1701) 

Ohkawa S. ix241 (728P) 

Ohkohchi N. ix543 (1696P) 

Öhlschlegel C. ix132 (370P) 

Ohmatsu H. ix515 (1598P), ix534 (1666P) 

Ohno S. ix104 (277P) 

Ohno Y. ix439 (1343) 

Ohta K. ix463 (1428P) 

Ohtsu A. ix449 (1378P), ix164 (474P), 

ix200 (587P), ix201 (590P), ix232 (694P) 

Ohyanagi F. ix418 (1274P), ix441 (1353) 

Oikawa M. ix71 (161P), ix211 (624) 

Oishi M. ix467 (1443) 

Oizumi S. ix412 (1256P), ix434 (1326), 

ix443 (1358), ix497 (1538P) 

Oka M. ix93 (237), ix159 (460P), ix240 (723P) 

Oka S. ix517 (1608P) 

Okada H. ix432 (1320), ix433 (1321) 

Okada K. ix185 (542P), ix197 (575P) 

ix207 (611P) 

Okada M. ix385 (1180PD), ix226 (672P) 

Okamoto A. ix327 (995P) 

Okamoto H. ix404 (1234PD) 

Okamoto I. ix385 (1181PD), ix233 (697P) 


author index 

Okamoto N. ix432 (1320), ix433 (1321) 

Okamoto R. ix381 (1171P) 

Okamoto W. ix167 (486P) 

Okamura T. ix441 (1351), ix497 (1537P), 

ix112 (305) 

Okayama N. ix93 (237) 

Oki M. ix517 (1608P) 

Okishio K. ix439 (1344) 

Okita K. ix244 (737P) 

Okita R. ix541 (1690P) 

Okizaki A. ix467 (1443) 

Oksuzoglu B. ix332 (1015) 

Oksuzoglu O.B. ix473 (1461), ix105 (279P) 

Okudera K. ix420 (1280P) 

Okuma T. ix439 (1344) 

Okuma Y. ix441 (1351), ix497 (1537P) 

Okumura N. ix542 (1693P), ix246 (742P) 

Okuno K. ix159 (460P) 

Okusaka T. ix241 (728P), ix244 (737P), 

ix254 (775), ix255 (776TiP) 

Okutur K. ix217 (645) 

Olaverri Hernandez A. ix457 (1404), ix459 (1412) 

Oldenburg H. ix532 (1658P) 

O’Leary J.J. ix68 (149P) 

O’Leary K. ix532 (1660P), ix73 (169O) 

Olier C. ix113 (310) 

Oliner K. ix334 (1016O) 

Oliner K.S. ix230 (687P) 

Oliva C. ix488 (1508P), ix490 (1518TiP) 

Olivares R. ix213 (632), ix323 (981P) 

Oliveira Â. ix357 (1095) 

Oliveira C. ix364 (1119P), ix365 (1121P), 

ix365 (1122P) 

Oliveira C.B.M. ix133 (374P) 

Oliveira I. ix357 (1095) 

Oliveira J. ix345 (1056) 

Oliveira M. ix531 (1656P), ix141 (404) 

Oliveira M.A. ix215 (637) 

Oliveira V. ix49 (77IN) 

Olivo Y.S. ix174 (509TiP) 

Öllers M. ix392 (1201P) 

Olmez F. ix129 (359P) 

Olmez S. ix469 (1448PD) 

Olmos D. ix162 (469P), ix298 (903P) 

Olsson A. ix303 (919P) 

Olszanski A.J. ix170 (497P) 

Omachi N. ix439 (1344) 

O’Mahony S. ix467 (1442) 

Omar A. ix288 (874) 

Omidi Ashrafi A. ix107 (287P), ix184 (538P) 

Omlin A.G. ix298 (903P), ix301 (913P) 

Omuro Y. ix381 (1171P) 

Onal C. ix526 (1641), ix526 (1642) 

Ondrus D. ix286 (865P) 

Onetti Muda ix530 (1653P), ix538 (1681P) 

Ong M. ix162 (469P) 

Onganía L. ix477 (1475) 

Onikubo T. ix513 (1591P) 

Onishi H. ix542 (1694P), ix79 (188P) 

Onland-Moret C. ix122 (335P) 

Ono A. ix430 (1310P) 

Onoda N. ix84 (205P) 

Onodera H. ix200 (585P) 

Onofri A. ix533 (1663P), ix290 (879) 

Onukwugha E. ix205 (603P), ix214 (634) 

Onuma H. ix201 (590P) 

Ooji K. ix518 (1610P), ix526 (1643) 

Oon L. ix412 (1257P) 

Oostendorp L. ix475 (1469P) 

Opatt McDowell D. ix363 (1116PD) 

Opinião A. ix175 (512PD), ix176 (514P) 

Opitz I. ix495 (1532P) 

Orel N. ix382 (1172) 

O’Reilly S. ix207 (610P), ix300 (909P) 

O’Riordain M. ix207 (610P) 

Orgiano L. ix516 (1604P), ix164 (476P) 

Orlandi A. ix84 (207P) 

Orlandi E. ix341 (1040P), ix342 (1045P) 

Orlandi F. ix290 (881) 

Orlando L. ix95 (248O) 

Orlando M. ix400 (1225O) 

Orlov S. ix405 (1236PD), ix406 (1239P) 

Orlowski T. ix395 (1211) 

Oro A. ix362 (1111PD), ix362 (1112PD) 

Orosz Z. ix493 (1523P) 

Ortega Ruiperez C. ix459 (1412) 

Ortega E. ix374 (1150) 

Ortega J.A. ix254 (773) 

Ortega L. ix377 (1157O) 

Ortega V. ix300 (910P) 

Ortiz Durán R.M. ix219 (651) 

Ortiz-Morales M.J. ix131 (365P), ix186 (546P) 

Ortiz Á. ix112 (307) 

Oruzio D. ix204 (599P) 

Orvieto E. ix124 (343P) 

Osório L. ix147 (423P) 

Osaka Y. ix89 (224P) 

Osaki Y. ix244 (737P) 

Osamu Taguchi O. ix439 (1343) 

Osanto S. ix256 (781TiP) 

Osborne M. ix215 (638) 

Osborne S. ix114 (315TiP) 

O’Shea T. ix108 (292P) 

Oshima T. ix220 (653) 

Oshiro M. ix514 (1595P) 

Osiadacz W. ix354 (1084P) 

Oskay-Özcelik G. ix172 (504) 

Osman I. ix363 (1113PD) 

Osores O. ix477 (1475) 

Ost P. ix325 (987P), ix330 (1007) 

Ostellino O. ix343 (1047P), ix346 (1058) 

Oster J. ix419 (1276P) 

Österlund P. ix190 (559P), ix195 (571P) 

Ostoros G. ix429 (1307P) 

Ostwal V.S. ix350 (1069PD) 

Ota S. ix239 (719P) 

Otero S. ix330 (1005P) 

Othman F. ix525 (1635) 

Otsuji T. ix196 (573P), ix233 (697P) 

Otsuka K. ix422 (1286P), ix423 (1289P), 

ix423 (1289P) 

Otsuka S. ix440 (1350) 

Ott G. ix440 (1347) 

Otterson G. ix424 (1291P) 

Ottevanger P.B. ix475 (1469P), ix160 (462P) 

Otto F. ix132 (370P) 

O’Toole D. ix378 (1159P) 

Otvos L.J. ix166 (483P) 

Ou D. ix253 (769) 

Ou S. ix401 (1228O) 

Ou S.I. ix389 (1191PD), ix415 (1267P), 

ix424 (1291P) 

Ouali M. ix483 (1493P) 

Oubel E. ix534 (1665P) 

Oudard S. ix499 (1545O), ix99 (258P), 

ix259 (786O), ix263 (797PD), ix271 (820P), 

ix278 (842P), ix280 (845P), ix282 (852P), 

ix294 (893O), ix307 (933P), ix312 (946) 

Ould Kaci M. ix155 (446PD) 

Ouyang M. ix438 (1341) 

Oven Ustaalioglu B. ix497 (1540) 

Overgaard J. ix96 (249PD) 

Overman M.J. ix220 (656) 

Oyama R. ix201 (590P) 

Oyen W.J.G. ix60 (115IN), ix192 (562P) 

Oyen W.J.G. ix160 (462P) 

Oza A.M. ix155 (448PD), ix156 (450PD), 

ix158 (455P), ix322 (978P) 

Ozaki Y. ix226 (673P) 

Ozatli T. ix105 (279P) 

Ozaydin S. ix286 (866P) 

Özçimen A. ix312 (947) 

Ozdemir N. ix332 (1015) 

Oze I. ix232 (692P) 

Ozen H. ix307 (932P), ix308 (934P) 

Ozer-Stillman I. ix283 (856P) 


Ozet A. ix227 (678P), ix277 (838P) 

Özgüroğlu M. ix307 (933P) 

Ozkan A. ix469 (1448PD) 

Ozkan L. ix291 (885) 

Ozkan M. ix332 (1015) 

Ozkan S. ix277 (838P) 

Ozsahin E.M. ix334 (1016O) 

Oztop I. ix234 (701P) 

Ozturk H. ix291 (885) 

Ozturk M. ix286 (866P) 

Ozturk M.A. ix186 (547P) 

Ozyilkan O. ix392 (1202P), ix425 (1294P), 

ix520 (1620), ix526 (1641), ix526 (1642), 

ix237 (711P), ix238 (715P) 

P 

Paccagnella A. ix335 (1020PD) 

Paccapelo A. ix148 (425P) 

Pachón V. ix377 (1157O) 

Pachow D. ix147 (420PD) 

Paesmans M. ix408 (1243P) 

Páez de La Cadena M. ix92 (234) 

Páez D. ix408 (1244P), ix183 (536P), ix185 (544P), 

ix216 (641) 

Paganelli G. ix47 (75IN) 

Pagani A. ix99 (260P) 

Pahwa P. ix182 (531P) 

Pai J. ix355 (1087P) 

Paik S. ix179 (523PD) 

Paillaud E. ix452 (1387P), ix460 (1419PD) 

Pailler M. ix414 (1265P) 

Pairet G. ix197 (578P) 

Paksoy Türköz F. ix543 (1698P) 

Paksoy F. ix104 (278P) 

Pal S. ix309 (938P) 

Palacios Ozores P. ix328 (1000P) 

Palacka P. ix293 (890TiP) 

Palassini E. ix484 (1496P), ix485 (1500P) 

Palazzo A. ix440 (1348), ix488 (1509P) 

Palka M. ix459 (1410), ix492 (1521PD), 

ix494 (1527P), ix112 (307) 

Pall G. ix494 (1528P) 

Palladini G. ix355 (1089P) 

Pallarés C. ix408 (1244P) 

Pallaud C. ix405 (1236PD), ix406 (1239P), 

ix531 (1657P), ix81 (198P) 

Palleschi D. ix145 (416PD) 

Pallier K. ix77 (180P) 

Pallisgaard N. ix530 (1654P), ix73 (168O) 

Palluzzi E. ix524 (1633) 

Palmer D. ix242 (731P), ix245 (740P) 

Palmer M. ix402 (1229PD) 

Palmieri C. ix532 (1660P) 

Palmieri G. ix364 (1118PD), ix540 (1687) 

Palomar L. ix106 (284P) 

Palou J. ix292 (888) 

Palozzo A.C. ix439 (1345), ix283 (854P) 

Palozzo A.C. ix447 (1370P) 

Palumbo A. ix360 (1108TiP) 

Palumbo R. ix123 (339P), ix138 (391) 

Pan E. ix146 (417PD) 

Pan H. ix256 (780TiP) 

Pan J. ix281 (847P) 

Pan K. ix227 (676P) 

Pan Q. ix256 (780TiP) 

Pan S. ix485 (1499P), ix485 (1501P), ix282 (851P) 

Pan Z. ix189 (556P) 

Panchapakesan B. ix87 (217P) 

Pandha H. ix68 (147P), ix292 (889TiP) 

Pandiella A. ix91 (231P) 

Pandite L.N. ix261 (791PD), ix275 (833P) 

Pandolfi P.P. ix59 (107IN) 

Pang H. ix389 (1193P) 

Panneerselvam A. ix376 (1154O), ix118 (324PD), 

ix126 (351P), ix278 (842P) 

Panni S. ix442 (1355) 

Paño B. ix282 (853P) 

Pant M.C. ix339 (1034P) 



Pantano F. ix489 (1512), ix516 (1603P), 

ix530 (1653P), ix538 (1681P), ix206 (606P) 

Pantuck A. ix292 (889TiP) 

Panzone F. ix462 (1422O), ix463 (1427P), 

ix466 (1438P) 

Pao W. ix401 (1227O) 

Paoletti X. ix464 (1430P) 

Paolicchi E. ix85 (208P) 

Paolini B. ix285 (861P) 

Paolini J. ix297 (901PD) 

Papa S. ix165 (479P) 

Papadaki C. ix381 (1170P), ix429 (1308P), 

ix213 (631) 

Papadatos G. ix100 (262P) 

Papadopolous N. ix454 (1392P) 

Papadopoulos K. ix165 (481P), ix169 (492P) 

Papadopoulos N. ix366 (1126P) 

Papadopoulou K. ix430 (1312) 

Papakostas P. ix213 (630) 

Papandreou C. ix95 (246O), ix255 (777TiP), 

ix289 (876), ix307 (932P) 

Papasotiriou I. ix136 (385) 

Papavassiliou A.G. ix92 (236) 

Papiani G. ix285 (863P) 

Paré L. ix408 (1244P), ix185 (544P) 

Parati M. ix102 (269P) 

Pardo F. ix239 (718P) 

Pardo N. ix265 (802P), ix266 (807P) 

Paredes J. ix127 (352P) 

Parekh B.B. ix356 (1092P), ix134 (377) 

Parente P. ix306 (931P) 

Parikh A. ix156 (449PD) 

Parikh B. ix356 (1092P), ix134 (377) 

Parikh P.M. ix301 (912P) 

Park C. ix492 (1520PD) 

Park I. ix480 (1481PD), ix227 (679P), 

ix234 (700P), ix276 (834P), ix287 (872) 

Park J. ix433 (1324), ix227 (679P) 

Park J.H. ix480 (1481PD) 

Park J.S. ix240 (722P) 

Park K. ix391 (1198P), ix424 (1292P), 

ix430 (1311P), ix276 (834P), ix287 (872) 

Park K.H. ix102 (271P), ix185 (543P) 

Park K.U. ix193 (566P) 

Park K.W. ix249 (752) 

Park K.W. ix250 (757) 

Park L.C. ix450 (1381P) 

Park S. ix375 (1153), ix430 (1311P), ix276 (834P) 

Park S.J. ix287 (872) 

Park W.S. ix353 (1080P) 

Park Y. ix352 (1077P) 

Park Y.S. ix450 (1381P), ix479 (1479PD), 

ix227 (679P) 

Parker C. ix38 (49IN), ix296 (898PD), 

ix301 (913P), ix308 (936P) 

Parker I. ix108 (292P) 

Parkes E.E. ix107 (288P) 

Parlak C. ix392 (1202P), ix425 (1294P), 

ix520 (1620), ix526 (1641), ix526 (1642), 

ix237 (711P), ix238 (715P) 

Parmar D. ix339 (1034P) 

Parmar M.K. ix324 (982P) 

Parno J. ix493 (1522PD) 

Parreira J. ix175 (512PD), ix176 (514P) 

Parrozzani R. ix371 (1140P) 

Parthan A. ix235 (704P) 

Pascual T. ix134 (378), ix325 (986P) 

Pasov V. ix311 (944P) 

Pass H.I. ix495 (1532P) 

Passalacqua R. ix474 (1462PD), ix232 (693P) 

Passardi A. ix240 (724P) 

Passaro A. ix488 (1509P) 

Passos Lima C.S. ix339 (1032P) 

Pastorek M. ix286 (865P) 

Pastorelli D. ix439 (1345), ix447 (1370P) 

Patané A.K. ix496 (1535P) 

Patard J. ix292 (889TiP) 

Patel A. ix292 (889TiP) 

Patel A.A. ix356 (1092P), ix134 (377) 

Patel K.M. ix356 (1092P), ix134 (377) 

Patel R. ix321 (974PD) 

Patel S. ix366 (1126P), ix454 (1392P) 

Patel T. ix124 (344P) 

Pathania S. ix358 (1103) 

Paties C. ix216 (642) 

Patil B.R. ix343 (1049P) 

Patil P.S. ix541 (1689P) 

Patil S. ix98 (257P) 

Patnaik A. ix165 (481P), ix169 (492P) 

Patnick J. ix53 (88IN) 

Paton V.E. ix445 (1364TiP), ix445 (1365TiP) 

Patrick D. ix509 (1580P) 

Patsouris E. ix541 (1691P) 

Patton S. ix86 (213P) 

Patuzzo R. ix484 (1496P) 

Patyna S. ix376 (1155O) 

Paule B. ix243 (733P) 

Pauly M. ix209 (615) 

Pautier P. ix329 (1001P), ix322 (977P), 

ix322 (978P), ix327 (993P) 

Pauwels P. ix481 (1487P) 

Pavel M. ix376 (1154O), ix377 (1156O) 

Pavesi L. ix99 (260P) 

Pavlakis K. ix338 (1031P) 

Pavlakis N. ix419 (1278P) 

Pavlick A. ix363 (1113PD), ix363 (1115PD) 

Pavlidis N. ix381 (1170P), ix95 (246O) 

Pawaskar D.K. ix155 (447PD) 

Pawaskar P. ix350 (1069PD) 

Pawitan Y. ix299 (906P) 

Pawlyn C. ix44 (67IN) 

Paye F. ix241 (727P) 

Paz-Ares L. ix404 (1235PD), ix407 (1241P), 

ix411 (1254P), ix418 (1275P), ix157 (454P), 

ix235 (705P) 

Paze E. ix291 (884) 

Peña J.A. ix292 (888) 

Pearlberg J. ix321 (974PD) 

Peat J.K. ix499 (1544O) 

Peck R. ix385 (1179O) 

Pécuchet N. ix499 (1545O), ix77 (180P), 

ix99 (258P) 

Pecorari G. ix343 (1047P), ix346 (1058) 

Pecori B. ix193 (567P) 

Pectasides D. ix95 (246O) 

Pedani F. ix346 (1058) 

Pedrazzani C. ix452 (1385P) 

Pedrazzi G. ix216 (642) 

Peeters M. ix190 (558P), ix194 (569P), 

ix194 (570P) 

Pelizon C. ix142 (407TiP), ix142 (408TiP) 

Pellegrino D. ix440 (1348) 

Pellegrino R. ix339 (1032P) 

Pelletier G. ix243 (733P) 

Pelling K. ix161 (464P) 

Pelov D. ix258 (783O) 

Pelt V.G. ix184 (540P) 

Pemberton K. ix161 (464P) 

Pena C. ix395 (1212) 

Penault-Llorca F. ix102 (270P), ix105 (281P), 

ix180 (525PD) 

Penel N. ix482 (1488P), ix488 (1510P) 

Peng Y. ix260 (788O) 

Peng Z. ix299 (906P) 

Pennert K. ix273 (827P) 

Pentheroudakis G. ix381 (1170P), ix239 (717P) 

Penzel R. ix390 (1194P) 

Pereira A.A.L. ix112 (306), ix181 (528PD) 

Pereira B.S.V. ix215 (637) 

Pereira D. ix132 (371P) 

Pereira J. ix447 (1372P) 

Pereira J.R. ix403 (1233PD) 

Pereira V. ix538 (1680P) 

Peretz-Yablonski T. ix88 (220P), ix109 (294P), 

ix142 (409TiP) 

Pérez R. ix406 (1238PD) 

Perez Alvarez S.I. ix184 (541P) 

Pérez-Callejo D. ix492 (1521PD) 

Pérez Callejo D. ix459 (1410), ix494 (1527P), 

ix112 (307) 

Perez Cano M. ix431 (1315) 

Pérez Gracia J.L. ix275 (832P), ix432 (1316) 

Perez Gracia J.L. ix508 (1577P) 

Pérez González N. ix183 (537P) 

Perez-Carrion R. ix125 (345P) 

Perez-Galan P. ix44 (66IN) 

Perez-Moreno P. ix419 (1278P) 

Pérez Ramírez S. ix176 (517P) 

Perez-Sánchez V. ix107 (289P) 

Pérez-Valderrama B. ix275 (832P), ix314 (953) 

Perez E.A. ix89 (226P), ix142 (408TiP) 

Perez J. ix370 (1136P) 

Perez Q. ix218 (647), ix314 (953) 

Pericay C. ix235 (705P) 

Pericleous L. ix370 (1134P), ix372 (1143P) 

Permyakova V.I. ix109 (293P) 

Pernot S. ix75 (174O) 

Perol D. ix397 (1219) 

Perol M. ix397 (1219), ix426 (1299P) 

Perracchio L. ix142 (406TiP) 

Perricone G. ix215 (636) 

Perrin C. ix105 (281P) 

Perrin P. ix299 (907P) 

Perrin S. ix461 (1420PD) 

Perrone F. ix342 (1045P), ix212 (628) 

Perrone G. ix538 (1681P) 

Perrone T. ix515 (1599P) 

Perruccio K. ix535 (1668P) 

Pertuželka L. ix81 (196P) 

Pescarmona E. ix142 (406TiP) 

Pesce I. ix364 (1117PD) 

Pesce V. ix379 (1164P) 

Peschel A. ix480 (1484PD) 

Pessi M.A. ix516 (1601P), ix520 (1617), 

ix524 (1631) 

Pessi M.A. ix516 (1602P) 

Petekkaya _I.H. ix543 (1698P) 

Peters F.P. ix501 (1553P) 

Peters G. ix537 (1676P) 

Peters K. ix146 (417PD) 

Peters S. ix385 (1179O), ix61 (119IN), 

ix403 (1232PD), ix73 (167O) 

Petersen I. ix394 (1208) 

Petersen I.A. ix329 (1002P) 

Peterson P. ix428 (1303P) 

Petit T. ix142 (408TiP) 

Petrakis D. ix381 (1170P) 

Petrelli F. ix435 (1328), ix467 (1440), 

ix515 (1599P), ix519 (1615P), ix131 (368P), 

ix192 (563P) 

Petremolo A. ix316 (962TiP) 

Petricoin E. ix533 (1664P) 

Petrillo A. ix193 (567P) 

Petrillo P. ix370 (1135P) 

Petruzelka L. ix513 (1593P), ix81 (197P), 

ix116 (317O) 

Petry Helena V. ix455 (1397P) 

Petrylak D.P. ix302 (918P), ix311 (943P) 

Petzer A.L. ix209 (616) 

Pezaro C. ix298 (903P), ix301 (913P), ix304 (924P) 

Pfeiffer P. ix188 (553P) 

Pfeiler G. ix100 (261P) 

Pfister S.M. ix31 (25IN) 

Pfisterer J. ix324 (982P) 

Pfreundschuh M. ix349 (1068PD) 

Phan V. ix499 (1544O) 

Phelip J. ix181 (529PD), ix218 (648) 

Phelip J.M. ix242 (730P) 

Philip P.A. ix244 (735P) 

Phillips H.S. ix505 (1566P) 

Phuan C. ix199 (583P) 

Piacentini F. ix101 (267P) 

Piard F. ix206 (607P) 

Piatek C. ix314 (952) 


author index 

Piau S. ix456 (1401P) 

Piazzalunga D. ix365 (1120P) 

Piccart M. ix58 (103IN), ix95 (247O), 

ix118 (324PD), ix126 (351P) 

Pichler J. ix147 (421P) 

Pichon E. ix419 (1276P) 

Pickering L. ix273 (827P) 

Picozzi V. ix236 (709P) 

Picquenot J.M. ix339 (1033P) 

Pienkowski T. ix103 (273P), ix116 (317O) 

Pierantoni C. ix387 (1184P) 

Pierdomenico F. ix357 (1096) 

Pietra C. ix520 (1618), ix161 (465P) 

Pietrantonio F. ix410 (1251P), ix212 (628) 

Pignon J. ix397 (1217), ix74 (170O), ix198 (580P) 

Pigozzo J. ix369 (1131P), ix371 (1140P) 

Piha-Paul S.A. ix154 (444PD) 

Pikó B. ix223 (665TiP) 

Pilati P.L. ix371 (1140P), ix486 (1504P) 

Pili F. ix287 (868) 

Pili R. ix303 (919P) 

Pilla L. ix369 (1133P) 

Pilotti S. ix342 (1045P), ix483 (1491P), 

ix484 (1496P), ix485 (1500P) 

Pilotto S. ix442 (1355), ix117 (322PD) 

Pinato D.J. ix381 (1169P) 

Pini A. ix448 (1373P) 

Pinitpatcharalerd A. ix339 (1035P) 

Pino M.S. ix237 (713P), ix240 (721P) 

Pinski J. ix261 (790O), ix306 (928P), ix314 (952), 

ix316 (961) 

Pinto A. ix511 (1585P), ix277 (839P) 

Pinto C. ix78 (183P) 

Piperi C. ix92 (236) 

Piquet J. ix455 (1396P) 

Pircher A. ix494 (1528P), ix76 (178P) 

Pirker R. ix417 (1272P) 

Pisconti S. ix370 (1135P) 

Piscopo G. ix539 (1682P) 

Pistelli M. ix250 (756) 

Pistilli B. ix116 (318O) 

Pitot H. ix222 (662TiP) 

Pittman K. ix208 (612P) 

Pitz C. ix425 (1296P) 

Piulats J.M. ix370 (1136P) 

Piulats J.R. ix294 (894O) 

Piutti M. ix206 (607P) 

Piva F. ix86 (215P) 

Piva S. ix511 (1585P) 

Pivette J. ix456 (1401P) 

Pivot X. ix332 (1014), ix470 (1452P), ix472 (1460), 

ix531 (1657P), ix103 (272P), ix114 (315TiP), 

ix128 (357P), ix249 (753) 

Pizzolitto S. ix457 (1405) 

Pizzuti L. ix142 (406TiP) 

Planchard D. ix496 (1534P), ix94 (244) 

Plante M. ix324 (982P) 

Plasswilm L. ix132 (370P) 

Plata Fernandez M.Y. ix101 (268P) 

Plaza J.C. ix233 (699P) 

Plazaola A. ix82 (200P) 

Pless M. ix396 (1214) 

Plestina S. ix86 (212P) 

Plummer R. ix374 (1149), ix129 (358P) 

Poddar S. ix356 (1091P), ix328 (997P) 

Podlipny J. ix474 (1464P) 

Podoll T. ix170 (498P) 

Poehlein C. ix267 (810P), ix269 (816P) 

Poggi R. ix145 (416PD), ix147 (424P) 

Poggio F. ix454 (1393P), ix501 (1551PD) 

Poitevin-Chacón A. ix329 (1003P) 

Polat O. ix227 (678P) 

Poleri C. ix496 (1535P) 

Poletti P. ix485 (1500P) 

Poli R. ix232 (693P) 

Pollak M. ix302 (917P) 

Polli A. ix402 (1230PD) 

Polyakova N.A. ix141 (403) 

Pompei L. ix105 (280P) 

Pompili C. ix387 (1184P) 

Pond G.R. ix265 (804P), ix297 (901PD) 

Pons Valladares F. ix233 (699P), ix278 (840P) 

Pontikakis S. ix429 (1308P) 

Poole C. ix142 (407TiP) 

Poon R. ix244 (736P) 

Pop S. ix519 (1614P) 

Popat S. ix409 (1246P) 

Popova M.E. ix398 (1223) 

Popovski T. ix99 (258P) 

Porneuf M. ix196 (572P) 

Porras I. ix131 (365P) 

Porta C. ix225 (669PD), ix261 (792PD), 

ix264 (798PD), ix271 (820P), ix273 (825P), 

ix278 (840P) 

Porta R. ix388 (1189P) 

Portela C. ix357 (1097) 

Porter D. ix487 (1507P) 

Portielje J.E.A. ix100 (263P) 

Portnoy S. ix130 (364P) 

Porzio R. ix216 (642) 

Postigo A. ix67 (145P) 

Potebnia G.P. ix536 (1672P) 

Potepan P. ix344 (1050P) 

Pottel H. ix341 (1042P) 

Pottel L. ix341 (1042P) 

Potter V. ix181 (530PD) 

Potthast M. ix520 (1618) 

Pouessel D. ix294 (893O) 

Poulain P. ix518 (1612P) 

Poupon M. ix312 (946) 

Pour L. ix348 (1064O) 

Pourali L. ix107 (287P) 

Pourel N. ix391 (1199P) 

Pourrli Neelakantan R. ix331 (1011) 

Poveda A.M. ix490 (1517TiP), ix324 (984P) 

Powderly J.D. ix258 (784O) 

Powell S. ix98 (257P) 

Power D.G. ix207 (610P), ix248 (750), 

ix300 (909P) 

Powers J. ix304 (922P) 

Powles T. ix172 (501), ix290 (880) 

Powles T.B. ix272 (822P), ix278 (840P), 

ix292 (887) 

Pozzi E. ix123 (339P), ix138 (391) 

Pozzo C. ix433 (1322), ix84 (207P) 

Prévost S. ix350 (1071P) 

Pradhan R. ix173 (507) 

Prager G. ix221 (659) 

Prasad Sahoo T. ix404 (1235PD) 

Prasad R.R. ix291 (883) 

Prasongsook N. ix339 (1035P) 

Prati V. ix290 (879) 

Prausova J. ix198 (581P) 

Precivale M. ix450 (1380P) 

Prestifilippo A. ix505 (1565P), ix137 (388) 

Prete A. ix440 (1348) 

Preusser M. ix145 (414PD), ix145 (415PD), 

ix147 (421P), ix148 (426P) 

Price N. ix73 (167O) 

Price T. ix178 (519O), ix182 (532P), ix187 (550P), 

ix194 (570P), ix208 (612P) 

Prickett T.D. ix25 (11IN) 

Primi C. ix516 (1601P) 

Principe E. ix113 (311) 

Prior J. ix480 (1482PD) 

Priou F. ix259 (786O), ix294 (893O) 

Pritchard K. ix118 (324PD), ix126 (351P) 

Procopio G. ix270 (818P), ix272 (824P), 

ix276 (836P), ix288 (873), ix305 (926P), 

ix315 (959) 

Proença M. ix458 (1409) 

Prohaszka Z. ix493 (1523P) 

Pronzato P. ix454 (1393P), ix463 (1425P), 

ix501 (1551PD), ix521 (1621), ix79 (187P), 

ix123 (340P) 

Proskorovsky I. ix279 (843P) 

Prot S. ix531 (1657P) 

Provencher L. ix531 (1657P) 

Provencio Pulla M. ix351 (1073P), ix414 (1264P), 

ix459 (1410), ix492 (1521PD), ix494 (1527P), 

ix510 (1582P), ix112 (307) 

Provent S. ix260 (789O) 

Prudkin L. ix154 (443PD) 

Pruegsanusak K. ix339 (1035P) 

Psyrri A. ix334 (1018O), ix42 (60IN), ix43 (63IN) 

Puccia F. ix215 (636) 

Puente J. ix438 (1342) 

Puertolas T. ix374 (1150) 

Puglia L. ix540 (1687), ix316 (962TiP) 

Puglisi F. ix142 (409TiP) 

Puhlmann M. ix321 (975PD) 

Pujade-Lauraine E. ix324 (984P), ix327 (993P) 

Pujol B. ix523 (1628) 

Pujol E. ix441 (1352) 

Pujol J. ix386 (1182P), ix418 (1275P) 

Pulatov D.A. ix71 (162P) 

Pulido G. ix131 (365P), ix140 (400), ix186 (546P) 

Puma E. ix102 (269P) 

Puma F. ix387 (1185P) 

Puneri G. ix83 (201P) 

Punt C.J.A. ix363 (1114PD), ix179 (521O), 

ix192 (562P) 

Puntoni M. ix119 (327PD) 

Puntus T. ix521 (1622) 

Purcell C. ix249 (754) 

Purohith S. ix358 (1102) 

Purushotham A. ix133 (372P) 

Pusceddu S. ix288 (873) 

Pusztai L. ix74 (172O), ix29 (19IN) 

Puyol J.R. ix448 (1373P) 

Puzanov I. ix170 (497P), ix259 (785O) 

Q 

Qi W. ix398 (1220), ix119 (326PD) 

Qi Y. ix74 (172O) 

Qian J. ix148 (428P), ix256 (779TiP) 

Qian W. ix378 (1161P) 

Qian Y. ix360 (1108TiP), ix479 (1480PD) 

Qiang L. ix416 (1269P) 

Qiang X. ix229 (686P) 

Qin J. ix495 (1530P) 

Qin S. ix416 (1269P), ix282 (851P) 

Qiu J. ix281 (847P) 

Qu X. ix437 (1337), ix93 (238), ix138 (394) 

Quadri P. ix452 (1385P) 

Quantin X. ix406 (1240P) 

Quaratino S. ix211 (622) 

Quarleri L. ix355 (1089P) 

Queirolo P. ix366 (1124P), ix367 (1128P), 

ix368 (1130P), ix369 (1131P), ix369 (1132P), 

ix369 (1133P), ix373 (1148) 

Queiroz L. ix357 (1095), ix357 (1097) 

Quek R. ix485 (1499P), ix485 (1501P) 

Queralt Herrero C. ix431 (1315) 

Queralt B. ix219 (651) 

Queralt C. ix418 (1273P), ix533 (1662P) 

Quercia S. ix130 (362P) 

Quero C. ix351 (1073P) 

Quidde J. ix459 (1413TiP) 

Quietzsch D. ix204 (599P) 

Quinn D.I. ix261 (790O), ix311 (942P), 

ix314 (952), ix316 (961) 

Quintavalle C. ix539 (1682P) 

Quintero G. ix440 (1349) 

Quintyne K.I. ix114 (312) 

Quirke P. ix179 (521O) 

Quoix E. ix419 (1276P) 

Quon D. ix480 (1483PD), ix166 (482P) 

Qvortrup C. ix188 (553P) 

R 

Rabault B. ix157 (454P) 

Radema S.A. ix122 (335P) 

Raderer M. ix352 (1076P) 




Raemdonck D.V. ix212 (626) 

Raggi D. ix285 (861P) 

Raghavan D. ix261 (790O), ix314 (952) 

Rahal A. ix486 (1502P) 

Rahal C. ix486 (1502P) 

Rahal M. ix337 (1028P) 

Rahhali R. ix110 (297P) 

Raies H. ix254 (774) 

Raikou M. ix236 (707P) 

Raimondo L. ix343 (1047P), ix346 (1058) 

Raimundo A. ix201 (591P), ix210 (620), 

ix221 (657) 

Raina P. ix312 (948) 

Raina V. ix349 (1067PD), ix354 (1085P), 

ix358 (1101), ix455 (1398P), ix110 (298P) 

Rais G. ix476 (1470P), ix476 (1472P) 

Raissouni S. ix476 (1470P), ix476 (1472P) 

Raja A. ix483 (1492P) 

Raja F.A. ix324 (982P) 

Rajappa S. ix174 (510TiP) 

Raje N. ix360 (1108TiP) 

Rajec J. ix293 (890TiP) 

Rajendranath R. ix490 (1515) 

Rajer M. ix446 (1368TiP) 

Rajic L. ix359 (1104) 

Rajkovic E. ix350 (1072P) 

Raju R. ix170 (496P) 

Rako I. ix86 (212P) 

Ramée J.F. ix196 (572P) 

Ramón Y Cajal T. ix408 (1244P) 

Ram Z. ix72 (163P) 

Ramaekers B.L.T. ix397 (1217) 

Ramalingam S.S. ix529 (1647PD) 

Ramirez Fallas R.A. ix184 (541P) 

Ramlau R. ix395 (1211) 

Rammer M. ix209 (616) 

Ramon Y Cajal S. ix84 (204P) 

Ramondino S. ix330 (1004P) 

Ramos Vazquez M. ix273 (826P) 

Ramos D. ix181 (527PD) 

Ramos T. ix432 (1316), ix183 (537P) 

Ramsey S. ix203 (596P) 

Rana D.N. ix93 (240) 

Ranade A.A. ix301 (912P) 

Rancic M. ix428 (1304P) 

Rangarajan, V. ix351 (1074P) 

Rangarajan B. ix174 (510TiP) 

Ransom D. ix178 (519O) 

Raoul J.L. ix376 (1155O), ix184 (539P), 

ix241 (727P) 

Rapetti S.G. ix442 (1355), ix444 (1360) 

Raphael J. ix496 (1534P), ix94 (244) 

Raponi M. ix236 (709P) 

Rasco D. ix165 (481P) 

Raspagliesi F. ix330 (1004P) 

Rastrelli M. ix486 (1504P) 

Ratain M.J. ix319 (966O) 

Rathkopf D. ix296 (897O), ix303 (920P), 

ix317 (964TiP) 

Rathkopf D.E. ix295 (895O) 

Rathmann N. ix480 (1484PD) 

Ratnayake J. ix83 (202P) 

Ratta R. ix530 (1653P) 

Ratti M. ix330 (1004P), ix232 (693P) 

Rauch E. ix348 (1064O) 

Rauh S. ix458 (1407) 

Rauscher B. ix373 (1145) 

Ravaioli A. ix232 (695P) 

Ravaud A. ix258 (783O), ix259 (786O), 

ix263 (797PD), ix292 (889TiP) 

Ravic M. ix350 (1072P) 

Ray-Coquard I. ix478 (1477O), ix488 (1511P), 

ix327 (993P) 

Ray-Coquard I.L. ix481 (1487P), ix482 (1488P) 

Ray U.K. ix356 (1093P) 

Raymond E. ix334 (1017O), ix376 (1155O), 

ix379 (1163P), ix167 (485P) 

Razak A.R.A. ix156 (450PD), ix158 (455P), 

ix158 (457P) 

Razis E. ix213 (630) 

Rea D. ix539 (1682P), ix97 (253PD), 

ix119 (325PD) 

Read J. ix499 (1544O) 

Reardon D.A. ix146 (417PD) 

Reck M. ix404 (1235PD), ix405 (1236PD), 

ix406 (1239P), ix408 (1245P), ix409 (1249P), 

ix410 (1250P), ix493 (1522PD), ix75 (175PD), 

ix52 (85IN) 

Reckova M. ix293 (890TiP) 

Reda W. ix150 (432) 

Reddy S. ix224 (666O) 

Reddy S.K. ix517 (1605P) 

Redekop W.K. ix450 (1379P) 

Redmond K. ix66 (142IN) 

Redondo A. ix490 (1517TiP) 

Reed G. ix223 (664TiP) 

Reed N. ix329 (1001P), ix378 (1161P) 

Rego J.F.M. ix181 (528PD) 

Reguart N. ix418 (1273P) 

Reichardt P. ix478 (1478O), ix479 (1480PD), 

ix481 (1486PD), ix482 (1490P) 

Reichert V. ix529 (1647PD), ix533 (1664P) 

Reid G. ix169 (493P) 

Reif M. ix237 (712P) 

Reig Torras O. ix282 (853P) 

Reig O. ix343 (1046P) 

Reijers J. ix103 (274P) 

Reijneveld J. ix145 (415PD) 

Reina J.J. ix380 (1165P) 

Reinisch S. ix340 (1038P) 

Reinmuth N. ix390 (1194P) 

Reis-Filho J. ix224 (667PD) 

Reis L.O. ix306 (929P) 

Reiser M. ix504 (1561P) 

Reisman A. ix403 (1231PD), ix416 (1268P) 

Reisman D. ix78 (186P) 

Ren L. ix190 (557P), ix201 (589P), ix217 (644) 

Ren S. ix81 (195P) 

Ren X. ix282 (851P) 

Rendleman J. ix363 (1113PD) 

Renehan A.G. ix207 (609P) 

Reni M. ix240 (724P) 

Renouf D. ix188 (551P), ix204 (601P), ix215 (635) 

Repana D. ix430 (1312) 

Rescigno P. ix439 (1345), ix447 (1370P), 

ix283 (854P), ix316 (962TiP) 

Resiga L. ix337 (1026P) 

Resteghini C. ix335 (1019O), ix341 (1040P) 

Reusch U. ix350 (1072P) 

Reuss A. ix390 (1194P), ix322 (976P), 

ix323 (980P) 

Reuter C.W.M. ix299 (908P) 

Rey A. ix410 (1250P) 

Reychler H. ix336 (1021PD) 

Reyderman L. ix129 (358P) 

Reyes-Rivera I. ix190 (559P), ix193 (565P), 

ix195 (571P) 

Reyes C. ix451 (1384P), ix477 (1474) 

Reymen B. ix396 (1213), ix425 (1296P) 

Reyners A.K.L. ix40 (57IN) 

Reyno L. ix317 (963TiP) 

Reynolds C. ix393 (1205P) 

Reynoso N. ix251 (763) 

Rezai M. ix117 (321PD) 

Rezazadeh M. ix459 (1411) 

Rha S.Y. ix185 (543P) 

Riahi K. ix321 (974PD) 

Ribal M.J. ix538 (1680P), ix312 (945) 

Ribas A. ix158 (456P) 

Ribeiro J. ix289 (878) 

Ribeiro K.B. ix112 (306) 

Ribelles N. ix101 (268P) 

Ribi K. ix462 (1423O) 

Riccardi A. ix123 (339P), ix138 (391) 

Ricchini F. ix507 (1571P) 

Ricci F. ix301 (914P) 

Ricci J. ix121 (334P), ix122 (336P) 

Ricci S. ix238 (714P), ix251 (761), ix251 (762) 

Ricciardi G.R.R. ix104 (276P) 

Ricciardi S. ix439 (1346) 

Ricevuto E. ix524 (1633), ix213 (629) 

Richard D. ix68 (149P) 

Richard F. ix241 (725P) 

Richards D. ix170 (496P) 

Richards J. ix368 (1129P) 

Richman S.D. ix179 (521O) 

Rick O. ix284 (858P) 

Ricker J.L. ix83 (203P), ix173 (505), ix173 (507) 

Rickmann M. ix67 (145P) 

Ridolfi L. ix367 (1128P) 

Ridolfi R. ix370 (1135P), ix373 (1148) 

Ridwelski K. ix228 (680P) 

Riechelmann R.P. ix450 (1380P), ix181 (528PD) 

Riely G.J. ix415 (1267P) 

Riera-Knorrenschild J. ix178 (518O) 

Riess H. ix255 (776TiP) 

Riet F. ix277 (837P) 

Rigaux P. ix488 (1510P) 

Rijavec E. ix79 (187P) 

Riley J. ix485 (1498P) 

Rimassa L. ix225 (669PD) 

Rimawi M.F. ix142 (407TiP) 

Rinaldi G. ix368 (1130P) 

Rinaldi L. ix524 (1633) 

Rinck-Junior J.A. ix364 (1119P), ix365 (1121P), 

ix365 (1122P) 

Rinck J.A.Jr ix308 (934P) 

Rinderknecht J.D. ix366 (1125P) 

Rindi G. ix47 (73IN) 

Rini B.I. ix259 (785O), ix262 (793PD) 

Rini B.I. ix268 (811P) 

Rios M. ix236 (708P) 

Ripamonti C.I. ix516 (1601P), ix516 (1602P), 

ix520 (1617), ix524 (1631) 

Riquelme A. ix205 (604P) 

Riquet M. ix77 (180P) 

Risi E. ix488 (1509P) 

Rittmeyer A. ix386 (1182P) 

Rittweger K. ix445 (1364TiP), ix187 (550P) 

Riva G. ix343 (1047P), ix346 (1058) 

Rivalland G. ix487 (1507P) 

Rivera Salceda A.D. ix126 (349P) 

Rivera D. ix126 (349P) 

Rivera F. ix233 (699P) 

Rivera P. ix198 (580P) 

Rivera V.M. ix152 (439O) 

Rivoire M. ix286 (864P) 

Rivoltini L. ix361 (1110O) 

Rixe O. ix170 (497P) 

Rizvi S. ix231 (691P) 

Rizzo G. ix99 (260P) 

Rizzo M. ix276 (836P) 

Rizzolo C.A. ix215 (636) 

Robert C. ix367 (1127P) 

Robert F. ix424 (1291P) 

Robinot G. ix426 (1299P) 

Roca E. ix379 (1164P) 

Rocca Cossu P. ix287 (868) 

Rocchetto M. ix326 (991P) 

Rocha E. ix524 (1632) 

Roche P. ix146 (419PD) 

Rochlitz C. ix372 (1144) 

Roda D. ix159 (458P) 

Roder H. ix407 (1241P) 

Rodionova M. ix130 (364P) 

Rodon J. ix537 (1675P), ix84 (204P), ix157 (454P), 

ix158 (457P) 

Rodrigues Pereira J. ix400 (1225O) 

Rodrigues A. ix331 (1010) 

Rodrigues H. ix132 (371P) 

Rodríguez Ariza A. ix530 (1652P) 


author index 

Rodríguez Rodríguez M. ix92 (234) 

Rodríguez Rubí D. ix218 (647) 

Rodríguez-Moreno J.F. ix276 (835P) 

Rodríguez R.M. ix131 (365P) 

Rodriguez Alonso M. ix198 (579P) 

Rodriguez Garrote M. ix206 (606P) 

Rodriguez Gayo L. ix198 (579P) 

Rodriguez Pantigoso W. ix224 (668PD) 

Rodriguez-Antona C. ix276 (835P) 

Rodriguez-Lescure A. ix140 (400) 

Rodriguez-Vida A. ix370 (1136P) 

Rodriguez C. ix281 (850P) 

Rodriguez I. ix533 (1661P) 

Rodriguez J. ix149 (429P), ix239 (718P) 

Roeffen M.H.S. ix484 (1497P) 

Rofe C. ix172 (501) 

Roganovic J. ix359 (1104) 

Roghanian A. ix70 (157P) 

Rogowski W. ix223 (665TiP) 

Roh J.K. ix185 (543P) 

Roh S.Y. ix250 (757) 

Rojas P. ix363 (1115PD) 

Rojo F. ix80 (194P), ix187 (549P) 

Roldão M. ix345 (1056) 

Rolfe L. ix236 (709P) 

Rolland F. ix294 (893O) 

Roman M.P. ix543 (1697P) 

Romeder F. ix249 (755) 

Romeira D. ix458 (1409) 

Romejko-Jarosinska J. ix354 (1084P) 

Romero Laorden N. ix113 (310) 

Romero-Ventosa E.Y. ix92 (234) 

Romero I. ix324 (984P) 

Romieu G. ix62 (121IN) 

Rommel D. ix336 (1021PD) 

Roncalli M. ix77 (181P) 

Roncella M. ix176 (515P) 

Rong A. ix194 (570P) 

Roos M. ix157 (452P) 

Rosa R. ix530 (1651P), ix532 (1659P), ix287 (869) 

Rosales-Pérez S. ix329 (1003P) 

Rosales A. ix496 (1535P) 

Rosas Camargo V. ix184 (541P) 

Rosati M.S. ix502 (1557P) 

Rosbrook B. ix262 (793PD) 

Rose C. ix409 (1249P), ix241 (725P) 

Rosell R. ix385 (1179O), ix418 (1273P), 

ix431 (1315), ix529 (1647PD), ix531 (1655P), 

ix533 (1661P), ix533 (1662P), ix533 (1664P), 

ix73 (167O), ix74 (170O), ix229 (686P), 

ix266 (807P) 

Rosen L.S. ix482 (1490P), ix156 (449PD), 

ix157 (452P), ix168 (489P) 

Rosen P. ix160 (461P) 

Rosenberg J.E. ix39 (50IN) 

Rosenberg M. ix496 (1535P) 

Rosenberg P. ix514 (1596P), ix539 (1683P), 

ix172 (504) 

Rosenberg R. ix179 (522PD) 

Rosenberg S.A. ix25 (11IN) 

Rosenblatt J.D. ix353 (1083P) 

Rosenfeld N. ix74 (171O) 

Rosenthal M.A. ix151 (437TiP) 

Roshan V. ix149 (430P) 

Ross G. ix83 (202P) 

Ross J.R. ix485 (1498P) 

Ross M. ix371 (1137P) 

Rossetto C. ix457 (1405) 

Rossi C.R. ix486 (1504P), ix131 (367P) 

Rossi E. ix489 (1512), ix77 (181P), ix91 (230P) 

Rossi J. ix349 (1068PD) 

Rossi M.S. ix215 (637) 

Rossi S. ix370 (1136P) 

Rossoni G. ix410 (1251P), ix167 (487P), 

ix172 (502) 

Rosti G. ix458 (1408), ix285 (863P) 

Rotarski M. ix499 (1547PD) 

Roth A.D. ix480 (1482PD), ix37 (45IN) 

Rothe A. ix350 (1072P) 

Rothe F. ix98 (255PD) 

Rothermundt C.A. ix302 (917P) 

Rotmensz N. ix83 (201P) 

Rottenberg G. ix275 (831P) 

Rottey S. ix341 (1042P), ix287 (870) 

Roué G. ix44 (66IN) 

Rouanne M. ix474 (1463P) 

Rouas G. ix98 (255PD) 

Rougier P. ix191 (561P), ix194 (568P) 

Rouleau E. ix175 (511PD) 

Roulstone V. ix537 (1677P) 

Rouquette I. ix388 (1190P) 

Rousseau V. ix389 (1192PD), ix474 (1463P) 

Rouyer M. ix219 (649) 

Roveta A. ix247 (747P) 

Rowen D. ix372 (1143P) 

Rowsell C. ix490 (1516) 

Roy P.S. ix351 (1074P) 

Roy R. ix284 (859P) 

Roy U.K. ix355 (1090P), ix359 (1105), 

ix359 (1106), ix133 (375P) 

Rozumna-Martynyuk N. ix300 (909P) 

Ruíz Vozmediano J. ix254 (773) 

Ru Q. ix116 (318O) 

Rubagotti A. ix301 (914P) 

Rubin J. ix222 (662TiP) 

Rubini F. ix440 (1348) 

Rubino C. ix364 (1118PD) 

Rubio B. ix441 (1352) 

Rubio G. ix80 (194P) 

Rubio I. ix212 (627) 

Rubio I.T. ix95 (247O) 

Rubio M. ix388 (1189P) 

Rucinska M. ix457 (1406), ix475 (1466P) 

Rudà R. ix140 (402) 

Rudd R. ix421 (1282P) 

Rudin C.M. ix319 (966O) 

Rudman S. ix275 (831P) 

Rueda A. ix351 (1073P) 

Ruers T.J.M. ix330 (1006P), ix532 (1658P), 

ix35 (39IN), ix211 (622) 

Ruff P. ix198 (581P) 

Ruffion A. ix299 (907P) 

Rugge M. ix533 (1661P), ix209 (618) 

Ruggeri E.M. ix105 (280P) 

Ruginescu I. ix341 (1041P), ix345 (1053) 

Rugo H. ix118 (324PD), ix121 (334P) 

Rugo H.S. ix130 (363P) 

Ruijter E. ix111 (301) 

Ruiperez C.O. ix457 (1404) 

Ruiz-Valdepeñas A. ix459 (1410), ix492 (1521PD), 

ix494 (1527P), ix112 (307) 

Ruíz Voxmediano J. ix254 (773) 

Ruiz E.B. ix251 (763) 

Ruiz G.C. ix251 (763) 

Ruiz L. ix218 (647), ix277 (839P) 

Rumpold H. ix209 (616) 

Ruperez Blanco A.B. ix176 (517P) 

Ruquet S. ix116 (318O) 

Rüssel J. ix357 (1098) 

Russell P. ix542 (1692P) 

Russo L. ix99 (259P) 

Ruszniewski P. ix378 (1160P), ix379 (1163P) 

Rutgers E. ix532 (1658P) 

Rutkowski P. ix478 (1478O), ix479 (1480PD), 

ix480 (1482PD), ix482 (1490P), ix484 (1495P), 

ix489 (1513) 

Ryabchikov D. ix130 (364P) 

Ryan C.J. ix294 (894O), ix295 (895O), 

ix303 (920P) 

Ryan C.J. ix317 (964TiP) 

Ryan D.P. ix156 (449PD), ix224 (666O) 

Rykov I.V. ix141 (403) 

Ryoo B. ix480 (1481PD), ix227 (679P), 

ix234 (700P) 


Ryu H. ix454 (1392P), ix541 (1688PD) 

Ryu M.H. ix480 (1481PD), ix227 (679P), 

ix234 (700P) 

Ryuge M. ix517 (1608P) 

Ryuge N. ix225 (671P) 

S 

Sá A. ix208 (614P) 

Sa-Cunha A. ix219 (649), ix238 (716P), 

ix243 (733P) 

Saad F. ix295 (896O), ix297 (899PD), ix315 (956), 

ix316 (960) 

Saada E. ix337 (1025P), ix340 (1037P), 

ix341 (1041P), ix345 (1053) 

Sabbatini R. ix290 (879) 

Saber M.M. ix134 (376) 

Sabin Domínguez P. ix264 (799P) 

Sablin M. ix519 (1614P) 

Sabourin J.C. ix416 (1270P), ix85 (210P), 

ix213 (629), ix252 (767) 

Sabry M. ix448 (1374P), ix449 (1376P) 

Saburi Y. ix348 (1062O) 

Sacco C. ix276 (836P) 

Sacconi A. ix183 (535P) 

Sachiko O. ix82 (199P) 

Sacks N. ix301 (915P) 

Sadaba B. ix508 (1577P) 

Sadahiro S. ix185 (542P), ix188 (552P), 

ix197 (575P), ix207 (611P) 

Sadikov A. ix522 (1625), ix523 (1630) 

Sadus-Wojciechowska M. ix353 (1082P) 

Saeb-Parsy K. ix93 (240) 

Safanda M. ix503 (1560P) 

Saffery C. ix224 (667PD) 

Safont M.J. ix529 (1648P) 

Sagaert X. ix222 (663TiP) 

Saghatchian M. ix128 (355P) 

Sagi M. ix109 (294P) 

Sahebjam S. ix155 (448PD) 

Sahin B. ix326 (990P) 

Sahmoud T. ix118 (324PD), ix121 (334P), 

ix126 (351P), ix231 (691P) 

Sahoo R.K. ix264 (800P) 

Sahoo T.P. ix400 (1225O) 

Said S. ix332 (1013) 

Saida Y. ix71 (159P) 

Saijo Y. ix420 (1280P) 

Sainato A. ix241 (726P) 

Sairi A. ix485 (1499P), ix485 (1501P) 

Saisho S. ix541 (1690P) 

Saito H. ix434 (1325), ix445 (1366TiP) 

Saito K. ix509 (1578P) 

Saito M. ix327 (995P) 

Saito N. ix210 (621) 

Saito Y. ix112 (305) 

Saiura A. ix211 (625) 

Saji S. ix104 (277P), ix188 (552P), 

ix200 (588P) 

Sajjady G. ix493 (1525P) 

Saka H. ix445 (1366TiP), ix517 (1608P) 

Sakai D. ix196 (573P) 

Sakai G. ix514 (1597P), ix203 (598P) 

Sakai H. ix404 (1234PD) 

Sakaida T. ix144 (412O) 

Sakamaki F. ix525 (1637) 

Sakamoto J. ix514 (1595P), ix93 (237), 

ix200 (588P), ix228 (681P), ix230 (688P) 

Sakamoto M. ix87 (216P) 

Sakata Y. ix202 (592P) 

Sakr H. ix129 (360P), ix216 (639) 

Sakurai N. ix211 (624) 

Salah A.F. ix109 (294P) 

Salamoon M.I. ix72 (164) 

Salat C. ix514 (1596P), ix539 (1683P) 

Salati M. ix387 (1184P) 

Salaun B. ix361 (1110O), ix386 (1182P) 

Salazar Blanco J. ix183 (536P), ix185 (544P) 



Salazar R. ix377 (1156O), ix377 (1157O), 

ix529 (1648P), ix178 (520O), ix179 (522PD) 

Salcedo M. ix496 (1533P) 

Saleh M. ix317 (964TiP) 

Salem M. ix342 (1043P), ix244 (735P) 

Salem N. ix150 (434) 

Saleri J. ix474 (1462PD) 

Salesi N. ix502 (1557P) 

Saletan S. ix122 (336P) 

Salgado M.A.V. ix205 (604P) 

Salgado M.L. ix147 (423P) 

Salgia R. ix403 (1231PD), ix416 (1268P), 

ix152 (439O) 

Salman T. ix234 (701P) 

Saloustros E. ix139 (395) 

Salud A. ix233 (699P) 

Salvador Garrido N. ix328 (1000P) 

Salvador C. ix106 (284P) 

Salvadori B. ix94 (243) 

Salvagni S. ix225 (669PD) 

Salvalaggio A. ix144 (411O) 

Salvi S. ix301 (914P) 

Salvini J. ix183 (535P) 

Salvioni R. ix88 (222P), ix285 (861P), ix315 (959) 

Salzberg M. ix396 (1214) 

Samantas E. ix337 (1026P), ix430 (1312), 

ix239 (717P) 

Samer C.F. ix538 (1678P) 

Sami A. ix503 (1559P), ix517 (1607P) 

Samoylenko I.V. ix371 (1138P) 

Samper E. ix67 (145P) 

Samper P. ix312 (945) 

Samuels Y. ix25 (11IN) 

Sánchez-Ollé G. ix302 (916P) 

Sánchez-Rovira P. ix101 (268P) 

Sanchez-Muñoz A. ix101 (268P) 

Sanchez-Muñoz A. ix140 (400) 

Sanchez-Tilo E. ix67 (145P) 

Sánchez J.J. ix533 (1661P), ix533 (1662P), 

ix229 (686P), ix265 (802P), ix266 (807P) 

Sánchez M.L. ix218 (647) 

Sánchez P. ix131 (365P), ix186 (546P) 

Sanchez A. ix314 (953) 

Sanchez B. ix266 (807P) 

Sanchez F.B. ix331 (1009) 

Sanchez R. ix82 (200P) 

Sancho Gutiérrez A. ix212 (627) 

Sandell M. ix384 (1178TiP) 

Sandhu S. ix298 (903P), ix304 (924P) 

Sandin R. ix269 (815P), ix279 (843P), 

ix281 (848P) 

Sandoval F. ix75 (174O) 

Sands R. ix312 (948) 

Sandström P. ix281 (848P) 

Sane S.P. ix101 (265P) 

Sanfilippo R. ix483 (1493P) 

Sanjuanbenito A. ix472 (1456P) 

Sankhala K. ix480 (1483PD) 

Sanmamed M.F. ix365 (1123P) 

Sanna S. ix496 (1536P) 

Sano M.V. ix104 (275P) 

Sanon M. ix235 (704P) 

Santaballa A. ix106 (284P) 

Santarpia L. ix74 (172O) 

Santegoets S. ix301 (915P) 

Santeufemia D. ix287 (868) 

Santi S. ix251 (761), ix251 (762) 

Santiago Crespo J. ix457 (1404), ix459 (1412) 

Santiesteban E. ix406 (1238PD) 

Santinelli A. ix387 (1184P), ix533 (1663P) 

Santini D. ix489 (1512), ix500 (1550PD), 

ix516 (1603P), ix530 (1653P), ix538 (1681P), 

ix130 (362P), ix206 (606P) 

Santini F.C. ix112 (306) 

Santisteban M. ix149 (429P) 

Santo A. ix496 (1536P) 

Santomé L. ix273 (826P) 

Santoni-Rugiu E. ix80 (191P) 

Santoni M. ix148 (425P), ix270 (818P), 

ix290 (879) 

Santoro A. ix407 (1241P), ix483 (1494P), 

ix487 (1506P), ix153 (440O), ix167 (488P), 

ix172 (504), ix225 (669PD) 

Santos A.A. ix464 (1429P) 

Santos S. ix175 (512PD), ix176 (514P) 

Sanz J. ix438 (1342) 

Sapino A. ix140 (402) 

Sarıcı F.S. ix543 (1698P) 

Saracino B. ix237 (713P) 

Sarangarajan R. ix166 (482P) 

Sarantopoulos J. ix168 (489P), ix303 (921P) 

Saretok M. ix149 (431) 

Sargent D.J. ix535 (1670P) 

Sargento I. ix345 (1056) 

Sari E. ix497 (1540) 

Saridaki Z. ix213 (631) 

Sarkar S.K. ix452 (1388P) 

Sarker D. ix165 (479P) 

Sarker S. ix272 (822P) 

Sárosi V. ix429 (1307P) 

Sarr C. ix158 (457P) 

Sarsık B. ix274 (830P) 

Sartor A.O. ix296 (898PD), ix307 (933P) 

Sartor O. ix38 (47IN), ix308 (936P) 

Sartor O.A. ix296 (897O) 

Sartorius U. ix188 (554P), ix191 (561P) 

Saruwatari K. ix438 (1340) 

Sarwar N. ix272 (822P) 

Sasajima Y. ix372 (1142P) 

Sasaki A. ix87 (216P) 

Sasaki E. ix381 (1171P) 

Sasaki H. ix327 (995P) 

Sasaki K. ix188 (552P) 

Sasaki R. ix510 (1581P) 

Sasaki T. ix381 (1171P) 

Sasaki Y. ix202 (593P) 

Sasatomi T. ix248 (751) 

Sasse A. ix513 (1594P), ix181 (528PD), 

ix306 (929P) 

Sastre J. ix377 (1157O), ix190 (559P), ix195 (571P) 

Sato E. ix508 (1576P) 

Sato K. ix509 (1579P) 

Sato S. ix220 (653) 

Sato T. ix196 (573P) 

Satoh T. ix167 (486P) 

Satouchi M. ix393 (1204P), ix424 (1293P) 

Satow R. ix536 (1673P) 

Satre J. ix183 (537P) 

Saunders M.P. ix199 (582P), ix206 (608P), 

ix207 (609P) 

Saura C. ix531 (1656P), ix116 (318O) 

Saura S. ix441 (1352) 

Savage R. ix244 (738P), ix245 (739P) 

Savarino G. ix79 (187P) 

Saveanu A. ix146 (419PD) 

Savic S. ix385 (1179O), ix73 (167O) 

Savini A. ix387 (1184P), ix533 (1663P) 

Savulsky C. ix129 (358P) 

Sawa T. ix439 (1343) 

Sawada T. ix383 (1175P), ix87 (216P) 

Sawaki A. ix231 (689P) 

Sawaki M. ix139 (396) 

Sawan B. ix350 (1071P) 

Sawicki S. ix320 (970PD) 

Sawkins K. ix151 (437TiP) 

Sawrycki P. ix409 (1246P) 

Sawyer E. ix139 (398) 

Sax C. ix145 (415PD), ix147 (421P) 

Sayaloune P. ix100 (262P) 

Sayer H.G. ix284 (858P) 

Scagliotti G. ix415 (1267P) 

Scagliotti G.V. ix444 (1360) 

Scalese M. ix127 (354P) 

Scaltriti M. ix126 (350P) 

Scambia G. ix514 (1596P), ix539 (1683P), 

ix323 (980P) 

Scaramellini G. ix341 (1040P), ix342 (1045P) 

Scarpa A. ix25 (12IN), ix226 (675P), ix287 (869) 

Scarpellini P. ix335 (1019O) 

Scartozzi M. ix431 (1313), ix86 (214P), 

ix86 (215P), ix219 (652), ix239 (720P), 

ix243 (734P), ix250 (756), ix274 (829P) 

Schöffski P. ix478 (1478O), ix518 (1609P), 

ix154 (445PD) 

Schützová M. ix504 (1562P) 

Schachar R. ix416 (1268P) 

Schad F. ix453 (1389P), ix466 (1437P) 

Schaeper C. ix409 (1249P) 

Schalhorn A. ix204 (599P) 

Scheithauer W. ix178 (518O), ix253 (768) 

Schellens J. ix153 (442O) 

Schellens J.H.M. ix538 (1678P), ix32 (29IN) 

Schellhammer P. ix310 (940P) 

Schelman W. ix224 (666O) 

Schepotin I. ix134 (379) 

Scher H.I. ix89 (223P), ix294 (894O), 

ix295 (896O), ix297 (899PD), ix317 (964TiP) 

Scherer S.J. ix390 (1194P), ix405 (1236PD), 

ix406 (1239P), ix531 (1657P), ix81 (198P) 

Scherpereel A. ix408 (1243P) 

Schiavon G. ix500 (1550PD), ix530 (1653P) 

Schiavone P. ix95 (248O) 

Schildhaus H. ix481 (1486PD) 

Schilf A. ix340 (1037P), ix341 (1041P), 

ix345 (1053) 

Schiller J.H. ix409 (1246P) 

Schinzari G. ix433 (1322) 

Schirmacher P. ix394 (1208) 

Schlenk R.F. ix349 (1068PD) 

Schlichting C. ix195 (571P) 

Schlichting M. ix188 (554P) 

Schlijper R. ix212 (626) 

Schlumberger M.J. ix154 (445PD) 

Schmalfeldt B. ix322 (976P) 

Schmid K.W. ix437 (1339) 

Schmid P. ix532 (1660P), ix537 (1675P), 

ix73 (169O), ix123 (341P) 

Schmid T. ix494 (1528P) 

Schmidinger M. ix278 (841P) 

Schmidt-Wolf I.G. ix268 (813P) 

Schmidt M. ix178 (518O), ix268 (813P) 

Schmitt F. ix127 (352P) 

Schmitz J. ix289 (876) 

Schmitz S. ix336 (1021PD), ix457 (1403), 

ix458 (1407), ix504 (1561P), ix42 (58IN) 

Schmoll H. ix357 (1098), ix187 (550P) 

Schmoll H.J. ix336 (1023PD), ix178 (518O) 

Schnabel P. ix390 (1194P) 

Schneeweiss A. ix514 (1596P), ix539 (1683P), 

ix83 (202P), ix142 (409TiP) 

Schneid H. ix518 (1612P) 

Schneider M. ix332 (1014) 

Schneider V. ix337 (1025P) 

Schnell C. ix537 (1675P) 

Schnell D. ix161 (464P), ix162 (468P) 

Schoenberg S.O. ix480 (1484PD) 

Schott E. ix255 (778TiP) 

Schreibelt G. ix363 (1114PD) 

Schrijvers D. ix452 (1386P) 

Schroff M. ix268 (813P) 

Schuckman A. ix261 (790O) 

Schuebbe G. ix487 (1505P) 

Schuette J. ix480 (1484PD), ix482 (1490P) 

Schuhmacher C. ix228 (680P) 

Schuler M. ix402 (1229PD), ix410 (1252P), 

ix437 (1339), ix157 (454P) 

Schultz N. ix89 (223P) 

Schulze M. ix306 (930P) 

Schumann A. ix237 (712P) 

Schusterbauer C. ix160 (461P) 

Schwabe C. ix162 (470P) 

Schwartz B. ix244 (738P), ix245 (739P) 

Schwartz G.K. ix319 (966O) 

Schwartz J. ix363 (1115PD) 


author index 

Scoggins C.R. ix371 (1137P) 

Scott A. ix542 (1692P) 

Scotte F. ix499 (1545O) 

Scudder C. ix181 (530PD) 

Sculier J. ix408 (1243P) 

Seah T. ix182 (533P) 

Seal B. ix205 (603P), ix214 (634) 

Sebag-Montefiori D. ix206 (608P) 

Sebagh M. ix243 (733P) 

Sebastia M.C. ix282 (853P) 

Sebastian F. ix388 (1189P) 

Seber E.S. ix217 (645) 

Seber S. ix497 (1540) 

Sebio Garcia A. ix183 (536P), ix185 (544P), 

ix216 (641) 

Secen N. ix428 (1304P) 

Seddon B. ix482 (1490P) 

Segagni D. ix535 (1669P) 

Segal-Eiras A. ix210 (619) 

Segelov E. ix181 (530PD) 

Segnan N. ix53 (88IN) 

Segota Z. ix498 (1543TiP) 

Sehouli J. ix514 (1596P), ix539 (1683P), 

ix172 (504), ix323 (980P) 

Seilanian Toosi M. ix107 (287P), ix184 (538P) 

Seilanian Tousi M. ix248 (749) 

Seiler R. ix148 (427P) 

Seitz J. ix378 (1159P), ix242 (730P) 

Sejda A. ix73 (167O) 

Seki A. ix426 (1298P) 

Seki N. ix442 (1354), ix469 (1447PD) 

Seki R. ix525 (1637) 

Seki Y. ix159 (459P) 

Sekiguchi R. ix393 (1206P), ix397 (1218) 

Sekimoto A. ix467 (1443) 

Sekine I. ix396 (1215) 

Sekulic A. ix362 (1112PD) 

Selby B. ix297 (899PD) 

Selek U. ix237 (711P) 

Seligmann J.F. ix500 (1549PD) 

Sella A. ix313 (950) 

Sella T. ix313 (950) 

Selle F. ix260 (789O), ix322 (978P), ix327 (993P) 

Selvarajah L. ix468 (1444) 

Selzer E. ix340 (1038P) 

Semiglazov V. ix103 (272P) 

Semiglazov V.F. ix139 (397) 

Semiglazov V.V. ix139 (397) 

Semiglazova T.Y. ix139 (397) 

Seminara P. ix105 (282P) 

Sempoux C. ix197 (578P) 

Şen S. ix274 (830P) 

Sen A.N. ix471 (1454P), ix471 (1455P), 

ix328 (997P) 

Senellart H. ix406 (1240P), ix426 (1299P), 

ix169 (494P), ix218 (648) 

Senetta R. ix140 (402) 

Sengar M. ix350 (1069PD), ix351 (1074P) 

Sengelov L. ix307 (932P) 

Senn-Schönenberger I.K. ix132 (370P) 

Senn H. ix132 (370P) 

Sensi E. ix183 (535P) 

Seoane J. ix531 (1656P) 

Seol Y.M. ix172 (503) 

Sepúlveda J. ix96 (250PD) 

Sepulveda Sanchez J. ix281 (850P) 

Sequist L.V. ix402 (1229PD), ix405 (1237PD), 

ix410 (1252P), ix152 (438O), ix51 (82IN) 

Serejo F. ix255 (777TiP) 

Sereno M. ix374 (1151), ix441 (1352) 

Sergi D. ix142 (406TiP) 

Sergi M. ix493 (1525P) 

Serke M. ix409 (1247P) 

Seronde A. ix85 (210P) 

Serpe R. ix462 (1422O), ix463 (1427P), 

ix466 (1438P), ix164 (476P) 

Serra V. ix84 (204P) 

Serrano D. ix83 (201P) 

Serrano G. ix187 (549P) 

Sersch M. ix191 (560P) 

Sersch M.A. ix190 (559P) 

Sertic J. ix86 (212P) 

Seruga B. ix91 (231P) 

Servent V. ix101 (266P) 

Sessa C. ix40 (56IN) 

Sestak I. ix75 (176PD) 

Seth A. ix264 (800P) 

Sethugavalar B. ix106 (283P) 

Seto T. ix387 (1187P), ix153 (441O) 

Severin K. ix504 (1561P) 

Sevilla I. ix377 (1157O), ix380 (1165P) 

Sevin E. ix263 (797PD) 

Seymour L. ix389 (1192PD) 

Seymour M. ix500 (1549PD) 

Sezer O. ix360 (1108TiP) 

Sfakianaki M. ix429 (1308P), ix213 (631) 

Sfiniadakis I. ix541 (1691P) 

Sforza V. ix67 (143PD) 

Sgargi P. ix175 (513PD) 

Sgouros J. ix239 (717P) 

Sgroi D. ix126 (350P) 

Shablak A. ix267 (808P) 

Shafaeddin-Schreve B. ix372 (1144) 

Shah M. ix376 (1154O), ix428 (1303P), 

ix154 (445PD) 

Shah P.M. ix356 (1092P), ix134 (377) 

Shah S.A. ix356 (1092P), ix134 (377) 

Shah V. ix70 (157P) 

Shahabi V. ix75 (175PD) 

Shahid R.K. ix182 (531P) 

Shahid T. ix301 (912P) 

Shahidi M. ix402 (1229PD), ix410 (1252P) 

Shak S. ix179 (523PD) 

Shaker M. ix253 (770) 

Shalenkov V. ix252 (765) 

Shamash J. ix272 (822P), ix290 (880) 

Shamseddine A. ix288 (874) 

Shang S. ix363 (1113PD) 

Shankar G. ix157 (452P) 

Shankar S. ix355 (1090P) 

Shankaran V. ix203 (596P) 

Shanks J. ix267 (808P) 

Shanmugam K. ix383 (1173P) 

Shao W. ix161 (466P) 

Shao Y. ix363 (1113PD) 

Shao Z. ix130 (361P) 

Shapiro G. ix163 (471P) 

Shapiro R. ix363 (1113PD) 

Shaplygin L.V. ix398 (1223), ix521 (1623) 

Sharan B. ix174 (510TiP) 

Sharawat S.K. ix349 (1067PD) 

Sharif S. ix179 (523PD) 

Sharifi H. ix396 (1216) 

Sharkar A.M. ix468 (1444) 

Sharma A. ix349 (1067PD), ix354 (1085P), 

ix358 (1101) 

Sharma M. ix304 (922P) 

Sharma R. ix381 (1169P) 

Sharma S. ix153 (440O) 

Sharma S.C. ix242 (729P) 

Sharp L. ix315 (957) 

Sharpe K. ix172 (501) 

Shaw Dulin R.J. ix107 (289P), ix126 (349P) 

Shaw A. ix402 (1230PD), ix416 (1268P) 

Shaw A.T. ix389 (1191PD), ix403 (1233PD), 

ix415 (1267P), ix423 (1290P), ix152 (439O), 

ix153 (440O) 

Shaw H. ix374 (1149) 

Shaw J. ix533 (1664P) 

Shay Levi L. ix463 (1426P) 

Shehata S. ix537 (1676P) 

Sheikh N. ix311 (942P), ix311 (943P) 

Shen K. ix117 (320PD) 

Shen L. ix217 (646), ix231 (690P), ix231 (691P), 

ix307 (933P) 

Shen P. ix501 (1552P) 


Shen W. ix421 (1281P) 

Shen Y. ix246 (744P) 

Shen Z. ix398 (1220), ix427 (1300P), 

ix119 (326PD), ix126 (348P) 

Shenjere P. ix90 (227P) 

Shepherd F.A. ix417 (1272P), ix74 (170O), 

ix78 (186P) 

Sherer S. ix82 (200P) 

Sherman S. ix154 (445PD) 

Sherrill B. ix191 (560P), ix192 (564P) 

Sheth S. ix425 (1297P) 

Shi G. ix501 (1552P) 

Shi J. ix138 (394) 

Shi N. ix267 (810P), ix269 (816P) 

Shi P. ix124 (342P) 

Shi S. ix138 (394) 

Shi Y. ix390 (1196P), ix394 (1209), ix424 (1292P), 

ix435 (1331), ix77 (182P), ix111 (302) 

Shia A. ix532 (1660P), ix73 (169O) 

Shiah H. ix246 (744P) 

Shibata T. ix492 (1519PD), ix159 (459P), 

ix233 (697P), ix327 (995P) 

Shibuya M. ix441 (1351), ix497 (1537P) 

Shieh F. ix432 (1316) 

Shields A.F. ix244 (735P) 

Shigeki Satoh S. ix439 (1343) 

Shih N. ix538 (1679P) 

Shim H. ix467 (1441) 

Shim H.J. ix468 (1446) 

Shimada A.K. ix112 (306) 

Shimada K. ix217 (646) 

Shimada M. ix442 (1356), ix225 (671P), 

ix326 (989P) 

Shimada T. ix510 (1581P) 

Shimada Y. ix512 (1590P), ix529 (1649P), 

ix202 (593P), ix203 (598P), ix251 (764) 

Shimamoto T. ix164 (474P) 

Shimamura H. ix211 (624) 

Shimizu C. ix90 (228P) 

Shimizu J. ix433 (1324) 

Shimizu K. ix360 (1108TiP), ix541 (1690P) 

Shimizu R. ix159 (460P) 

Shimizu T. ix407 (1242P) 

Shimoi T. ix381 (1171P) 

Shimoyama T. ix381 (1171P) 

Shimozuma K. ix512 (1590P) 

Shin D. ix414 (1262P) 

Shin S.J. ix185 (543P) 

Shindo Y. ix514 (1595P), ix240 (723P) 

Shindoh J. ix439 (1343), ix445 (1366TiP) 

Shingler S.L. ix476 (1473P) 

Shingyoji M. ix144 (412O) 

Shinohara T. ix436 (1334) 

Shinozaki E. ix87 (218P), ix196 (574P) 

Shinozaki K. ix512 (1590P) 

Shirahashi A. ix508 (1576P) 

Shirane M. ix534 (1666P), ix112 (305) 

Shiroiwa T. ix200 (588P), ix320 (973PD) 

Shirouzu K. ix248 (751) 

Shitara K. ix232 (692P), ix232 (694P) 

Shmeeda H. ix164 (477P) 

Shoji H. ix251 (764) 

Shore N.D. ix303 (920P), ix309 (937P), 

ix317 (964TiP) 

Shreeve S.M. ix423 (1290P) 

Shridhar E. ix351 (1074P) 

Shucai Z. ix416 (1269P) 

Shukla N.K. ix455 (1398P), ix110 (298P) 

Shukla P. ix149 (430P) 

Shukla S.N. ix356 (1092P), ix134 (377) 

Shukuya T. ix430 (1310P) 

Shun L. ix443 (1359) 

Shustov A.R. ix348 (1063O), ix353 (1083P) 

Siannis F. ix373 (1146), ix85 (211P), ix94 (242) 

Sica L. ix102 (269P) 

Sicard E. ix169 (493P) 

Siddiqui N. ix358 (1100), ix497 (1539P), 

ix327 (994P) 



Siddqui N. ix285 (860P) 

Sidhu R. ix190 (558P), ix192 (564P), ix194 (570P) 

Sidoni A. ix387 (1185P) 

Sieber O. ix383 (1173P) 

Sieber P. ix309 (937P) 

Sieczkowski E. ix72 (165) 

Siemens D.R. ix260 (788O) 

Siena S. ix190 (558P), ix194 (570P), ix205 (605P) 

Sigal D.S. ix224 (666O) 

Silletta M. ix489 (1512) 

Silva J.R.D. ix331 (1009) 

Silvestris N. ix206 (606P), ix229 (685P) 

Simões C. ix175 (512PD), ix176 (514P) 

Simeon C. ix347 (1061TiP) 

Simeone E. ix368 (1130P), ix369 (1132P), 

ix375 (1152) 

Simes R.J. ix151 (437TiP), ix178 (519O), 

ix182 (532P) 

Simko J. ix310 (939P) 

Simmonds P.D. ix283 (857P) 

Simon H. ix499 (1547PD), ix128 (355P) 

Simon I. ix179 (522PD) 

Simoncini E. ix338 (1029P) 

Simonelli M. ix167 (488P) 

Simons W.R. ix120 (330P), ix121 (332P) 

Simos D. ix493 (1525P) 

Sims R.B. ix310 (939P), ix310 (940P) 

Sinagra D. ix215 (636) 

Sinagra E. ix215 (636) 

Singh A.O. ix242 (729P) 

Singh J.K. ix301 (912P) 

Singh M. ix301 (912P) 

Singh P. ix291 (883) 

Singh R.B. ix358 (1103) 

Singh S. ix339 (1034P), ix377 (1158P), 

ix380 (1167P), ix383 (1173P) 

Sini C. ix79 (187P) 

Sini M. ix364 (1118PD) 

Siow T. ix139 (398) 

Sirbu D. ix116 (317O) 

Sisani M. ix315 (958) 

Sitko V.V. ix536 (1672P) 

Sittampalam K. ix485 (1499P), ix485 (1501P) 

Siu L. ix155 (448PD), ix156 (450PD), ix158 (455P) 

Siu L.L. ix319 (966O) 

Sivakumar A.T. ix343 (1049P), ix345 (1055) 

Sizoo E. ix145 (415PD) 

Skachkova O.V. ix536 (1672P) 

Skailes G. ix421 (1282P) 

Skalidaki E. ix431 (1314) 

Skarlos D. ix95 (246O) 

Skladowski K. ix334 (1016O) 

Skoblar Vidmar M. ix229 (683P) 

Skock-Lober R. ix409 (1249P) 

Skoog L. ix299 (906P) 

Slanarˇ O. ix81 (196P) 

Slater S. ix319 (966O) 

Sleeboom H. ix447 (1372P) 

Slichenmyer W. ix391 (1198P) 

Slimane K. ix334 (1017O), ix511 (1584P), 

ix264 (798PD), ix289 (876) 

Sloane R. ix87 (219P) 

Small A. ix451 (1384P) 

Small E. ix294 (894O) 

Small E.J. ix310 (939P), ix311 (942P) 

Smethurst D.P. ix354 (1086P) 

Sminia P. ix537 (1676P) 

Smit E. ix385 (1179O), ix152 (438O) 

Smit E.F. ix401 (1227O) 

Smit J.M. ix211 (622) 

Smith C. ix485 (1498P) 

Smith C.G. ix179 (521O) 

Smith C.J. ix395 (1210) 

Smith D. ix378 (1159P), ix393 (1205P), 

ix194 (568P), ix219 (649), ix242 (730P) 

Smith D.A. ix153 (442O) 

Smith D.C. ix157 (453P), ix296 (897O) 

Smith D.C. ix258 (784O) 

Smith H. ix231 (691P) 

Smith I. ix403 (1233PD) 

Smith M. ix108 (290P) 

Smith M.R. ix295 (895O), ix296 (897O), 

ix297 (901PD), ix303 (920P) 

Smithers B.M. ix371 (1137P) 

Smorczewska M. ix354 (1084P) 

Smorenburg C. ix100 (263P) 

Smoter M. ix268 (812P) 

Smyth E.N. ix421 (1281P) 

So S. ix227 (676P) 

Soares L.M.C. ix524 (1632) 

Soares P. ix208 (614P) 

Soberino García J. ix254 (773) 

Sobrero A. ix35 (41IN), ix205 (605P) 

Soejima K. ix422 (1285P) 

Soerensen A.V. ix271 (819P) 

Soetekouw P.M.M.B. ix319 (966O) 

Sohaib A. ix273 (827P) 

Sohn J. ix120 (329P) 

Solís Hernández M.D.P. ix218 (647) 

Solak M. ix543 (1698P), ix104 (278P) 

Soldatenkova V. ix395 (1211) 

Solitro F. ix444 (1360) 

Söling U. ix505 (1567P) 

Solomon B. ix416 (1268P), ix423 (1290P) 

Solomon J.A. ix362 (1111PD) 

Solsona E. ix312 (945) 

Soltermann A. ix495 (1532P), ix73 (167O) 

Somers A. ix287 (870) 

Sommariva A. ix486 (1504P) 

Son B.H. ix108 (291P) 

Sonderen M.J. ix160 (462P) 

Song C. ix217 (643), ix276 (834P), ix287 (872) 

Song I.C. ix541 (1688PD) 

Song J. ix161 (466P) 

Song P. ix166 (482P) 

Song X. ix438 (1341) 

Song X.Q. ix400 (1225O) 

Song Y.M. ix202 (595P) 

Sonke G.S. ix124 (342P) 

Sonke J. ix396 (1213) 

Sonmez O.U. ix332 (1015), ix105 (279P) 

Sonpavde G. ix260 (787O), ix265 (804P), 

ix297 (901PD) 

Sorbye H. ix188 (553P) 

Sorensen J.B. ix443 (1357), ix80 (191P) 

Soria I. ix165 (480P) 

Soria J. ix426 (1299P), ix474 (1463P), 

ix496 (1534P), ix74 (170O), ix94 (244), 

ix116 (319O), ix155 (446PD), ix168 (491P), 

ix174 (509TiP), ix24 (7IN) 

Soriano J. ix219 (651) 

Sosman J. ix361 (1109O) 

Sosman J.A. ix158 (456P) 

Sotiriou C. ix57 (100IN), ix98 (255PD) 

Soto-Matos A. ix166 (484P) 

Sottotetti F. ix123 (339P), ix138 (391) 

Souahli S. ix528 (1645PD) 

Soubeyran P. ix501 (1554P), ix504 (1563P), 

ix506 (1568P), ix506 (1569P) 

Souglakos I. ix429 (1308P) 

Souglakos J. ix381 (1170P), ix531 (1655P), 

ix213 (631) 

Soulières D. ix395 (1210), ix411 (1254P) 

Soulie M. ix294 (893O) 

Souquet P. ix416 (1270P) 

Sousa B. ix127 (352P) 

Sousa N. ix201 (591P), ix210 (620), ix221 (657), 

ix222 (661) 

Soussan P. ix340 (1036P) 

Souverein P. ix122 (335P) 

Souza A.I. ix464 (1429P) 

Sovak M. ix81 (198P) 

Sowmya P. ix345 (1055) 

Spadaro P. ix140 (399) 

Spahn G. ix453 (1389P), ix466 (1437P) 

Spanik S. ix286 (865P) 

Sparreboom A. ix534 (1667P) 

Specht J. ix153 (442O) 

Speel E-J.M. ix73 (167O) 

Speel E.J. ix80 (193P) 

Speelers B. ix330 (1007) 

Speers C. ix188 (551P) 

Spencer-Shaw A. ix267 (808P) 

Spencer M. ix314 (954) 

Spengler W. ix440 (1347) 

Sperduti I. ix105 (280P), ix226 (675P), 

ix237 (713P), ix240 (721P) 

Spicer J. ix422 (1287P), ix119 (325PD), 

ix161 (464P), ix165 (479P) 

Spiegl Kreinecker S. ix147 (421P) 

Spigel D. ix405 (1237PD), ix408 (1245P) 

Spigel D.R. ix420 (1279P), ix498 (1543TiP) 

Spigno F. ix80 (192P) 

Spina R. ix486 (1504P) 

Spindler K. ix530 (1654P), ix73 (168O) 

Spira A. ix393 (1205P) 

Spittler A. ix539 (1685P) 

Spliid H. ix271 (819P) 

Spoto C. ix500 (1550PD), ix516 (1603P) 

Squiban P. ix165 (478P), ix169 (494P) 

Squire J. ix304 (922P) 

Sreenivas V. ix349 (1067PD) 

Sridhar S.S. ix260 (787O), ix265 (804P), 

ix315 (956), ix316 (960) 

Sridharan N. ix331 (1011) 

Srimuninnimit V. ix400 (1226O), ix97 (254PD) 

Srinivasan P. ix275 (831P) 

Sriram Y. ix466 (1439) 

Srisuthep A. ix339 (1035P) 

Srivastava M. ix174 (510TiP) 

Stål P. ix255 (777TiP) 

Störkel S. ix417 (1272P) 

Stacchiotti S. ix484 (1496P), ix485 (1500P) 

Stadler W.M. ix265 (804P), ix303 (919P) 

Staehler M. ix292 (889TiP) 

Stagni S. ix305 (926P) 

Stahel R.A. ix58 (105IN), ix385 (1179O), 

ix66 (138IN), ix73 (167O), ix80 (193P), 

ix86 (213P) 

Staines H. ix155 (446PD) 

Stalmeier P.F.M. ix475 (1469P) 

Stam A. ix301 (915P) 

Stamatis G. ix49 (79IN) 

Stanczak A. ix544 (1700) 

Stanković N. ix237 (712P) 

Starikov A.V. ix109 (293P) 

Staroslawska E. ix103 (273P) 

Stasi I. ix94 (243), ix176 (515P) 

Stathopoulos G. ix493 (1524P) 

Stathopoulos J. ix493 (1524P) 

Stauber R. ix255 (778TiP) 

Stauch K. ix270 (817P), ix279 (844P) 

Staudacher K. ix296 (898PD), ix308 (936P) 

Stebbing J. ix132 (369P) 

Stec R. ix268 (812P) 

Steeghs N. ix157 (454P) 

Steelman L. ix293 (892TiP) 

Steenbergen R.D. ix88 (221P) 

Stefanescu M. ix67 (146P) 

Steffens C. ix190 (559P) 

Steger G. ix116 (317O) 

Steger G.G. ix145 (414PD) 

Stein A. ix35 (40IN) 

Steiner M.S. ix304 (923P) 

Steiner T. ix274 (828P) 

Steinmetz H.T. ix504 (1561P), ix505 (1567P) 

Stelitano C. ix523 (1628) 

Stemke-Hale K. ix84 (204P) 

Stemmer S.M. ix116 (317O) 

Stephenson J. ix224 (666O) 

Stephenson P. ix389 (1191PD) 

Stephenson R.A. ix310 (939P) 

Stergiopoulos S. ix376 (1154O), ix272 (823P) 

Sterlacci W. ix494 (1528P) 


author index 

Stern L. ix272 (823P) 

Sternberg C.N. ix260 (787O), ix262 (795PD), 

ix265 (804P), ix270 (818P), ix278 (840P), 

ix295 (896O), ix297 (899PD) 

Sternberg D.W. ix116 (318O), ix158 (457P) 

Sternfeld T. ix465 (1435P) 

Steven J.H. ix97 (253PD) 

Stevens L. ix508 (1575P) 

Stewart D. ix78 (185P) 

Stewart F. ix311 (942P), ix311 (943P) 

Stewart G. ix93 (240) 

Stewart S. ix156 (449PD), ix157 (452P) 

Stilidi I. ix252 (765) 

Stinchi S. ix154 (444PD) 

Stintzing S. ix180 (526PD), ix188 (554P), 

ix204 (599P) 

Stjepanovic N. ix496 (1533P) 

St.-Laurent Thibault C. ix316 (960) 

Stoeckle E. ix482 (1488P) 

Stoehlmacher-Williams J. ix336 (1022PD) 

Stoltidis D. ix436 (1335) 

Stoltz M. ix223 (664TiP) 

Stopfer P. ix162 (468P) 

Storino C. ix330 (1005P) 

Stork-Sloots L. ix96 (251PD) 

Stouthard J.M. ix501 (1553P) 

Sträter J. ix440 (1347) 

Strøm H.H. ix392 (1200P) 

Stradella A. ix216 (641) 

Stragliotto S. ix369 (1132P), ix371 (1140P) 

Strasser F. ix64 (131IN), ix462 (1423O) 

Stratton M. ix25 (10IN) 

Straubinger R.M. ix155 (447PD) 

Strausz J. ix429 (1307P) 

Stravodimou A. ix138 (393) 

Strebel R. ix302 (917P) 

Streich G. ix448 (1373P) 

Strippoli A. ix84 (207P) 

Strola G. ix528 (1644PD) 

Stroyakovskiy D. ix97 (254PD) 

Studeny M. ix245 (740P) 

Sturgeon J. ix200 (586P) 

Stylianou S. ix160 (463P) 

Su N. ix345 (1052) 

Su W. ix246 (744P), ix247 (746P) 

Su Y. ix267 (810P), ix269 (816P) 

Suarez C. ix266 (806P), ix277 (839P), ix302 (916P) 

Subiza J.L. ix165 (480P) 

Subramanian S. ix174 (510TiP) 

Subtil F. ix178 (520O), ix242 (730P) 

Suder A. ix275 (831P) 

Sudo K. ix200 (585P) 

Suenaga M. ix542 (1693P), ix87 (218P), 

ix246 (742P) 

Sugawara S. ix412 (1256P), ix413 (1259P), 

ix427 (1301P), ix443 (1358) 

Sugihara K. ix197 (576P), ix200 (587P) 

Sugimoto H. ix542 (1693P) 

Sugino T. ix69 (153P) 

Sugino Y. ix434 (1325) 

Sugio K. ix387 (1187P) 

Sugito M. ix210 (621) 

Sugiyama T. ix326 (989P) 

Sukari A. ix342 (1043P) 

Sukhaboon J. ix339 (1035P) 

Sukumaran S. ix503 (1558P) 

Sullivan I.G. ix408 (1244P), ix292 (888) 

Sullivan R. ix66 (141INIS) 

Sultan A. ix347 (1061TiP) 

Sumi M. ix396 (1215) 

Summers Y. ix493 (1525P), ix507 (1573P) 

Sun F.F. ix202 (595P) 

Sun H. ix283 (857P) 

Sun J. ix413 (1261P), ix424 (1292P), 

ix150 (435TiP) 

Sun L. ix247 (745P) 

Sun M. ix216 (640) 

Sun S. ix412 (1255P) 

Sun T. ix438 (1341) 

Sun X.J. ix226 (674P) 

Sun Y. ix394 (1209), ix119 (326PD) 

Sundarraj S. ix70 (158P) 

Sundstrøm S. ix392 (1200P) 

Sunguroglu K. ix469 (1448PD) 

Sunnetci N. ix394 (1207P) 

Supernat A.M. ix320 (970PD) 

Surmacz E. ix166 (483P) 

Susnerwala S. ix206 (608P) 

Suurmeijer A.J.H. ix484 (1497P) 

Suzuki H. ix388 (1188P), ix432 (1320), 

ix433 (1321) 

Suzuki K. ix233 (697P), ix320 (973PD) 

Suzuki N. ix240 (723P) 

Suzuki R. ix434 (1325), ix445 (1366TiP) 

Suzuki S. ix518 (1611P), ix156 (451P), 

ix164 (475P) 

Suzuki T. ix185 (542P), ix197 (575P), 

ix207 (611P), ix244 (737P) 

Suzuki Y. ix112 (305) 

Suzumiya J. ix348 (1062O) 

Suzumura T. ix79 (189P), ix79 (190P), ix92 (235) 

Svedman C. ix97 (252PD) 

Svegliati Baroni G. ix243 (734P) 

Svergun N.M. ix536 (1672P) 

Svetlovska D. ix293 (890TiP) 

Svoboda T. ix474 (1464P) 

Svrcek M. ix234 (703P) 

Swain S. ix124 (344P) 

Sweeney C. ix296 (897O) 

Swellam M. ix352 (1079P) 

Swennenhuis J.F. ix91 (230P) 

Swieboda-Sadlej A. ix409 (1246P) 

Swinson D. ix500 (1549PD) 

Switaj T. ix484 (1495P) 

Sycova-Mila Z. ix293 (890TiP) 

Syed N. ix532 (1660P) 

Synowiec A. ix320 (971PD) 

Szczylik C. ix255 (776TiP), ix264 (798PD), 

ix268 (812P), ix271 (820P), ix320 (971PD), 

ix323 (979P) 

Szilagyi A. ix493 (1523P) 

Szima B. ix405 (1236PD), ix406 (1239P) 

Sznol M. ix361 (1109O), ix157 (453P), 

ix258 (784O) 

Szyldergemajn S. ix166 (484P) 

Szymczyk M. ix354 (1084P) 

T 

Tabernero J. ix451 (1382P), ix531 (1656P), 

ix84 (204P), ix116 (319O), ix154 (443PD), 

ix159 (458P), ix179 (522PD), ix187 (550P), 

ix189 (555P), ix190 (558P), ix198 (581P), 

ix214 (633) 

Tablot D. ix378 (1161P) 

Taboada B. ix328 (1000P), ix395 (1212) 

Tabouret E. ix150 (434) 

Tachikawa R. ix423 (1289P) 

Tachikawa T. ix87 (216P) 

Tada H. ix385 (1181PD) 

Taddei G.L. ix78 (183P) 

Taffurelli M. ix130 (362P) 

Taghizadeh Kermani A. ix107 (287P), ix184 (538P) 

Tagliaferri B. ix123 (339P), ix138 (391) 

Tagliapietra A. ix300 (910P) 

Taguchi K. ix387 (1187P) 

Tahara K. ix159 (460P) 

Tahara M. ix518 (1611P), ix344 (1706P) 

Tahri A. ix476 (1471P) 

Tai D.W.M. ix199 (583P) 

Taibi E. ix104 (275P) 

Taieb J. ix511 (1587P), ix75 (174O), ix178 (520O), 

ix234 (703P), ix237 (710P), ix238 (716P) 

Taira K. ix432 (1320), ix433 (1321) 

Taira N. ix74 (172O) 

Taira T. ix430 (1310P) 

Takada M. ix104 (277P) 


Takagi M. ix230 (688P) 

Takagi Y. ix441 (1351), ix497 (1537P) 

Takaguchi S. ix481 (1485PD) 

Takahari D. ix232 (692P) 

Takahashi K. ix434 (1325) 

Takahashi N. ix407 (1242P), ix442 (1354), 

ix69 (153P), ix529 (1649P) 

Takahashi O. ix200 (585P) 

Takahashi T. ix424 (1293P), ix430 (1310P), 

ix481 (1485PD), ix200 (585P) 

Takahashi T.K. ix455 (1397P) 

Takakura S. ix327 (995P) 

Takamatsu Y. ix508 (1576P) 

Takamura K. ix420 (1280P), ix434 (1326), 

ix443 (1358), ix497 (1538P) 

Takao T. ix442 (1354) 

Takasa A. ix436 (1334) 

Takashima A. ix231 (689P) 

Takashima T. ix84 (205P) 

Takaya H. ix433 (1323) 

Takayama K. ix438 (1340) 

Takayama T. ix449 (1378P), ix211 (625) 

Takeda K. ix424 (1293P), ix432 (1320), 

ix433 (1321) 

Takeda S. ix542 (1693P), ix246 (742P) 

Takeda Y. ix161 (465P) 

Takenaka T. ix387 (1187P) 

Takeshima N. ix326 (989P) 

Takeshita J. ix437 (1338) 

Takeuchi K. ix418 (1274P) 

Takeuchi M. ix404 (1234PD) 

Takeuchi N. ix439 (1344) 

Takhar H. ix503 (1558P) 

Takigawa N. ix434 (1327) 

Takiguchi S. ix227 (677P) 

Taku K. ix220 (653) 

Talati S.S. ix356 (1092P) 

Talati S.S. ix134 (377) 

Tamagnini I. ix216 (642) 

Tamaru S. ix509 (1578P) 

Tamas K. ix458 (1407) 

Tamasi L. ix493 (1523P) 

Tamborini E. ix483 (1491P) 

Tamiya M. ix432 (1320), ix433 (1321) 

Tamkovich S.N. ix109 (293P) 

Tampellini M. ix205 (605P) 

Tamura K. ix348 (1062O), ix508 (1576P), 

ix90 (228P), ix164 (474P) 

Tamura S. ix230 (688P) 

Tamura T. ix174 (1708PD), ix383 (1175P), 

ix393 (1206P), ix396 (1215), ix397 (1218), 

ix413 (1260P), ix492 (1519PD), ix153 (441O), 

ix156 (451P), ix159 (459P), ix161 (467P), 

ix164 (475P) 

Tamura Y. ix156 (451P), ix159 (459P), 

ix161 (467P), ix164 (475P) 

Tan A.R. ix153 (442O) 

Tan C. ix499 (1544O), ix199 (583P) 

Tan D.S.W. ix412 (1257P), ix153 (440O) 

Tan E.H. ix391 (1198P), ix409 (1247P), 

ix412 (1257P) 

Tan I.B. ix182 (533P), ix199 (583P), ix245 (741P) 

Tan M.H. ix245 (741P) 

Tan W. ix424 (1291P) 

Tanabe H. ix327 (995P) 

Tanabe K.K. ix542 (1693P), ix246 (742P) 

Tanabe Y. ix159 (459P), ix164 (474P) 

Tanaka A. ix185 (542P), ix197 (575P), 

ix207 (611P) 

Tanaka H. ix509 (1579P), ix159 (460P) 

Tanaka J. ix509 (1579P) 

Tanaka K. ix167 (486P) 

Tanaka M. ix79 (188P) 

Tanaka R. ix372 (1142P) 

Tanaka T. ix508 (1576P), ix71 (159P), 

ix243 (732P) 

Tanaka Y. ix536 (1671P), ix225 (671P) 

Tanase T. ix449 (1378P) 



Tanasienko O.A. ix536 (1672P) 

Tanca F.M. ix516 (1604P) 

Tancredi R. ix99 (260P) 

Tane S. ix92 (233) 

Tang L. ix119 (326PD) 

Tang R. ix314 (952) 

Tang V. ix244 (736P) 

Tang Y. ix415 (1267P), ix423 (1290P), 

ix453 (1391P) 

Tangsakar E. ix248 (748) 

Tani K. ix536 (1671P) 

Taniguchi H. ix445 (1366TiP), ix529 (1649P) 

Tanii M. ix168 (490P) 

Tanimoto M. ix434 (1327) 

Taniyama D. ix525 (1637) 

Tannir N. ix83 (203P) 

Tannock I.F. ix158 (455P), ix260 (788O) 

Tanovic A. ix324 (984P) 

Tao J. ix126 (350P) 

Tapia Rico G. ix264 (799P) 

Taplin M. ix297 (899PD) 

Taran T. ix118 (324PD), ix121 (334P), 

ix126 (351P) 

Tarazi J. ix262 (793PD) 

Targarona E. ix216 (641) 

Taron M. ix418 (1273P), ix266 (807P) 

Tartour E. ix75 (174O) 

Tas P. ix105 (281P) 

Tatangelo F. ix193 (567P) 

Tateyama M. ix202 (592P) 

Taube J.M. ix157 (453P) 

Tauchert F.K. ix459 (1413TiP) 

Tauchi K. ix513 (1591P) 

Tauchi S. ix92 (233) 

Tausch C. ix83 (202P) 

Tawashi M. ix169 (492P) 

Taylo S. ix342 (1043P) 

Taylor A. ix133 (372P) 

Taylor C. ix76 (177PD) 

Taylor D. ix76 (177PD) 

Taylor I. ix401 (1228O) 

Taylor P.D. ix507 (1573P) 

Taylor R.P. ix304 (923P) 

Taylor S. ix244 (735P) 

Tazawa-Ogata N. ix161 (465P) 

Teague T. ix451 (1382P) 

Teama S. ix216 (639) 

Tebbutt N. ix182 (532P), ix231 (691P) 

Tebbutt N.C. ix178 (519O), ix189 (555P) 

Teer J.K. ix25 (11IN) 

Teghom C. ix282 (852P) 

Teh B.T. ix39 (51IN) 

Tehard B. ix488 (1511P) 

Tehfe M. ix408 (1245P) 

Teixeira T. ix208 (614P) 

Tejedor A. ix520 (1619) 

Tejpar S. ix451 (1382P), ix75 (173O), ix213 (630) 

Teker F. ix221 (660) 

Telfah A. ix462 (1424P) 

Telli F. ix186 (547P) 

Temam S. ix340 (1037P) 

Temby I. ix260 (789O) 

Temiz S. ix110 (300) 

Tempero M.A. ix37 (42IN) 

Templeton A. ix302 (917P) 

Temraz S. ix398 (1221) 

Tenali S.G. ix490 (1515) 

Teng Y. ix437 (1337), ix93 (238), ix138 (394) 

Teo M. ix485 (1499P), ix485 (1501P) 

Teo M.Y. ix248 (750), ix300 (909P) 

Teofilovici F. ix436 (1332), ix529 (1647PD), 

ix533 (1664P), ix125 (347P) 

Tepavac A. ix428 (1304P) 

Ter Voert E.E.G.W. ix192 (562P) 

Teragni C.M. ix123 (339P), ix138 (391) 

Terai H. ix422 (1285P) 

Terekhov O. ix311 (944P) 

Terme M. ix75 (174O) 

Terpos E. ix360 (1108TiP), ix447 (1372P) 

Terracciano L. ix77 (181P) 

Terret C. ix461 (1420PD) 

Terrier P. ix486 (1502P) 

Terstappen L.W. ix91 (230P) 

Tesch H. ix502 (1557P) 

Tessari A. ix102 (269P) 

Tessen H.W. ix504 (1561P) 

Testa I. ix272 (824P), ix288 (873), ix305 (926P) 

Testa L. ix455 (1397P) 

Testori A. ix361 (1110O), ix367 (1127P), 

ix367 (1128P), ix368 (1130P), ix373 (1148) 

Testori O. ix247 (747P) 

Teti A. ix524 (1633) 

Tettamanti M. ix452 (1385P) 

Teulé A. ix377 (1157O) 

Théodore C. ix294 (893O) 

Thürlimann B. ix132 (370P) 

Thacoor A. ix483 (1492P) 

Thaler J. ix178 (520O), ix249 (755) 

Tham C.K. ix182 (533P) 

Thatcher N. ix419 (1278P) 

Theegarten D. ix437 (1339) 

Theocharis S. ix541 (1691P) 

Theodore C. ix263 (797PD), ix289 (876) 

Thiesse P. ix478 (1477O) 

Thillai K. ix275 (831P) 

Thippeswamy R. ix350 (1069PD) 

Thirot-Bidault A. ix237 (710P) 

Thistlethwaite F. ix267 (808P) 

Thng C.H. ix70 (155P) 

Thomale J. ix68 (149P) 

Thomas D. ix479 (1480PD) 

Thomas L. ix367 (1127P) 

Thomas M. ix390 (1194P), ix407 (1241P), 

ix418 (1275P) 

Thomas S. ix408 (1245P) 

Thompson A.M. ix532 (1660P) 

Thompson J. ix363 (1115PD), ix278 (842P) 

Thompson J.F. ix371 (1137P) 

Thongprasert S. ix393 (1205P), ix400 (1226O) 

Thottakam B.M. ix93 (240) 

Thunnissen E. ix73 (167O), ix80 (193P), 

ix86 (213P) 

Tian H. ix415 (1266P) 

Tibollo V. ix535 (1669P) 

Tie J. ix220 (656) 

Tierno Garcia M. ix431 (1315) 

Tiftik N. ix312 (947) 

Timotheadou E. ix95 (246O) 

Tiseo M. ix442 (1355) 

Tito J. ix298 (904P) 

Tjørnelund J. ix349 (1068PD) 

Tjan-Heijnen V.C. ix501 (1553P) 

Tjulandin S. ix230 (687P) 

Tkaczuk K.H.R. ix108 (290P) 

Tobeña Puyal M. ix183 (536P), ix185 (544P), 

ix216 (641) 

Tocchetti C.G. ix539 (1682P) 

Tochino Y. ix412 (1258P) 

Tod M. ix299 (907P) 

Toda M. ix515 (1598P) 

Todisco G. ix167 (487P), ix172 (502) 

Tofanetti F.R. ix387 (1185P) 

Toffoli G. ix144 (411O) 

Toh H.C. ix83 (203P), ix245 (741P) 

Toh Y. ix217 (646) 

Toi M. ix104 (277P) 

Tokluoğlu S. ix332 (1015) 

Tokuda Y. ix112 (305) 

Tokui T. ix244 (738P) 

Tokunaga S. ix432 (1320), ix433 (1321), 

ix230 (688P) 

Tolcher A.W. ix165 (481P), ix169 (492P) 

Tolia M. ix541 (1691P) 

Tollenaar R. ix184 (540P) 

Tolnay E. ix429 (1307P) 

Toloudi M. ix136 (385) 

Tolunay S. ix129 (359P) 

Tomar P. ix242 (729P) 

Tomasello G. ix232 (693P) 

Tomasevic Z. ix544 (1702), ix544 (1702) 

Tomasich E. ix539 (1685P) 

Tomczak P. ix262 (793PD), ix262 (795PD) 

Tomezzoli A. ix226 (675P) 

Tomii K. ix423 (1289P) 

Tomita N. ix200 (588P) 

Tondini C. ix365 (1120P) 

Toner S. ix468 (1444) 

Tonini G. ix489 (1512), ix500 (1550PD), 

ix516 (1603P), ix530 (1653P), ix538 (1681P), 

ix206 (606P) 

Tono Y. ix509 (1578P) 

Topal U. ix129 (359P) 

Topalian S.L. ix361 (1109O), ix157 (453P) 

Topkan E. ix392 (1202P), ix520 (1620), 

ix526 (1641), ix526 (1642), ix237 (711P), 

ix238 (715P) 

Topolcan O. ix474 (1464P) 

Topp M. ix350 (1072P) 

Toppo L. ix232 (693P) 

Topuk S. ix392 (1202P), ix520 (1620), 

ix526 (1642) 

Torchio M. ix529 (1650P) 

Toriihara A. ix441 (1351) 

Torrejon Castro D. ix496 (1533P), ix140 (400), 

ix302 (916P) 

Torres S. ix345 (1056) 

Torricelli F. ix528 (1646PD) 

Tortora G. ix117 (322PD), ix39 (52IN), 

ix226 (675P), ix240 (721P), ix273 (825P), 

ix287 (869) 

Tosi M. ix213 (629) 

Touboul C. ix470 (1452P), ix472 (1460) 

Touchefeu Y. ix537 (1677P) 

Toure E. ix252 (767) 

Tovanabutra C. ix339 (1035P) 

Tóth E. ix503 (1560P), ix504 (1562P) 

Townsend A. ix182 (532P), ix208 (612P) 

Towse A. ix476 (1473P) 

Toyazaki T. ix442 (1356) 

Toyoda M. ix510 (1581P) 

Toyokawa G. ix387 (1187P) 

Tozzi V. ix457 (1405) 

Tröger W. ix237 (712P) 

Trager J.B. ix311 (942P) 

Traina T.A. ix98 (257P) 

Traldi Macedo L. ix513 (1594P) 

Tran B. ix220 (656) 

Tran H.T. ix261 (791PD), ix275 (833P) 

Traphalis D. ix493 (1524P) 

Trask P. ix323 (981P) 

Traversa M. ix370 (1135P) 

Tredan O. ix125 (346P) 

Trejo-Duran G. ix329 (1003P) 

Trejo E. ix251 (763) 

Trenta P. ix440 (1348), ix488 (1509P) 

Triggs M. ix468 (1444) 

Trigo J.M. ix334 (1016O) 

Trill J.D. ix205 (604P) 

Trillet-Lenoir V. ix170 (498P) 

Trindade I. ix357 (1097) 

Triolo R. ix99 (259P) 

Troch M. ix352 (1076P) 

Troiani T. ix430 (1309P), ix67 (143PD), 

ix75 (173O) 

Trojniak M.P. ix439 (1345), ix447 (1370P), 

ix283 (854P) 

Troncone G. ix530 (1651P), ix78 (183P) 

Trouilloud I. ix237 (710P), ix238 (716P) 

Truini M. ix79 (187P), ix301 (914P) 

Truman M.I. ix400 (1226O) 

Truscelli K. ix488 (1509P) 

Trusilova E. ix250 (760) 

Tryfonopoulos D. ix108 (292P) 

Tryon P. ix309 (938P) 


author index 

Trypaki M. ix429 (1308P), ix213 (631) 

Tsai H. ix351 (1075P) 

Tsakalaki E. ix429 (1308P), ix213 (631) 

Tsao-Wei D. ix261 (790O), ix316 (961) 

Tsao M. ix389 (1192PD), ix74 (170O), ix78 (186P) 

Tsavaris N. ix92 (236) 

Tsavdaridis D. ix493 (1524P) 

Tschaika M. ix178 (518O), ix268 (813P) 

Tschechne B. ix523 (1627) 

Tschoepe I. ix165 (478P), ix169 (494P) 

Tsolaki E. ix213 (630) 

Tsolakis K. ix541 (1691P) 

Tsoukalas N.G. ix541 (1691P) 

Tsuboi R. ix517 (1608P) 

Tsuburaya A. ix228 (681P) 

Tsuchida A. ix89 (224P) 

Tsuchihara K. ix196 (574P) 

Tsuchiya T. ix188 (552P) 

Tsuda H. ix372 (1142P), ix383 (1174P), 

ix387 (1186P) 

Tsuda T. ix232 (692P) 

Tsui D. ix74 (171O) 

Tsuji A. ix233 (697P) 

Tsuji Y. ix232 (692P) 

Tsujinaka T. ix230 (688P) 

Tsujino I. ix407 (1242P), ix442 (1354) 

Tsujino K. ix393 (1204P) 

Tsujitani S. ix168 (490P) 

Tsunoda A. ix211 (623) 

Tsunoda T. ix536 (1671P), ix159 (460P) 

Tsunoda Y. ix87 (216P), ix211 (623) 

Tsuta K. ix383 (1174P), ix387 (1186P) 

Tsutani Y. ix385 (1180PD) 

Tsutsumida A. ix372 (1142P) 

Tsuzuki T. ix225 (671P) 

Tu L. ix247 (745P) 

Tuccari G. ix104 (276P) 

Tummers P. ix330 (1007), ix325 (987P) 

Tumolo S. ix287 (868) 

Tun T.T. ix319 (969PD) 

Tunali D. ix274 (830P) 

Tunariu N. ix296 (897O), ix301 (913P), 

ix320 (972PD) 

Turcotte É. ix350 (1071P) 

Turhal N.S. ix394 (1207P) 

Turhal S.N. ix497 (1540), ix186 (547P), 

ix217 (645) 

Turker I. ix473 (1461), ix105 (279P) 

Turker T. ix286 (866P) 

Turkington R.C. ix249 (754) 

Turner B. ix93 (240) 

Turner J.H. ix379 (1162P) 

Turner M. ix502 (1555P), ix502 (1557P) 

Turner N. ix29 (20IN) 

Turner N.H. ix27 (13IN) 

Turner P. ix123 (341P) 

Turner R. ix517 (1605P) 

Turnes J. ix255 (777TiP) 

Turpin A. ix106 (285P) 

Turrini O. ix241 (727P) 

Turtoi I. ix398 (1222) 

Turtschi C. ix366 (1125P) 

Tutrone R. ix317 (964TiP) 

Tuydjanova K.K. ix71 (162P) 

Tuyev H. ix229 (684P), ix254 (772) 

Twardowski P. ix309 (938P) 

Twelves C. ix409 (1246P), ix476 (1473P), 

ix171 (500P) 

Twelves C.J. ix129 (358P), ix132 (369P) 

Tye L. ix389 (1191PD) 

Tzardi M. ix213 (631) 

Tzeng C. ix355 (1087P) 

Tzeng Y. ix351 (1075P) 

Tzovaras A. ix541 (1691P) 

U 

Uchida J. ix185 (542P) 

Uchiyama A. ix79 (188P) 

Ueda K. ix226 (673P) 

Ueda M. ix91 (232) 

Uehara K. ix220 (655) 

Uehara Y. ix383 (1175P) 

Ueno H. ix200 (587P) 

Ueno T. ix104 (277P), ix240 (723P) 

Uetake H. ix197 (576P) 

Ulker M. ix326 (990P) 

Ulyanov A. ix311 (944P) 

Umarova N. ix325 (985P) 

Umekawa K. ix79 (189P), ix79 (190P), 

ix92 (235) 

Umemura S. ix515 (1598P), ix534 (1666P) 

Umezawa K. ix495 (1531P) 

Unal O.U. ix234 (701P) 

Unek I.T. ix234 (701P) 

Uner A. ix227 (678P) 

Unno M. ix211 (624) 

Untergasser G. ix76 (178P) 

Upadhyay S. ix421 (1282P) 

Urakci Z. ix137 (387) 

Urata N. ix225 (671P) 

Urban T. ix403 (1232PD) 

Urban Z. ix320 (970PD) 

Urbanski M. ix456 (1401P) 

Uronis H. ix224 (666O) 

Urosa Velasco D. ix264 (799P) 

Urruticoechea A. ix116 (318O) 

Uruga H. ix433 (1323) 

Urzua L. ix126 (349P) 

Usakova V. ix286 (865P) 

Usari T. ix424 (1291P) 

Ussetti P. ix459 (1410) 

Usui K. ix427 (1301P) 

Utikal J. ix361 (1110O) 

Utsunomiya A. ix348 (1062O) 

Uttenreuther-Fischer M. ix161 (464P), 

ix162 (468P) 

Uyeturk U. ix473 (1461), ix105 (279P) 

Uygun K. ix110 (300) 

Uyl-De Groot C.A. ix450 (1379P) 

Uysal Sonmez O. ix473 (1461) 

Uyterlinde W. ix392 (1203P) 

Uzan C. ix322 (977P) 

Uzzan B. ix414 (1265P) 

V 

Vaccaro V. ix237 (713P), ix240 (721P) 

Vacher-Lavenu M. ix327 (993P) 

Vaira F. ix123 (340P) 

Vaisman O. ix498 (1541) 

Val P.C. ix215 (637) 

Valdagni R. ix305 (926P), ix315 (959) 

Valdez Bocanegra D. ix184 (541P) 

Valdivia J. ix374 (1150) 

Valduga F. ix276 (836P) 

Valent F. ix457 (1405) 

Validire P. ix388 (1190P) 

Valigi P. ix535 (1668P) 

Vallati G. ix237 (713P) 

Valle J. ix378 (1161P), ix381 (1168P) 

Valle J.W. ix376 (1155O), ix377 (1156O), 

ix242 (731P) 

Valleix F. ix170 (498P) 

Vallejos-Sologuren C. ix65 (133IN) 

Vallieres E. ix386 (1182P) 

Valota O. ix262 (794PD) 

Valpione S. ix371 (1140P), ix486 (1504P), 

ix124 (343P), ix131 (367P) 

Valverde Estepa A.M. ix530 (1652), 

ix425 (1296P) 

Valverde Morales C. ix302 (916P) 

van Baardwijk A. ix396 (1213), ix425 (1296P) 

van Belle S. ix325 (987P), ix330 (1007), 

ix287 (870) 

van Beurden M. ix330 (1006P) 

van Bortel L. ix287 (870) 

van Boven H.H. ix330 (1006P) 


Van Cutsem E. ix178 (520O), ix187 (550P), 

ix191 (561P), ix198 (581P), ix212 (626), 

ix214 (633), ix222 (663TiP) 

Van Cutsem E.J.D. ix193 (565P), ix195 (571P) 

van Dam G.M. ix40 (57IN) 

van den Bent M.J. ix31 (23IN) 

Van den Broecke R. ix330 (1007), ix325 (987P) 

van den Eertwegh A. ix301 (915P) 

van den Eynde M. ix194 (569P), ix197 (578P), 

ix211 (622) 

van den Heuvel M. ix392 (1203P) 

van den Noortgate N. ix341 (1042P) 

van den Wyngaert T. ix510 (1583P) 

van der Akker J. ix179 (522PD) 

van der Graaf W.T.A. ix475 (1469P), 

ix483 (1493P), ix484 (1497P), ix160 (462P), 

ix54 (91IN) 

van der Hage J. ix532 (1658P) 

van der Heijden G. ix484 (1497P) 

van der Holt B. ix534 (1667P) 

van der Horst T. ix97 (254PD), ix103 (272P) 

van der Noll R. ix153 (442O) 

van der Zee A.G.J. ix40 (57IN) 

van Dongen G.A.M.S. ix450 (1379P) 

van Elmpt W. ix392 (1201P), ix396 (1213), 

ix396 (1216) 

van Fraeyenhove F. ix452 (1386P) 

van Gaal J.C. ix484 (1497P) 

van Gelder T. ix456 (1402P), ix109 (295P) 

van Gool R. ix296 (898PD) 

van Halteren H.K. ix111 (301) 

van Herk-Sukel M.P.P. ix109 (295P) 

van Herpen C.M.L. ix160 (462P) 

van Laarhoven H.W. ix501 (1553P) 

van Laarhoven H.W.M. ix192 (562P) 

van Laethem J. ix178 (520O), ix225 (669PD), 

ix255 (776TiP) 

van Leeuwen R.W. ix456 (1402P) 

van Leeuwen T.G. ix330 (1006P) 

van Os S. ix103 (274P) 

van Praagh-Doreau I. ix102 (270P) 

van Rossum M. ix363 (1114PD) 

van Schaik R.H. ix534 (1667P) 

van Vlierberghe H. ix225 (669PD) 

van Warmerdam L.J. ix501 (1553P) 

Vandebroek A. ix452 (1386P) 

Vandecasteele K. ix330 (1007), ix325 (987P) 

Vandendries R. ix396 (1216) 

Vanderpuye V.D.N.K. ix257 (782TiP) 

Vanderwalde A. ix334 (1016O) 

Vanella P. ix73 (169O), ix113 (311) 

Vanhoutte N. ix361 (1110O), ix386 (1182P) 

Vannucci J. ix387 (1185P) 

Vano Y. ix499 (1545O) 

Vansteenkiste J. ix385 (1179O) 

Vansteenkiste J.F. ix403 (1233PD), ix407 (1241P), 

ix451 (1382P), ix153 (440O) 

Vaquero E.C. ix67 (145P) 

Vardakis N. ix435 (1329), ix436 (1335) 

Vardja M. ix146 (418PD), ix149 (431) 

Varea R. ix395 (1211) 

Varela S. ix436 (1333), ix440 (1349) 

Varella-Garcia M. ix389 (1191PD) 

Varga A. ix474 (1463P), ix155 (446PD), 

ix168 (491P) 

Varricchio C. ix83 (201P) 

Varthalitis I. ix239 (717P) 

Varughese T. ix346 (1060) 

Vasile E. ix206 (606P), ix238 (714P), ix241 (726P), 

ix251 (761), ix251 (762) 

Vasiliou V. ix337 (1026P) 

Vasquez S. ix513 (1592P) 

Vaughan A.T. ix70 (157P) 

Vavala T. ix444 (1360) 

Vavrova L. ix513 (1593P) 

Vaz F. ix175 (512PD), ix176 (514P) 

Vaz G. ix478 (1477O) 

Vazquez-Estevez S. ix440 (1349), ix273 (826P) 



Vazquez-Sequeiros E. ix472 (1456P) 

Vázquez A.M. ix406 (1238PD) 

Vázquez F. ix312 (945) 

Vazquez S. ix395 (1212), ix436 (1333) 

Vecchiato A. ix486 (1504P) 

Vecchione L. ix75 (173O) 

Védrine L. ix477 (1476), ix150 (433), ix285 (862P) 

Veerabudun K. ix460 (1419PD) 

Vehling-Kaiser U. ix465 (1435P), ix505 (1567P), 

ix180 (526PD), ix204 (599P) 

Velástegui A. ix113 (310) 

Velasco A. ix166 (484P) 

Velasco G. ix281 (850P), ix314 (953) 

ix325 (986P) 

Velinovic M. ix428 (1304P) 

Velten M. ix109 (296P), ix120 (331P) 

Veltri A. ix444 (1360) 

Venat-Bouvet L. ix181 (529PD) 

Venderbosch S. ix179 (521O) 

Venditti O. ix500 (1550PD) 

Vendrely V. ix242 (730P) 

Venkatakrishnan K. ix168 (489P) 

Vennin P. ix106 (285P) 

Venook A. ix225 (670PD) 

Vera Badillo F. ix91 (231P) 

Vera R. ix219 (651) 

Verardi R. ix338 (1029P) 

Vergauwe P. ix222 (663TiP) 

Vergnenegre A. ix397 (1219) 

Vergote I.B. ix514 (1596P), ix539 (1683P), 

ix172 (504), ix321 (975PD), ix324 (982P) 

Verheul H.M. ix240 (724P) 

Verhoef G. ix518 (1609P) 

Verillaud B. ix337 (1025P) 

Verlicchi A. ix496 (1536P) 

Verma S. ix408 (1245P) 

Vermaete N. ix518 (1609P) 

Vermorken J.B. ix334 (1018O), ix336 (1022PD) 

Verna L. ix466 (1436P) 

Veronese L. ix366 (1124P), ix366 (1125P) 

Verpoort K. ix502 (1557P) 

Verri E. ix335 (1020PD) 

Versleijen-Jonkers Y.M.H. ix484 (1497P) 

Versluis J. ix301 (915P) 

Verso M. ix515 (1599P) 

Verstraete M. ix222 (663TiP) 

Verweij J. ix534 (1667P), ix55 (94IN) 

Verzoni E. ix272 (824P), ix288 (873), 

ix305 (926P), ix315 (959) 

Vetsika E.K. ix431 (1314) 

Viada C. ix406 (1238PD) 

Vibert E. ix243 (733P) 

Vici P. ix142 (406TiP) 

Victor A. ix211 (622) 

Victoria I. ix343 (1046P), ix282 (853P) 

Vidal M. ix91 (229P) 

Vieillefond A. ix259 (786O) 

Viéitez J.M. ix218 (647) 

Vieitez de Prado J.M. ix193 (565P) 

Vieito Villar M. ix328 (1000P), ix395 (1212) 

Viens P. ix150 (434) 

Viganò M.G. ix167 (487P), ix172 (502) 

Viguier J. ix470 (1452P), ix472 (1460), ix85 (210P) 

Vilalta A. ix343 (1046P) 

Vilar E. ix34 (36IN), ix220 (656) 

Vilardell L. ix388 (1189P) 

Vilchez V. ix496 (1535P) 

Vilcot L. ix486 (1502P) 

Villa E. ix280 (846P) 

Villa S. ix305 (926P), ix315 (959) 

Villacampa F. ix281 (850P) 

Villanueva C.B. ix499 (1547PD), ix128 (355P), 

ix128 (357P) 

Villanueva M.J. ix436 (1333) 

Villarreal-Garza C. ix107 (289P), ix126 (349P) 

Villavicencio H. ix292 (888) 

Villegas T. ix254 (773) 

Vinayek N. ix76 (177PD) 

Vince-Ranchere D. ix478 (1477O) 

Vincent A.D. ix330 (1006P), ix392 (1203P) 

Vincenzi B. ix485 (1500P), ix489 (1512), 

ix500 (1550PD), ix516 (1603P), ix530 (1653P), 

ix538 (1681P), ix206 (606P) 

Vinolas Segarra N. ix414 (1264P) 

Viqueira A. ix277 (839P) 

Visa L. ix67 (145P) 

Visich J. ix124 (344P) 

Vismara C. ix335 (1019O) 

Visseren-Grul C.M. ix395 (1211), ix404 (1235PD), 

ix418 (1275P) 

Vitagliano D. ix430 (1309P), ix67 (143PD) 

Viterbo L. ix357 (1095) 

Viteri S. ix531 (1655P) 

Viudez A. ix219 (651) 

Vivaldi C. ix85 (208P) 

Vivancos A. ix531 (1656P), ix84 (204P) 

Vivenza D. ix528 (1644PD) 

Vizor S. ix165 (479P) 

Vlassak S. ix451 (1382P) 

Vlassov V.V. ix109 (293P) 

Vocka M. ix81 (197P) 

Voest E. ix153 (442O) 

Vogelzang N. ix296 (898PD), ix308 (936P), 

ix316 (961) 

Voigt A. ix453 (1389P) 

Voisin D. ix507 (1572P), ix507 (1574P) 

Volovitz I. ix72 (163P) 

von Heydebreck A. ix417 (1272P) 

von Karsa L. ix53 (88IN) 

von Laffert M. ix390 (1195P), ix394 (1208) 

von Mehren M. ix478 (1478O) 

von Minckwitz G. ix117 (321PD), ix118 (323PD) 

von Moos R. ix396 (1214), ix447 (1372P), 

ix462 (1423O), ix480 (1482PD), ix509 (1580P), 

ix157 (454P), ix190 (559P), ix193 (565P), 

ix283 (857P) 

von Pawel J. ix410 (1250P) 

von Roemeling R. ix225 (669PD), ix245 (739P) 

Voortman G. ix103 (274P) 

Vorotnikov I. ix130 (364P) 

Voutsadakis I.A. ix138 (393) 

Vrankar M. ix446 (1368TiP) 

Vranken Peeters M.J. ix532 (1658P) 

Vredenburgh J.J. ix146 (417PD) 

Vrignaud P. ix312 (946) 

Vrzalova J. ix474 (1464P) 

Vuillemin A. ix332 (1014), ix289 (876) 

Vukobradovic Djoric N. ix428 (1304P) 

Vukovic V. ix436 (1332), ix529 (1647PD), 

ix533 (1664P), ix125 (347P) 

Vuong T. ix200 (586P) 

Vynnychenko I. ix224 (668PD) 

W 

Waaka D.S. ix162 (470P) 

Wachter E. ix371 (1137P) 

Waddell T.S. ix224 (667PD) 

Wadsley J. ix224 (667PD) 

Wagner L. ix148 (426P) 

Wahab M.M.A.M. ix352 (1079P) 

Wahba H. ix353 (1081P) 

Wahlgren T. ix281 (848P) 

Wakelee H. ix445 (1364TiP) 

Wakui H. ix156 (451P), ix161 (467P), 

ix174 (1708PD) 

Walewski J.A. ix354 (1084P) 

Walkiewicz M. ix542 (1692P) 

Wallerek S. ix443 (1357) 

Wallin B. ix493 (1522PD) 

Wallis M. ix74 (171O) 

Walsh E. ix469 (1449PD) 

Walsh N. ix528 (1645PD), ix108 (292P) 

Walter E. ix121 (333P) 

Walter T.A. ix378 (1160P) 

Wan D. ix189 (556P) 

Wan M. ix89 (223P) 

Wanders J. ix129 (358P) 

Wanders R. ix396 (1213), ix425 (1296P) 

Wang-Lopez Q. ix102 (270P) 

Wang D. ix148 (428P), ix227 (676P) 

Wang F. ix111 (302), ix148 (428P), ix219 (650) 

Wang H. ix351 (1075P), ix435 (1331) 

Wang J. ix400 (1225O), ix443 (1359), ix93 (238), 

ix140 (401), ix163 (471P), ix169 (493P), 

ix192 (564P), ix231 (690P), ix247 (745P), 

ix248 (748), ix282 (851P) 

Wang J.W. ix202 (595P) 

Wang L. ix70 (155P), ix158 (457P), ix281 (847P) 

Wang M. ix77 (182P) 

Wang P. ix421 (1281P) 

Wang Q. ix282 (851P), ix306 (928P) 

Wang S. ix394 (1209), ix297 (901PD) 

Wang W. ix227 (676P) 

Wang X. ix394 (1209), ix400 (1225O), 

ix495 (1530P), ix501 (1552P) 

Wang Y. ix435 (1331), ix84 (204P) 

Wang Y.Z. ix438 (1341) 

Wang Z. ix435 (1331), ix219 (650) 

Ward S.E. ix235 (706P) 

Wardelmann E. ix481 (1486PD) 

Waring P. ix383 (1173P) 

Wasan H. ix242 (731P) 

Wasinger C. ix72 (165) 

Wass M. ix357 (1098) 

Watanabe H. ix492 (1519PD) 

Watanabe K. ix511 (1586P) 

Watanabe M. ix383 (1175P), ix220 (653), 

ix320 (973PD) 

Watanabe S. ix413 (1259P), ix509 (1579P), 

ix71 (159P), ix320 (973PD) 

Watanabe T. ix233 (698P) 

Waterkamp D. ix189 (555P) 

Waters J. ix242 (731P) 

Watt F. ix539 (1684P) 

Waxman I. ix267 (810P), ix269 (816P) 

Wcisło G. ix323 (979P) 

Weaver A. ix181 (530PD) 

Weber H. ix102 (271P) 

Weber J.S. ix363 (1116PD), ix368 (1129P), 

ix46 (71IN) 

Weber M. ix459 (1413TiP) 

Webersinke G. ix209 (616) 

Weder W. ix385 (1179O) 

Weekes C. ix155 (447PD) 

Wei J. ix229 (686P) 

Wei R. ix449 (1377P), ix309 (937P) 

Wei X. ix25 (11IN) 

Wei Y. ix190 (557P), ix201 (589P), ix217 (644) 

Weickhardt A. ix182 (532P) 

Weijl N. ix256 (781TiP) 

Weikert S. ix268 (813P), ix288 (875) 

Weinberg V. ix310 (939P) 

Weinstein M. ix202 (594P) 

Weiss G.J. ix362 (1111PD), ix152 (439O) 

Weith E. ix268 (813P) 

Weller M. ix31 (24IN) 

Wells K. ix467 (1442) 

Welslau M. ix120 (329P) 

Wen P.Y. ix146 (417PD) 

Wen Y.H. ix98 (257P) 

Werner P. ix171 (499P) 

Werner T.L. ix153 (442O) 

Wesley J.D. ix311 (942P) 

Wesseling J. ix532 (1658P) 

Wessels R. ix330 (1006P) 

West H. ix422 (1287P) 

West N. ix206 (608P) 

Westeel V. ix419 (1276P) 

Weynand B. ix336 (1021PD) 

Wheater M. ix283 (857P) 

Wheatley Price P. ix314 (954) 

Wheatley-Price P. ix493 (1525P) 

Wheeler H. ix151 (437TiP) 

White S. ix493 (1525P), ix526 (1640) 


author index 

Whitmore J.B. ix310 (940P), ix310 (941P) 

Wiater K. ix484 (1495P), ix489 (1513) 

Widhalm G. ix148 (426P) 

Wieczorek M. ix544 (1700) 

Wiedenmann B. ix377 (1156O) 

Wieland S. ix480 (1483PD) 

Wiemer E.A.C. ix534 (1667P), ix109 (295P) 

Wigginton J.M. ix361 (1109O), ix405 (1237PD), 

ix157 (453P), ix258 (784O) 

Wilbaux M. ix299 (907P) 

Wildberger J.E. ix212 (626) 

Wildiers H. ix510 (1583P) 

Wilkerson J. ix198 (579P) 

Wilkins D. ix166 (484P) 

Wilkinson N. ix320 (972PD) 

Willems L. ix408 (1243P) 

Willenbacher E. ix352 (1076P) 

Willenbacher W. ix352 (1076P), ix360 (1108TiP) 

Williams C. ix49 (77IN) 

Williams D. ix383 (1173P) 

Williams E. ix206 (608P) 

Williams J.A. ix262 (794PD) 

Williamson S. ix223 (664TiP) 

Wilner K. ix389 (1191PD), ix403 (1231PD), 

ix415 (1267P), ix416 (1268P) 

Wilson A. ix93 (240) 

Wilson K. ix178 (519O), ix182 (532P) 

Wilson P. ix290 (880) 

Wilson R.H. ix249 (754) 

Wiltshire R. ix259 (785O) 

Wimberger P. ix514 (1596P), ix539 (1683P) 

Wind S. ix162 (468P) 

Winfree K.B. ix421 (1281P), ix428 (1303P) 

Winkfield B. ix204 (600P) 

Winn B. ix370 (1134P), ix372 (1143P) 

Winquist E. ix304 (922P), ix315 (956), ix316 (960) 

Winterhalder R.C. ix302 (917P) 

Wintherhalder R. ix372 (1144) 

Wischnewsky M. ix73 (169O) 

Wisman L. ix103 (274P) 

Wisniewska H. ix544 (1700) 

Witkowski M. ix284 (859P) 

Wittig B. ix178 (518O), ix268 (813P) 

Wöhrer A. ix147 (421P), ix148 (426P) 

Wojciechowska-Lampka E. ix504 (1562P) 

Wojtowicz-Praga S. ix419 (1277P) 

Wolchok J. ix363 (1115PD), ix367 (1127P) 

Wolchok J.D. ix363 (1116PD), ix368 (1129P), 

ix75 (175PD) 

Wolf M. ix390 (1194P) 

Wolff J.M. ix299 (905P) 

Wolff R.A. ix451 (1383P) 

Wöll E. ix228 (680P), ix249 (755) 

Wollner M. ix498 (1541) 

Wolmark N. ix179 (523PD) 

Wolter P. ix518 (1609P) 

Won H.S. ix250 (757) 

Wong H. ix244 (736P) 

Wong J. ix309 (938P) 

Wong M. ix538 (1678P) 

Wong M.K. ix383 (1176P) 

Wong S. ix220 (656), ix298 (902P), ix321 (975PD) 

Wong Y. ix260 (787O), ix265 (804P) 

Wood B.A. ix297 (901PD) 

Wood K. ix269 (814P) 

Wood L. ix262 (794PD) 

Woods R. ix188 (551P) 

Worm K. ix437 (1339) 

Wormanns D. ix534 (1665P) 

Wotherspoon A. ix224 (667PD) 

Woulfe B. ix114 (312) 

Wouters C. ix510 (1583P) 

Wouters K. ix510 (1583P) 

Wozniak A. ix420 (1279P) 

Wright A. ix319 (969PD) 

Wright G. ix542 (1692P) 

Wright L. ix223 (664TiP) 

Wrin J. ix182 (532P) 

Wrona A. ix385 (1179O) 

Wu B. ix321 (975PD) 

Wu D. ix415 (1266P) 

Wu G. ix77 (182P) 

Wu H. ix217 (644) 

Wu J. ix130 (361P) 

Wu M. ix351 (1075P) 

Wu X. ix189 (556P) 

Wu Y-L ix444 (1362TiP) 

Wu Y. ix58 (106IN), ix400 (1226O), 

ix415 (1266P), ix437 (1336), ix443 (1359) 

Wu Y.L. ix438 (1341) 

Wu Z. ix437 (1336) 

Wydra D. ix320 (970PD) 

Wynne C. ix162 (470P) 

X 

Xanthaki D. ix278 (841P) 

Xanthakis I. ix213 (630) 

Xavier P. ix236 (708P) 

Xi M. ix343 (1048P) 

Xia J. ix227 (676P) 

Xiao X. ix281 (847P) 

Xiaoqing L. ix416 (1269P) 

Xie M. ix337 (1027P) 

Xie Z. ix415 (1266P) 

Xiong L. ix413 (1261P), ix454 (1395P) 

Xiong S. ix306 (928P) 

Xu B. ix114 (313), ix140 (401) 

Xu D. ix202 (595P) 

Xu F. ix346 (1057), ix219 (650) 

Xu J. ix478 (1478O), ix190 (557P), ix201 (589P), 

ix217 (643), ix217 (644), ix217 (646), 

ix231 (690P), ix231 (691P) 

Xu L. ix138 (394) 

Xu N. ix256 (779TiP) 

Xu R. ix217 (646), ix231 (690P) 

Xu W. ix78 (186P) 

Xu Y. ix203 (597P), ix217 (643), ix226 (674P), 

ix247 (745P) 

Xue C. ix219 (650) 

Xyrafas A. ix435 (1329), ix436 (1335) 

Y 

Yabusaki H. ix234 (702P) 

Yachi Y. ix201 (590P) 

Yacoubene K. ix517 (1607P) 

Yagata H. ix82 (199P), ix100 (264P), ix133 (373P) 

Yajima Y. ix518 (1611P), ix344 (1706P) 

Yakobson A. ix373 (1147) 

Yakout T. ix355 (1088P) 

Yalcin S. ix482 (1490P), ix258 (783O) 

Yalcintas Arslan U. ix473 (1461), ix105 (279P) 

Yamada K. ix438 (1340), ix543 (1696P) 

Yamada S. ix542 (1693P), ix246 (742P) 

Yamada T. ix383 (1174P), ix387 (1186P), 

ix536 (1673P), ix536 (1674P), ix89 (224P), 

ix170 (498P) 

Yamada Y. ix529 (1649P), ix156 (451P), 

ix159 (459P), ix161 (467P), ix164 (475P), 

ix174 (1708PD), ix202 (593P), ix231 (689P), 

ix251 (764) 

Yamaguchi H. ix233 (698P) 

Yamaguchi K. ix241 (728P) 

Yamaguchi M. ix387 (1187P) 

Yamaguchi O. ix436 (1334), ix69 (153P) 

Yamaguchi T. ix469 (1447PD) 

Yamakado K. ix243 (732P) 

Yamamoto G. ix87 (216P) 

Yamamoto H. ix514 (1597P), ix90 (228P) 

Yamamoto J. ix211 (625) 

Yamamoto M. ix434 (1325) 

Yamamoto N. ix393 (1204P), ix402 (1229PD), 

ix410 (1252P), ix413 (1260P), ix424 (1293P), 

ix430 (1310P), ix492 (1519PD), ix492 (1519PD), 

ix156 (451P), ix159 (459P), ix161 (467P), 

ix164 (475P), ix174 (1708PD) 

Yamamoto S. ix411 (1253P) 


Yamamoto T. ix243 (732P) 

Yamamoto Y. ix442 (1356), ix104 (277P) 

Yaman M. ix277 (838P) 

Yamanaka T. ix348 (1062O), ix385 (1181PD) 

Yamasaki M. ix481 (1485PD) 

Yamashita H. ix104 (277P) 

Yamashita Y. ix509 (1578P) 

Yamatsuji T. ix250 (758) 

Yamauchi H. ix82 (199P), ix100 (264P), 

ix133 (373P) 

Yamauchi J. ix211 (624) 

Yamauchi M. ix527 (1705) 

Yamazaki K. ix196 (574P), ix201 (590P), 

ix220 (653) 

Yamazaki N. ix372 (1142P), ix426 (1298P), 

ix514 (1597P), ix156 (451P), ix164 (475P), 

ix200 (587P) 

Yan H. ix415 (1266P), ix437 (1336) 

Yan S. ix416 (1269P) 

Yan Y. ix512 (1588P) 

Yanagida T. ix69 (153P) 

Yanagitani N. ix418 (1274P), ix441 (1353) 

Yanai T. ix514 (1597P) 

Yang C.J. ix414 (1263P) 

Yang H. ix389 (1193P), ix495 (1530P), ix111 (302) 

Yang J. ix415 (1266P), ix437 (1336) 

Yang J.C. ix402 (1229PD), ix410 (1252P) 

Yang M. ix89 (225P) 

Yang P. ix402 (1230PD), ix515 (1600P) 

Yang S. ix492 (1520PD), ix77 (182P) 

Yang S.H. ix414 (1262P) 

Yang X. ix321 (975PD) 

Yano H. ix71 (161P) 

Yao J.C. ix376 (1154O), ix47 (76IN) 

Yao Y. ix398 (1220), ix119 (326PD) 

Yasar N. ix497 (1540) 

Yashiro M. ix84 (205P) 

Yassine M. ix477 (1476) 

Yasuda H. ix422 (1285P) 

Yasuda K. ix541 (1690P) 

Yasui H. ix514 (1597P), ix203 (598P), 

ix231 (689P) 

Yatabe Y. ix433 (1324) 

Yau T. ix244 (736P) 

Yazbek G. ix499 (1547PD) 

Ychou M. ix85 (209P) 

Ye D-W. ix453 (1390P) 

Ye D. ix282 (851P) 

Ye G. ix117 (320PD), ix281 (847P) 

Ye L. ix190 (557P), ix281 (847P) 

Ye S. ix225 (670PD) 

Ye W. ix309 (938P) 

Yeh K. ix351 (1075P), ix522 (1626), ix253 (769) 

Yeh S. ix349 (1066PD) 

Yelle L. ix119 (328PD) 

Yelsengekar A. ix541 (1689P) 

Yen C. ix538 (1679P), ix246 (744P) 

Yermachenkova A.M. ix141 (403) 

Yerragudi S.R. ix150 (435TiP) 

Yetimoglu E. ix110 (300) 

Yeung Y. ix526 (1640) 

Yildirim A. ix308 (934P) 

Yilmaz A.U. ix173 (508), ix234 (701P) 

Yilmaz B. ix221 (660) 

Yim Y.M. ix477 (1474), ix203 (596P) 

Yin J. ix170 (497P) 

Yin W. ix154 (443PD), ix263 (796PD) 

Yip D. ix178 (519O) 

Yirmibesoglu E. ix110 (300) 

Yoda S. ix422 (1285P) 

Yoh K. ix429 (1306P), ix515 (1598P), 

ix534 (1666P) 

Yokoi S. ix144 (412O) 

Yokota M. ix210 (621) 

Yokota S. ix411 (1253P), ix422 (1286P), 

ix437 (1338) 

Yokouchi H. ix434 (1326) 

Yokoyama A. ix511 (1586P) 



Yokoyama T. ix434 (1325), ix442 (1354), 

ix511 (1586P) 

Yokoyama Y. ix326 (989P) 

Yomoda M. ix497 (1537P) 

Yonemitsu Y. ix168 (490P) 

Yonemori K. ix90 (228P), ix164 (474P) 

Yoo C. ix234 (700P) 

Yoo G. ix342 (1043P) 

Yoo S. ix362 (1112PD) 

Yook J.H. ix227 (679P) 

Yoon D.S. ix240 (722P) 

Yoshida A. ix82 (199P), ix100 (264P), 

ix133 (373P) 

Yoshida K. ix433 (1324), ix536 (1671P), 

ix159 (460P) 

Yoshida M. ix436 (1334), ix518 (1611P), 

ix196 (573P) 

Yoshida T. ix515 (1598P) 

Yoshifumi H. ix442 (1354) 

Yoshikawa H. ix327 (995P) 

Yoshimatsu K. ix159 (460P) 

Yoshimura K. ix203 (598P), ix240 (723P) 

Yoshimura M. ix385 (1181PD), ix92 (233) 

Yoshimura N. ix412 (1258P), ix79 (189P), 

ix79 (190P) 

Yoshino I. ix385 (1181PD) 

Yoshino S. ix228 (681P), ix240 (723P) 

Yoshino T. ix63 (126IN), ix449 (1378P), 

ix196 (574P), ix200 (587P), ix201 (590P) 

Yoshioka H. ix385 (1181PD), ix422 (1286P), 

ix434 (1327), ix437 (1338), ix91 (232), 

ix153 (441O) 

Yoshiura K. ix71 (161P) 

Yoshiya T. ix385 (1180PD) 

Yoshizawa A. ix463 (1428P) 

Yoshizawa C. ix107 (289P) 

Yoshizawa H. ix397 (1218), ix413 (1259P), 

ix509 (1579P), ix71 (159P) 

Yossef T. ix129 (360P) 

Yothers G. ix179 (523PD) 

You B. ix125 (346P), ix299 (907P) 

You S.Y. ix209 (617) 

Youcef L. ix72 (164) 

Younes A. ix350 (1072P) 

Young-Lin N. ix460 (1416PD) 

Young A. ix500 (1549PD) 

Young A.M. ix162 (469P) 

Yousif M.G. ix327 (996P) 

Yousif N.G. ix327 (996P) 

Yu C. ix400 (1226O), ix405 (1236PD), 

ix406 (1239P), ix515 (1600P) 

Yu E. ix203 (596P) 

Yu E.Y. ix297 (900PD) 

Yu J. ix156 (449PD), ix270 (817P), ix279 (844P) 

Yu L. ix501 (1552P), ix229 (686P) 

Yu P. ix437 (1337) 

Yu Q. ix216 (640) 

Yu W. ix445 (1364TiP), ix445 (1365TiP) 

Yu Y. ix355 (1087P) 

Yuan J.Y. ix281 (847P) 

Yuan P. ix140 (401) 

Yuanfeng X. ix161 (465P) 

Yuankai S. ix416 (1269P) 

Yücel I. ix221 (660) 

Yue H. ix362 (1112PD) 

Yukawa T. ix541 (1690P) 

Yuki S. ix196 (574P), ix201 (590P), ix202 (592P), 

ix232 (692P) 

Yuksel O. ix526 (1641) 

Yuksel S. ix525 (1636) 

Yuldasheva N.S. ix325 (985P) 

Yumuk P.F. ix394 (1207P), ix186 (547P), 

ix217 (645) 

Yun H.J. ix541 (1688PD) 

Yun Y.H. ix465 (1434P), ix512 (1589P) 

Yunger S. ix202 (594P) 

Yunokawa M. ix90 (228P) 

Yurasov S. ix408 (1245P), ix422 (1287P) 

Yvonnet V. ix312 (946) 

Z 

Zaanan A. ix234 (703P) 

Zabotina T.N. ix371 (1138P) 

Zaczek A.J. ix320 (970PD) 

Zade B.P. ix101 (265P) 

Zaegel M. ix455 (1396P) 

Zafar S.Y. ix191 (560P) 

Zaffaroni N. ix88 (222P) 

Zaghloul M.S. ix145 (413PD) 

Zagloul H. ix337 (1028P) 

Zagonel V. ix466 (1436P), ix91 (230P), 

ix144 (411O), ix209 (618), ix326 (991P) 

Zahir H. ix244 (738P), ix245 (739P) 

Zaim R. ix450 (1379P) 

Zairi F. ix332 (1013) 

Zaivelieva J. ix134 (379) 

Zak A. ix513 (1593P) 

Zakaria H. ix523 (1627) 

Zakharova N.A. ix470 (1451P) 

Zakotnik B. ix112 (308) 

Zalcman G. ix397 (1219), ix419 (1276P) 

Zalipsky S. ix164 (477P) 

Zamagni C. ix130 (362P) 

Zaman K. ix138 (393) 

Zamarchi R. ix489 (1512), ix91 (230P) 

Zambelli A. ix535 (1669P) 

Zambrana F. ix374 (1151) 

Zanelli P. ix175 (513PD) 

Zanetta S. ix165 (478P), ix263 (797PD), 

ix294 (893O) 

Zang D.Y. ix193 (566P) 

Zang R. ix323 (980P) 

Zangerl G. ix494 (1528P) 

Zanon A. ix486 (1504P) 

Zapf A. ix336 (1023PD) 

Zappa M. ix379 (1163P) 

Zarogoulidis K. ix509 (1580P) 

Zavadova E. ix81 (197P) 

Zavaglia K. ix94 (243) 

Zavagno G. ix131 (367P) 

Zayed D. ix114 (314), ix216 (639) 

Zazo S. ix80 (194P), ix183 (537P), ix187 (549P) 

Zazpe C. ix219 (651) 

Zazulina V. ix410 (1252P) 

Zdzienicki M. ix489 (1513) 

Zebisch A. ix352 (1076P) 

Zehnder M. ix89 (223P) 

Zeimet A. ix323 (980P) 

Zelek L. ix414 (1265P) 

Zemanova M. ix270 (817P), ix279 (844P) 

Zengin N. ix332 (1015) 

Zerbi V. ix192 (562P) 

Zhang A. ix334 (1016O) 

Zhang B. ix160 (461P), ix303 (921P) 

Zhang B.X. ix141 (405TiP) 

Zhang C. ix117 (320PD) 

Zhang H. ix401 (1228O) 

Zhang J. ix93 (238), ix141 (405TiP), ix152 (439O), 

ix192 (564P), ix248 (748) 

Zhang K. ix281 (847P) 

Zhang L. ix343 (1048P), ix346 (1057), 

ix400 (1226O), ix421 (1283P), ix444 (1362TiP), 

ix447 (1369P), ix138 (394) 

Zhang N.N. ix390 (1196P) 

Zhang P. ix140 (401) 

Zhang R. ix189 (556P) 

Zhang S. ix77 (182P), ix141 (405TiP) 

Zhang S.Z. ix202 (595P) 

Zhang W. ix432 (1319), ix216 (640), ix217 (643) 

Zhang X. ix415 (1266P), ix435 (1331), 

ix437 (1336), ix501 (1552P), ix256 (779TiP), 

ix281 (847P) 

Zhang Y. ix413 (1261P), ix443 (1359), 

ix67 (144PD), ix495 (1530P), ix300 (911P) 

Zhang Z. ix216 (640) 

Zhao C. ix346 (1057) 

Zhao H. ix438 (1341), ix219 (650) 

Zhao J. ix216 (640), ix227 (676P) 

Zhao L. ix346 (1057), ix394 (1209), ix93 (238), 

ix219 (650) 

Zhao M. ix389 (1193P), ix437 (1337) 

Zhao P. ix256 (779TiP) 

Zhao Z. ix192 (564P), ix248 (748) 

Zheng L. ix389 (1193P) 

Zheng S. ix93 (238) 

Zheng Y. ix256 (779TiP), ix256 (779TiP) 

Zheng Y.D. ix226 (674P) 

Zhi X. ix170 (497P) 

Zhong Y. ix201 (589P), ix217 (644) 

Zhong Z. ix321 (975PD) 

Zhou A. ix453 (1390P) 

Zhou C. ix407 (1241P), ix416 (1269P), 

ix443 (1359), ix444 (1362TiP), ix76 (179P), 

ix81 (195P), ix87 (219P) 

Zhou F. ix282 (851P) 

Zhou J. ix202 (595P) 

Zhou J.J. ix202 (595P) 

Zhou J.X. ix389 (1193P) 

Zhou L. ix247 (745P) 

Zhou Q. ix444 (1362TiP) 

Zhou X. ix158 (456P), ix168 (489P), ix247 (745P), 

ix303 (921P) 

Zhou Y. ix443 (1359) 

Zhu D. ix201 (589P), ix216 (640), ix217 (644) 

Zhu J. ix421 (1283P) 

Zhu M. ix230 (687P) 

Zhukovsky E. ix350 (1072P) 

Zielinski C. ix116 (317O), ix145 (414PD), 

ix221 (659), ix253 (768) 

Zilembo N. ix410 (1251P) 

Zima T. ix81 (196P) 

Zimmermann A. ix404 (1235PD), ix418 (1275P), 

ix457 (1403) 

Zimmermann C. ix464 (1432P) 

Zimovjanova M. ix513 (1593P) 

Zinner R. ix49 (77IN) 

Zinoli L. ix301 (914P) 

Zippelius A. ix372 (1144) 

Zitvogel L. ix169 (495P) 

Zizi-Sermpetzoglou A. ix92 (236) 

Zoccoli A. ix489 (1512), ix516 (1603P), 

ix530 (1653P) 

Zojer N. ix348 (1064O) 

Zong J.H. ix447 (1369P) 

Zörner A. ix336 (1023PD) 

Zotov O. ix134 (379) 

Zou J. ix308 (936P) 

Zou Z. ix229 (686P) 

Zoubir T. ix314 (955) 

Zubiri L. ix149 (429P), ix239 (718P), ix305 (927P) 

Zucali P.A. ix167 (488P), ix276 (836P) 

Zucchini G. ix130 (362P) 

Zudaire J.J. ix291 (886) 

Zudaire M.E. ix291 (886), ix305 (927P) 

Zugazabeitia Olabarria L. ix510 (1582P) 

Zugazagoitia J. ix438 (1342) 

Zulato E. ix209 (618) 

Zulueta J. ix432 (1316) 

Zuniga R.M. ix150 (435TiP) 

Zuo Y. ix427 (1300P) 

Zurita Saavedra A.J. ix275 (833P) 

Zurita-Saavedra A. ix261 (791PD) 

Zustovich F. ix144 (411O) 

Zvirbule Z. ix116 (317O) 

Zwenger A. ix210 (619) 

Zwierzina H. ix543 (1695P) 

Zwierzina M. ix543 (1695P), ix446 (1368TiP) 


subject 

index 

subject index 

A 

AAV-HGFK1, ix126 (348P) 

abiraterone acetate, comorbidity, ix305 (926P) 

abiraterone acetate, ix294 (894O), ix315 (958) 

abiraterone, ix119 (325PD) 

abiraterone, ix38 (48IN), ix304 (924P), ix305 

(925P), ix313 (951) 

ablation, ix371 (1137P), ix35 (40IN) 

AC-T, ix135 (382) 

ACC, ix209 (618) 

accelerated radiotherapy, ix397 (1217) 

access to clinical trials, ix165 (479P) 

acetic acid, ix471 (1455P) 

acquired resistance, ix401 (1227O), ix51 (82IN) 

acral melanoma, ix374 (1149), ix90 (227P) 

actinin-4, ix383 (1174P) 

activating EGFR kinase mutation, ix542 (1692P) 

active cellular therapy, ix268 (813P), ix310 (939P), 

ix310 (941P), ix311 (942P) 

ACTN4, ix387 (1186P) 

acute exacerbation, ix497 (1538P) 

acute lymphoblastic leukemia (ALL), ix359 (1104), 

ix359 (1106) 

acute myelogenous leukemia (AML), ix349 

(1067PD), ix349 (1068PD) 

acute myeloid leukemia, ix349 (1066PD), ix356 

(1092P) 

acute oncology, ix519 (1613P) 

AD, ix135 (382) 

adapalene, ix514 (1597P) 

adaptive radiotherapy, ix35 (40IN) 

ADC, ix498 (1543TiP) 

ADCC, ix90 (228P), ix93 (237) 

adenocarcinoma, ix388 (1189P), ix429 (1307P), 

ix430 (1310P), ix435 (1331), ix439 (1343), ix446 

(1367TiP), ix455 (1396P), ix544 (1699P), ix77 

(182P), ix152 (438O), ix249 (753) 

adherence, ix460 (1419PD), ix476 (1473P), ix518 

(1611P) 

adipokines, ix79 (190P) 

adiponectin, ix79 (190P) 

adjuvant chemo-radiotherapy, ix345 (1056), ix97 

(253PD) 

adjuvant chemotherapy timing, ix210 (620) 

adjuvant chemotherapy, ix330 (1004P), ix385 

(1181PD), ix386 (1183P), ix389 (1192PD), ix95 

(246O), ix112 (306), ix121 (333P), ix178 

(520O), ix188 (551P), ix197 (576P), ix200 

(586P), ix200 (588P), ix210 (621), ix211 (625), 

ix212 (627), ix228 (681P) 

adjuvant docetaxel, ix108 (291P) 

adjuvant endocrine therapy, ix105 (282P) 

adjuvant mFOLFOX6, ix201 (591P), ix221 (657) 

adjuvant radiochemotherapy, ix229 (683P) 

adjuvant radiotherapy, ix386 (1183P) 

adjuvant therapy, ix113 (311), ix235 (706P), ix281 

(847P), ix286 (867P), ix292 (889TiP) 

adjuvant treatment, ix96 (251PD), ix100 (261P), 

ix112 (308), ix181 (530PD) 

adjuvant, ix107 (288P), ix264 (799P) 

adme, ix508 (1575P) 

Adoptive Immunotherapy, ix240 (723P) 

adrenoceptors, ix110 (299) 

adrenocortical carcinoma, ix293 (891TiP) 

Adult T-cell Leukemia/Lymphoma, ix348 (1062O) 

advanced basal cell carcinoma, ix362 (1111PD), 

ix362 (1112PD), ix477 (1474) 

advanced biliary cancers, ix288 (873) 

advanced breast cancer, ix123 (341P), ix138 (394), 

ix140 (400) 

advanced cancer patients, ix475 (1469P) 

advanced cancer, ix499 (1544O) 

advanced cervical cancer, ix327 (995P) 

advanced colorectal cancer, ix63 (127IN), ix511 

(1587P), ix35 (41IN), ix181 (528PD), ix181 

(529PD), ix183 (537P), ix185 (544P) 

advanced colorectal neoplasms, ix216 (640) 

advanced gastric cancer, ix228 (682P), ix93 (238), 

ix230 (688P), ix231 (691P), ix234 (701P), ix250 

(758) 

advanced gastroesophageal cancer, ix224 (667PD) 

advanced kidney cancer, ix258 (783O), ix264 

(798PD), ix278 (841P), ix278 (842P), ix280 

(845P) 

advanced lung cancer, ix515 (1600P), ix522 

(1625), ix523 (1630) 

advanced neuroendocrine tumours, ix378 (1161P), 

ix85 (209P) 

advanced non-small cell lung cancer, ix391 

(1199P), ix398 (1221), ix422 (1285P), ix434 

(1325), ix442 (1354), ix173 (505), ix422 (1286P) 

advanced NSCLC, ix398 (1223), ix411 (1253P), 

ix440 (1349), ix153 (440O) 

advanced prostate cancer, ix295 (895O) 

advanced soft tissue sarcoma, ix480 (1483PD) 

advanced solid tumors, ix157 (454P) 

advanced stage breast cancer, ix121 (332P) 

advanced urothelial carcinoma, ix259 (786O) 

advanced/metastatic NSCLC, ix408 (1244P), ix423 

(1288P), ix436 (1335), ix444 (1361), ix78 

(186P), ix80 (194P) 

adverse event, ix519 (1614P), ix230 (688P) 

adverse events, ix203 (596P), ix259 (785O), ix280 

(845P) 

afatinib, ix401 (1227O), ix402 (1229PD), ix410 

(1252P), ix423 (1288P), ix424 (1292P), ix437 

(1339), ix155 (446PD), ix161 (464P), ix162 

(468P), ix165 (478P), ix169 (494P), ix174 

(509TiP) 

aflibercept, ix198 (581P), ix214 (633) 

Africa, ix65 (135IN) 

AGC, ix224 (668PD), ix232 (695P) 

aggressive disease, ix307 (933P) 

aggressive fibromatosis (desmoid tumor), ix479 

(1479PD) 

8.1 AH haplotype, ix493 (1523P) 

AI / EIA, ix487 (1505P) 

airway stenosis, ix517 (1608P) 

airway stent, ix517 (1608P) 

AITL, ix352 (1077P) 

AJCC, ix245 (741P) 

AKT inhibitor, ix159 (458P) 

Akt, ix338 (1031P) 

AKT, ix164 (474P) 

albumin-bound paclitaxel, ix141 (405TiP), ix256 

(780TiP) 

ALC, ix75 (175PD) 

alisertib, ix168 (489P) 

ALK rearrangement, ix390 (1195P) 

alk-positive diffuse large b-cell lymphoma, ix357 

(1098) 

ALK-positive NSCLC, ix402 (1230PD) 

ALK-positive, ix416 (1268P), ix80 (193P) 

ALK1, ix43 (62IN) 

ALK, ix387 (1187P), ix389 (1193P), ix73 (167O), 

ix153 (440O), ix153 (441O), ix51 (81IN) 

Alkaline phosphatase, ix306 (930P) 

all-case surveillance, ix200 (587P) 

allopurinol, ix358 (1103) 

alpha v-integrin, ix317 (965TiP) 

alpha-emitter pharmaceutical, ix296 (898PD), 

ix308 (936P) 

amatuximab, ix493 (1522PD) 

ambulatory oncology, ix475 (1468P) 


Annals of Oncology 23 (Supplement 9): ix586–600, 2012 


amino acid metabolism, ix532 (1660P) 

Amphinex, ix347 (1061TiP) 

amphiregulin, ix180 (526PD), ix183 (536P) 

AMPK, ix209 (618) 

amrubicin, ix443 (1358), ix492 (1519PD), ix92 

(235) 

amrubicinol, ix92 (235) 

anaemia, ix504 (1562P), ix505 (1564P), ix505 

(1566P), ix523 (1629) 

anamorelin, ix512 (1588P), ix161 (465P) 

anand, ix339 (1034P) 

anaplastic glioma, ix31 (23IN) 

anaplastic large cell lymphoma, ix348 (1063O), 

ix353 (1083P) 

Anaplastic Lymphoma Kinase (ALK) Gene 

Rearrangement, ix394 (1208) 

anaplastic lymphoma kinase (ALK), ix415 

(1266P), ix418 (1274P), ix484 (1497P), ix152 

(439O), ix390 (1196P), ix433 (1324) 

anastrozole, ix123 (341P) 

androgen deprivation therapy, ix309 (938P), ix314 

(952) 

androgen receptor, ix344 (1706P), ix98 (257P), 

ix38 (48IN), ix295 (896O), ix297 (899PD) 

androgen, ix104 (277P) 

anemia point prevalence, ix523 (1628) 

anemia, ix499 (1545O), ix519 (1615P), ix523 

(1630) 

angiogenesis inhibitor, ix150 (435TiP), ix154 

(445PD), ix47 (76IN) 

angiogenesis inhibitors, ix40 (54IN) 

angiogenesis, ix59 (110IN), ix70 (155P), ix76 

(178P), ix88 (222P), ix39 (52IN), ix243 (734P), 

ix287 (869), ix54 (91IN), ix321 (975PD) 

angiogenic factor, ix286 (865P) 

angiopoietin (ANG), ix78 (184P) 

angiopoietins (ANGs), ix321 (975PD) 

announcing, ix476 (1471P) 

ANOVA models, ix164 (474P) 

anthracycline rechallenge, ix128 (357P) 

anthracycline-based chemotherapy, ix352 (1077P) 

anthracycline, ix117 (320PD) 

anti HER-2 therapy, ix164 (476P) 

anti VEGF therapies, ix278 (840P) 

anti-androgen therapy, ix344 (1706P), ix303 

(920P) 

anti-angiogenesis, ix220 (654) 

anti-angiogenic TKI, ix272 (822P), ix296 (897O) 

anti-CD26 monoclonal antibody, ix170 (498P) 

anti-EGFR therapy, ix86 (214P), ix42 (58IN), 

ix224 (667PD) 

anti-EGFR, ix336 (1021PD) 

anti-emetic, ix508 (1575P), ix520 (1618) 

anti-emetics, ix507 (1573P), ix508 (1576P) 

anti-estrogen treatment, ix126 (350P) 

anti-idiotype monoclonal antibodies, ix406 

(1238PD) 

anti-microbial resistance, ix503 (1559P) 

anti-tumor activity, ix163 (472P), ix169 (495P) 

anti-tumor immunity, ix541 (1690P) 

anti-VEGF, ix269 (814P) 

antiangiogenic therapy, ix186 (546P) 

antibiotics, ix351 (1075P) 

antibody-dependent cell-mediated cytotoxicity 

(ADCC), ix350 (1072P), ix528 (1644PD) 

antibody-drug conjugate, ix348 (1063O) 

antidepressant, ix109 (295P) 

antiemetic control, ix64 (129IN) 

antiemetic prevention, ix508 (1577P) 

antigen-specific cancer immunotherapy, ix536 

(1671P) 

antineoplastic chemotherapy, ix516 (1604P)

Annals of Oncology subject index 

antiprogressive treatment, ix303 (919P) 

antitumor activity, ix361 (1109O), ix405 

(1237PD), ix157 (453P), ix160 (461P), ix258 

(784O) 

anthracycline induced left ventricle dysfunction 

prediction, ix513 (1593P) 

AP26113, ix152 (439O) 

aplastic anemia, ix357 (1095) 

apoptosis, ix365 (1122P), ix72 (165), ix197 

(575P), ix253 (769) 

appendix carcinoma, ix222 (661) 

aprepitant, ix500 (1550PD), ix509 (1578P) 

ARN-509, ix303 (920P) 

aromatase inhibitor, ix27 (14IN), ix28 (17IN), 

ix104 (277P), ix105 (280P), ix105 (282P), ix124 

(342P) 

ARQ 197, ix225 (669PD) 

array CGH, ix71 (161P) 

arthralgia, ix113 (310) 

asbestos exposure, ix469 (1447PD) 

ASG-5ME, ix317 (963TiP) 

ASPS, ix484 (1495P) 

assessment, ix517 (1607P) 

association, ix260 (787O) 

asymptomatic brain metastases, ix137 (387) 

asymptomatic distant metastasis, ix106 (285P) 

aurora A kinase inhibitor, ix160 (461P) 

Aurora A kinase, ix168 (489P) 

Aurora-A, ix134 (376) 

autologous stem cell transplantation, ix353 

(1082P), ix353 (1083P), ix354 (1084P), ix260 

(789O) 

autologous transplantation, ix354 (1086P) 

automated quantitative protein expression analysis 

(AQUA), ix534 (1666P) 

autophagy, ix538 (1679P) 

avb3 integrin, ix86 (214P) 

awareness and willingness to participate, ix450 

(1381P) 

Awareness, ix472 (1458P) 

axitinib, ix409 (1246P), ix453 (1391P), ix268 

(811P), ix279 (843P), ix283 (856P) 

ayurveda, ix452 (1388P) 

5-azacytidine, ix357 (1096) 

B 

53BP1, ix533 (1661P), ix229 (686P) 

B-cell receptor, ix44 (65IN) 

bacteremia, ix503 (1559P) 

BAP 1, ix427 (1300P) 

barriers, ix65 (136IN) 

basal cell carcinoma, ix477 (1474) 

basal cell nevus syndrome, ix477 (1474) 

base of tongue squamous cell carcinoma, ix339 

(1032P) 

Bax, ix212 (628) 

BCC, ix362 (1111PD), ix362 (1112PD) 

BDNF, ix474 (1464P), ix79 (188P) 

BELIEF, ix58 (105IN) 

belinostat, ix349 (1068PD) 

Belotean, ix492 (1520PD) 

bendamustine, ix348 (1064O) 

benefit, ix332 (1014) 

best response, ix282 (852P) 

bevacizumab beyond progression, ix140 (400), 

ix192 (562P), ix220 (655) 

bevacizumab, ix118 (323PD), ix220 (653), ix378 

(1159P), ix378 (1160P), ix390 (1194P), ix405 

(1236PD), ix406 (1239P), ix406 (1240P), ix419 

(1277P), ix419 (1278P), ix420 (1279P), ix426 

(1299P), ix428 (1303P), ix441 (1351), ix441 

(1352), ix441 (1353), ix445 (1364TiP), ix70 

(155P), ix529 (1648P), ix530 (1653P), ix531 

(1657P), ix75 (174O), ix81 (198P), ix85 (209P), 

ix108 (292P), ix116 (317O), ix122 (335P), ix125 

(345P), ix127 (354P), ix128 (356P), ix139 (395), 

ix146 (417PD), ix151 (437TiP), ix161 (464P), 

ix171 (499P), ix181 (530PD), ix182 (532P), 

ix189 (555P), ix190 (559P), ix191 (560P), ix193 

(565P), ix193 (567P), ix195 (571P), ix196 

(573P), ix202 (592P), ix202 (594P), ix203 

(596P), ix206 (607P), ix209 (618), ix211 (624), 

ix218 (648), ix219 (651), ix219 (652), ix221 

(659), ix249 (755), ix267 (809P), ix289 (876), 

ix319 (967O), ix320 (973PD), ix322 (978P), 

ix325 (986P) 

beyond PD, ix439 (1343), ix439 (1344) 

BEZ235, ix157 (454P) 

BI-RADS classification, ix107 (286P) 

BIBF 1120, ix245 (740P), ix246 (744P) 

bilateral breast cancer, ix175 (513PD) 

biliary tract cancer, ix241 (725P), ix242 (730P), 

ix242 (731P), ix245 (739P) 

biliary tract cancers, ix254 (773) 

bioavailability, ix507 (1574P) 

biobank, ix385 (1179O), ix535 (1669P) 

Biobanking, ix61 (117IN) 

biochemotherapy, ix373 (1147) 

bioequivalence, ix507 (1574P) 

biological characteristics, ix215 (638) 

biological marker, ix85 (211P) 

biological markers, ix474 (1464P) 

biological response, ix354 (1086P), ix303 (919P) 

biological therapy, ix500 (1550PD) 

biology of colorectal cancer, ix92 (236) 

biomarker discovery, ix262 (794PD) 

biomarker, ix451 (1382P), ix529 (1647PD), ix531 

(1656P), ix531 (1657P), ix73 (169O), ix77 

(180P), ix78 (186P), ix81 (198P), ix83 (202P), 

ix84 (206P), ix88 (220P), ix89 (226P), ix93 

(238), ix93 (240), ix158 (457P), ix173 (505), 

ix187 (550P), ix212 (628), ix263 (796PD), ix275 

(832P), ix278 (842P), ix285 (861P), ix300 

(910P) 

biomarkers for antihormone responsiveness, ix96 

(249PD) 

biomarkers, ix59 (110IN), ix383 (1173P), ix390 

(1194P), ix400 (1226O), ix405 (1236PD), ix406 

(1239P), ix406 (1240P), ix430 (1312), ix529 

(1648P), ix47 (1703IN), ix76 (177PD), ix78 

(183P), ix80 (194P), ix84 (207P), ix86 (213P), 

ix87 (219P), ix32 (28IN), ix124 (343P), ix259 

(785O), ix49 (78IN), ix301 (915P) 

biomolecular analysis, ix483 (1491P) 

biosimilar, ix351 (1074P), ix103 (274P) 

biosimilars, ix504 (1563P), ix506 (1568P), ix506 

(1569P) 

biotherapeutics, ix488 (1508P) 

bispecific monoclonal antibody, ix350 (1072P) 

bispecific, ix170 (496P) 

bisphosphates, ix443 (1359) 

bisphosphonate, ix511 (1584P), ix511 (1585P) 

bisphosphonates, ix524 (1633) 

biweekly carboplatin and paclitaxel, ix422 (1285P) 

BKM120, ix116 (318O), ix157 (454P), ix223 

(664TiP) 

bladder cancer, ix39 (50IN), ix39 (53IN), ix260 

(788O), ix264 (799P), ix265 (802P), ix266 

(805P), ix266 (806P), ix266 (807P), ix290 (882), 

ix291 (884), ix291 (885) 

bladder preservation, ix265 (801P), ix291 (883) 

bladder, ix93 (239), ix265 (803P) 

bleomycin, ix347 (1061TiP), ix285 (862P) 

blood flow in tumor, ix134 (379) 

blood pressure monitoring, ix268 (811P) 

blood vessels, ix149 (431) 

blood–brain barrier, ix537 (1675P) 

blood-brain barrier permeability, ix61 (120IN) 

BOADICEA, ix34 (35IN) 

body composition, ix168 (491P) 

Body Mass Index (BMI), ix206 (606P) 

body mass index, ix515 (1599P), ix119 (327PD), 

ix135 (380) 

bone disease, ix126 (351P) 

bone growth, ix526 (1642) 

bone health, ix449 (1377P) 

bone marker, ix126 (351P) 

bone marrow transplantation, ix357 (1095) 

bone marrow, ix69 (152P) 

bone metastases, ix447 (1372P), ix509 (1580P), 

ix510 (1583P), ix511 (1585P), ix133 (372P), 

ix140 (401), ix309 (937P) 

Bone Metastasis, c-MET, ix296 (897O) 

bone metastasis, ix344 (1050P), ix432 (1320), 

ix433 (1321), ix443 (1359), ix126 (348P), ix229 

(685P) 

bone metastatic patients, ix524 (1633) 

bone mineral density, ix105 (282P) 

bone resorption biomarker, ix432 (1320) 

bone turnover markers, ix266 (805P), ix312 (945) 

bone-targeted treatment, ix38 (49IN) 

borderline ovarian cancer, ix322 (976P) 

borderline subgroup (12-20% split signals), ix390 

(1195P) 

bortezomib, ix348 (1064O), ix249 (754) 

bowel obstruction, ix326 (992P) 

brachytherapy, ix329 (1003P) 

BRAF inhibitor, ix366 (1125P) 

BRAF mutation, ix365 (1123P), ix373 (1145), 

ix383 (1173P), ix94 (242), ix220 (656) 

BRAF status, ix383 (1173P) 

BRAF-mutations, ix373 (1147) 

BRAF, ix387 (1187P), ix529 (1649P), ix196 

(574P), ix216 (641), ix46 (69IN), ix46 (70IN) 

brain metastases, ix366 (1125P), ix369 (1132P), 

ix394 (1207P), ix61 (120IN), ix62 (123IN), 

ix421 (1283P), ix421 (1284P), ix428 (1305P), 

ix435 (1330), ix446 (1368TiP), ix489 (1514), 

ix537 (1675P), ix31 (26IN), ix144 (412O), ix145 

(414PD), ix148 (427P), ix148 (428P), ix150 

(433), ix253 (771) 

brain metastasis, ix62 (121IN), ix414 (1262P) 

brain, ix221 (660) 

BRCA 1/2 mutations, ix109 (294P) 

BRCA mutation, ix176 (515P), ix319 (969PD) 

BRCA1/2, ix469 (1449PD), ix34 (35IN), ix175 

(512PD), ix175 (513PD) 

BRCA1, ix498 (1542TiP), ix531 (1655P), ix533 

(1661P), ix34 (34IN), ix229 (686P), ix266 

(807P) 

BRCA2 mutation, ix176 (514P) 

BRCA2, ix34 (34IN) 

breakthrough cancer pain (BTcP), ix518 (1612P) 

breast cancer screening, ix469 (1449PD) 

Breast Cancer Stem Cells (BCSCs), ix133 (375P) 

breast cancer stem cells, ix110 (300) 

breast cancer subtypes, ix100 (261P), ix110 

(297P), ix131 (366P) 

breast cancer, HER2, EGFR, ix127 (353P) 

breast cancer, ix57 (100IN), ix57 (101IN), ix57 

(102IN), ix58 (103IN), ix58 (104IN), ix59 

(108IN), ix384 (1178TiP), ix61 (120IN), ix62 

(121IN), ix452 (1388P), ix453 (1389P), ix454 

(1393P), ix454 (1394P), ix455 (1397P), ix455 

(1398P), ix27 (13IN), ix460 (1417PD), ix470 

(1450P), ix470 (1451P), ix67 (146P), ix477 

(1476), ix501 (1552P), ix501 (1553P), ix506 

(1568P), ix70 (156P), ix513 (1593P), ix27 

(15IN), ix521 (1621), ix525 (1636), ix72 (164), 

ix531 (1656P), ix532 (1658P), ix532 (1660P), 

ix543 (1698P), ix74 (172O), ix29 (18IN), ix82 

(200P), ix83 (202P), ix84 (204P), ix84 (206P), 

ix87 (216P), ix87 (217P), ix94 (243), ix95 

(246O), ix96 (249PD), ix96 (250PD), ix97 

(253PD), ix97 (254PD), ix100 (261P), ix100 

(264P), ix101 (265P), ix101 (266P), ix101 

(268P), ix102 (269P), ix102 (270P), ix103 

(273P), ix104 (276P), ix104 (277P), ix104 

(278P), ix105 (279P), ix105 (281P), ix106 

(283P), ix106 (284P), ix107 (286P), ix107 

(288P), ix108 (290P), ix109 (293P), ix110 

(297P), ix110 (299), ix110 (300), ix111 (302), 

ix112 (305), ix112 (306), ix112 (308), ix113 

(309), ix113 (311), ix114 (313), ix114 (314), 


subject index 

ix115 (316TiP), ix116 (318O), ix116 (319O), 

ix117 (320PD), ix117 (321PD), ix117 (322PD), 

ix118 (323PD), ix118 (324PD), ix119 (325PD), 

ix120 (331P), ix121 (333P), ix121 (334P), ix124 

(343P), ix125 (347P), ix126 (348P), ix126 

(349P), ix34 (34IN), ix126 (350P), ix126 (351P), 

ix127 (352P), ix129 (359P), ix34 (35IN), ix130 

(362P), ix130 (363P), ix131 (365P), ix131 

(367P), ix133 (372P), ix133 (373P), ix133 

(374P), ix134 (376), ix137 (387), ix137 (388), 

ix139 (396), ix139 (397), ix139 (398), ix140 

(402), ix141 (405TiP), ix142 (406TiP), ix162 

(470P), ix166 (483P), ix175 (511PD), ix175 

(512PD), ix176 (515P), ix321 (974PD), ix57 

(99IN), ix25 (9IN) 

breast carcinoma, ix107 (287P) 

breast self examination, ix136 (383), ix136 (383) 

brentuximab vedotin, ix348 (1063O), ix353 

(1083P) 

brivanib, ix319 (966O) 

Brm, ix78 (186P) 

bronchoscopic intervention, ix517 (1608P) 

brown fat, ix108 (290P) 

BTK inhibitors, immunotoxins, ix45 (68IN) 

C 

c-kit, heat shock protein 90 inhibitor, ix538 

(1679P) 

c-kit, ix365 (1123P), ix498 (1541) 

c-Met inhibitor, ix67 (143PD), ix154 (444PD), 

ix174 (1708PD) 

c-MET, ix424 (1293P), ix76 (179P), ix84 (205P) 

c-Myc, statin, ix302 (916P) 

c-Myc, ix275 (832P) 

C-reactive protein, prognosis, ix381 (1169P) 

C-reactive protein, ix525 (1637) 

Ca 125, ix324 (983P) 

cabazitaxel, ix170 (497P), ix306 (931P), ix307 

(932P), ix307 (933P), ix312 (946), ix312 (948), 

ix313 (951), ix314 (953), ix314 (955), ix315 

(956), ix315 (958), ix316 (960), ix316 (962TiP) 

cachexia, ix499 (1544O), ix512 (1588P), ix161 

(465P) 

CagA, ix351 (1075P) 

calendula officinalis,, ix346 (1059) 

CAM, ix452 (1388P) 

cancer and chemotherapy, ix515 (1599P) 

cancer associated anemia, ix504 (1561P) 

cancer awareness, ix380 (1166P), ix448 (1375P), 

ix472 (1457P) 

cancer burden, ix65 (137IN) 

cancer cachexia, ix64 (131IN), ix511 (1586P) 

cancer clinical trial, ix450 (1381P), ix483 (1493P) 

cancer genomics, ix544 (1699P) 

cancer immunotherapy, ix406 (1238PD), ix536 

(1672P), ix268 (813P), ix301 (915P), ix313 (949) 

cancer informatics, ix449 (1376P) 

cancer nanotechnology, ix87 (217P) 

cancer of unknown primary origin (CUP), ix381 

(1169P), ix381 (1170P), ix381 (1171P) 

cancer patient, ix457 (1404) 

cancer policy, ix66 (141INIS) 

cancer registry implementation, ix460 (1414TiP) 

cancer registry, ix449 (1376P), ix175 (513PD), 

ix241 (725P) 

cancer risk, ix53 (89IN) 

cancer screening, ix460 (1419PD), ix470 (1452P), 

ix471 (1453P), ix473 (1461) 

cancer stem cells therapeutics, ix160 (463P) 

cancer stem cells, ix71 (159P), ix72 (164), ix539 

(1685P), ix543 (1696P), ix86 (215P), ix136 

(385), ix160 (463P) 

cancer, ix65 (135IN), ix447 (1369P), ix456 

(1401P), ix458 (1408), ix459 (1412), ix476 

(1471P), ix478 (1477O), ix519 (1616P), ix71 

(161P), ix242 (729P), ix56 (98IN) 

capecitabine, ix128 (356P), ix129 (358P), ix138 

(394), ix139 (398), ix140 (399), ix187 (550P), 

ix193 (566P), ix200 (588P), ix234 (700P), ix240 

(722P), ix250 (757), ix256 (781TiP), ix257 

(782TiP), ix229 (683P) 

CAPOX, ix218 (647) 

carboplatin and pemetrexed, ix434 (1326) 

carboplatin plus paclitaxel, ix398 (1221) 

carboplatin, ix340 (1037P), ix397 (1218), ix409 

(1246P), ix151 (437TiP), ix283 (857P), ix286 

(867P) 

carcinoembryonic antigen (CEA), ix199 (583P), 

ix221 (659) 

carcinoids, ix47 (73IN) 

carcinoma cervix, ix328 (997P) 

cardiac safety, ix128 (357P), ix178 (519O) 

cardiac toxicity, ix113 (309) 

cardio-toxicity, cardio-protection, anthracyclines, 

echocardiography, ix539 (1682P) 

cardiotoxicity, ix455 (1397P) 

care satisfaction, ix475 (1468P) 

caregiver, ix343 (1047P) 

cargiverś burden, ix145 (415PD) 

castrate-resistant prostate cancer (CRPC), PSA, 

ix304 (923P) 

castrate-resistant prostate cancer (CRPC), ix296 

(897O), ix298 (902P), ix298 (903P), ix300 

(909P), ix301 (913P), ix301 (915P), ix305 

(927P), ix308 (934P), ix315 (958), ix316 (960), 

ix317 (964TiP) 

castrate-resistant prostate cancer, ix38 (47IN), 

ix296 (898PD), ix308 (936P) 

castration resistant prostate cancer, ix300 (911P), 

ix302 (917P), ix303 (921P), ix305 (926P), ix314 

(954), ix317 (963TiP) 

castration-resistant prostate cancer, ix304 (924P), 

ix305 (925P) 

catumaxomab, ix514 (1596P), ix539 (1683P), 

ix163 (472P), ix172 (504), ix228 (680P) 

caucasian patients, ix337 (1026P), ix439 (1346) 

CD10, ix107 (287P) 

CD117, ix349 (1067PD) 

CD133-positive blood vessels, ix146 (418PD) 

CD133, ix205 (604P) 

CD135, ix349 (1067PD) 

CD20, ix70 (157P) 

CD24, ix87 (216P) 

CD30+ lymphomas, ix348 (1063O) 

CD30 + , ix285 (861P) 

CD32, ix70 (157P) 

CD34+ stem cell mobilization and collection, 

ix353 (1082P), ix353 (1083P) 

CD40, ix529 (1650P) 

CD44 + /CD24-/Lin-cells, ix110 (300) 

CD44, ix87 (216P) 

2 CdA, ix352 (1076P) 

cediranib, ix155 (448PD), ix207 (609P) 

cell growth, ix88 (220P) 

cell-free DNA, ix73 (168O) 

CellSearch, ix338 (1029P), ix90 (227P) 

CellSearchSystem, ix489 (1512) 

central nerve system metastasis, ix251 (764) 

cervical cancer screening, ix471 (1454P), ix471 

(1455P) 

cervical cancer, ix328 (1000P), ix330 (1007), ix330 

(1007), ix331 (1008), ix331 (1009), ix331 (1010), 

ix475 (1466P), ix524 (1632), ix22 (3IN), ix327 

(996P), ix328 (998P), ix328 (999P) 

cetuximab resistance, ix67 (143PD), ix530 

(1651P), ix42 (59IN), ix334 (1018O) 

cetuximab, ix340 (1036P), ix342 (1044P), ix345 

(1052), ix372 (1144), ix396 (1213), ix396 (1216), 

ix417 (1272P), ix528 (1644PD), ix87 (218P), 

ix93 (237), ix178 (520O), ix180 (526PD), ix183 

(535P), ix190 (557P), ix191 (561P), ix192 

(563P), ix194 (568P), ix196 (572P), ix198 

(580P), ix199 (582P), ix206 (606P), ix206 

(608P), ix213 (630), ix217 (643), ix233 (696P) 

cfDNA, ix533 (1664P) 

CH5424802, ix153 (441O) 


challenges, ix65 (135IN) 

Charson comorbidity index, ix349 (1065O) 

checklist, ix524 (1634) 

checkpoint protein biomarker antibody, ix46 

(71IN) 

chemo-radiotherapy, ix342 (1045P), ix206 (608P), 

ix208 (612P), ix225 (671P), ix328 (999P) 

chemo-resistance, ix159 (458P) 

chemoembolisation, ix35 (40IN), ix254 (772) 

chemokine ligand 2, ix277 (838P) 

chemomodulation, ix370 (1135P) 

chemoprevention, ix34 (36IN) 

chemoradiation, ix330 (1007), ix215 (638) 

chemoradiotherapy, ix520 (1620), ix207 (609P), 

ix215 (637), ix226 (673P), ix237 (711P) 

chemoresistance, ix370 (1135P) 

chemosensitivity, ix429 (1308P) 

chemotherapeutic drugs, ix38 (47IN) 

chemotherapy combination, ix371 (1138P), ix138 

(391), ix166 (484P) 

chemotherapy holiday, ix181 (528PD) 

chemotherapy induced peripheral neuropathy, 

ix521 (1622) 

chemotherapy regimens, ix214 (634), ix320 

(972PD) 

chemotherapy toxicity, ix452 (1386P), ix511 

(1587P) 

chemotherapy-induced anaemia, ix504 (1563P), 

ix506 (1568P), ix506 (1569P), ix523 (1627) 

chemotherapy-induced anemia, ix505 (1565P), 

ix505 (1567P) 

chemotherapy-induced mucositis, ix163 (473P) 

chemotherapy-induced nausea and vomiting, 

ix509 (1579P) 

chemotherapy-induced neutropenia, ix499 

(1547PD), ix500 (1548PD) 

chemotherapy-induced oral mucositis, ix514 

(1595P) 

chemotherapy-induced peripheral neurotoxicity, 

ix512 (1590P), ix513 (1591P) 

chemotherapy-naive, ix294 (894O) 

chemotherapy, ix331 (1010), ix332 (1013), ix340 

(1036P), ix342 (1044P), ix352 (1076P), ix378 

(1159P), ix378 (1160P), ix378 (1161P), ix381 

(1171P), ix391 (1199P), ix62 (121IN), ix398 

(1222), ix398 (1223), ix408 (1243P), ix408 

(1244P), ix411 (1254P), ix427 (1301P), ix429 

(1306P), ix429 (1308P), ix435 (1331), ix440 

(1348), ix443 (1357), ix447 (1369P), ix457 

(1406), ix459 (1411), ix459 (1412), ix484 

(1496P), ix485 (1500P), ix493 (1525P), ix496 

(1536P), ix497 (1537P), ix500 (1549PD), ix503 

(1558P), ix504 (1562P), ix513 (1592P), ix515 

(1598P), ix27 (15IN), ix518 (1609P), ix518 

(1611P), ix521 (1623), ix523 (1628), ix526 

(1640), ix72 (164), ix75 (175PD), ix85 (209P), 

ix29 (21IN), ix31 (24IN), ix107 (288P), ix113 

(309), ix117 (321PD), ix122 (336P), ix133 

(373P), ix37 (45IN), ix164 (477P), ix171 (500P), 

ix172 (504), ix194 (569P), ix208 (614P), ix212 

(628), ix218 (647), ix218 (648), ix222 (661), 

ix231 (690P), ix242 (730P), ix242 (731P), ix244 

(736P), ix250 (756), ix250 (757), ix256 

(780TiP), ix260 (788O), ix264 (799P), ix265 

(803P), ix307 (932P), ix56 (96IN), ix325 (985P), 

ix327 (995P) 

chest CT screening, ix469 (1447PD) 

chest wall irradiation, ix114 (314) 

chest wall, ix130 (363P), ix131 (367P) 

Child-Pugh status, ix244 (736P) 

children, ix359 (1104), ix517 (1606P) 

chimeric anti-mesothelin monoclonal antibody, 

ix493 (1522PD) 

China, ix501 (1552P), ix114 (313) 

Chinese, ix282 (851P) 

chk1, ix42 (61IN) 

chlorhexidine, ix522 (1626) 

choi response criteria, ix379 (1163P) 

ix588 | subject index Volume 23 | Supplement 9 | September 2012


Choi response criteria, ix487 (1506P) 

Choriocarcinoma, ix330 (1005P) 

chromosomal aberration (CA), ix91 (230P) 

chromosome 7 polysomy, ix287 (868) 

chromothripsis, ix31 (25IN) 

chronic lymphocytic leukemia (CLL), ix350 

(1070PD), ix451 (1384P) 

chronic myeloid leukemia, ix355 (1090P), ix359 

(1105) 

cigarette smoking, ix469 (1448PD) 

cilastatin, ix520 (1619) 

CINV, ix507 (1573P), ix508 (1576P) 

circulating DNA, ix74 (171O), ix109 (293P) 

circulating endothelial cells, ix85 (209P), ix193 

(567P) 

circulating free DNA, ix87 (219P) 

circulating melanoma cells, ix533 (1664P), ix87 

(219P) 

circulating tumor cells, ix383 (1175P), ix431 

(1313), ix489 (1512), ix529 (1650P), ix74 

(171O), ix87 (217P), ix87 (218P), ix89 (223P), 

ix91 (230P), ix98 (255PD), ix111 (304), ix199 

(582P), ix300 (910P), ix300 (911P), ix304 

(922P) 

circulating tumour cells, ix338 (1029P), ix90 

(227P), ix94 (244) 

cirrhosis, ix243 (733P) 

cisplatin doxorubicin, ix487 (1507P) 

cisplatin plus S-1, ix385 (1181PD) 

cisplatin-based chemotherapy, ix266 (807P) 

cisplatin, ix336 (1022PD), ix346 (1058), ix396 

(1215), ix68 (148P), ix68 (149P), ix507 (1573P), 

ix70 (158P), ix515 (1598P), ix520 (1619), ix525 

(1639), ix129 (359P), ix138 (394), ix139 (397), 

ix225 (671P), ix234 (700P), ix234 (701P), ix247 

(745P), ix247 (746P) 

citrulline, ix91 (229P) 

clear renal cell carcinoma, ix287 (868) 

clinical benefit, ix536 (1672P), ix128 (357P) 

clinical cancer research, ix65 (136IN) 

clinical feature, ix140 (400) 

clinical management, ix61 (116IN), ix284 (859P) 

clinical oncology, ix538 (1678P) 

clinical practice, ix447 (1370P) 

clinical practices guidelines, ix481 (1487P), ix505 

(1567P) 

clinical predictors, ix490 (1515) 

clinical profile, ix441 (1352) 

clinical research, ix65 (133IN), ix448 (1374P) 

clinical significance, ix248 (748) 

clinical staging, surgical staging, ix384 (1177P) 

clinical study, ix518 (1612P) 

clinical trial design, ix460 (1416PD), ix35 (41IN) 

clinical trial, ix404 (1235PD), ix63 (124IN), ix507 

(1573P), ix158 (457P), ix295 (895O) 

clinical trials, ix58 (106IN), ix535 (1670P), ix37 

(43IN), ix43 (63IN) 

clinicopathological feature, ix99 (258P) 

clinicopathological parameters, ix94 (242) 

CNS metastases, ix406 (1240P), ix426 (1299P), 

ix132 (370P) 

co-clinical, ix59 (107IN) 

Cockroft-Gault, ix283 (857P) 

cognitive function, ix144 (412O) 

cohort study, ix218 (648) 

collaborative clinical T = trials, ix64 (131IN) 

colon cancer, ix86 (214P), ix178 (520O), ix179 

(522PD), ix179 (523PD), ix183 (534P), ix183 

(535P), ix187 (550P), ix188 (551P), ix188 

(552P), ix197 (576P), ix200 (588P), ix201 

(591P), ix205 (603P), ix205 (604P), ix205 

(605P), ix209 (616), ix210 (620), ix219 (652), 

ix221 (657), ix223 (664TiP) 

colon, ix86 (215P) 

ColoPrint, ix179 (522PD) 

colorectal cancer cells, ix220 (654) 

colorectal cancer screening, ix472 (1460) 

colorectal cancer, ix383 (1173P), ix460 (1419PD), 

ix67 (143PD), ix474 (1465P), ix512 (1590P), 

ix529 (1649P), ix529 (1650P), ix530 (1654P), 

ix542 (1694P), ix75 (174O), ix85 (208P), ix35 

(40IN), ix157 (452P), ix159 (460P), ix166 

(483P), ix180 (526PD), ix181 (530PD), ix182 

(531P), ix182 (533P), ix183 (536P), ix184 

(539P), ix184 (540P), ix185 (542P), ix185 

(543P), ix186 (546P), ix186 (547P), ix186 

(548P), ix189 (555P), ix191 (560P), ix193 

(566P), ix194 (568P), ix196 (572P), ix198 

(579P), ix198 (580P), ix199 (582P), ix199 

(583P), ix200 (585P), ix200 (587P), ix201 

(590P), ix202 (592P), ix202 (593P), ix202 

(594P), ix203 (598P), ix205 (605P), ix208 

(613P), ix209 (615), ix209 (617), ix210 (619), 

ix211 (623), ix212 (626), ix212 (628), ix213 

(630), ix215 (636), ix216 (641), ix217 (643), 

ix218 (647), ix219 (649), ix219 (651), ix220 

(653), ix220 (655), ix221 (659), ix223 (665TiP) 

colorectal carcinogenesis, ix86 (212P) 

colorectal liver metastases, ix190 (557P), ix197 

(577P), ix211 (624), ix211 (625), ix217 (644) 

colorectal surgery, ix202 (595P) 

colorectal, ix209 (618), ix220 (656) 

Colposcopy, ix471 (1454P) 

combination therapy, ix75 (173O), ix258 (783O) 

combined modality therapy, ix334 (1016O), ix396 

(1213), ix425 (1296P), ix49 (80IN) 

community cancer awareness, ix471 (1453P) 

community oncology, ix458 (1407) 

community-based clinical trial, ix442 (1354) 

comorbidities, ix279 (844P) 

comorbidity, ix349 (1065O) 

compassionate use programme, ix306 (931P) 

complete pathological remission (PCR), ix95 

(247O), ix130 (361P) 

complete pathological response, ix101 (268P) 

compliance, ix481 (1487P), ix511 (1584P), ix200 

(586P), ix287 (870) 

complications, ix252 (765) 

comprehensive geriatric assessment, ix341 

(1042P), ix452 (1385P), ix452 (1386P), ix452 

(1387P) 

computed tomography, ix60 (112IN), ix534 

(1665P), ix301 (913P) 

concomitant chemoradiation, ix328 (1000P), 

ix392 (1200P) 

concomitant chemoradiotherapy, ix335 (1020PD), 

ix341 (1039P) 

concordance index (c-index), ix241 (727P) 

concurrent chemoradiotherapy, ix392 (1202P), 

ix393 (1204P), ix395 (1212) 

concurrent radiochemotherapy, ix339 (1035P), 

ix238 (715P), ix242 (730P) 

conditional probability of survival, ix144 (410O) 

conservative treatment, ix322 (977P) 

consolidation treatment, ix351 (1073P) 

constipation, ix510 (1582P) 

continuous administration of EGFR-TKI, ix423 

(1289P) 

contra-lateral breast cancer, ix544 (1702) 

copy number gain/loss, ix39 (50IN) 

correlation, ix350 (1070PD), ix119 (328PD) 

cosmesis, ix97 (253PD) 

cost analysis, ix448 (1373P) 

cost effectiveness, ix428 (1303P), ix501 (1553P), 

ix202 (594P), ix235 (704P), ix235 (706P), ix236 

(707P), ix320 (973PD) 

cost utility, ix121 (333P) 

cost-effectiveness, ix447 (1370P), ix450 (1379P), 

ix283 (854P), ix283 (856P) 

cost, ix448 (1373P), ix269 (816P) 

costs, ix122 (336P), ix205 (602P) 

COX-2, ix530 (1652P), ix184 (538P) 

crizotinib, ix357 (1098), ix389 (1191PD), ix402 

(1230PD), ix403 (1231PD), ix415 (1267P), ix416 

(1268P), ix424 (1291P), ix153 (441O) 

crossover, ix376 (1155O) 

CRPC, ix303 (920P), ix313 (951), ix314 (953) 

CT density, ix396 (1216) 

CT imaging, ix483 (1492P) 

CT induction, ix344 (1051) 

CT perfusion, ix60 (113IN) 

CT-guided lung biopsy, ix425 (1295P) 

curative resection, ix197 (578P) 

cutaneous melanoma, ix364 (1119P), ix365 

(1122P), ix87 (219P) 

CXCL12, ix541 (1688PD) 

CXCR7, ix541 (1688PD) 

Cyclin D1, ix338 (1031P) 

cyclin-dependent kinase inhibitor, ix253 (769) 

cyclophosphamide, ix509 (1578P), ix273 (827P), 

ix308 (935P), ix325 (986P) 

CYFRA 21-1, ix430 (1310P) 

CYP1A1, ix133 (374P) 

CYP2C19, ix424 (1293P) 

CYP2D6 inhibitors, ix81 (196P) 

CYP2D6 polymorphism, ix79 (189P) 

CYP2D6, ix109 (295P) 

cytarabine, ix353 (1082P) 

cytochrome P450 isoenzyme, ix520 (1618) 

Cytokine, ix286 (865P) 

Cytokines, ix21 (1IN) 

cytology samples, ix365 (1123P), ix431 (1315), 

ix432 (1316) 

cytoreductive surgery, ix323 (980P), ix254 (774) 

cytototoxic effect, ix220 (654) 

cytotoxic chemotherapy, ix308 (936P) 

cytotoxic drugs, ix29 (21IN) 

cytotoxic T-lymphocyte antigen-4, ix75 (175PD) 

D 

dacarbazine (DTIC), ix363 (1115PD) 

dacomitinib, ix401 (1228O) 

darbepoetin alfa, ix504 (1561P), ix504 (1562P), 

ix505 (1567P), ix284 (858P) 

dasatinib, ix480 (1482PD) 

DCE-MRI (dynamic contrast-enhanced magnetic 

resonance imaging), ix59 (109IN), ix70 (155P) 

DCIS, ix83 (201P) 

DCS, ix228 (682P) 

DDS, ix247 (746P) 

debulking, ix321 (975PD) 

decision-making, ix475 (1469P) 

dedifferentiated liposarcoma, ix54 (93IN) 

definitive chemoradiotherapy, ix425 (1294P) 

degarelix, ix299 (905P), ix306 (930P) 

dendritic cell therapy in recurrent solid tumors, 

ix174 (510TiP), ix239 (719P) 

dendritic cell vaccine, ix363 (1114PD), ix371 

(1138P), ix168 (490P), ix174 (510TiP) 

dendritic cell, ix172 (503) 

dendritic cells, ix536 (1672P), ix240 (723P) 

denosumab, ix360 (1108TiP), ix479 (1480PD), 

ix509 (1580P), ix115 (316TiP), ix309 (937P) 

dental examination, ix511 (1585P) 

depression, ix474 (1464P) 

DESKTOP Study, ix323 (980P) 

desmoplastic small round cell tumor, ix483 

(1494P) 

dethylstilbestrol, ix306 (929P) 

developing countries, ix448 (1374P), ix65 (137IN) 

developing country, cost, ix356 (1092P) 

developmental therapeutics, ix154 (443PD) 

diabetes, ix500 (1549PD), ix126 (349P), ix215 

(636) 

diagnosis, ix380 (1166P), ix383 (1174P), ix476 

(1471P), ix532 (1658P) 

diagnostic, ix60 (114IN) 

diagnostics, ix109 (293P) 

diarrhea, ix120 (329P) 

Dicer, ix530 (1653P) 

differentiation, ix454 (1395P) 

diffuse large B cell lymphoma, ix352 (1078P), 

ix353 (1080P) 


subject index 

diffuse large B-cell lymphoma, ix351 (1074P) 

diffuse reflectance spectroscopy, ix532 (1658P) 

diffuse type, ix175 (511PD) 

diffuse, ix250 (756) 

dignity related-distress, ix516 (1601P) 

diltiazem, ix173 (508) 

discordance, ix373 (1146), ix82 (199P) 

disease progression, ix231 (689P), ix301 (912P) 

disease-free survival (DFS), ix99 (260P), ix208 

(612P), ix328 (997P) 

DNA repair, ix408 (1244P) 

do not resuscitate order, ix517 (1605P) 

docetaxel failure, ix314 (953) 

docetaxel plus cisplatin, ix404 (1234PD) 

docetaxel, body mass index, ix300 (909P) 

docetaxel, ix437 (1338), ix438 (1341), ix441 

(1353), ix114 (313), ix119 (326PD), ix129 

(359P), ix129 (360P), ix139 (395), ix169 (494P), 

ix226 (673P), ix231 (690P), ix234 (701P), ix250 

(760), ix251 (761), ix294 (893O), ix298 (904P), 

ix303 (921P), ix308 (934P), ix312 (946), ix314 

(952) 

dose escalation, ix154 (444PD), ix164 (475P), 

ix245 (740P), ix246 (744P), ix49 (80IN) 

dose-dense chemotherapy, ix320 (973PD) 

dose-intensity, ix201 (591P) 

doublet, ix398 (1220) 

dovitinib, ix480 (1481PD), ix293 (891TiP) 

doxorubicin and hyperthermia, ix130 (363P) 

doxorubicin, ix490 (1517TiP) 

driver mutation, ix61 (119IN) 

drug development, ix58 (103IN), ix33 (31IN), 

ix158 (455P) 

drug interaction, ix520 (1618) 

drug resistance, ix423 (1290P), ix172 (501) 

drug sensitivity, ix133 (375P) 

drug therapy, ix216 (640) 

drug uptake, ix460 (1417PD) 

drug–drug interaction, ix456 (1402P) 

dual energy CT, ix60 (113IN) 

dual-colored in situ hybridization (DISH), ix372 

(1142P) 

Ductal Intraepithelial neoplasia, ix83 (201P) 

duodenal Gist, ix482 (1489P) 

dysadherin, ix277 (838P) 

dysphonia, ix122 (335P) 

E 

E-3810, ix116 (319O) 

E-cadherin, ix277 (838P) 

E7080, ix244 (737P) 

early access programme, ix306 (931P) 

early breast cancer, ix95 (247O), ix96 (251PD), 

ix97 (252PD), ix98 (256P), ix100 (262P), ix100 

(263P), ix102 (271P), ix106 (285P), ix111 (301), 

ix111 (304), ix113 (310), ix114 (315TiP) 

early detection, ix88 (221P) 

early drug development - personalized medicine, 

ix33 (32IN) 

early evaluation, ix392 (1201P) 

early nsclc, ix386 (1183P), ix387 (1185P), ix49 

(78IN) 

early phase trials, ix150 (435TiP), ix165 (479P) 

early response assessment, ix63 (127IN) 

early response evaluation, ix130 (362P) 

early response, ix199 (584P) 

early stage breast cancer, ix107 (289P), ix108 

(292P), ix111 (303) 

early stage disease, ix329 (1002P), ix99 (258P) 

early tumor shrinkage (ETS), ix190 (558P), ix204 

(599P) 

economic evaluation, ix397 (1217) 

Edmonton Symptom Assessment Scale, ix520 

(1617), ix524 (1631) 

efatutazone, ix201 (590P) 

effectiveness, ix428 (1303P) 

efficacy, ix402 (1230PD), ix419 (1277P), ix460 

(1416PD), ix516 (1604P), ix117 (320PD), ix316 

(962TiP) 

egf mutations, ix414 (1264P) 

EGFR expression, ix338 (1029P), ix417 (1272P), 

ix433 (1322), ix87 (218P) 

EGFR IHC, ix417 (1271P) 

EGFR inhibitor, ix372 (1144), ix391 (1199P), 

ix414 (1265P), ix421 (1283P), ix430 (1309P), 

ix79 (190P), ix85 (210P), ix180 (525PD) 

EGFR mutant lung adenocarcinoma, ix412 

(1257P) 

EGFR mutant NSCLC, ix401 (1227O), ix401 

(1228O) 

EGFR mutation aqcuired resistance erlotinib, 

ix418 (1273P) 

EGFR mutation, ix412 (1258P), ix413 (1260P), 

ix414 (1262P), ix416 (1269P), ix416 (1270P), 

ix417 (1272P), ix418 (1274P), ix420 (1280P), 

ix430 (1310P), ix431 (1315), ix432 (1318), ix433 

(1322), ix434 (1325), ix437 (1339), ix438 (1340), 

ix439 (1343), ix439 (1344), ix440 (1347), ix531 

(1655P), ix533 (1662P), ix534 (1666P), ix77 

(182P), ix78 (183P), ix152 (438O) 

EGFR mutations, ix411 (1254P), ix412 (1256P), 

ix413 (1259P), ix86 (213P), ix144 (412O) 

EGFR TKI, ix411 (1254P) 

EGFR TKIs, ix433 (1323), ix435 (1330) 

EGFR tyrosine kinase inhibitor, ix412 (1256P), 

ix437 (1338), ix76 (179P) 

EGFR-HER3, ix43 (62IN) 

EGFR-TKI, ix416 (1269P), ix437 (1336), ix440 

(1347), ix79 (189P) 

EGFR, ix338 (1031P), ix387 (1187P), ix390 

(1197P), ix414 (1263P), ix423 (1290P), ix425 

(1295P), ix427 (1302P), ix432 (1316), ix495 

(1530P), ix530 (1652P), ix542 (1692P), ix74 

(170O), ix78 (183P), ix86 (213P), ix98 (257P), 

ix152 (439O), ix42 (59IN), ix42 (60IN), ix239 

(720P), ix51 (81IN) 

Elastic Laminal Invasion (ELI), ix210 (621) 

elderly cancer patients, ix374 (1151), ix433 (1323), 

ix452 (1385P), ix476 (1472P), ix516 (1604P), 

ix100 (261P), ix100 (263P), ix205 (603P), ix307 

(932P), ix326 (991P) 

elderly Medicare patients, ix214 (634) 

elderly patients, ix345 (1053), ix422 (1285P), 

ix436 (1333), ix442 (1354), ix181 (529PD), 

ix203 (596P), ix427 (1301P), ix443 (1357) 

elderly, ix331 (1009), ix392 (1202P), ix398 (1220), 

ix419 (1276P), ix422 (1286P), ix434 (1325), 

ix442 (1356), ix443 (1358), ix452 (1387P), ix459 

(1412), ix476 (1470P), ix101 (266P), ix221 

(657), ix229 (684P), ix232 (693P), ix279 (844P), 

ix308 (934P) 

Electrochemotherapy, ix343 (1046P), ix131 (367P) 

electroporation, ix343 (1046P), ix131 (367P) 

ELISA (enzyme-linked immunosorbent assay), 

ix111 (302) 

EMD 1214063, ix154 (444PD) 

EMD 525797, ix317 (965TiP) 

emergency visit, ix517 (1607P) 

EML4-ALK fusion gene, ix415 (1266P) 

EML4-ALK, ix81 (195P) 

EMPHASIS, ix58 (105IN) 

end-of-life care, ix145 (415PD) 

endobronchial ultrasound guided transbronchial 

needle aspiration, ix383 (1176P) 

endocrine therapy response, ix57 (102IN) 

endocrine therapy, ix75 (176PD), ix105 (281P) 

endometrial cancer, ix329 (1001P), ix329 (1002P), 

ix329 (1003P), ix40 (56IN), ix320 (970PD) 

endoscopic ultrasonography, ix472 (1456P), ix252 

(767) 

endostar, ix437 (1337) 

endpoints, ix535 (1670P) 

enhancer of zeste homolog 2, ix349 (1066PD) 


enzalutamide, ix38 (48IN), ix295 (896O), ix297 

(899PD) 

EphA4, ix541 (1691P) 

ephrin receptor A4, ix541 (1691P) 

epidemiology, ix403 (1232PD), ix428 (1304P), 

ix213 (632), ix298 (902P), ix323 (981P) 

epidermal growth factor (EGF), ix246 (742P), 

ix287 (868) 

epidermal growth factor receptor (EGFR), ix412 

(1255P), ix514 (1597P), ix203 (598P) 

epidermal growth factor receptor mutation-positive 

non-small cell lung cancer, ix433 (1323) 

epidermal growth factor receptor, ix70 (158P) 

epigenetics, ix68 (150P) 

epiregulin, ix180 (526PD), ix183 (536P) 

epirubicin, ix129 (359P) 

epithelial cancer, ix539 (1683P) 

epithelial ovarian cancer (EOC), ix320 (971PD) 

epithelial ovarian carcinoma, ix320 (972PD) 

epithelial to mesenchymal transition, ix67 (145P), 

ix542 (1693P), ix543 (1695P) 

epithelial-mesenchymal transition, ix432 (1319) 

epoetin zeta, ix505 (1566P) 

epoetin, ix504 (1563P), ix506 (1568P), ix506 

(1569P) 

Epstein-Barr virus (EBV), ix88 (221P) 

ER status, ix69 (151P) 

ercc 1 and rrm1, ix528 (1646PD) 

ERCC1, ix84 (207P) 

eribulin mesilate, ix393 (1205P), ix129 (358P) 

eribulin, ix120 (330P) 

ERIVANCE, ix362 (1112PD) 

erlotinib, ix390 (1194P), ix390 (1197P), ix393 

(1205P), ix397 (1219), ix398 (1222), ix400 

(1225O), ix400 (1226O), ix413 (1260P), ix414 

(1263P), ix417 (1271P), ix419 (1276P), ix420 

(1280P), ix421 (1282P), ix424 (1291P), ix424 

(1293P), ix426 (1298P), ix429 (1307P), ix433 

(1322), ix435 (1328), ix436 (1333), ix437 (1338), 

ix438 (1340), ix438 (1342), ix439 (1345), ix439 

(1346), ix445 (1366TiP), ix446 (1367TiP), ix533 

(1662P), ix533 (1663P), ix91 (232), ix174 

(509TiP), ix240 (722P) 

erythropoiesis-stimulating agents, ix523 (1628) 

esophageal cancer, ix89 (224P), ix225 (671P), 

ix226 (672P), ix226 (674P) 

esophageal carcinoma, ix248 (749) 

esophageal squamous cell carcinoma, ix248 (748) 

esophagectomy, ix226 (672P), ix226 (674P) 

essential thrombocythemia, ix355 (1087P), ix356 

(1094) 

estrogen receptor, ix87 (216P), ix388 (1190P), 

ix27 (15IN), ix119 (325PD), ix126 (350P), ix183 

(534P) 

estrogen, ix104 (277P) 

ethical aspects, ix64 (128IN) 

ethnic minority, ix100 (262P) 

ETOP, ix58 (105IN) 

etoposide intravenous and oral, ix494 (1527P) 

Europe, ix447 (1372P), ix97 (252PD), ix132 

(369P) 

European Society for Medical Oncology, ix458 

(1407) 

Euroqol EQ-5D, ix315 (956) 

evaluation, ix481 (1487P) 

everolimus, ix376 (1154O), ix377 (1156O), ix379 

(1162P), ix118 (324PD), ix121 (334P), ix126 

(351P), ix127 (352P), ix155 (447PD), ix231 

(691P), ix256 (781TiP), ix271 (821P), ix279 

(843P), ix283 (855P), ix288 (873), ix288 (875), 

ix289 (876), ix290 (879), ix293 (890TiP) 

evidence-based guidelines, ix53 (88IN) 

Ewing sarcoma, ix488 (1509P), ix54 (90IN) 

expanded access program, ix367 (1128P), ix368 

(1130P), ix369 (1131P), ix369 (1132P), ix369 

(1133P), ix374 (1149), ix374 (1151), ix271 

(821P) 

expanded access study, ix362 (1111PD) 



expanded access, ix271 (820P) 

expert center, ix327 (993P) 

exposure, ix91 (229P), ix231 (691P) 

external quality control, ix80 (193P) 

external-beam irradiation, ix309 (938P) 

extracellular matrix (ECM), ix301 (914P) 

extramammary Paget’s disease, ix372 (1142P) 

Extranodal Non-Hodgkin Lymphomas, ix357 

(1097) 

EXTREME, ix334 (1018O) 

EZH2, ix85 (208P) 

F 

52 kDa, ix93 (239) 

factor analysis, ix109 (296P) 

failure, ix437 (1336) 

familial cancer, ix34 (36IN) 

family caregivers, ix476 (1470P) 

family physicians, ix517 (1607P) 

fast-track surgery, ix202 (595P) 

Fasting Blood Glucose (FBG), ix206 (606P) 

FcGR polymorphisms, ix93 (237), ix163 (472P) 

18F-FDG PET/CT, ix370 (1136P), ix60 (114IN), 

ix392 (1201P), ix130 (362P), ix193 (567P), 

ix199 (584P) 

18FDG-PET, ix63 (127IN), ix160 (462P) 

feasibility study, ix228 (681P), ix250 (758) 

febrile neutropenia, ix499 (1547PD), ix501 

(1553P), ix502 (1556P), ix503 (1560P), ix522 

(1625) 

fecal pH, ix200 (585P) 

female patients, ix388 (1190P) 

female, ix414 (1264P) 

fentanyl bucal tablet (FBT), ix518 (1612P) 

fertility preservation, ix521 (1621) 

fertility sparing surgery(FSS), ix331 (1011) 

FFPE tissue, ix71 (161P), ix148 (426P) 

FGF (fibroblast growth factor), ix116 (319O), 

ix269 (814P), ix272 (822P) 

FGFR-1, ix77 (181P) 

FGFR1, ix116 (319O) 

fibroblast growth factor receptor (FGFR), ix27 

(16IN) 

fibrosis, ix396 (1216) 

fibrous solitary tumor, ix485 (1500P) 

filgrastim, ix502 (1555P), ix502 (1557P) 

film, ix458 (1408) 

Firmagon, ix299 (905P) 

first line therapy, ix401 (1228O) 

first line treatment, ix435 (1329), ix436 (1333), 

ix118 (323PD) 

first line, ix402 (1229PD), ix410 (1252P), ix138 

(392) 

first-line chemotherapy, ix434 (1326), ix528 

(1646PD), ix116 (317O), ix224 (667PD) 

first-line therapy, ix413 (1260P), ix434 (1325) 

first-line, ix400 (1226O), ix405 (1236PD), ix406 

(1239P), ix445 (1365TiP) 

FISH analysis, ix364 (1118PD) 

FISH, ix355 (1088P) 

FLEX, ix417 (1272P) 

flow cytometry, ix359 (1106), ix72 (163P), ix529 

(1650P), ix356 (1093P) 

flu vaccine in cancer patients, ix56 (97IN) 

fluorescent in situ hybridization (FISH), ix372 

(1142P) 

fluorescent in situ hybridization, ix390 (1196P) 

fluorine-18 fluorodeoxyglucose, ix72 (166) 

fluoropyrimidine, ix178 (519O) 

5-fluorouracil, ix234 (701P) 

FOLFIRI, ix181 (529PD), ix191 (561P), ix201 

(590P), ix203 (597P), ix222 (662TiP), ix251 

(762) 

FOLFIRINOX, ix238 (716P), ix240 (721P) 

FOLFOX4, ix178 (520O) 

FOLFOX, ix203 (597P) 

FOLFOXIRI, ix238 (714P), ix241 (726P) 

follicular lymphoma, ix351 (1073P) 

follow-up, ix324 (983P) 

food effects, ix168 (489P), ix169 (493P) 

frail patients, ix196 (573P) 

frailty, ix459 (1412) 

France, ix416 (1270P), ix488 (1511P) 

French Regional Health Insurance System, ix456 

(1401P) 

front-line treatment, ix436 (1335) 

front-line, ix322 (978P) 

fulvestrant, ix123 (339P), ix123 (340P), ix123 

(341P), ix136 (384) 

5-FU, ix346 (1057) 

function sparing surgeries, ix331 (1008) 

functional imaging, ix60 (113IN), ix392 (1201P), 

ix192 (562P) 

functional status, pain, ix295 (895O) 

functional tumor volume, ix199 (584P) 

fusion gene, ix81 (195P) 

G 

G-CSF primary prophylaxis, ix501 (1553P), ix502 

(1556P), ix522 (1625) 

G-CSF, ix499 (1547PD), ix500 (1548PD), ix501 

(1552P), ix501 (1554P), ix502 (1555P), ix502 

(1557P), ix503 (1560P), ix522 (1624) 

G719X, ix413 (1259P) 

G8, ix345 (1053) 

gamma knife, ix150 (432) 

ganetespib, ix436 (1332), ix529 (1647PD), ix533 

(1664P) 

ganitumab, ix255 (776TiP) 

gastric cancer, ix538 (1681P), ix89 (225P), ix175 

(511PD), ix176 (514P), ix226 (675P), ix227 

(676P), ix227 (677P), ix227 (678P), ix228 

(680P), ix228 (681P), ix229 (683P), ix229 

(684P), ix229 (685P), ix229 (686P), ix230 

(687P), ix231 (689P), ix231 (690P), ix232 

(692P), ix232 (693P), ix232 (694P), ix233 

(696P), ix233 (697P), ix233 (698P), ix233 

(699P), ix234 (700P), ix234 (702P), ix249 (752), 

ix249 (754), ix249 (755), ix250 (756), ix250 

(757), ix250 (760), ix251 (761), ix251 (762), 

ix251 (763), ix251 (764), ix256 (779TiP), ix256 

(780TiP), ix257 (782TiP) 

gastric GIST, ix481 (1486PD) 

gastric lymphoma, ix252 (765) 

gastric submucosal tumor, ix481 (1485PD) 

gastroesophageal cancer, ix169 (492P), ix248 

(750), ix249 (754) 

gastroesophageal junction cancer, ix227 (678P) 

gastrointestinal cancer, ix221 (660) 

gastrointestinal lymphoma, ix252 (766) 

gastrointestinal stromal tumor (GIST), ix478 

(1478O), ix480 (1482PD), ix480 (1484PD), 

ix483 (1492P), ix490 (1516), ix538 (1679P), 

ix235 (705P), ix236 (707P), ix236 (708P) 

gastrointestinal stromal tumor, ix480 (1481PD) 

gastrointestinal toxicity, ix64 (130IN) 

GBM, ix146 (417PD) 

GDC-0980, ix157 (452P) 

gefitinib; drug resistance, lung cancer, ix32 (30IN) 

gefitinib, ix411 (1253P), ix412 (1255P), ix412 

(1258P), ix413 (1259P), ix414 (1263P), ix423 

(1289P), ix432 (1319), ix435 (1328), ix435 

(1331), ix439 (1343), ix439 (1344), ix79 (189P) 

Gem-refractory, ix241 (728P) 

gemcitabine, ix67 (144PD), ix537 (1676P), ix139 

(395), ix139 (397), ix165 (478P), ix170 (497P), 

ix236 (709P), ix239 (717P), ix240 (722P), ix259 

(786O), ix291 (885), ix320 (972PD) 

GEMOX plus erlotinib, ix253 (768) 

gene amplification, ix387 (1186P) 

gene dosage, ix320 (970PD) 

gene expression profile, ix349 (1068PD) 

gene expression signatures, ix299 (906P) 

gene expresssion profiling, ix57 (100IN) 

gene signature, ix112 (305) 

general population, ix188 (553P) 

genetic counseling, ix34 (37IN) 

genetic polymorphism, ix365 (1122P), ix134 (376) 

genetic polymorphisms, ix364 (1119P), ix127 

(354P), ix133 (374P) 

genetic screening, epithelial-mesenchymal 

transition, ix32 (30IN) 

genetic susceptibility, ix544 (1702), ix34 (37IN) 

70-gene prognostic profile, ix96 (251PD) 

genitourinary cancer, ix266 (805P), ix291 (886), 

ix312 (945) 

genome profile, ix51 (83IN) 

genomic profile, ix107 (289P), ix179 (522PD), 

ix179 (523PD), ix54 (92IN) 

genomics, ix57 (101IN) 

geriatric oncology, ix461 (1420PD), ix475 

(1467P), ix501 (1554P), ix526 (1640) 

geriatric screening tool, ix461 (1420PD) 

germ cell tumor, ix285 (860P), ix285 (861P), 

ix286 (866P) 

germ cell tumors, ix260 (789O), ix261 (790O), 

ix285 (862P), ix285 (863P), ix286 (864P), ix293 

(890TiP) 

Germany, ix121 (333P) 

GEST QOL, ix254 (775) 

Gestational Trophoblastic Neoplasia GTN, ix330 

(1005P) 

GETNE, ix377 (1157O) 

GFR, ix49 (78IN) 

ghrelin agonist, ix161 (465P) 

giant cell tumor of bone, ix479 (1480PD) 

GIDEON, ix255 (777TiP) 

GIST, ix481 (1485PD), ix481 (1486PD), ix482 

(1490P), ix483 (1491P), ix235 (704P), ix235 

(705P), ix235 (706P) 

Gli3, ix542 (1694P) 

glioblastoma multiforme, ix72 (163P), ix144 

(410O), ix145 (415PD), ix147 (423P) 

glioblastoma, ix31 (24IN), ix145 (416PD), ix146 

(418PD), ix147 (424P), ix148 (426P), ix149 

(431), ix150 (435TiP), ix151 (437TiP) 

glioma cell lines, ix537 (1676P) 

glioma, ix144 (411O), ix148 (425P) 

global cancer research, ix65 (132IN) 

global estimates, ix323 (981P) 

global research, ix65 (132IN) 

glucose transporters, ix385 (1180PD) 

glucose, ix71 (160P) 

glutamine supplementation, ix520 (1620) 

γ-glutamyl hydrolase (GGH), ix185 (542P) 

glycolysis, ix72 (166) 

GnRH agonist, ix501 (1551PD) 

good use, ix456 (1401P) 

GRANITE, ix231 (691P) 

great vessels sarcoma, ix489 (1513) 

Greece, ix236 (707P) 

GSTM1, ix352 (1078P) 

GSTT1, ix352 (1078P) 

guidelines, ix458 (1407), ix478 (1477O) 

gynecologic cancer, ix501 (1554P), ix321 (974PD) 

gynecologic malignancy, ix506 (1570P) 

H 

haemodialysis, ix290 (879) 

hallmarks of cancer, ix23 (5IN) 

hand-foot syndrome (HFS), ix513 (1594P) 

hazard ratio, ix313 (949) 

HBV reactivation, ix56 (96IN) 

HCC, ix253 (771), ix255 (777TiP) 

HCT-CI, ix354 (1085P) 

HCV, ix352 (1079P) 

HDAC, ix43 (62IN) 

head and neck cancer, ix335 (1020PD), ix341 

(1042P), ix343 (1047P), ix345 (1056), ix347 

(1061TiP), ix510 (1581P), ix528 (1644PD), 

ix537 (1677P), ix42 (59IN) 

head and neck squamous cell carcinoma 

(HNSCC), ix334 (1016O), ix338 (1029P), ix339 


subject index 

(1033P), ix340 (1036P), ix340 (1038P), ix345 

(1052), ix539 (1684P) 

head and neck squamous cell carcinoma, ix340 

(1037P), ix450 (1379P) 

health care costs, ix299 (905P) 

health economics, ix397 (1219), ix451 (1383P), 

ix66 (141INIS), ix122 (337P) 

health resource utilisation, ix447 (1372P), ix449 

(1377P) 

health services research, ix260 (788O) 

health state utilities, ix121 (332P) 

health-related quality of life (HRQoL), ix372 

(1143P), ix299 (905P) 

health-related quality of life, ix109 (296P), ix200 

(588P) 

heat shock protein 27, ix297 (900PD) 

HEC, ix507 (1571P) 

Hedgehog signal, ix533 (1663P), ix542 (1694P) 

Hedgehog signalling pathway, ix156 (449PD) 

Hedgehog, ix430 (1309P), ix43 (62IN) 

heme oxygenase, ix320 (971PD) 

hemodialysis, ix473 (1461), ix524 (1632) 

hENT1, ix236 (709P) 

hepatic arterial infusion chemotherapy, ix194 

(568P), ix198 (580P) 

hepatic impairment, ix162 (468P) 

hepatic metastases, ix371 (1141P), ix212 (627), 

ix246 (743P) 

hepatic resection, ix254 (772) 

hepatic toxicity, ix454 (1393P) 

hepatitis B virus, ix454 (1393P), ix56 (96IN) 

hepatitis C virus, ix352 (1079P), ix454 (1393P), 

ix56 (96IN) 

hepatocellular carcinoma (HCC), ix70 (155P), 

ix536 (1673P), ix542 (1693P), ix161 (466P), 

ix225 (669PD), ix243 (733P), ix243 (734P), 

ix244 (735P), ix244 (736P), ix244 (737P), ix245 

(740P), ix245 (741P), ix246 (742P), ix246 

(744P), ix253 (770), ix255 (778TiP) 

hepatocellular carcinoma, ix63 (124IN), ix225 

(670PD), ix243 (732P), ix244 (738P), ix245 

(739P), ix254 (772), ix256 (781TiP) 

hepatocyte growth factor (HGF), ix154 (443PD), 

ix230 (687P) 

HER (ErbB) receptors, ix86 (214P), ix248 (750), 

ix320 (970PD) 

HER receptors, ix541 (1690P) 

HER2 dimerization, ix84 (206P) 

HER2 extracellular domain, ix111 (302) 

HER2 negative breast cancer, ix108 (292P) 

HER2 overexpressing breast cancer, ix528 

(1645PD) 

HER2 overexpression, ix372 (1142P), ix89 (226P), 

ix102 (270P), ix137 (387), ix227 (678P), ix259 

(786O) 

HER2 positive breast cancer, ix82 (199P), ix102 

(271P), ix124 (344P), ix125 (346P), ix132 

(370P), ix142 (407TiP), ix142 (408TiP), ix142 

(409TiP) 

HER2 treatment, ix98 (255PD) 

HER2-positive, ix62 (121IN), ix117 (322PD), 

ix120 (329P) 

HER2/HER3, ix170 (496P) 

HER2, ix401 (1228O), ix403 (1232PD), ix74 

(172O), ix83 (202P), ix97 (254PD), ix103 

(273P), ix104 (276P), ix125 (345P), ix141 (404), 

ix162 (470P), ix226 (675P), ix227 (677P), ix233 

(699P), ix234 (703P) 

HER3 inhibitor, ix161 (467P) 

HER3, ix91 (231P) 

hereditary cancer, ix34 (33IN), ix34 (36IN), ix176 

(517P) 

heregulin, ix170 (496P) 

herpes simplex virus, ix71 (162P) 

heterogeneity, ix25 (12IN), ix534 (1666P) 

2HG, ix144 (411O) 

HIF-1α, ix248 (751) 

high-dose chemotherapy, ix260 (789O), ix284 

(858P), ix285 (863P), ix286 (866P) 

high-grade neuroendocrine tumour, ix383 (1174P) 

high-risk gestational trophoblastic neoplasia, ix330 

(1005P) 

high-risk, ix281 (847P) 

high-throughput genotype, ix430 (1311P) 

HIPEC, ix35 (38IN) 

histologic grade, ix112 (306) 

histological grade, ix135 (381) 

histological type, ix393 (1204P) 

histology, ix388 (1189P) 

histone deacetylase (HDAC) inhibitor, ix349 

(1068PD), ix304 (922P) 

histopathological diagnosis, ix241 (725P) 

histopathology, neuroendocrine tumours, ix381 

(1168P) 

HNC, ix346 (1057) 

Hodgkin lymphoma, ix350 (1072P) 

Hodgkin, ix492 (1521PD) 

homeopathy, ix452 (1388P) 

homologous recombination deficiency, PARP 

inhibitor, BRCA associated ovarian cancer, ix40 

(55IN) 

Hope Herth Index (HHI) Italian version, ix516 

(1602P) 

horizontal lateral thyroidectomy, ix346 (1060) 

hormonal therapy, ix329 (1001P), ix113 (310), 

ix113 (311), ix123 (340P), ix299 (906P) 

hormone receptor (HR), ix142 (407TiP) 

hormone receptor-positive, ix96 (249PD) 

hormone-resistant, ix312 (946) 

hormone-senstive metastatic prostate cancer, 

ix294 (893O) 

hospitalization, ix526 (1640) 

HOX (homeobox) genes, ix325 (988P) 

HOX genes, ix68 (147P) 

HPV vaccination, cervical screening, ix53 (86IN) 

HPV, ix342 (1045P) 

HRAS, ix42 (60IN) 

HRQOL, ix402 (1229PD), ix483 (1493P) 

Hsp90, ix70 (156P), ix42 (61IN) 

HTA, ix460 (1417PD) 

human genome DNA sequence, ix57 (102IN), 

ix25 (10IN) 

human papillomavirus (HPV), ix334 (1018O), 

ix22 (3IN) 

hyperbaric oxygenation, ix398 (1223) 

hyperfibrinogenemia, ix93 (238) 

hyperfractionated radiotherapy, ix397 (1217) 

hyperglycemia, ix126 (349P) 

hypertension, ix263 (796PD) 

hyperthermia, ix487 (1505P) 

hyperthermic intraperitoneal chemotherapy 

(HIPEC), ix222 (661) 

hypofractionation, ix145 (413PD) 

hyponatremia, ix494 (1526P), ix509 (1578P) 

hypoxia, ix339 (1033P), ix539 (1685P), ix78 

(185P), ix150 (435TiP), ix224 (666O), ix248 

(751) 

I 

iatrogeny, ix456 (1400P) 

ICAM-1, ix531 (1657P) 

ICD, catumaxomab, ix169 (495P) 

icotinib, ix416 (1269P) 

idh, ix31 (23IN), ix144 (411O) 

idiopathic pulmonary fibrosis, ix436 (1334) 

IHC and FISH, ix394 (1208) 

IHC score, ix75 (176PD) 

IHC subtypes, ix99 (259P) 

IHC, ix73 (167O) 

IIIA N2 NSCLC, ix413 (1261P) 

IL-1, leptin, ix163 (473P) 

IL-23, ix68 (150P) 

IL-6, ix355 (1088P), ix72 (165) 

imaging staging, ix106 (285P), ix241 (727P) 

imaging test, ix449 (1378P) 


imaging, ix59 (109IN), ix384 (1178TiP) 

IMAT, ix325 (987P) 

imatinib mesylate, ix358 (1102), ix490 (1516), 

ix236 (708P) 

imatinib, ix355 (1090P), ix359 (1105), ix482 

(1489P), ix483 (1494P), ix235 (704P), ix235 

(705P) 

IMC-1121B, ix363 (1115PD), ix408 (1245P), 

ix422 (1287P) 

immune response, ix503 (1558P), ix211 (622) 

immune studies, ix165 (480P) 

immune system, ix29 (22IN) 

immune tolerance, ix536 (1671P) 

immunodeficiency, ix81 (197P) 

immunogenic cell death, ix169 (495P) 

immunohistochemical predictors, ix130 (364P) 

immunohistochemical prognostic factors, ix111 

(303) 

immunohistochemistry, ix337 (1026P), ix390 

(1196P), ix80 (193P), ix107 (287P), ix135 (381) 

immunologic, ix371 (1137P) 

immunomodulator, ix178 (518O) 

immunomodulatory treatment, ix303 (919P) 

immunophenotyping, ix359 (1106) 

immunosuppressive therapy, ix357 (1095) 

immunotherapy, ix361 (1109O), ix361 (1110O), 

ix363 (1116PD), ix367 (1127P), ix367 (1128P), 

ix368 (1129P), ix369 (1131P), ix369 (1132P), 

ix373 (1148), ix386 (1182P), ix395 (1210), ix405 

(1237PD), ix72 (163P), ix21 (1IN), ix157 

(453P), ix38 (46IN), ix172 (503), ix258 (784O), 

ix267 (808P), ix310 (939P), ix310 (941P), ix311 

(942P) 

immunotoxins, ix44 (64IN) 

in vitro, ix484 (1497P) 

Inadequate Medical Intervention (IMI), ix330 

(1005P) 

incidence, ix454 (1392P), ix94 (242) 

independent research, ix65 (132IN) 

India, ix101 (265P) 

indicators, ix457 (1403) 

indirect comparison, ix279 (843P) 

individual patient data, ix324 (982P) 

induction chemotherapy, ix335 (1020PD), ix340 

(1037P), ix341 (1039P), ix341 (1040P) 

induction therapy, ix340 (1036P), ix356 (1092P) 

infection, ix335 (1019O) 

inflammation, ix239 (720P) 

influenza, ix503 (1558P) 

information process, ix474 (1462PD) 

information technology, ix535 (1669P) 

information, ix66 (142IN) 

inmunohistochemistry, ix186 (546P) 

INNO-206, ix480 (1483PD) 

insulin-like growth factor (IGF), ix54 (90IN) 

insulin-like growth factor 1 receptor, ix432 (1319), 

ix32 (30IN) 

insulin-like growth factor receptor (IGFR), ix338 

(1030P), ix484 (1497P), ix27 (16IN), ix255 

(776TiP), ix54 (90IN) 

integrated care pathways, ix457 (1405) 

integration of oncology and palliative care, ix64 

(131IN) 

integrin, ix76 (179P) 

intensity-modulated radiotherapy, ix247 (745P) 

interferon alpha-2a, ix267 (809P) 

interleukin 6, ix69 (153P) 

interleukin 8, ix88 (222P) 

interleukin-2, ix267 (808P) 

Intermittent androgen deprivation therapy, ix306 

(930P) 

intermittent chemotherapy, ix181 (528PD) 

international research, ix65 (136IN) 

international survey, ix386 (1183P) 

Internet 3.0, ix449 (1376P) 

internet use, ix457 (1404) 

interstitial lung disease, ix436 (1334), ix497 

(1538P), ix91 (232) 



interstitial pneumonitis, ix283 (855P) 

interstitial pulmonary disorder, ix226 (673P) 

interval debulking surgery, ix332 (1013) 

intestine, ix69 (152P) 

intralesional, ix371 (1137P) 

intraperitoneal chemotherapy, ix233 (698P), ix234 

(702P), ix254 (774) 

intratechal trastuzumab, ix141 (404) 

intratumor heterogeneity, ix69 (151P), ix51 

(83IN) 

intratumoral heterogeneity, ix373 (1146), ix531 

(1656P) 

intravenous iron, ix504 (1561P), ix523 (1627) 

intravisical chemotherapy, ix290 (882) 

intrinsic subtypes, ix131 (366P) 

invasion, ix345 (1055) 

invasive lobular carcinoma, ix175 (511PD) 

invasiveness, ix136 (384) 

investigational, ix158 (456P) 

iodine, ix522 (1626) 

IPCW, ix194 (570P) 

ipilimumab, ix363 (1116PD), ix364 (1117PD), 

ix366 (1126P), ix366 (1126P), ix367 (1127P), 

ix367 (1128P), ix368 (1129P), ix368 (1130P), 

ix369 (1131P), ix369 (1132P), ix369 (1133P), 

ix370 (1134P), ix372 (1143P), ix373 (1148), 

ix374 (1149), ix374 (1150), ix374 (1151), ix375 

(1152), ix75 (175PD), ix38 (46IN) 

irinotecan, ix204 (599P), ix205 (602P), ix230 

(688P), ix237 (710P), ix249 (755) 

IRIS, ix202 (592P) 

iron supplementation, ix523 (1627) 

ISET, ix338 (1029P), ix90 (227P) 

isolation perfusion, ix486 (1504P) 

item response theory, ix109 (296P) 

J 

Japanese population, ix167 (486P), ix220 (653) 

jaw osteonecrosis, ix511 (1585P), ix56 (95IN) 

juvenile glioblastoma, ix147 (421P) 

K 

K-RAS mutation, ix530 (1652P), ix234 (703P) 

K-ras status, ix80 (194P) 

K-RAS, ix429 (1307P), ix216 (641) 

ketoconazole, ix305 (927P) 

Ki-67 antigen, ix377 (1158P), ix184 (538P) 

Ki-67, ix80 (191P), ix83 (201P), ix101 (268P), 

ix131 (366P) 

Ki67, ix92 (233), ix112 (305) 

kidney cancer, ix266 (805P), ix272 (822P), ix276 

(835P), ix281 (849P) 

kidney failure, ix444 (1361), ix458 (1409) 

kidney, ix267 (810P), ix269 (816P), ix290 (879) 

kinase inhibitor, ix433 (1324), ix124 (342P) 

kinases, ix21 (1IN) 

KIT exon 9 mutation, ix481 (1486PD) 

knowledge about cancer, ix457 (1406) 

Kochers’ thyroidectomy, ix346 (1060) 

KRAS and BRAF, ix85 (208P), ix182 (532P), 

ix183 (537P), ix186 (548P), ix187 (549P) 

KRAS genotyping, ix85 (210P) 

KRAS mutations, ix431 (1315) 

KRAS wild-type metastatic colorectal cancer, 

ix191 (561P), ix202 (594P) 

KRAS, ix387 (1187P), ix403 (1233PD), ix427 

(1302P), ix432 (1316), ix530 (1654P), ix74 

(170O), ix84 (207P), ix85 (211P), ix182 (533P), 

ix185 (543P), ix196 (574P) 

L 

L-BLP25, ix395 (1210), ix211 (622) 

L861Q, ix413 (1259P) 

lactobacterin, ix290 (882) 

laparoscopic surgery, ix292 (888) 

lapatinib resistance, ix532 (1659P) 

lapatinib, ix58 (104IN), ix101 (267P), ix139 (396) 

large cell neuroendocrine carcinoma (LCNEC), 

ix79 (188P) 

laryngeal carcinoma, ix338 (1031P) 

late relapse, ix75 (176PD) 

late stage, ix136 (383) 

Latin America, ix65 (133IN) 

LDK378, ix153 (440O) 

leaflet, ix518 (1611P) 

lean body mass, ix512 (1588P) 

lenalidomide, ix44 (67IN) 

length of hospital stay, ix354 (1085P) 

lenvatinib, ix244 (737P) 

leptin receptor antagonist, ix166 (483P) 

leptin, ix516 (1603P), ix166 (483P) 

leptomeningeal carcinomatosis, ix140 (402), ix149 

(429P) 

leptomeningeal metastasis, ix141 (404) 

leucovorin, ix217 (646) 

lidocain patch, ix521 (1622) 

life extending, ix132 (369P) 

limb-sparing surgery, ix486 (1504P) 

linifanib, ix83 (203P), ix173 (505), ix173 (507) 

liposarcoma, ix54 (93IN) 

liposomal cytarabine, ix149 (429P) 

liposomal doxorubicin, ix160 (462P) 

liposome, ix164 (477P) 

liver cancer, ix63 (125IN), ix245 (741P) 

liver limited disease, ix217 (643) 

liver metastases, ix358 (1100), ix370 (1136P), 

ix198 (580P), ix219 (651) 

liver toxicity, ix290 (880) 

LKB1, ix77 (180P) 

LMO4, ix531 (1655P) 

lobular carcinoma, ix544 (1702) 

local advanced triple negative breast cancer 

(LATNBC), ix130 (361P) 

local radiation-induced damages, ix311 (944P) 

locally advanced breast cancer, ix120 (330P), 

ix134 (377), ix135 (380), ix137 (389) 

locally advanced cervical cancer, ix330 (1007) 

locally advanced disease, ix241 (726P) 

locally advanced head and neck cancer, ix335 

(1020PD), ix341 (1039P) 

locally advanced non-small cell lung cancer, ix520 

(1620) 

locally advanced stage III NSCLC, ix392 (1200P), 

ix392 (1203P), ix330 (1007), ix330 (1007) 

locally advanced, ix331 (1008), ix395 (1211), 

ix238 (716P) 

locally-advanced pancreas cancer, ix238 (715P) 

locally-advanced pancreatic carcinoma, ix237 

(711P) 

longitudinal study, ix515 (1600P) 

long QTc, ix173 (508) 

long-term follow-up, ix522 (1624), ix148 (425P), 

ix273 (826P) 

long-term responders, ix125 (346P) 

long-term response, ix446 (1367TiP) 

long-term survival, ix412 (1256P), ix307 (933P) 

long-term use, ix510 (1583P) 

loss of mismatch repair protein expression, ix176 

(516P) 

low doses, ix139 (397) 

low malignant potential tumor, ix331 (1011) 

low molecular weight heparin, ix519 (1616P) 

low-dose radiotherapy in lymphoma, ix353 

(1081P) 

low-grade lymphoma, ix353 (1081P) 

LRIG, ix185 (544P) 

luminal A and B, ix102 (270P) 

luminal A, ix27 (13IN) 

luminal B, ix27 (13IN) 

lung adenocarcinoma, ix391 (1198P), ix412 

(1255P), ix414 (1262P), ix432 (1318), ix444 

(1362TiP), ix454 (1395P), ix92 (233) 

lung cancer stem cells, ix454 (1395P) 

lung cancer, ix383 (1175P), ix383 (1176P), ix385 

(1180PD), ix388 (1188P), ix388 (1190P), ix396 

(1214), ix414 (1264P), ix414 (1265P), ix423 

(1290P), ix425 (1297P), ix430 (1310P), ix432 

(1320), ix433 (1321), ix446 (1368TiP), ix457 

(1406), ix497 (1538P), ix506 (1569P), ix525 

(1637), ix541 (1691P), ix544 (1699P), ix73 

(169O), ix544 (1701), ix76 (177PD), ix78 

(183P), ix79 (188P), ix79 (190P), ix92 (235), 

ix49 (78IN), ix24 (7IN) 

lung metastases, ix212 (626) 

lung toxicity, ix396 (1213), ix396 (1216) 

lung, ix492 (1521PD) 

Lungscape, ix58 (105IN) 

lutenizing hormone releasing harmone, ix306 

(928P), ix321 (928P) 

lymph node, ix207 (611P), ix254 (773) 

lymph nodes, ix387 (1184P), ix135 (381) 

lymphadenectomy, ix112 (307) 

lymphoid malignancies, ix353 (1082P) 

lymphoma, ix352 (1079P), ix358 (1100), ix492 

(1521PD), ix518 (1609P), ix44 (64IN) 

lymphoplasmacytic reaction, ix99 (260P) 

lymphovascular invasion (LVI), ix186 (547P) 

Lynch syndrome, ix176 (516P) 

M 

macrocytosis, ix442 (1355) 

magnetic resonance imaging (MRI), ix207 (610P) 

maintenance chemotherapy, ix397 (1219), ix409 

(1247P), ix486 (1503P), ix128 (356P) 

maintenance pem beva, ix434 (1327) 

maintenance therapy, ix393 (1206P), ix397 (1218), 

ix404 (1235PD), ix417 (1271P), ix418 (1275P), 

ix305 (927P) 

maintenance, ix421 (1281P) 

male breast cancer, ix110 (298P), ix132 (371P) 

malignancies, ix492 (1521PD), ix158 (456P) 

malignant ascites, ix514 (1596P), ix539 (1683P), 

ix172 (504) 

malignant lymphoma, ix44 (65IN) 

malignant melanoma, ix365 (1120P), ix373 (1147) 

malignant mesothelioma, ix469 (1447PD) 

malignant pleural mesothelioma (MPM), ix78 

(185P), ix496 (1533P), ix496 (1534P), ix94 (244) 

malignant transformation, ix286 (864P) 

malnutrition, ix350 (1069PD), ix355 (1089P), 

ix356 (1091P), ix455 (1399P), ix499 (1544O), 

ix511 (1587P) 

MALT lymphoma, ix351 (1075P), ix352 (1076P) 

mammaglobin, ix111 (304) 

mammographic breast density, ix34 (35IN) 

mammography screening, ix470 (1451P) 

management decision, ix485 (1498P), ix237 

(711P) 

management of soft tissue sarcoma, ix478 

(1477O) 

management, ix482 (1488P), ix236 (708P) 

mantle cell lymphoma, ix354 (1084P), ix359 

(1107TiP), ix44 (66IN) 

manual for diabetic patients, ix527 (1705) 

MAP kinase, ix338 (1030P) 

MAPK, ix156 (451P), ix164 (475P) 

MASS criteria, ix244 (735P) 

mass screening, ix53 (88IN) 

mastectomy, ix477 (1476), ix137 (389) 

maximum tolerated dose, ix170 (497P) 

MCC, ix365 (1121P) 

MCPH1, ix533 (1662P) 

mCRC, ix93 (237), ix178 (518O), ix188 (554P), 

ix198 (581P), ix213 (632), ix214 (633), ix217 

(646), ix222 (662TiP) 

mCRPC, ix311 (943P), ix312 (948), ix316 

(962TiP), ix317 (965TiP) 

MDM2, ix54 (93IN) 

MDV3100, ix295 (896O), ix297 (899PD), ix304 

(924P), ix305 (925P) 

measurement of glomerular filtration rate, ix171 

(500P), ix283 (857P) 

media, ix66 (142IN) 


subject index 

medical information, ix457 (1404) 

medical oncology, ix451 (1383P) 

medical practice, ix478 (1477O) 

medical treatment, ix488 (1509P) 

medullary thyroid carcinoma, ix154 (445PD) 

medulloblastoma, ix31 (25IN) 

MEK inhibitor, ix403 (1233PD), ix69 (154P), ix75 

(173O), ix156 (451P), ix158 (456P) 

MEK1, ix389 (1193P) 

melanoma, ix361 (1109O), ix361 (1110O), ix363 

(1113PD), ix363 (1114PD), ix363 (1116PD), 

ix364 (1117PD), ix365 (1121P), ix365 (1123P), 

ix366 (1125P), ix366 (1126P), ix367 (1127P), 

ix367 (1128P), ix368 (1129P), ix369 (1131P), 

ix369 (1132P), ix370 (1134P), ix371 (1137P), 

ix371 (1138P), ix371 (1141P), ix373 (1148), 

ix374 (1149), ix374 (1151), ix375 (1152), ix454 

(1392P), ix72 (165), ix72 (166), ix540 (1686P), 

ix94 (242), ix46 (69IN), ix46 (70IN) 

melphalan, ix371 (1141P), ix246 (743P) 

meningioma, ix147 (420PD), ix150 (432) 

meningiomas, ix146 (419PD) 

menthol, ix513 (1591P) 

mesoporous silica nanoparticle, ix70 (158P) 

mesothelioma, ix495 (1531P), ix495 (1532P), 

ix496 (1535P), ix498 (1542TiP), ix80 (192P) 

MET, ix423 (1290P), ix42 (60IN), ix225 (669PD), 

ix230 (687P) 

meta-analyses, ix414 (1265P) 

meta-analysis, ix414 (1263P), ix454 (1394P), ix501 

(1551PD), ix513 (1594P), ix119 (326PD), ix181 

(528PD), ix324 (982P) 

metabolic imaging, ix63 (127IN) 

metabolic response, ix194 (569P) 

metabolic syndrome, ix111 (301) 

metabolism, ix21 (2IN) 

metastasectomy, ix186 (545P), ix275 (831P) 

metastases, ix488 (1508P), ix184 (539P), ix221 

(660), ix270 (817P), ix298 (904P), ix497 (1537P) 

metastasis, ix209 (616) 

metastatic breast cancer, ix531 (1657P), ix74 

(171O), ix89 (226P), ix116 (317O), ix119 

(326PD), ix119 (327PD), ix119 (328PD), ix122 

(335P), ix122 (336P), ix122 (337P), ix122 

(338P), ix123 (339P), ix123 (340P), ix124 

(342P), ix127 (354P), ix128 (356P), ix128 

(357P), ix131 (368P), ix132 (369P), ix132 

(370P), ix137 (389), ix138 (391), ix138 (392), 

ix138 (393), ix139 (395), ix140 (399), ix141 

(403), ix142 (407TiP), ix142 (408TiP), ix142 

(409TiP), ix145 (414PD) 

metastatic ca prostate, ix301 (912P) 

metastatic castration resistant prostate cancer, 

ix297 (900PD), ix297 (901PD), ix307 (932P) 

metastatic castration-resistant prostate cancer, 

ix294 (894O), ix300 (910P), ix302 (918P), ix306 

(929P), ix306 (931P), ix307 (933P), ix308 

(935P), ix315 (956) 

metastatic colorectal cancer, ix63 (126IN), ix449 

(1378P), ix514 (1595P), ix528 (1644PD), ix530 

(1653P), ix180 (525PD), ix187 (549P), ix188 

(553P), ix190 (558P), ix190 (559P), ix192 

(564P), ix193 (565P), ix194 (569P), ix194 

(570P), ix195 (571P), ix197 (578P), ix203 

(596P), ix203 (597P), ix204 (599P), ix205 

(602P), ix206 (606P), ix213 (631), ix217 (645), 

ix218 (648) 

metastatic colorectal carcinoma, ix85 (210P) 

metastatic head and neck squamous cell 

carcinoma, ix342 (1043P) 

metastatic melanoma, ix363 (1115PD), ix366 

(1124P), ix370 (1134P), ix370 (1135P), ix372 

(1143P), ix375 (1153) 

metastatic NSCLC, ix429 (1308P), ix440 (1350) 

metastatic pancreatic cancer, ix239 (717P) 

metastatic renal cell carcinoma (mRCC), ix261 

(791PD), ix269 (815P), ix271 (821P), ix275 

(831P), ix275 (833P), ix282 (851P), ix282 

(852P), ix288 (873) 

metastatic renal cell carcinoma, ix259 (785O), 

ix271 (819P), ix271 (820P), ix272 (824P), ix287 

(870), ix289 (878) 

metastatic renal-cell carcinoma, ix290 (881) 

metastatic sarcoma, ix484 (1495P) 

metastatic soft tissue sarcoma, ix488 (1511P) 

metastatic spinal cord compression, ix150 (434), 

ix301 (913P) 

metastatic, ix384 (1178TiP), ix425 (1297P), ix435 

(1329), ix438 (1341), ix139 (397), ix240 (724P), 

ix294 (893O), ix308 (934P) 

metformin, ix470 (1450P), ix126 (349P), ix302 

(917P) 

11C methionine PET, ix148 (425P) 

methodological pitfall, ix390 (1195P) 

methodology, ix158 (455P) 

methylation marker, ix88 (221P) 

methylation-specific PCR, ix109 (293P) 

methylation, ix73 (169O), ix532 (1660P), ix89 

(225P), ix185 (543P) 

metoprolol, ix173 (508) 

metronomic chemotherapy, ix486 (1503P) 

Mexican, ix251 (763) 

mFOLFOX-6, ix217 (643) 

mFOLFOX6, ix210 (620) 

MGMT, ix31 (23IN), ix186 (548P), ix274 (830P) 

MICA, ix71 (160P) 

microarray gene-expression profiling, ix300 (910P) 

microarray technology, ix71 (161P) 

microarray, ix57 (100IN) 

microbial stimuli, ix536 (1672P) 

microbiota, ix200 (585P) 

microenvironment, ix29 (22IN) 

micrometastasis, ix106 (284P), ix112 (307) 

microRNA (miRNA), ix408 (1243P), ix528 

(1645PD), ix96 (250PD), ix148 (426P), ix180 

(525PD), ix183 (535P), ix209 (616) 

microRNA, ix68 (149P) 

microsatellite instability (MSI), ix220 (656) 

mifamurtide, ix488 (1508P), ix490 (1518TiP) 

migration, ix539 (1684P) 

minichromosome maintenance (MCM) protein, 

ix93 (240) 

miR-BART, ix337 (1025P) 

mistletoe extract, ix237 (712P) 

mitomycin C,, ix164 (477P) 

mixed mullerian tumor, ix330 (1004P) 

MK 2206, ix537 (1676P) 

MLH1, ix239 (720P) 

MLN8237, ix160 (461P), ix168 (489P), ix303 

(921P) 

MM-111, ix170 (496P) 

MMMT, ix332 (1012) 

MMP9, ix186 (545P) 

MMPs, ix67 (146P) 

MMSET, ix229 (686P) 

mode, ix437 (1336) 

modelling, ix459 (1411) 

modified FOLFIRI, ix233 (696P) 

modified RECIST, ix243 (732P) 

modified RPMI, ix196 (573P) 

molecular biology, ix37 (43IN) 

molecular biomarker, ix31 (24IN), ix51 (84IN), 

ix52 (85IN) 

molecular biomarkers, ix89 (223P), ix33 (31IN) 

molecular characterization, ix61 (119IN) 

molecular cytogenetics, ix91 (230P) 

molecular diagnosis, ix60 (114IN), ix61 (116IN), 

ix430 (1311P) 

molecular epidemiology, ix412 (1257P) 

molecular imaging, ix60 (115IN), ix47 (1703IN), 

ix40 (57IN), ix47 (74IN) 

molecular marker, ix66 (140IN), ix134 (377) 

molecular modeling, ix535 (1668P) 

molecular subtype, ix543 (1698P) 

molecular subtypes, ix111 (303) 


molecular targeted agents, ix474 (1463P), ix519 

(1614P), ix84 (205P) 

molecular targeted therapy, ix290 (881) 

molecular telomere, ix350 (1071P) 

molecular therapeutics, ix450 (1379P) 

molecular-based risk assessment, ix179 (522PD) 

monoclonal antibody 806, ix542 (1692P) 

monoclonal antibody, ix32 (29IN), ix192 (564P), 

ix44 (64IN), ix222 (662TiP) 

morbidity, ix226 (672P) 

Moroccan, ix432 (1318), ix476 (1470P) 

mortality, ix355 (1089P) 

mouse model, ix51 (84IN) 

movies, ix458 (1408) 

MSP, ix495 (1532P) 

MST2, ix539 (1684P) 

MTD, ix155 (446PD), ix165 (478P), ix169 (494P) 

mTOR inhibitor, ix336 (1023PD), ix27 (16IN), 

ix147 (420PD), ix47 (76IN), ix258 (783O), ix264 

(798PD), ix268 (812P), ix270 (818P), ix272 

(822P), ix277 (837P), ix278 (841P), ix278 

(842P) 

mTor inhibitors, ix334 (1017O), ix146 (419PD), 

ix44 (65IN), ix280 (845P), ix282 (852P) 

mTOR signaling pathway, ix92 (236) 

mTOR, prostate cancer, ix539 (1685P) 

mTOR, ix338 (1031P), ix377 (1156O), ix290 (881) 

MUC1, ix395 (1210), ix240 (723P) 

mucin, ix184 (541P) 

mucinous carcinoma, ix184 (541P) 

mucins, ix210 (619) 

mucosa adjacent, ix210 (619) 

mucosal melanoma, ix368 (1130P) 

mucositis, ix510 (1581P) 

multicenter phase II study, ix436 (1335), ix208 

(1704P), ix545 (1704P) 

multi-cycle, ix507 (1572P) 

multi-targeting, ix75 (173O) 

multidisciplinary approach, ix239 (718P), ix315 

(959) 

multifocal multicentric, ix117 (321PD) 

multimodal personalized therapy, ix423 (1289P) 

multimodality therapy, ix496 (1535P) 

multimodality treatment, ix222 (663TiP) 

multiple chemotherapy lines, ix214 (634) 

multiple melanoma, ix364 (1118PD) 

multiple myeloma, ix349 (1065O), ix355 (1088P), 

ix360 (1108TiP), ix510 (1583P) 

multitargeted drug, ix32 (29IN) 

muscle invasive carcinoma of urinary bladder, 

ix264 (800P) 

muscle-invasive, ix265 (802P) 

mutant-enriched liquidchip technology, ix495 

(1530P) 

mutation analysis, ix364 (1118PD), ix213 (631) 

mutation, ix59 (108IN), ix390 (1197P), ix92 (234) 

mutational analysis, ix490 (1516) 

mutations, ix86 (212P) 

myelodysplastic syndrome, ix357 (1096) 

myeloid-derived suppressor cells, ix431 (1314) 

myeloma, ix348 (1064O), ix354 (1086P) 

myelomonocytic cells, ix69 (152P) 

myofibroblasts, ix345 (1055) 

N 

N-telopeptide of type 1 collagen (NTX), ix433 

(1321) 

N-telopeptides of type I collogen, ix432 (1320) 

NANOG, ix205 (604P) 

nasopharyngeal cancer, ix337 (1026P), ix337 

(1027P), ix339 (1035P) 

nasopharyngeal carcinoma, ix337 (1025P), ix337 

(1028P), ix343 (1048P), ix88 (221P) 

nation wide survey, ix348 (1062O), ix501 (1554P), 

ix315 (957) 

national cohort, ix271 (819P) 

nausea, ix507 (1571P) 

NC-6004, ix247 (746P) 



NCAG report 2008, ix519 (1613P) 

near miss events, ix456 (1400P) 

need of information, ix476 (1472P) 

negative predictive value, ix373 (1146) 

neo adjuvant chemotherapy, ix328 (1000P), ix487 

(1507P), ix80 (191P), ix82 (199P), ix228 (682P) 

neo-adjuvant therapy, ix134 (378), ix141 (405TiP) 

neoadjuvant chemoradiation, ix237 (713P), ix248 

(749) 

neoadjuvant chemoradiotherapy, ix334 (1017O), 

ix131 (366P), ix226 (672P) 

neoadjuvant chemotherapy, ix332 (1013), ix339 

(1035P), ix95 (247O), ix101 (268P), ix102 

(269P), ix117 (320PD), ix124 (343P), ix130 

(361P), ix131 (365P), ix134 (377), ix135 (380), 

ix135 (382), ix142 (406TiP), ix211 (624), ix264 

(800P), ix265 (802P), ix328 (997P) 

neoadjuvant endocrine therapy, ix27 (15IN) 

neoadjuvant therapy, ix395 (1211), ix98 (255PD), 

ix101 (267P), ix184 (538P), ix200 (586P), ix206 

(607P) 

neoadjuvant, ix58 (103IN), ix413 (1261P), ix97 

(254PD), ix102 (270P), ix117 (321PD), ix117 

(322PD), ix37 (45IN), ix129 (359P) 

neoplastic disease, ix458 (1409) 

neoplastic fever, ix525 (1637) 

nephrectomy, ix289 (878) 

nephrotoxicity, ix515 (1598P), ix520 (1619) 

NETNs, ix47 (73IN) 

NETs, ix377 (1157O), ix47 (73IN) 

netupitant, ix508 (1575P) 

network, ix482 (1488P) 

neural cell adhesion molecule, ix72 (166) 

neuroectodermal tumor, ix488 (1509P), ix47 

(76IN) 

neuroendocrine tumor, ix377 (1158P), ix379 

(1164P), ix380 (1167P), ix288 (873) 

neuroendocrine tumors, ix377 (1156O), ix378 

(1160P), ix379 (1162P), ix380 (1165P), ix47 

(1703IN), ix47 (74IN), ix47 (75IN), ix380 

(1166P), ix382 (1172) 

neurokinin 1, ix508 (1575P), ix520 (1618) 

neuron-specific enolase, ix291 (886) 

neurotoxicity, ix534 (1667P) 

neutropenia, ix521 (1623), ix522 (1624), ix232 

(692P), ix244 (738P) 

neutrophil to lymphocyte ratio, ix313 (950) 

neutrophils, ix500 (1548PD) 

never-smoker, ix414 (1264P) 

new drugs, ix63 (126IN) 

new therapies, ix355 (1088P) 

next generation sequencing, ix61 (116IN), ix25 

(12IN), ix34 (33IN) 

NF II, ix150 (432) 

NFkB, ix68 (148P) 

NGR-hTNF, ix410 (1251P), ix167 (487P), ix167 

(488P), ix172 (502) 

NICE, ix460 (1417PD) 

nintedanib, ix155 (446PD), ix245 (740P), ix246 

(744P) 

nitroglycerin, ix409 (1249P) 

NK cells, ix350 (1072P) 

NKG2D, ix71 (160P) 

NMP-52, ix93 (239) 

nodal metastasis, ix345 (1055) 

node negative, ix104 (278P) 

node-positive breast cancer, ix129 (360P) 

non metastatic, ix490 (1515), ix303 (920P) 

non small cell lung cancer, ix386 (1182P), ix396 

(1213), ix396 (1214), ix396 (1215), ix403 

(1232PD), ix403 (1233PD), ix408 (1243P), ix408 

(1245P), ix412 (1256P), ix421 (1284P), ix425 

(1294P), ix430 (1312), ix431 (1314), ix436 

(1334), ix438 (1340), ix439 (1346), ix440 (1348), 

ix442 (1356), ix443 (1358), ix444 (1360), ix445 

(1366TiP), ix66 (138IN), ix457 (1405), ix67 

(144PD), ix528 (1646PD), ix533 (1663P), ix534 

(1665P), ix535 (1668P), ix542 (1692P), ix543 

(1695P), ix76 (178P), ix77 (180P), ix80 (193P), 

ix91 (232), ix49 (77IN), ix427 (1300P) 

non smokers, ix388 (1190P) 

non-Hodgkin lymphoma, ix353 (1080P), ix252 

(765) 

Non-Hodgkin’s lymphoma (NHL), ix451 (1384P) 

non-Hodgkins lymphoma, ix71 (162P) 

non-inferiority, ix224 (668PD) 

non-interventional, ix225 (670PD), ix255 

(778TiP), ix288 (875) 

non-myeloid tumors, ix523 (1628) 

non-seminomatous germ-cell tumor, ix292 (888) 

non-small cell lung cancer (NSCLC), ix387 

(1184P), ix390 (1194P), ix392 (1201P), ix397 

(1219), ix400 (1226O), ix404 (1234PD), ix405 

(1236PD), ix406 (1239P), ix406 (1240P), ix409 

(1247P), ix411 (1254P), ix415 (1266P), ix417 

(1271P), ix418 (1274P), ix420 (1280P), ix425 

(1296P), ix426 (1299P), ix429 (1306P), ix430 

(1311P), ix433 (1324), ix437 (1337), ix441 

(1351), ix446 (1367TiP), ix76 (179P), ix49 

(80IN) 

non-small cell lung cancer, ix174 (1708PD), ix391 

(1198P), ix393 (1205P), ix394 (1207P), ix395 

(1212), ix405 (1237PD), ix421 (1283P), ix427 

(1302P), ix428 (1305P), ix435 (1330), ix435 

(1331), ix439 (1344), ix441 (1352), ix443 (1359), 

ix150 (433) 

non-small-cell lung cancer (NSCLC), ix397 

(1217), ix455 (1396P) 

non-small-cell lung cancer, ix398 (1220) 

non-squamous non-small cell lung cancer, ix434 

(1326), ix438 (1342), ix441 (1352) 

non-squamous, ix442 (1356) 

noncompletion treatment, ix452 (1387P) 

nonhematologic tumor, ix156 (449PD) 

nonhematological, ix158 (456P) 

noninterventional trial, ix274 (828P) 

nonsq NSCLC, ix441 (1353) 

not advanced cancer patients, ix516 (1601P), 

ix520 (1617) 

not advanced cancer, ix516 (1602P) 

Notch1, ix327 (996P) 

NPC, ix344 (1051) 

NPRA, ix248 (748) 

NRAS, ix529 (1649P), ix196 (574P) 

NRP-1 (neuropilin 1), ix186 (546P) 

NSCLC, EGFR, EGFR ligands, ix394 (1209) 

NSCLC, ix58 (106IN), ix385 (1179O), ix388 

(1189P), ix389 (1191PD), ix389 (1192PD), ix389 

(1193P), ix390 (1196P), ix393 (1206P), ix394 

(1208), ix395 (1210), ix395 (1211), ix397 (1218), 

ix398 (1222), ix400 (1225O), ix401 (1227O), 

ix402 (1229PD), ix403 (1231PD), ix404 

(1235PD), ix406 (1238PD), ix408 (1245P), ix409 

(1246P), ix409 (1249P), ix410 (1250P), ix410 

(1252P), ix412 (1258P), ix415 (1267P), ix416 

(1268P), ix416 (1269P), ix416 (1270P), ix418 

(1273P), ix418 (1274P), ix419 (1276P), ix419 

(1277P), ix419 (1278P), ix420 (1279P), ix421 

(1282P), ix422 (1287P), ix423 (1289P), ix423 

(1290P), ix424 (1291P), ix424 (1292P), ix424 

(1293P), ix427 (1301P), ix428 (1304P), ix429 

(1307P), ix430 (1309P), ix431 (1315), ix432 

(1316), ix433 (1322), ix435 (1329), ix436 (1332), 

ix436 (1333), ix437 (1336), ix437 (1339), ix438 

(1341), ix439 (1343), ix440 (1347), ix442 (1355), 

ix443 (1357), ix445 (1364TiP), ix445 (1365TiP), 

ix68 (148P), ix68 (149P), ix68 (150P), ix69 

(154P), ix70 (158P), ix529 (1647PD), ix531 

(1655P), ix533 (1661P), ix533 (1662P), ix533 

(1664P), ix534 (1666P), ix73 (167O), ix73 

(168O), ix74 (170O), ix77 (181P), ix77 (182P), 

ix78 (184P), ix79 (187P), ix80 (191P), ix81 

(195P), ix85 (211P), ix152 (438O), ix152 

(439O), ix166 (484P), ix169 (492P), ix49 

(79IN), ix51 (84IN), ix52 (85IN) 

nuclear factor-κB, ix249 (752) 

nucleotide excision repair, ix345 (1052) 

nurses, ix517 (1605P) 

nutrition, ix541 (1689P) 

O 

observational study, ix416 (1270P), ix449 (1377P), 

ix452 (1385P), ix502 (1556P), ix191 (560P), 

ix314 (954) 

octreotide, ix382 (1172) 

ocular melanoma, ix369 (1133P) 

oestrus cycles, ix69 (151P) 

old age, ix494 (1527P) 

older cancer patients, ix461 (1420PD) 

older patients, ix341 (1041P) 

oligometastases, ix425 (1296P) 

oligometastatic disease, ix309 (938P) 

oligonucleotide microarray chip, ix536 (1673P) 

OMAS (Oral Mucositis Assessment Scale), ix346 

(1059) 

ombrabulin, ix410 (1250P) 

onartuzumab, ix445 (1364TiP), ix445 (1365TiP) 

oncogene addiction, ix61 (119IN), ix51 (81IN) 

oncogene, ix46 (70IN) 

oncologic imaging, ix60 (113IN) 

oncological emergencies, ix519 (1613P) 

oncologist, ix64 (128IN) 

oncology care, ix474 (1464P) 

oncology, ix456 (1402P), ix457 (1403), ix476 

(1473P) 

oncolytic virus, ix537 (1677P) 

Oncotype DX, ix97 (252PD), ix107 (289P), ix112 

(306) 

ong-term responders to first-line Bevacizumab in 

metastatic breast cancer, ix128 (355P) 

ONO-4538, ix159 (459P) 

operable laryngeal cancer, ix338 (1030P) 

opioids, ix510 (1582P) 

opportunities, ix65 (136IN) 

optical coherence tomography, ix330 (1006P) 

oral administration, ix507 (1572P), ix524 (1634) 

oral chemotherapy, ix456 (1401P), ix524 (1634), 

ix138 (392) 

oral form, ix507 (1574P) 

oral liposomal iron, ix505 (1565P) 

oral microflora, ix343 (1049P) 

oral squamous cell carcinoma, ix345 (1055) 

oral squamus cell carcinoma, ix343 (1049P) 

oral taxane, ix167 (486P) 

oral vinorelbine, ix409 (1247P), ix409 (1249P), 

ix138 (392), ix140 (399) 

organisation of care, ix315 (959) 

oropharyngeal cancer, ix341 (1040P), ix342 

(1045P) 

OSNA, ix106 (284P) 

osteonecrosis of the jaw, ix524 (1633) 

osteosarcoma, ix487 (1507P), ix488 (1508P), ix490 

(1515), ix490 (1518TiP), ix54 (93IN) 

outcome results, ix65 (137IN) 

outcome, ix385 (1179O), ix168 (491P) 

outcomes, ix440 (1350), ix500 (1549PD), ix260 

(788O), ix328 (999P) 

outpatient, ix518 (1610P) 

ovarian cancer, ix332 (1013), ix68 (147P), ix81 

(198P), ix34 (34IN), ix175 (512PD), ix40 

(54IN), ix40 (56IN), ix40 (57IN), ix319 (966O), 

ix319 (967O), ix320 (973PD), ix322 (978P), 

ix323 (979P), ix323 (981P), ix324 (983P), ix325 

(985P), ix325 (986P), ix325 (987P), ix325 

(987P), ix325 (988P), ix326 (990P), ix326 

(991P), ix326 (992P), ix327 (993P) 

ovarian epithelial cancer, ix332 (1014) 

ovarian failure, ix501 (1551PD) 

ovarian germ cell tumors, ix327 (994P) 

ovarian mucinous adenocarcinoma, ix326 (989P) 

ovary, ix322 (977P) 

overall survival (OS), ix350 (1070PD), ix415 

(1266P), ix437 (1339), ix441 (1351), ix453 

(1391P), ix485 (1498P), ix499 (1544O), ix119 

(328PD), ix148 (425P), ix204 (599P), ix208 


subject index 

(612P), ix214 (633), ix232 (694P), ix237 (712P), 

ix260 (787O), ix272 (824P), ix273 (825P) 

overall survival, ix376 (1155O), ix496 (1534P), 

ix87 (219P), ix271 (819P), ix296 (898PD) 

overtreatment, ix105 (281P) 

oxaliplatin, ix84 (207P), ix179 (523PD), ix193 

(566P), ix201 (591P), ix205 (602P), ix220 (653), 

ix237 (713P), ix241 (728P), ix249 (755), ix261 

(790O) 

oxycodone/naloxone, ix510 (1582P) 

P 

1p/19q co-deletion, ix31 (23IN) 

p-medicine, ix66 (141INIS) 

p16INK4a, ix185 (543P) 

p40, ix77 (181P) 

p53, ix389 (1192PD), ix74 (170O), ix98 (257P), 

ix108 (291P), ix323 (979P) 

p95-HER2, ix94 (243), ix101 (267P) 

paclitaxel plus gemcitabine, ix342 (1043P) 

paclitaxel/carboplatin, ix375 (1153) 

paclitaxel, ix409 (1246P), ix534 (1667P), ix116 

(317O), ix119 (326PD), ix157 (454P), ix161 

(464P), ix228 (681P), ix232 (692P), ix233 

(698P), ix247 (745P), ix261 (790O), ix265 

(801P), ix321 (974PD) 

pain control, ix510 (1581P) 

pain, ix488 (1510P), ix509 (1580P), ix510 (1582P) 

pAkt, ix78 (185P) 

palliative care, ix64 (128IN) 

palliative chemotherapy, ix343 (1046P), ix440 

(1350) 

palonosetron subcutaneous, ix508 (1577P) 

palonosetron, ix507 (1571P), ix507 (1572P), ix507 

(1574P), ix508 (1576P) 

pancreatic adenocarcinoma, ix543 (1697P), ix37 

(42IN), ix224 (666O), ix252 (767), ix253 (768) 

pancreatic cancer, ix25 (12IN), ix472 (1456P), 

ix543 (1696P), ix37 (43IN), ix155 (447PD), 

ix237 (710P), ix237 (712P), ix237 (713P), ix238 

(714P), ix238 (716P), ix239 (718P), ix239 

(720P), ix240 (721P), ix240 (722P), ix240 

(723P), ix240 (724P), ix241 (725P), ix241 

(726P), ix241 (727P), ix241 (728P), ix252 (767), 

ix255 (776TiP) 

pancreatic ductal adenocarcinoma, ix236 (709P) 

pancreatic fibroblast, ix67 (145P) 

pancreatic neuroendocrine tumor, ix376 (1155O) 

pancreatic neuroendocrine tumors, ix376 (1154O), 

ix378 (1159P) 

panitumumab, ix334 (1016O), ix514 (1597P), 

ix190 (558P), ix192 (563P), ix194 (570P), ix196 

(572P), ix200 (587P), ix203 (598P), ix205 

(605P), ix223 (665TiP) 

PaP Score, ix516 (1603P) 

papillary renal cell cancer, ix263 (797PD) 

papillary renal cell carcinoma, ix277 (837P) 

papillomavirus general, ix71 (162P) 

paradoxical pathway activation, ix46 (69IN) 

parental cancer, ix517 (1606P) 

PARP, ix42 (61IN), ix43 (63IN) 

pat. selection on molecular bases, ix32 (27IN) 

pathological complete response, ix135 (380), ix215 

(637), ix222 (663TiP) 

pathological response, ix219 (651) 

pathological tumor response, ix197 (578P) 

patient benefit, ix66 (142IN) 

patient characteristics, ix453 (1390P) 

patient consent, ix61 (117IN) 

patient enrichment, ix32 (28IN) 

patient management, ix525 (1635) 

patient physician communication, ix474 (1462PD) 

patient preferences, ix476 (1473P) 

patient reported outcomes, ix403 (1231PD), ix477 

(1474), ix512 (1590P) 

patient safety, ix418 (1275P), ix522 (1624) 

patient satisfaction, ix475 (1468P) 

patient stratification, ix85 (211P) 

patient survey, ix451 (1382P), ix132 (369P) 

patient-reported outcomes, ix120 (329P) 

patient, ix293 (892TiP) 

pattern of failure, ix393 (1204P) 

patterns of progression, ix441 (1352), ix238 

(715P) 

PAZONET, ix377 (1157O) 

pazopanib, ix377 (1157O), ix483 (1493P), ix88 

(222P), ix173 (508), ix261 (791PD), ix261 

(792PD), ix275 (833P), ix278 (840P), ix290 

(880) 

PD-1, ix361 (1109O), ix405 (1237PD), ix157 

(453P), ix159 (459P), ix258 (784O) 

PD-L1, ix159 (459P) 

PDGFRA mutation, ix483 (1491P) 

PDM08, ix165 (480P) 

pediatric cancer, ix455 (1399P) 

pediatric, ix358 (1102), ix145 (413PD) 

pegfilgrastim, ix500 (1548PD), ix503 (1560P) 

pemetrexed, cetuximab, ix336 (1022PD) 

pemetrexed, ix393 (1206P), ix395 (1211), ix396 

(1214), ix396 (1215), ix397 (1218), ix400 

(1225O), ix404 (1235PD), ix407 (1242P), ix409 

(1247P), ix412 (1258P), ix415 (1267P), ix418 

(1275P), ix421 (1281P), ix422 (1286P), ix428 

(1303P), ix437 (1338), ix438 (1342), ix442 

(1354), ix442 (1355), ix442 (1356), ix444 (1361) 

peptide, ix159 (460P) 

percutaneous hepatic perfusion, ix371 (1141P), 

ix246 (743P) 

performance status, ix541 (1689P) 

perfusion CT, ix282 (853P) 

periampullary, ix242 (729P) 

perineural invasion, ix186 (547P) 

perioperative chemotherapy, ix249 (753), ix292 

(887) 

periostin, ix301 (914P) 

peripheral neuropathy, ix513 (1592P) 

peritoneal carcinoma, ix326 (992P) 

peritoneal carcinomatosis, ix35 (38IN), ix202 

(593P) 

peritoneal mesothelioma, ix247 (747P) 

peritoneal metastasis, ix233 (698P), ix234 (702P) 

peritumoral vascular invasion, ix99 (260P) 

personalized medicine, ix65 (137IN), ix451 

(1382P), ix66 (140IN), ix66 (142IN), ix81 

(196P), ix88 (220P) 

personalized treatment, ix54 (92IN) 

perspectives, ix23 (6IN) 

pertuzumab, ix124 (344P) 

pesonalized therapy, ix66 (138IN) 

PET/CT, ix60 (114IN), ix385 (1180PD), ix37 

(45IN) 

PET/TC, ix137 (388) 

PET, ix33 (31IN), ix47 (74IN) 

Ph positive CML, ix358 (1102) 

pharmaco-épidémiology, ix219 (649) 

pharmacodynamic, ix346 (1057), ix167 (485P), 

ix219 (650), ix263 (796PD) 

pharmacodynamics, ix158 (457P) 

pharmacoepidemiology, ix456 (1402P) 

pharmacogenetic analysis, ix381 (1170P) 

pharmacogenetics, ix534 (1667P) 

pharmacogenomics, ix81 (196P), ix281 (850P) 

pharmacokinetics, ix346 (1057), ix498 (1543TiP), 

ix534 (1667P), ix538 (1678P), ix103 (274P), 

ix124 (344P), ix129 (358P), ix155 (447PD), 

ix162 (468P), ix169 (493P), ix219 (650), ix244 

(738P), ix245 (739P), ix246 (743P) 

phase 1 drugs, ix166 (482P) 

phase 1 study, ix163 (471P), ix164 (474P) 

phase 1 trials, ix158 (455P), ix167 (486P) 

phase 1, ix103 (274P), ix148 (428P), ix153 

(440O), ix156 (449PD), ix156 (450PD), ix159 

(458P), ix159 (459P), ix160 (462P), ix165 

(480P), ix165 (481P), ix173 (507) 

phase 2, ix378 (1159P), ix378 (1160P), ix63 

(126IN), ix435 (1329), ix438 (1340), ix152 


(438O), ix159 (460P), ix211 (624), ix263 

(797PD) 

phase 3 clinical trial, ix188 (552P), ix309 (937P), 

ix319 (967O) 

phase 3, ix418 (1275P), ix421 (1282P) 

phase I clinical trial, ix536 (1671P), ix153 (442O), 

ix154 (444PD) 

phase I clinical trials, ix162 (469P) 

phase I study, ix155 (448PD), ix156 (451P), ix164 

(475P) 

phase I trial, ix474 (1463P) 

phase I trials, ix32 (27IN) 

phase I/II study, ix336 (1021PD) 

phase I, ix424 (1291P), ix496 (1534P), ix155 

(446PD), ix161 (464P), ix161 (467P), ix167 

(485P), ix168 (491P), ix170 (497P), ix207 

(609P), ix239 (717P) 

phase II clinical trial, ix425 (1296P), ix228 (682P), 

ix275 (833P), ix304 (922P) 

phase II, sunitinib, ix479 (1479PD) 

phase II, ix441 (1353), ix512 (1588P) 

phase III clinical trial, ix404 (1234PD), ix231 

(689P), ix233 (697P) 

phase IV studies, ix282 (851P) 

phenotype, ix538 (1678P) 

phosphatase and tensin homolog (PTEN), ix84 

(204P), ix182 (532P) 

phospho-Met, ix154 (443PD) 

physical activity, ix518 (1609P) 

physical and emotional symptoms in not advanced 

cancer patients, ix524 (1631) 

physical examination, ix324 (983P) 

physical fitness, ix518 (1609P) 

physician survey, ix380 (1166P) 

physiotherapy, ix513 (1592P) 

PI3K alternations, ix40 (56IN) 

PI3K inhibitor, ix69 (154P), ix126 (350P), ix158 

(457P) 

PI3K inhibitors, ix27 (16IN), ix78 (185P), ix45 

(68IN) 

PI3K mTOR inhibitor, ix59 (108IN), ix69 (154P), 

ix153 (442O) 

PI3K pathway inhibitor, ix153 (442O), ix159 

(458P) 

PI3K pathway, ix531 (1656P), ix94 (243), ix223 

(664TiP) 

PI3K/Akt pathway, ix268 (812P) 

PI3K/mTOR, ix157 (452P) 

PI3K, ix537 (1675P), ix21 (2IN), ix42 (60IN), 

ix213 (630) 

PI3KCA mutation, ix153 (442O) 

PIH, ix454 (1394P) 

PIK3CA mutation, ix84 (204P) 

PIK3CA, ix59 (108IN), ix389 (1193P), ix196 

(574P) 

PKM2 expression, ix429 (1308P) 

placental growth factor, ix83 (203P) 

plasma biomarkers, ix73 (168O) 

plasma VEGF-A, ix81 (198P) 

plasma, ix495 (1530P), ix530 (1654P) 

platin sensitivity, ix497 (1540) 

platinum and trastuzumab, ix259 (786O) 

platinum resistance, ix320 (972PD) 

platinum-based chemotherapy, ix329 (1002P), 

ix427 (1302P) 

platinum-based regimens, ix130 (361P), ix323 

(981P) 

platinum-resistant, ix336 (1023PD) 

platinum-sensitive, ix324 (982P) 

platinum, ix533 (1661P), ix320 (972PD) 

pleural mesothelioma, ix493 (1522PD) 

pleural plaque, ix469 (1447PD) 

POLARSTAR, ix426 (1298P) 

policy, ix451 (1383P) 

polycystins, ix92 (236) 

polycythemia vera3hemorrhage, ix355 (1087P) 

polymer micelle, ix247 (746P) 

polymorphism of genes, ix240 (724P) 



polymorphism, ix183 (536P), ix208 (613P), ix216 

(640) 

polymorphisms, ix352 (1078P), ix185 (544P), 

ix281 (850P) 

pontine glioma, ix145 (413PD) 

pooled analysis, ix273 (825P) 

poor PS, ix421 (1282P), ix433 (1323) 

poorly differentiated carcinoma, ix89 (225P) 

population-based programme, ix53 (88IN) 

population-based study, ix53 (89IN) 

port central venous catheters, ix522 (1626) 

positive predictive value, ix373 (1146) 

positron emission tomography (PET), ix480 

(1482PD) 

post-induction therapy, ix419 (1278P) 

post-marketing surveillance, ix505 (1566P) 

post-marketing, ix504 (1563P) 

post-PD, ix482 (1490P) 

postoperative radiation, ix226 (674P) 

postoperative radiotherapy, ix216 (639) 

power doppler, ix134 (379) 

ppar, ix201 (590P) 

PRAME antigen, ix361 (1110O), ix386 (1182P) 

pre-menopausal cancer patients, ix501 (1551PD) 

pre-operative chemoradiotherapy, ix197 (575P), 

ix207 (610P) 

pre-operative staging, ix384 (1177P) 

preclinical model, ix337 (1027P) 

preclinical models, ix61 (120IN) 

preclinical, ix537 (1675P) 

prediction of response, ix504 (1561P), ix282 

(852P) 

predictive biomarker, ix84 (204P), ix107 (289P) 

predictive biomarkers, ix180 (525PD), ix197 

(575P), ix275 (833P) 

predictive factors, ix407 (1241P), ix429 (1306P), 

ix218 (647) 

predictive impact, ix182 (532P) 

predictive marker, ix74 (172O), ix265 (803P) 

predictive markers, ix364 (1117PD) 

predictive role, ix216 (640) 

predictive significance, ix381 (1170P) 

predictive/ prognostic value, ix431 (1314) 

predictors factors, ix276 (835P) 

prednisone, ix302 (918P) 

preeclampsia, ix454 (1394P) 

preference, ix293 (892TiP) 

pregnancy, ix355 (1090P), ix133 (373P) 

preoperative chemotherapy, ix130 (362P) 

preoperative concomitant chemoradiotherapy, 

ix89 (224P) 

preoperative radiochemotherapy, ix208 (1704P), 

ix545 (1704P) 

preoperative radiotherapy, ix216 (639) 

preoperative treatment, ix197 (578P) 

pretreated patients, ix325 (986P) 

prevalence, ix298 (902P), ix213 (632) 

prevention, ix473 (1461), ix477 (1475), ix513 

(1594P), ix173 (508) 

prgnosis, ix119 (327PD) 

primary cardiac sarcoma, ix489 (1513) 

primary endocrine therapy, ix100 (263P) 

primary lesion, ix276 (834P) 

primary mediastinal germ cell tumour, ix497 

(1539P) 

primary tumor, ix131 (368P), ix182 (531P) 

procalcitonin, ix525 (1637) 

progesteron reseptor, ix105 (279P) 

progesterone receptor, ix104 (278P) 

prognosis factors, ix94 (244) 

prognosis, SIADH, small cell lung cancer (SCLC), 

retrospective study, ix494 (1528P) 

prognosis, ix348 (1062O), ix353 (1080P), ix365 

(1120P), ix427 (1300P), ix516 (1603P), ix538 

(1681P), ix541 (1688PD), ix83 (201P), ix100 

(264P), ix110 (299), ix184 (539P), ix184 (540P), 

ix201 (589P), ix208 (613P), ix217 (644), ix287 

(868), ix53 (89IN) 

prognostic biomarker, ix338 (1030P), ix350 

(1071P), ix76 (178P), ix79 (187P), ix92 (233), 

ix199 (582P), ix226 (675P), ix261 (791PD), 

ix300 (911P) 

prognostic factor, ix332 (1015), ix350 (1069PD), 

ix387 (1186P), ix430 (1310P), ix496 (1533P), 

ix73 (168O), ix145 (414PD), ix186 (547P), ix253 

(771), ix265 (804P) 

prognostic factors, ix332 (1012), ix357 (1097), 

ix380 (1167P), ix387 (1184P), ix387 (1185P), 

ix392 (1203P), ix441 (1351), ix485 (1498P), 

ix497 (1537P), ix497 (1538P), ix497 (1540), ix79 

(187P), ix99 (258P), ix107 (288P), ix132 (371P), 

ix197 (577P), ix216 (641), ix262 (793PD), ix276 

(836P), ix298 (903P), ix328 (999P) 

prognostic marker, ix530 (1654P), ix74 (172O), 

ix182 (533P) 

prognostic model, ix299 (907P) 

prognostic score, ix162 (469P), ix298 (903P) 

prognostic significance, ix381 (1170P) 

prognostic, ix338 (1031P), ix339 (1033P) 

progression free survival, ix339 (1035P), ix392 

(1203P), ix217 (645) 

progression, survival, ix297 (901PD) 

progression-free survival (PFS), ix331 (1011), 

ix350 (1070PD), ix381 (1171P), ix453 (1391P), 

ix526 (1643), ix119 (328PD), ix232 (694P), 

ix260 (787O), ix273 (825P) 

progression-free survival, ix449 (1378P), ix231 

(690P) 

proliferation, ix112 (305) 

promoter methylation, ix186 (548P) 

prophylactic cranial irradiation, ix394 (1207P) 

prophylaxis, ix521 (1623) 

prospective cohort, ix488 (1511P) 

prostate cancer ibandronate y-27632 rho-kinase 

inhibitor, ix312 (947) 

prostate cancer screening, ix53 (87IN) 

prostate cancer working group (PCWG)-2, ix297 

(901PD) 

prostate cancer, ix384 (1178TiP), ix538 (1680P), 

ix89 (223P), ix38 (49IN), ix291 (884), ix294 

(893O), ix295 (896O), ix297 (899PD), ix298 

(902P), ix298 (904P), ix299 (906P), ix301 

(914P), ix302 (916P), ix304 (922P), ix306 

(928P), ix309 (937P), ix309 (938P), ix310 

(939P), ix310 (941P), ix311 (942P), ix311 

(944P), ix312 (945), ix313 (950), ix314 (952), 

ix314 (953), ix314 (955), ix315 (957), ix315 

(959), ix316 (961) 

prostate tumor xenograft, ix312 (946) 

prostate volume, ix306 (930P) 

prostate-specific antigen (PSA), ix299 (907P) 

prostate, ix39 (53IN) 

prostvac, ix38 (46IN) 

proteasome inhibitor, ix44 (66IN) 

protein S, ix356 (1094) 

protein tyrosine phosphatase non-receptor type 12 

(PTPN 12), ix127 (353P) 

protein-expression profiling, ix337 (1026P) 

proteinuria, ix171 (499P) 

proteomic biomaker, ix89 (224P), ix91 (232) 

proteomics, ix407 (1241P) 

prophylactic cranial irradiation, ix98 (256P) 

PRRT, ix47 (75IN) 

pruritus, ix500 (1550PD) 

PSA response, ix313 (951) 

PSA, mCRPC, ix310 (940P) 

pseudomyxoma peritonei, ix254 (774) 

PSF3, ix92 (233) 

psycho-oncology, ix474 (1462PD), ix475 (1467P), 

ix476 (1470P) 

psycho-social outcomes, ix474 (1462PD), ix475 

(1466P) 

psychological distress, ix343 (1047P), ix517 

(1606P) 

psychometric properties of Patient Dignity 

Inventory Italian version, ix516 (1601P) 

psychometric properties, ix516 (1602P) 

psychooncology, ix477 (1475) 

PTCH1, ix365 (1121P) 

PTEN, ix213 (630) 

PTK7, ix184 (539P) 

pulmonary adenocarcinoma, ix391 (1198P) 

pulmonary embolism, ix444 (1360) 

pulmonary neoplasm, ix383 (1174P) 

Q 

13q deletion, ix355 (1088P) 

QOL, ix511 (1586P), ix232 (695P) 

QTc, ix173 (507) 

quality assurance, ix86 (213P) 

quality of care indicators, ix457 (1405) 

quality of care, ix457 (1403), ix458 (1407), ix53 

(89IN) 

quality of documentation, ix448 (1374P) 

quality of life (QOL) assessment, ix512 (1590P), 

ix141 (403), ix211 (623), ix314 (954) 

quality of life (QoL), ix346 (1060), ix436 (1332), 

ix512 (1589P), ix514 (1596P), ix515 (1600P), 

ix120 (330P), ix120 (331P), ix145 (415PD), 

ix237 (712P), ix261 (792PD), ix269 (815P) 

quality of life, ix343 (1047P), ix459 (1413TiP), 

ix474 (1463P), ix475 (1468P), ix121 (334P), 

ix191 (561P), ix296 (898PD), ix315 (956), ix328 

(998P) 

quality-adjusted survival, ix192 (564P) 

R 

radiation therapy, ix148 (428P), ix200 (586P) 

radiation-induced malignancy, ix343 (1048P) 

radiation, ix69 (152P), ix537 (1676P), ix257 

(782TiP) 

radical mastectomy, ix131 (365P) 

radical prostatectomy, ix299 (907P) 

radical treatment, ix212 (626) 

radiochemotherapy, ix37 (45IN) 

radiographic progression-free survival, ix294 

(894O) 

radiopeptide therapy, ix379 (1162P) 

radiosensitiser, ix42 (61IN) 

radiosensitization, ix537 (1677P) 

radiotherapy induced epiphyseal injury, ix526 

(1642) 

radiotherapy-induced epiphyseal injury, ix526 

(1641) 

radiotherapy-induced oral mucositis, ix346 (1059) 

radiotherapy, ix329 (1003P), ix334 (1016O), ix343 

(1048P), ix343 (1049P), ix391 (1199P), ix457 

(1406), ix475 (1466P), ix496 (1536P), ix70 

(156P), ix525 (1636), ix537 (1677P), ix31 

(26IN), ix131 (365P), ix148 (427P), ix150 (433), 

ix172 (503), ix206 (607P), ix207 (611P), ix208 

(614P), ix242 (729P), ix265 (801P), ix265 

(803P), ix291 (885) 

Raf/MEK inhibitor, ix164 (475P) 

raltitrexed, ix178 (519O) 

ramucirumab, ix363 (1115PD), ix408 (1245P), 

ix422 (1287P) 

randomised phase II trial, ix378 (1161P) 

randomized clinical trial, ix410 (1250P), ix450 

(1380P) 

randomized discontinuation trial, ix319 (966O) 

randomized phase II trial, ix224 (666O), ix242 

(730P), ix297 (900PD) 

randomized phase III trial, ix211 (625) 

randomized trial, ix145 (413PD) 

Rapalogues, ix334 (1017O) 

rare cancer, ix66 (140IN) 

rare tumor, ix488 (1509P), ix110 (297P), ix327 

(993P) 

RAS, ix46 (69IN) 

rash, ix426 (1298P), ix435 (1328), ix79 (189P), 

ix192 (563P) 

rat food intake, ix161 (465P) 

rat model, ix526 (1641), ix526 (1642) 


subject index 

RCC, ix274 (830P) 

re-staging PET-CT, ix237 (711P) 

re-surgery, ix145 (416PD) 

receptor tyrosine kinase inhibitor, ix319 (966O) 

rechallenge, ix281 (849P) 

RECIST, ix60 (112IN), ix487 (1506P), ix188 

(554P), ix276 (834P) 

rectal cancer, ix529 (1648P), ix208 (1704P), ix545 

(1704P), ix197 (575P), ix206 (607P), ix206 

(608P), ix207 (609P), ix207 (610P), ix207 

(611P), ix208 (612P), ix208 (614P), ix211 (622), 

ix215 (637), ix215 (638), ix222 (663TiP) 

rectal cancers, ix184 (538P), ix193 (567P) 

recurrence factor, ix132 (371P) 

recurrence risk, ix179 (523PD) 

recurrence, ix148 (426P), ix322 (977P) 

recurrent cervical cancer, ix327 (995P) 

recurrent ovarian cancer, ix323 (980P), ix324 

(982P) 

recurrent/metastatic salivary gland malignancies, 

ix346 (1058) 

recurrent, ix332 (1014), ix147 (424P) 

reflex screening, ix176 (516P) 

refractory Hodgkin’s lymphoma, ix350 (1071P) 

refractory, ix492 (1519PD), ix286 (866P) 

regorafenib, ix478 (1478O) 

regulatory T-cells, ix75 (174O) 

rehabilitation, ix513 (1592P) 

reinforcement learning, ix459 (1411) 

relapse, disease-free survival (DFS), ix356 (1091P) 

relapse, ix227 (679P) 

relapsed non-Hodgkin’s lymphoma, ix353 (1081P) 

reliability, ix534 (1665P) 

renal cancer, ix39 (51IN), ix39 (52IN), ix267 

(808P) 

renal cell cancer, ix274 (828P), ix281 (848P), 

ix281 (850P), ix287 (869), ix288 (875), ix290 

(880) 

renal cell carcinoma (RCC), ix268 (811P), ix273 

(827P), ix278 (840P), ix282 (853P), ix283 

(856P) 

renal cell carcinoma, ix453 (1390P), ix453 

(1391P), ix454 (1392P), ix69 (153P), ix172 

(501), ix39 (53IN), ix258 (784O), ix261 

(792PD), ix262 (793PD), ix262 (794PD), ix262 

(795PD), ix267 (809P), ix268 (812P), ix268 

(813P), ix270 (817P), ix270 (818P), ix272 

(823P), ix273 (825P), ix273 (826P), ix274 

(829P), ix275 (832P), ix276 (834P), ix276 

(836P), ix277 (838P), ix277 (839P), ix279 

(844P), ix280 (846P), ix281 (847P), ix283 

(855P), ix287 (872), ix288 (874), ix289 (876), 

ix289 (877), ix289 (878), ix292 (889TiP) 

renal function, ix171 (500P) 

renal, ix267 (810P), ix269 (816P) 

reproductive age, ix328 (998P) 

research informatics, ix449 (1376P) 

research, ix65 (135IN) 

resectable gastroesophageal carcinoma, ix249 

(753) 

resectable locally-advanced, ix265 (802P) 

resectable muscle-invasive, ix266 (807P) 

resectable rectal cancer, ix216 (639) 

resistance to treatment, ix287 (869) 

resistance, ix390 (1197P), ix68 (148P), ix68 

(149P), ix116 (318O), ix39 (52IN) 

resource utilization, ix122 (336P) 

response-shift, ix120 (331P) 

response criteria, ix289 (877) 

Response Evaluation Criteria in Solid Tumors 

(RECIST), ix60 (111IN), ix535 (1670P), ix198 

(579P) 

response evaluation, ix483 (1492P) 

response prediction, ix29 (19IN), ix37 (44IN) 

response rate, ix389 (1191PD), ix415 (1267P), 

ix496 (1534P) 

response shift, ix109 (296P) 

response to therapy, ix534 (1665P) 

response to tyrosine kinase inhibitors, ix412 

(1257P) 

response, ix358 (1100) 

retinoblastoma, ix149 (430P) 

retroperitoneal lymph nodes, ix292 (888) 

retrospective analysis, ix526 (1640) 

retrospective study, ix370 (1136P), ix487 (1505P), 

ix525 (1635), ix114 (313) 

reverse-phase protein microarrays, ix536 (1674P) 

review, ix49 (78IN) 

RFA, ix35 (39IN) 

rhabdomyosarcoma, ix484 (1497P) 

rilotumumab, ix230 (687P) 

risk factors, ix543 (1698P), ix134 (376), ix227 

(679P), ix284 (859P) 

risk, ix339 (1032P), ix364 (1119P), ix365 (1121P), 

ix365 (1122P), ix133 (374P) 

rituximab, ix351 (1074P), ix352 (1076P), ix352 

(1079P), ix451 (1384P), ix70 (157P) 

RNA sequencing, ix57 (100IN) 

RNA, ix76 (177PD) 

RO4929097, ix155 (448PD), ix156 (450PD) 

RON, ix495 (1532P) 

ROS1, ix389 (1191PD), ix81 (195P) 

round robin panel testing, ix394 (1208) 

Rrca1 mutant breast cancer mouse models, ix108 

(290P) 

RRM 1, ix67 (144PD) 

S 

S-1 plus cisplatin, ix404 (1234PD) 

S-1 plus oxaliplatin, ix256 (779TiP), ix326 (989P) 

s-1 plus paclitaxel, ix256 (779TiP) 

S-1, ix385 (1181PD), ix436 (1334), ix193 (566P), 

ix197 (576P), ix224 (668PD), ix225 (671P), 

ix232 (695P), ix241 (728P), ix250 (758) 

S1, ix217 (646) 

safety and tolerability, ix403 (1231PD), ix163 

(471P), ix240 (721P) 

safety, cardio-toxicity, ix164 (476P) 

safety, ix366 (1124P), ix402 (1230PD), ix419 

(1277P), ix508 (1576P), ix516 (1604P), ix114 

(315TiP), ix171 (499P), ix173 (507), ix224 

(668PD), ix262 (795PD), ix308 (936P) 

salivary duct carcinoma, ix344 (1706P) 

salvage chemotherapy N, ix375 (1153) 

salvage chemotherapy, ix63 (126IN), ix285 (860P) 

sample size calculation, ix450 (1380P) 

sarcoma, ix481 (1487P), ix482 (1488P), ix485 

(1500P), ix485 (1501P), ix486 (1502P), ix486 

(1504P), ix487 (1505P), ix489 (1514), ix490 

(1517TiP), ix21 (1IN), ix166 (482P), ix54 

(91IN), ix54 (92IN), ix55 (94IN) 

satisfaction, ix511 (1584P) 

SCCHN, ix334 (1018O) 

schwannoma, ix150 (432) 

SCLC, ix492 (1519PD), ix494 (1529P), ix498 

(1543TiP) 

screening process, ix53 (88IN) 

screening tools, ix452 (1386P) 

screening, ix456 (1402P), ix472 (1456P), ix252 

(767) 

second line therapy, ix438 (1342), ix497 (1540), 

ix203 (597P), ix213 (632), ix242 (731P), ix265 

(804P), ix277 (837P), ix314 (955) 

second line, ix251 (761) 

second-line chemotherapy, ix381 (1171P), ix429 

(1306P), ix230 (688P), ix233 (697P) 

second-line therapy, ix419 (1276P), ix232 (692P), 

ix280 (846P) 

second-line treatment, ix400 (1225O) 

second-line, ix438 (1341) 

secondary prophyalaxis, ix499 (1547PD) 

secondary resection, ix190 (557P) 

SEER-Medicare, ix205 (603P) 

selective targeted drug, ix32 (29IN) 

aelumetinib, ix403 (1233PD) 

seminoma Stage 1, ix283 (857P) 


seminoma, ix284 (859P), ix286 (867P) 

semuloparin, ix543 (1697P) 

sensitive EGFR mutations, ix391 (1198P) 

sensitivity analyses trabectedin progression-free 

survival, ix324 (984P) 

sentinel lymph node, ix112 (307) 

sentinel node, ix106 (284P) 

sequencing, ix38 (47IN) 

sequential adjuvant chemotherapy, ix129 (360P) 

sequential treatment, ix97 (253PD), ix272 (824P), 

ix278 (840P), ix290 (881), ix314 (952), ix315 

(958) 

sequential, ix289 (876) 

Serbian patients, ix428 (1304P) 

serial evaluation, ix341 (1042P) 

SERM, ix28 (17IN) 

serous borderline tumor, ix322 (977P) 

serous ovarian carcinoma, ix319 (969PD) 

serum albumin levels, ix356 (1091P) 

serum chromogranin-A, ix301 (912P) 

serum HER2, ix136 (386) 

serum tumor markers, ix80 (192P) 

serum, ix78 (184P) 

sex hormone binding globulin, ix304 (923P) 

sex, ix455 (1396P) 

sexual dysfunctions, ix474 (1463P) 

sexuality, ix477 (1476) 

shared, ix475 (1469P) 

SHH, ix31 (25IN) 

short chain fatty acid, ix200 (585P) 

short-time infusion, ix203 (598P) 

side-effects, ix518 (1610P), ix526 (1643) 

signaling pathways, ix541 (1690P), ix40 (56IN) 

signet ring cell, ix89 (225P), ix184 (541P), ix249 

(753) 

simultaneous resection, ix201 (589P) 

simvastatin, ix72 (165) 

single agent, ix398 (1220) 

single institutional review, ix133 (373P) 

single nucleotide polymorphism (SNP), ix434 

(1326), ix528 (1646PD), ix85 (208P), ix92 (235), 

ix209 (615), ix246 (742P) 

sipuleucel-t, ix38 (46IN), ix310 (939P), ix310 

(940P), ix310 (941P), ix311 (942P), ix311 

(943P), ix313 (949) 

siRNA (short-interfering RNA), ix536 (1673P) 

skeletal–related events, ix447 (1372P), ix524 

(1633) 

skeletal-related event (SRE), ix360 (1108TiP), 

ix449 (1377P) 

skin toxicity, ix426 (1298P), ix435 (1328), ix514 

(1597P), ix192 (563P) 

skin-test infiltrating lymphocytes, ix363 (1114PD) 

sleep difficulties, ix474 (1465P) 

SMAD7, ix209 (615) 

small bowel adenocarcinoma, ix234 (703P) 

small breast cancer, ix111 (303) 

small cell cancer, ix291 (886) 

small cell lung cancer (SCLC), ix492 (1520PD), 

ix493 (1525P), ix494 (1526P), ix494 (1527P), 

ix497 (1540) 

small cell lung cancer, ix493 (1523P), ix495 

(1530P) 

small molecule, ix32 (29IN) 

small tumors, ix104 (276P) 

smoking status, ix412 (1257P), ix420 (1280P), 

ix455 (1396P), ix469 (1448PD) 

SN-38, ix167 (485P) 

SNPs, ix339 (1032P), ix243 (734P) 

socio-econonomic status, ix165 (479P) 

SOCS (suppressor of cytokine signaling), ix69 

(153P) 

sodium folinic acid (S-FA), ix185 (542P) 

soft tissue sarcoma, ix483 (1493P), ix484 (1496P), 

ix486 (1503P), ix487 (1506P), ix54 (91IN) 

soft tissue sarcomas, ix485 (1498P), ix489 (1512) 

solid and haematological malignancies, ix520 

(1617), ix524 (1631) 



solid tumor, ix503 (1559P) 

solid tumors, ix59 (108IN), ix452 (1387P), ix83 

(203P), ix154 (443PD), ix160 (461P), ix165 

(478P), ix166 (482P), ix169 (494P), ix170 

(498P), ix303 (921P) 

solitary brain metastasis, ix425 (1294P) 

somatic mutation#melanoma, DNA sequencing, 

ix25 (11IN) 

somatic mutation, ix430 (1311P) 

somatostatin analogs, ix380 (1165P), ix146 

(419PD) 

somatostatin receptor expression, ix379 (1164P) 

somatostatin receptor, ix47 (74IN) 

sorafenib, ix407 (1241P), ix63 (124IN), ix440 

(1349), ix444 (1362TiP), ix453 (1390P), ix483 

(1491P), ix487 (1506P), ix519 (1615P), ix536 

(1674P), ix91 (229P), ix155 (447PD), ix161 

(466P), ix194 (569P), ix220 (654), ix225 

(670PD), ix243 (734P), ix244 (736P), ix253 

(769), ix255 (777TiP), ix255 (778TiP), ix270 

(817P), ix279 (844P), ix283 (856P), ix287 (872), 

ix288 (874) 

Spanish Melanoma Group (GEM), ix374 (1150) 

speckle tracking echocardiography, ix164 (476P) 

squamous carcinoma head and neck, ix336 

(1023PD) 

squamous cell cancer of the skin, ix372 (1144) 

squamous cell carcinoma of head and neck 

(SSCHN), ix336 (1022PD) 

squamous cell carcinoma, ix174 (509TiP), ix328 

(997P) 

Src, ix540 (1686P), ix172 (501) 

stage 1 gastric cancer, ix227 (679P) 

stage I adenocarcinoma of the lung, ix387 (1186P) 

stage II colon cancer, ix188 (551P), ix210 (621) 

stage III, ix49 (79IN) 

stage IIIB non-small cell lung cancer, ix392 

(1202P) 

stage IV colon cancer, ix214 (634) 

stage IV, ix409 (1249P) 

staging, ix106 (283P) 

statistical analysis, ix449 (1378P) 

stem cells, ix354 (1086P), ix110 (300), ix146 

(418PD), ix205 (604P), ix299 (906P) 

stereotactic radiosurgery, ix62 (123IN) 

stereotactic radiotherapy, ix62 (123IN) 

steroid sulphatase inhibitor, ix329 (1001P) 

steroidogenesis, ix306 (928P) 

STK11, ix77 (180P) 

stomach cancer, ix512 (1589P), ix541 (1688PD) 

stomach, ix351 (1075P) 

stromal cell, ix107 (287P), ix184 (540P) 

structural equation modeling, ix511 (1586P) 

subcutaneous trastuzumab, ix97 (254PD), ix103 

(272P), ix114 (315TiP) 

subcutaneous, ix103 (273P), ix162 (470P) 

subtypes, ix250 (756) 

subtyping NSCLC, ix425 (1295P) 

suicide ideation, ix512 (1589P) 

sunitinib, patient-reported outcomes, ix269 (815P) 

sunitinib, ix376 (1155O), ix482 (1490P), ix484 

(1495P), ix484 (1496P), ix519 (1615P), ix538 

(1678P), ix91 (229P), ix235 (705P), ix240 

(724P), ix259 (785O), ix276 (835P), ix283 

(854P), ix262 (794PD), ix263 (797PD), ix271 

(820P), ix273 (826P), ix273 (827P), ix274 

(829P), ix275 (832P), ix281 (847P), ix281 

(849P), ix281 (850P), ix282 (851P), ix287 (870), 

ix287 (872), ix292 (889TiP), ix293 (892TiP), 

ix290 (881) 

supportive care, ix64 (128IN) 

supportive therapy, ix425 (1297P), ix518 (1611P), 

ix284 (858P) 

surgery, ix329 (1003P), ix496 (1536P), ix131 

(368P), ix35 (38IN), ix217 (644), ix229 (684P), 

ix49 (79IN) 

surgical immunology, ix202 (595P) 

surgical nutriology, ix202 (595P) 

surgical resection, ix388 (1189P), ix182 (531P) 

surgical treatment, ix342 (1045P) 

surrogate decision-making, ix475 (1469P) 

surveillance, ix292 (887) 

survey, ix450 (1381P), ix110 (297P), ix229 (685P) 

survival analysis, ix370 (1134P), ix380 (1167P), 

ix439 (1345), ix494 (1529P), ix145 (414PD), 

ix175 (512PD), ix201 (589P), ix327 (996P) 

survival outcome, ix392 (1202P), ix393 (1204P) 

survival prediction factors, ix149 (429P) 

survival, ix350 (1069PD), ix387 (1185P), ix421 

(1281P), ix455 (1398P), ix487 (1507P), ix511 

(1586P), ix101 (266P), ix131 (368P), ix149 

(431), ix188 (553P), ix189 (555P), ix226 (674P), 

ix233 (699P), ix248 (749), ix298 (903P), ix319 

(967O), ix327 (994P) 

Survivin, ix323 (979P) 

symptom assessment, ix141 (403) 

symptom management, ix64 (129IN) 

symptom, ix517 (1607P) 

symptoms, ix421 (1281P), ix459 (1413TiP) 

synchronous hepatic metastases, ix201 (589P) 

systematic review, ix450 (1379P), ix123 (341P) 

systemic chemotherapy, ix202 (593P), ix213 (631) 

systemic immunoglobulin light-chain amyloidosis, 

ix355 (1089P) 

systemic inflammation, ix381 (1169P) 

systems biology, ix535 (1668P) 

T 

3D cell culture, ix543 (1695P) 

3D interactive digital anatomy, ix346 (1060) 

3D radiotherapy, ix114 (314) 

3D-Q-FISH, ix350 (1071P) 

3rd line, ix493 (1525P) 

T-DM1, ix89 (226P), ix120 (329P) 

T790M mutation, ix418 (1273P) 

TACE, ix371 (1140P) 

TAK-441, ix156 (449PD) 

TAK-700, docetaxel, ix302 (918P) 

TAK1/p38 MAPK, ix126 (348P) 

tamoxifen, ix109 (295P), ix136 (384) 

target lesion, ix276 (834P) 

target therapies, ix345 (1053), ix66 (140IN) 

target therapy, ix40 (56IN) 

targeted agent, ix276 (836P) 

targeted agents, ix31 (26IN) 

targeted therapies, ix334 (1017O), ix379 (1163P), 

ix380 (1165P), ix519 (1614P), ix34 (36IN), ix39 

(50IN), ix39 (53IN), ix23 (5IN), ix43 (63IN), 

ix46 (70IN), ix270 (818P), ix272 (824P), ix52 

(85IN), ix55 (94IN), ix321 (975PD) 

targeted therapy, ix51 (81IN), ix32 (28IN), ix44 

(66IN), ix23 (6IN), ix271 (819P), ix289 (877) 

targeted treatment, ix54 (92IN) 

targeted, ix267 (810P), ix269 (816P) 

taxane, ix407 (1242P) 

taxanes, ix325 (985P) 

taxotere chemotherapy, ix298 (904P) 

TCF dose-dense, ix232 (693P) 

teamwork, ix477 (1475) 

TEC, ix501 (1552P) 

temozolomide, ix147 (424P), ix366 (1126P), ix446 

(1368TiP), ix494 (1529P), ix540 (1686P), ix144 

(410O) 

temsirolimus, ix336 (1023PD), ix359 (1107TiP), 

ix156 (450PD), ix160 (462P), ix239 (717P), 

ix274 (828P), ix277 (839P), ix280 (846P), ix290 

(879) 

teratoma, ix286 (864P) 

tesetaxel, ix165 (481P), ix167 (486P) 

testicular cancer, ix261 (790O) 

testicular germ cell cancer, ix286 (865P) 

testicular nonseminomatous germ cell tumor 

(NSGCT), ix284 (858P) 

testis cancer, ix286 (866P) 

testosterone prostate cancer chemotherapy, ix299 

(908P) 

testosterone, ix304 (923P) 

tetraploidy, ix31 (25IN) 

TGase-2, ix274 (830P) 

TGF-ß (transforming growth factor beta), ix209 

(615) 

TGF, ix81 (197P) 

TH-302, ix224 (666O) 

theoretical model, ix476 (1473P) 

theragnostics, ix32 (27IN) 

therapeutic target, ix532 (1660P) 

therapeutic targets, ix536 (1673P) 

therapeutic vaccine, ix406 (1238PD) 

therapy-related, ix357 (1096) 

third- or fourth-line chemotherapy, ix443 (1358) 

third- or fourth-line treatment, ix440 (1349) 

third-line therapy, ix276 (836P) 

third-line treatment, ix424 (1292P) 

third-line, ix251 (762) 

thoracic oncology, ix515 (1598P) 

thoracic radiotherapy, ix396 (1215) 

thoracic tumours, ix497 (1539P) 

three cytotoxic agents SCLC, ix493 (1524P) 

three year imatinib, ix235 (706P) 

thrombin generation, ix543 (1697P) 

thrombocytopenia, ix506 (1570P) 

thromboembolic disease, ix519 (1616P) 

thromboembolism, ix519 (1616P) 

thromboses, ix356 (1094) 

thrombosis, ix515 (1599P) 

thymic carcinoma, ix497 (1537P), ix498 (1541) 

thymic epithelial tumor, ix498 (1541) 

thymic epithelial tumors, ix540 (1687) 

thymic tumors, ix496 (1536P) 

thymidine kinase 1, ix88 (220P), ix217 (645) 

thymidylate synthase (TS), ix407 (1242P) 

thymoma, ix498 (1541) 

thyroid cancer, ix344 (1050P) 

thyroid dysfunction, ix525 (1636) 

thyroid tumor, ix517 (1608P) 

time from prior chemotherapy, ix265 (804P) 

time of disease control, ix332 (1014) 

time to progression, ix80 (194P) 

time to QoL deterioration, ix120 (331P) 

time-dependent analysis, ix420 (1279P) 

time-trend, ix365 (1120P) 

TIMPs, ix67 (146P) 

tissue microarray, ix276 (835P) 

tissue repository, ix61 (117IN) 

tivantinib, ix424 (1293P), ix225 (669PD), ix244 

(738P), ix245 (739P) 

tivozanib, ix262 (795PD), ix263 (796PD) 

TJ-14, ix514 (1595P) 

TKI, ix440 (1348), ix290 (881) 

TKIs, ix51 (82IN), ix290 (881) 

TNBC metastaticum first line tretment, ix137 

(390) 

TNF-a (tumor necrosis factor alpha), ix486 

(1504P) 

TNM classification, ix388 (1188P), ix414 (1262P) 

TNM, ix385 (1179O) 

tobacco habit, ix343 (1049P) 

tobacco smoking, ix472 (1458P) 

tocilizumab, ix69 (153P) 

tolerability, ix238 (714P), ix267 (810P), ix280 

(845P) 

toll-like receptor agonist, ix342 (1044P) 

topoisomerase I, ix167 (485P) 

topotecan, ix492 (1520PD), ix494 (1529P) 

total body irradiation, ix354 (1084P) 

total lesion glycolysis, ix199 (584P) 

toxicities, ix64 (131IN) 

toxicity score, ix354 (1085P) 

toxicity, ix342 (1044P), ix346 (1057), ix460 

(1416PD), ix500 (1549PD), ix519 (1614P), ix168 

(491P), ix181 (530PD), ix219 (650), ix229 

(683P), ix273 (826P) 

TP53, ix234 (703P) 

TPF, ix341 (1041P), ix344 (1051) 


subject index 

TR-FRET, ix84 (206P) 

trabectedin, ix490 (1517TiP) 

training, ix65 (133IN) 

transarterial chemoembolization, ix161 (466P), 

ix243 (732P) 

transforming alteration, ix61 (119IN) 

translational research, ix336 (1021PD), ix451 

(1383P), ix535 (1668P), ix535 (1669P), ix42 

(58IN), ix224 (667PD), ix300 (911P) 

transplantation-related malignancy, ix459 (1410) 

trastuzumab her2 small tumors, ix104 (275P) 

trastuzumab resistance, ix528 (1645PD) 

trastuzumab retreatment, ix139 (396) 

trastuzumab, ix58 (104IN), ix455 (1397P), ix94 

(243), ix101 (267P), ix103 (273P), ix103 (274P), 

ix104 (276P), ix112 (308), ix113 (309), ix116 

(318O), ix124 (343P), ix124 (344P), ix125 

(346P), ix138 (391), ix142 (406TiP), ix162 

(470P), ix233 (699P) 

treatment across multiple lines, ix190 (559P), 

ix193 (565P), ix195 (571P) 

treatment algorithm, ix52 (85IN) 

treatment beyond progression, ix440 (1347), ix190 

(559P), ix193 (565P), ix195 (571P) 

treatment duration, ix188 (552P) 

treatment failure, ix345 (1056) 

treatment monitoring, ix483 (1492P) 

treatment patterns, ix451 (1384P) 

treatment selection, ix407 (1242P) 

treatment-use, ix482 (1490P) 

treatment, ix359 (1104), ix458 (1408), ix488 

(1511P), ix315 (957) 

tregs, ix431 (1314) 

trial design, ix31 (26IN), ix55 (94IN) 

trial in progress, ix57 (101IN), ix174 (1708PD), 

ix347 (1061TiP), ix359 (1107TiP), ix360 

(1108TiP), ix444 (1362TiP), ix445 (1364TiP), 

ix445 (1365TiP), ix445 (1366TiP), ix446 

(1367TiP), ix446 (1368TiP), ix459 (1413TiP), 

ix460 (1414TiP), ix490 (1517TiP), ix490 

(1518TiP), ix493 (1522PD), ix498 (1542TiP), 

ix498 (1543TiP), ix119 (325PD), ix141 

(405TiP), ix142 (406TiP), ix142 (407TiP), ix142 


(441O), ix156 (451P), ix157 (452P), ix170 

(498P), ix172 (501), ix174 (509TiP), ix174 


(664TiP), ix223 (665TiP), ix225 (670PD), ix255 





(963TiP), ix317 (965TiP), ix321 (974PD) 

trials in progress, ix114 (315TiP), ix115 (316TiP), 

ix142 (408TiP), ix211 (622), ix317 (964TiP), 

ix322 (978P) 

trigger tools, ix456 (1400P) 

triple negative breast cancer, ix84 (205P), ix29 

(20IN), ix29 (21IN), ix29 (22IN), ix98 (257P), 

ix99 (260P), ix132 (370P), ix135 (381), ix140 

(401), ix175 (513PD) 

triple negative, ix102 (270P) 

triple-negative breast cancer (TNBC), ix99 (258P), 

ix134 (378) 

TrkB, ix79 (188P) 

TS-1, ix250 (757) 

TSU-68, ix243 (732P) 

TTF1, ix77 (181P) 

tumor antigen, ix386 (1182P) 

Tumor Associated Macrophages (TAM), ix538 

(1681P) 

tumor cell division, ix111 (301) 

tumor endothelial cells, ix76 (178P) 

tumor growth rate, ix198 (579P) 

tumor marker, ix93 (239) 

tumor markers, ix123 (339P) 

tumor metabolism, ix339 (1033P) 

tumor response, ix535 (1670P) 

tumor tolerance, ix303 (919P) 

tumor treating fields (TTFields), ix396 (1214) 

tumor volume, ix188 (554P) 

tumour response, ix60 (112IN) 

tumour, ix458 (1408), ix190 (558P) 

tyrosine kinase inhibitor (TKI), ix413 (1261P), 

ix478 (1478O), ix83 (203P), ix154 (445PD), 

ix163 (471P), ix169 (492P), ix169 (493P), ix244 

(737P), ix270 (818P) 

tyrosine kinase inhibitors (TKIs), ix480 (1482PD), 

ix144 (412O), ix261 (792PD) 

tyrosine kinase receptor, ix154 (445PD) 

U 

U3-1287, ix161 (467P) 

ubidecaranone, ix166 (482P) 

UFT, ix188 (552P) 

uncommon EGFR mutations, ix410 (1252P) 

undifferentiated pleomorphic sarcoma, ix485 

(1499P) 

unresectable colorectal liver metastases, ix35 

(39IN) 

unresectable liver metastases, ix194 (568P), ix205 

(605P) 

upper esophageal carcinoma, ix247 (745P) 

upper tract urothelial cancer, ix292 (887) 

uracil-tegafur (UFT), ix185 (542P), ix197 (576P) 

ureteric cancer, ix292 (887) 

urinary bladder, ix291 (883) 

urine, ix144 (411O) 

urothelial bladder carcinoma, ix93 (240) 

urothelial cancer, ix88 (222P), ix266 (806P) 

urothelial carcinoma, ix39 (50IN), ix260 (787O), 

ix265 (804P) 

uterine leiomyosarcoma, ix332 (1015) 

utility, ix372 (1143P) 

uveal melanoma, ix370 (1136P), ix371 (1140P), 

ix374 (1149), ix90 (227P) 

V 

vaccine, ix503 (1558P), ix159 (460P) 

vaginal brachytherapy, ix329 (1002P) 

valproic acid, ix147 (423P) 

vascular disrupting agent, ix410 (1250P) 

vascular endothelial growth factor (VEGF), ix353 

(1080P) 

vascular endothelial growth factor receptor 

(VEGFR), ix376 (1154O), ix186 (545P), ix271 

(821P) 

vascular endothelial growth factor, ix249 (752) 

vascular invasion, ix387 (1184P) 

vascular permeability factor (VPF), ix59 (109IN) 

VEGF inhibitor, ix146 (417PD), ix277 (837P) 

VEGF receptor inhibitor, ix173 (505) 

VEGF-targeted therapy, ix258 (783O), ix264 

(798PD), ix278 (841P), ix278 (842P) 

VEGF-trap, ix198 (581P), ix214 (633) 

VEGF, ix540 (1687), ix75 (174O), ix78 (184P), 

ix81 (197P), ix108 (292P), ix248 (751), ix274 

(829P), ix54 (91IN) 

VEGFR-2, ix422 (1287P) 

VEGFR, ix540 (1687) 

veliparib, ix148 (428P) 

VELOUR Study, ix198 (581P) 

vemurafenib, ix366 (1124P), ix366 (1125P) 

venous thromboembolic disease, ix543 (1697P) 

venous thromboembolism, ix447 (1369P), ix56 

(98IN) 

VeriStrat, ix407 (1241P) 

vinorelbine, ix346 (1058), ix498 (1542TiP), ix138 

(393), ix138 (394) 

virus infection, ix71 (162P) 

vismodegib, ix362 (1111PD), ix362 (1112PD) 

visual effects, ix416 (1268P) 

vitamin D3, ix526 (1642) 

vitamin D, ix454 (1395P) 

vorinostat, ix234 (700P) 

vulnerability, ix477 (1475) 

W 

Warburg, ix71 (160P) 

WB DWI, ix344 (1050P) 

web-based network, ix327 (993P) 

weekly paclitaxel, ix398 (1221) 

weight gain, breast cancer, ix95 (248O) 

weight loss, ix520 (1620), ix541 (1689P) 

Wertheim surgery, ix330 (1007) 

Wertheim surgery post chemoradiation, ix330 

(1007) 

wild type EGFR, ix424 (1292P), ix439 (1346), 

ix445 (1366TiP) 

willingness to pay, ix122 (338P) 

window study, ix336 (1021PD), ix42 (58IN) 

Wnt signaling pathway, ix544 (1700), ix209 (617) 

Wnt, ix43 (62IN) 

WT1, ix496 (1533P) 

X 

XELOX, ix187 (550P) 


Y 

Y90-ibritumomab tiuxetan, ix351 (1073P) 

young adults, ix490 (1515) 

Young CLL, ix358 (1101) 

young women, ix455 (1398P), ix100 (264P) 

young, ix101 (265P) 

yttrium-90 microsphere radioembolization (SIRT), 

ix480 (1484PD), ix244 (735P) 

zeb, ix67 (145P) 

zoledronic acid, ix509 (1580P), ix510 (1583P), 

ix511 (1584P), ix526 (1641) 

ix447 (1369P) 


drug index 

17AAG: 156P 

2CdA: 1076P 

3-Aminobenzamide: 988P 

5-Azacytidine: 1096P 

5-Fluorouracil: 39IN, 42IN, 155P, 208P, 209P, 

224P, 228P, 245O, 246O, 253PD, 267P, 269P, 

333P, 360P, 377, 373P, 390, 452P, 458P, 460P, 

515P, 518O, 519O, 520O, 523PD, 524PD, 

527PD, 529PD, 542P, 543P, 547P, 550P, 557P, 

558P, 560P, 561P, 564P, 567P, 568P, 570P, 573P, 

577P, 580P, 581P, 586P, 587P, 590P, 591P, 592P, 

597P, 599P, 600P, 601P, 602P, 603P, 607P, 610P, 

618, 620, 624, 627, 633, 634, 635, 637, 639, 640, 

643, 650, 653, 655, 656, 657, 659, 661, 662TiP, 

665TiP, 668PD, 672P, 683P, 686P, 689P, 690P, 

693P, 695P, 696P, 701P, 710P, 711P, 714P, 715P, 

716P, 721P, 726P, 730P, 731P, 745P, 749, 753, 

760, 762, 782TiP, 989P, 1018O, 1020PD, 1028P, 

1034P, 1035P, 1036P, 1037P, 1038P, 1039P, 

1040P, 1041P, 1044P, 1045P, 1051, 1054, 1057, 

1159P, 1595P, 1161P, 1644PD 

AAV-HGFK1: 348P 

Abiraterone acetate: 47IN, 53IN, 325P, 894O, 

895O, 897O, 918P, 920P, 924P, 925P, 926P, 946, 

951, 958, 964TiP, 920P, 924P, 946, 950 

ABT-510: 505 

ABT-751: 505 

AEE788: 1652P 

Afatinib: 7IN, 78IN, 446PD, 464P, 468P, 478P, 

494P, 509TiP, 1227O, 1229PD, 1232PD, 1252P, 

1288P, 1292P, 1288P, 1339 

Aflibercept: 53IN, 581P, 597P, 633 

Alemtuzumab: 1095 

Allo-aca: 483P 

Allopurinol: 1103 

Alpharadin: 53IN 

Altretamine: 986P 

Amatuximab: 1522PD 

AMEP: 1139P 

AMG 102: 687P 

AMG 386: 975PD 

AMG 479: 776TiP 

Amrubicin: 235, 1358, 1519PD 

Anastrozole: 280P, 310, 341P, 407TiP 

AP26113: 7IN, 439O 

APC8015F: 941P 

APD421: 1573P 

Aprepitant: 721P, 1550PD, 1571P, 1578P, 1579P 

ARN-509: 920P, 964TiP 

ARQ 197: 7IN, 669PD, 1293P, 669PD, 1293P 

AS703026: 7IN 

ASG-5ME: 963TiP 

ASP 3026: 7IN 

AT-101: 901PD 

AUY922: 438O, 1679P 

Axitinib: 43IN, 53IN, 793PD, 811P, 824P, 843P, 

856P, 1246P, 1391P, 1391P, 1615P 

AZD0530: 1686P 

AZD4547: 7IN 

BCNU: 1147 

Belinostat: 1068PD 

Belotecan: 1520PD 

Bendamustine: 65IN, 1064O 

Bevacizumab: 18IN, 21IN, 24IN, 39IN, 43IN, 

53IN, 54IN, 57IN, 76IN, 78IN, 95IN, 105IN, 

115IN, 126IN, 154P, 155P, 174O, 194P, 198P, 

200P, 208P, 209P, 241, 292P, 317O, 323PD, 

335P, 337P, 345P, 354P, 355P, 356P, 395, 400, 

417PD, 435TiP, 437TiP, 452P, 464P, 499P, 

518O, 530PD, 532P, 555P, 559P, 560P, 562P, 

565P, 567P, 571P, 573P, 577P, 592P, 593P, 594P, 

596P, 597P, 600P, 602P, 603P, 607P, 618, 624, 

629, 633, 634, 635, 642, 648, 651, 652, 653, 654, 

655, 659, 663TiP, 755, 783O, 793PD, 809P, 

810P, 816P, 818P, 824P, 837P, 840P, 846P, 876, 

877, 966O, 967O, 973PD, 978P, 986P, 1159P, 

1160P, 1165P, 1194P, 1224O, 1236PD, 1239P, 

1240P, 1242P, 1246P, 1264P, 1277P, 1278P, 

1279P, 1287P, 1297P, 1299P, 1302P, 1303P, 

1327, 1329, 1335, 1351, 1352, 1353, 1364TiP, 

1365TiP, 1370P, 1373P, 1615P, 1648P, 1653P, 

1657P 

Bicalutamide: 48IN, 929P 

Biosimilar epoetin zeta: 1563P 

Biosimilar filgrastim: 1555P, 1624 

Biosimilar G-CSF: 1557P 

BJG398: 7IN 

BKM 120: 7IN, 318O, 454P, 457P, 664TiP, 1675P 

Bleomycin: 862P, 888, 1046P, 1061TiP, 1071P, 

1152, 1539P, 1061TiP 

Blinotumumab: 68IN 

BMS-36558: 453P 

BMS-936558: 459P, 784O, 1109O, 1237PD 

Bortezomib: 66IN, 68IN, 754, 1064O, 

1088P,1064O, 1088, 1622 

BPM 31510: 482P 

Brentixumab: 68IN, 1063O, 1083P 

Brivanib: 966O 

Budesonide: 1116PD 

Buserelin: 928P 

BYL 719: 7IN, 350P 

Cabazitaxel: 47IN, 53IN, 497P, 897O, 931P, 932P, 

933P, 946, 948, 951, 953, 955, 956, 958, 960, 

962TiP 

Cabozantinib: 7IN, 445PD, 840P, 897O 

CAL 101: 68IN 

Capecitabine: 21IN, 121IN, 154P, 209P, 245O, 

317O, 330P, 355P, 356P, 358P, 391, 394, 397, 

398, 399, 401, 452P, 496P, 518O, 519O, 524PD, 

526PD, 527PD, 530PD, 532P, 538P, 550P, 560P, 

562P, 566P, 569P, 586P, 588P, 592P, 600P, 601P, 

605P, 608P, 609P, 622, 635, 640, 647, 653, 

663TiP, 667PD, 683P, 687P, 700P, 718P, 722P, 

731P, 736P, 754, 757, 759, 770, 781TiP, 782TiP, 

1160P, 1161P, 1169P, 1355, 1591P, 1594P, 

1595P, 1648P, 1703IN 

Carboplatin: 55IN, 80IN, 154P, 168O, 175PD, 

191P, 194P, 202P, 430P, 433, 437TiP, 505, 754, 

789O, 799P, 857P, 859P, 863P, 866P, 867P, 887, 

908P, 952, 967O, 972PD, 973PD, 975PD, 978P, 

985P, 986P, 991P, 995P, 997P, 1004P, 1009, 

1010, 1017O, 1035P, 1037P, 1040P, 1153, 

1062O, 1183P, 1200P, 1204P, 1206P, 1218, 1221, 

1224O, 1226O, 1236PD, 1239P, 1240P, 1242P, 

1245P, 1246P, 1250P, 1255P, 1256P, 1259P, 

1276P, 1285P, 1287P, 1297P, 1299P, 1301P, 

1303P, 1326, 1334, 1352, 1357, 1361, 1363TiP, 

1365TiP, 1444, 1526P, 1527P, 1529P, 1543TiP, 

1625 

Catumaxomab: 459P, 504, 680P, 1596P, 1683P 

Cediranib: 54IN, 448PD, 501, 609P, 840P, 877, 

840P 

Celecoxib: 1422O, 1594P 

Cetuximab: 28IN, 29IN, 43IN, 53IN, 58IN, 62IN, 

78IN, 80IN, 126IN, 143PD, 210P, 214P, 218P, 

237, 520O, 525PD, 526PD, 535P, 536P, 543P, 

557P, 561P, 563P, 568P, 572P, 574P, 580P, 582P, 

594P, 598P, 599P, 603P, 606P, 608P, 630, 631, 

634, 643, 649, 652, 654, 659, 696P, 755, 804P, 

1018O, 1020PD, 1021PD, 1022PD, 1023PD, 

1027P, 1036P, 1038P, 1044P, 1052, 1053, 1054, 

1144, 1199P, 1213, 1216, 1227O, 1271P, 1272P, 

1370P, 1379P, 1550PD, 1581P, 1644PD, 1651P, 

1659P 


Annals Of Oncology 23 (Supplement 9): ix601–ix603, 2012 


CH5424802: 7IN, 441O 

CI-1040: 1674P 

Cilastatin: 1619P 

Cilengitide: 24IN 

Cisplatin: 77IN, 80IN, 148P, 149P, 158P, 194P, 

224P, 359P, 375P, 390, 394, 397, 433, 496P, 

668PD, 671P, 672P, 682P, 686P, 687P, 688P, 

689P, 690P, 693P, 695P, 700P, 701P, 730P, 731P, 

745P, 746P, 749, 753, 757, 759, 760, 761, 

782TiP, 786O, 789O, 799P, 801P, 802P, 803P, 

807P, 858P, 860P, 862P, 864P, 883, 887, 888, 

890TiP, 972PD, 988P, 990P, 995P, 999P, 1000P, 

1004P, 1007, 1009, 1010, 1012, 1016O, 1018O, 

1020PD, 1022PD, 1023PD, 1028P, 1034P, 

1035P, 1036P, 1037P, 1038P, 1039P, 1040P, 

1041P, 1044P, 1045P, 1051, 1054, 1057, 1058, 

1138P, 1144, 1147, 1161P, 1169P, 1181PD, 

1183P, 1191P, 1194P, 1199P, 1201P, 1202P, 

1203P, 1204P, 1211, 1212, 1213, 1215, 1219, 

1223, 1224O, 1226O, 1229PD, 1234PD, 

1235PD, 1241P, 1242P, 1243P, 1245P, 1247P, 

1249P, 1250P, 1251P, 1252P, 1272P, 1274P, 

1275P, 1294P, 1303P, 1308P, 1327, 1329, 1335, 

1337, 1352, 1365TiP, 1507P, 1520PD, 1522PD, 

1524P, 1529P, 1531P, 1539P, 1571P, 1573P, 

1581P, 1598P, 1611P, 1619, 1620, 1625, 1632, 

1639, 1645PD, 1687 

Cladribine: 1076P 

Combrastatin A4: 1250P 

Crizotinib: 7IN, 78IN, 81IN, 119IN, 138IN, 438O, 

439O, 440O, 441O, 508, 1098, 1191PD, 1195P, 

1208P, 1230PD, 1231PD, 1267P, 1268P, 1267P, 

1268P, 1290P, 1291P, 1312, 1324, 1383P 

Custirsen: 53IN 

Cyclopamine: 1095, 1309P 

Cyclophosphamide: 228P, 245O, 246O, 253PD, 

267P, 268P, 269P, 291P, 292P, 313, 320PD, 

333P, 360P, 373P, 377, 382, 390, 405TiP, 

406TiP, 515P, 622, 799P, 827P, 935P, 936P, 

986P, 1062O, 1063O, 1073P, 1074P, 1079P, 

1080P, 1082P, 1083P, 1098, 1210, 1503P, 1503P, 

1525P, 1529P, 1552P, 1578P, 1623, 1671P 

Cytarabine: 429P, 1082P, 1084P, 1092P, 1102, 

1105 

Dacarbazine: 175PD, 426P, 1115PD, 1127P, 

1138P, 1147, 1511P 

Dacomitinib: 7IN, 1228O, 1290P 

Darbepoetin alfa: 858P, 1561P, 1562P, 1567P 

Dasatinib: 53IN, 508, 1481PD, 1686P 

Daunorubicin: 1092P 

Degarelix: 905P, 930P 

Dendritic cell vaccines: 490P, 502, 510TiP, 719P, 

723P, 1114PD, 1138P, 1363TiP, 1672P 

Denosumab: 49IN, 95IN, 316TiP, 937P, 1108TiP, 

1400PD, 1480PD, 1580P 

DHMEQ: 148P, 1531P 

Dicarbamin: 1623 

Docetaxel: 47IN, 48IN, 53IN, 105IN, 106IN, 194P, 

200P, 224P, 226P, 245O, 246O, 271P, 291P, 

292P, 309, 313, 320PD, 326PD, 333P, 344P, 

345P, 355P, 356P, 359P, 360P, 375P, 382, 390, 

391, 395, 406TiP, 407TiP, 408TiP, 409TiP, 458P, 

478P, 492P, 493P, 494P, 497P, 505, 515P, 519P, 

672P, 673P, 682P, 686P, 690P, 693P, 701P, 702P, 

753, 755, 759, 760, 761, 762, 804P, 893O, 896O, 

897O, 898PD, 899PD, 901PD, 903P, 904P, 908P, 

909P, 910P, 918P, 921P, 924P, 925P, 926P, 927P, 

931P, 932P, 933P, 934P, 935P, 936P, 943P, 946, 

948, 950, 951, 952, 953, 955, 956, 958, 960, 

962TiP, 1012, 1020PD, 1028P, 1035P, 1036P, 

1037P, 1038P, 1039P, 1040P, 1041P, 1045P, 

1051, 1199P, 1202P, 1212, 1233PD, 1234PD, 

drug index

drug index 

drug index 

1248P, 1250P, 1286P, 1297P, 1301P, 1327, 1329, 

1332, 1335, 1338, 1341, 1342, 1345, 1353, 1356, 

1511P, 1552P, 1578P, 1594P, 1611P, 1623, 

1645PD, 1647PD, 1657P, 1664P, 1680P 

Dovitinib (TKI258): 7IN, 822P, 875, 891TiP, 

1483PD 

Doxorubicin: 68IN, 200P, 268P, 269P, 291P, 313, 

320PD, 333P, 357P, 363P, 373P, 377, 382, 462P, 

487P, 495P, 502, 772, 799P, 882, 984P, 986P, 

1062O, 1063O, 1071P, 1073P, 1074P, 1077P, 

1079P, 1080P, 1084P, 1098, 1482PD, 1500P, 

1503P, 1504P, 1505P, 1507P, 1511P, 1517TiP, 

1525P, 1594P, 1623, 1682P 

DTS-108: 485P 

E-3810: 319O 

Efatutazone: 590P 

EMD 1214063: 444PD 

EMD 525797 (DI17E6): 965TiP 

Enzastaurin: 342P 

EOS 3810: 7IN 

Epirubicin: 44IN, 228P, 245O, 246O, 267P, 268P, 

320PD, 333P, 359P, 360P, 377, 405TiP, 406TiP, 

667PD, 687P, 754, 762, 782TiP, 789O, 1077P, 

1169P, 1500P, 1529P, 1552P, 1529P 

Epoetin alfa: 858P, 1561P, 1562P, 1565P, 1567P, 

1630 

Epoetin zeta: 1566P, 1568P, 1569P 

Eribulin mesylate: 21IN, 330P, 337P, 358P, 1205P 

Erlotinib: 7IN, 28IN, 29IN, 78IN, 105IN, 106IN, 

138IN, 189P, 211P, 234, 412O, 492P, 506, 

509TiP, 722P, 768, 1194P, 1197P, 1205P, 1219, 

1222, 125O, 1226O, 1227O, 1240P, 1254P, 

1257P, 1260P, 1261P, 1263P, 1265P, 1271P, 

1273P, 1276P, 1277P, 1280P, 1282P, 1283P, 

1290P, 1291P, 1293P, 1298P, 1299P, 1304P, 

1307P, 1309P, 1311P, 1322, 1323, 1328, 1330, 

1333, 1338, 1339, 1340, 1342, 1343, 1345, 1346, 

1347, 1348, 1362TiP, 1365TiP, 1366TiP, 

1367TiP, 1370P, 1401P, 1550PD, 1655P, 1662P, 

1663P 

Estramustine: 952 

Etoposide: 80IN, 789O, 858P, 860P, 862P, 863P, 

866P, 888, 1062O, 1083P, 1199P, 1213, 1223, 

1304P, 1505P, 1520PD, 1524P, 1525P, 1526P, 

1527P, 1529P, 1543TiP 

Everolimus: 53IN, 76IN, 83IN, 173O, 324PD, 

334P, 351P, 352P, 419PD, 447PD, 690P, 781TiP, 

783O, 798PD, 810P, 812P, 814P, 816P, 818P, 

821P, 822P, 823P, 824P, 837P, 840P, 841P, 842P, 

843P, 845P, 852P, 855P, 869, 873, 875, 876, 879, 

881, 890TiP, 1017O, 1154O, 1156O, 1162P, 

1163P, 1165P, 1401P, 1703IN 

Exemestane: 277P, 280P, 310, 311, 334P, 351P 

Fentanyl: 1612P 

Ficlatuzumab: 443PD, 1198P 

Figitumumab: 58IN, 90IN 

Filgrastim: 863P, 1547P, 1552P, 1555P 

Fingolimod: 1651P 

Fluoropyrimidine: 126IN, 218P, 237, 452P, 620, 

653 

Flutamide: 929P 

Folinic acid: 567P, 597P, 662TiP, 643, 710P, 714P, 

726P 

Foretinib: 1027P 

Fotemustine: 426P, 1135P, 1140P 

Fulvestrant: 323PD, 337P, 339P, 340P, 341P, 342P, 

350P, 384 

Gabapentin: 1581P 

Ganetespib (STA-9090): 347P, 1248P, 1332, 

1664P, 1647PD 

Ganitumab: 776TiP 

G-CSF: 693P, 714P, 716P, 721P, 790O, 931P, 951, 

953, 1037P, 1039P, 1051, 1082P, 1356, 1357, 

1547PD, 1548PD, 1552P, 1553P, 1554P, 1555P, 

1556P, 1557P, 1560P, 1625 

GDC-0068: 458P 

GDC-0941: 7IN, 154P, 1675P 

GDC-0973: 154P 

GDC-0980: 7IN, 154P, 452P 

Gefitinib: 7IN, 53IN, 78IN, 106IN, 138IN, 179P, 

189P, 211P, 412O, 1198P, 1227O, 1253P, 1254P, 

1255P, 1256P, 1257P, 1258P, 1259P, 1263P, 

1265P, 1269P, 1270P, 1283P, 1289P, 1290P, 

1309P, 1319, 1323, 1325, 1328, 1330, 1331, 

1339, 1343, 1344, 1348, 1362TiP, 1401P, 

1550PD 

Gemcitabine: 42IN, 77IN, 144PD, 150P, 268P, 

337P, 395,397, 447PD, 478P, 484P, 497P, 666O, 

709P, 710P, 711P, 713P, 715P, 717P, 718P, 719P, 

722P, 723P, 728P, 730P, 731P, 746P, 768, 773, 

775, 776TiP, 786O, 790O, 799P, 800P, 802P, 

804P, 807P, 883, 885, 887, 967O, 972PD, 985P, 

986P, 1043P, 1183P, 1194P, 1219, 1224O, 

1226O, 1236PD, 1239P, 1241P, 1251P, 1276P, 

1286P, 1297P, 1301P, 1304P, 1329, 1356, 1511P, 

1645PD, 1654P, 1676P 

GM-CSF: 436TiP, 510TiP, 1147 

GS-1101: 65IN 

GSK1120212: 7IN 

GSK1363089: 1027P 

GSK2126458 (GSK458): 442O 

GTX-758: 923P 

Ibandronate: 947, 1633 

Icotonib: 1269P, 

Idarubicin: 1068PD 

IFN alpha: 53IN, 153P, 783O, 793PD, 809P, 810P, 

815P, 816P, 825P, 839P, 876, 877, 1147 

IFN beta: 747P 

Ifosfamide: 789O, 858P, 860P, 863P, 866P, 1004P, 

1083P, 1498P, 1500P, 1503P, 1505P, 1511P 

IL-2: 808P, 1147 

IMA50: 436TiP 

Imatinib: 6IN, 29IN, 92IN, 94IN, 704P, 705P, 

706P, 707P, 708P, 1090P, 1478O, 1483PD, 

1484PD, 1489P, 1490P, 1492P, 1494P, 1102, 

1105, 1123P, 1516, 1550PD, 1679P 

IMO-2055: 1044P 

Iniparib: 18IN 

INO-206: 1482PD 

Inotuzumab ozogamicin: 68IN 

Interferon: 76IN 

IPI-504: 66IN 

Ipilimumab: 53IN, 71IN, 175PD, 1116PD, 

1117PD, 1124P, 1126P, 1127P, 1128P, 1129P, 

1130P, 1131P, 1132P, 1133P, 1134P, 1143P, 

1148, 1149, 1150, 1151, 1152 

Irinotecan: 42IN, 126IN, 208P, 214IN, 218P, 

518O, 525PD, 526PD, 529PD, 536P, 543P, 559P, 

561P, 565P, 568P, 570P, 571P, 573P, 578P, 579P, 

581P, 582P, 587P, 590P, 592P, 593P, 597P, 598P, 

599P, 600P, 602P, 603P, 606P, 608P, 618, 627, 

628, 630, 633, 634, 635, 640, 646, 649, 650, 656, 

659, 662TiP, 664TiP, 665TiP, 688P, 689P, 696P, 

697P, 710P, 714P, 716P, 721P, 726P, 755, 762, 

1204P, 1526P, 1591P, 1595P, 1644PD 

Irosustat (BN83495): 1001P 

K252a: 188P 

Ketoconazole: 927P, 953 

KNTR-102: 21IN 

Lapatinib: 53IN, 103IN, 104IN, 115IN, 121IN, 

247O, 255PD, 267P, 318O, 322PD, 337P, 

407TiP, 409TiP, 496P, 1232PD, 1550PD, 1659P 

L-BLP25: 622, 1210 

Annals Of Oncology 

LDK-378: 7IN, 440O 

Lenalidomide: 68IN, 1064O 

Lenograstim: 1547PD 

Lenvatinib (E7080) : 417PD, 737P, 814P 

Letrozole: 280P, 310, 323PD, 407TiP 

Leucovorin: 39IN, 42IN, 208P, 452P, 458P, 460P, 

518O, 519O, 520O, 523PD, 524PD, 527PD, 

529PD, 542P, 543P, 550P, 552P, 557P, 558P, 

560P, 561P, 564P, 570P, 573P, 576P, 577P, 580P, 

581P, 586P, 587P, 590P, 591P, 592P, 597P, 600P, 

601P, 602P, 603P, 607P, 618, 620, 623, 624, 625, 

627, 628, 633, 634, 635, 640, 643, 646, 650, 653, 

655, 657, 659, 661, 662TiP, 683P, 686P, 696P, 

701P, 710P, 716P, 721P, 731P, 760, 762, 

Linifanib (ABT-869) : 203P, 505, 507 

Lipegfilgrastim: 1548PD 

Lorvotuzumab mertansine: 1543TiP 

LU-DOTATATE: 75IN, 1703IN 

Lurbinectedin (PM01183): 484P, 968O 

Lutelium-177 octreotate: 1162P 

LY24002: 185P 

Masitinib: 174O 

MDV3100: 47IN, 48IN, 53IN, 896O, 899PD, 924P, 

925P 

Megestrol acetate: 1001P 

MEK162: 7IN 

Melphalan: 743P, 1085P, 1141P 

Metformin: 1450P 

Methotrexate: 130IN, 246O, 253PD, 269P, 333P, 

390, 404, 515P, 799P, 802P, 807P, 1507P 

MetMAb: 7IN, 1364TiP, 1365TiP 

MG132: 144 PD 

MGCD265: 471P, 492P, 493P 

MGN1601: 813P 

MGN1703: 518O 

Mifamurtide: 1508P, 1518TiP 

Mitomycin C: 477P, 532P, 756P, 1204P 

Mitoxantrone: 497P, 931P, 932P, 933P, 936P, 952 

MK-2206: 474P, 1676P 

MLN8237 (alisertib): 461P, 489P, 921P 

MM-111: 496P 

MM-121: 974PD 

Nab-paclitaxel: 409TiP, 780TiP, 804P 

Naloxone: 1582P 

NC-6004: 746P 

Netupitant: 1575P, 1618 

NGR-hTNF: 487P, 488P, 502, 1251P 

Nilotinib: 740P, 744P, 1483PD 

Nintedanib: 54IN, 446PD 

NKTR-102: 21IN 

NVP-AUY22: 61IN 

NVP-TAE684: 1497P 

Octreotide: 419PD, 1172 

OGX-427: 900PD 

OK432: 719P 

Olaparib (AZD2281): 18IN, 55IN 

Omrabulin: 1250P 

Ondansetron: 1573P 

ONO-7643: 465P 

Oxaliplatin: 39IN, 42IN, 208P, 126IN, 207P, 218P, 

452P, 458P, 460P, 495P, 518O, 519O, 520O, 

523PD, 524PD, 526PD, 527PD, 544P, 547P, 

556P, 557P, 558P, 559P, 560P, 562P, 564P, 565P, 

566P, 567P, 568P, 570P, 571P, 573P, 577P, 578P, 

579P, 580P, 582P, 586P, 587P, 591P, 592P, 593P, 

597P, 598P, 599P, 600P, 601P, 602P, 603P, 605P, 

607P, 620, 624, 627, 628, 630, 633, 635, 640, 

643, 646, 647, 649, 650, 653, 655, 656, 657, 659, 

661, 663TiP, 665TiP, 667PD, 686P, 713P, 714P, 

716P, 718P, 721P, 726P, 728P, 730P, 731P, 736P, 

755, 768, 779TiP, 780TiP, 782TiP, 790O, 989P, 

1590P, 1591P, 1595P, 1638 

ix602 | drug index Volume 23 | Supplement 9 | September 2012

Annals Of Oncology drug index 

Oxycodone: 1582P 

Paclitaxel: 55IN, 80IN, 103IN, 115IN, 154P, 

175PD, 191P, 228P, 245O, 246O, 247O, 255PD, 

267P, 268P, 269P, 313, 317O, 326PD, 335P, 

337P, 345P, 355P, 373P, 382, 405TiP, 454P, 

464P, 496P, 505, 681P, 692P, 697P, 698P, 745P, 

762, 779TiP, 780TiP, 789O, 790O, 801P, 803P, 

804P, 863P, 883, 971PD, 973PD, 974PD, 975PD, 

978P, 985P, 986P, 991P, 995P, 997P, 1000P, 

1004P, 1010, 1012, 1013, 1017O, 1034P, 1043P, 

1153, 1183P, 1204P, 1221, 1224O, 1236PD, 

1239P, 1240P, 1242P, 1246P, 1250P, 1255P, 

1256P, 1259P, 1276P, 1285P, 1287P, 1297P, 

1299P, 1301P, 1303P, 1304P, 1363TiP, 1364TiP, 

1524P, 1591P, 1667P 

Palonosetron: 721P, 1571P, 1572P, 1574P, 1576P, 

1577P, 1579P 

Pamidronic acid: 1585P, 1633 

Panitumumab: 29IN, 126IN, 525PD, 535P, 536P, 

558P, 563P, 564P, 570P, 572P, 587P, 594P, 598P, 

603P, 605P, 631, 634, 652, 665TiP, 667PD, 

1016O, 1370P, 1597P 

Panobinostat: 68IN 

Pasireotide: 419PD 

Pazopanib: 29IN, 52IN, 53IN, 54IN, 91IN, 92IN, 

222P, 508, 791PD, 792PD, 810P, 816P, 833P, 

837P, 840P, 875, 880, 1157O, 1165P, 1493P 

PDM08: 480P 

Pegfilgrastim: 1004P, 1547PD, 1548PD, 1553P, 

1560P 

Pegylated liposomal doxorubicin: 984P, 986P, 

1594P 

Pemetrexed: 106IN, 433, 505, 747P, 1022PD, 

1206P, 1214, 1215, 1218, 1224O, 1225O, 

1235PD, 1242P, 1245P, 1247P, 1251P, 1252P, 

1258P, 1267P, 1274P, 1275P, 1281P, 1286P, 

1297P, 1302P, 1303P, 1304P, 1326, 1327, 1338, 

1342, 1345, 1347, 1354, 1355, 1356, 1361, 

1362TiP, 1364TiP, 1370P, 1522PD, 1535P, 

1654P 

Pertuzumab: 202P, 322PD, 344P, 407TiP, 408TiP, 

409TiP 

PF-05212384: 7IN 

PLX4032: 70IN 

Pralatrexate: 68IN 

Prostvac-VF Tricom: 46IN 

PRRgama: 1703IN 

PV-10: 1137P 

R1507: 1497P 

Racotumomab: 1238PD 

Radium-223 chloride: 49IN, 898PD, 936P 

Raltitrexed: 519O, 567P, 747P 

Ramucirumab: 1115PD, 1245P, 1287P, 

Ranimustine: 1062O 

Ranolazine: 1682P 

Rasburicase: 1103 

recPRAME: 1110O, 1182P 

Regorafenib: 92IN, 173O, 1478O, 1483PD 

Ridaforolimus (MK-8669): 92IN 

Rilotumumab: 687P 

Rituximab: 29IN, 64IN, 65IN, 68IN, 96IN, 97IN, 

157P, 1073P, 1076P, 1079P, 1080P, 1373P, 

1384P 

RO4929097: 448PD, 450PD 

RO4987655: 7IN, 451P 

RO5126766: 475P 

Romidepsin: 68IN 

Rosiglitazone: 590P 

S-1: 566P, 575P, 576P, 592P, 611P, 646, 668PD, 

671PD, 681P, 682P, 688P, 689P, 693P, 698P, 

702P, 719P, 728P, 757, 758, 775, 779TiP, 989P, 

1181PD, 1234PD, 1334, 1704P 

Sandostatin-LAR: 1172 

SAR-020106: 61IN, 1677P 

Saracatinib (AZD0530): 501, 1659P 

SB203580: 348P 

SB939: 922P 

Selumetinib: 7IN, 609P, 1233PD 

Silumarin: 473P 

Sipuleucel-T: 46IN, 53IN, 939P, 940P, 941P, 942P, 

943P, 949, 950 

SLO101: 1674P 

SN38: 485P, 664TiP 

Somatostatin: 75IN, 419PD, 873, 1167P, 1172 

Sorafenib: 7IN, 29IN, 43IN, 53IN, 124IN, 173O, 

229P, 447PD, 466P, 569P, 654, 670PD, 734P, 

736P, 737P, 744P, 770, 777TiP, 778TiP, 781TiP, 

793PD, 795PD, 810P, 812P, 816P, 817P, 818P, 

823P, 824P, 837P, 840P, 843P, 844P, 846P, 848P, 

856P, 869, 871, 872, 874, 875, 877, 879, 881, 

1165P, 1241P, 1349, 1362TiP, 1370P, 1390P, 

1391P, 1401P, 1491P, 1506P, 1594P, 1615P, 

1674P 

Streptozocin: 209P, 1159P, 1161P 

Sunitinib: 29IN, 52IN, 53IN, 58IN, 76IN, 92IN, 

95IN, 174O, 229P, 508, 705P, 724P, 785O, 

792PD, 793PD, 794PD, 797PD, 81OP, 812P, 

815P, 816P, 818P, 820P, 821P, 823P, 824P, 826P, 

827P, 829P, 830P, 832P, 834P, 835P, 837P, 840P, 

843P, 846P, 847P, 848P,849P, 850P, 851P, 853P, 

854P, 856P, 869, 870, 872, 875, 877, 879, 881, 

889TiP, 892TIP, 901PD, 1155O, 1163P, 1165P, 

1370P, 1401P, 1478O, 1483PD, 1484PD, 1490P, 

1491P, 1495P, 1496P, 1550PD, 1615P, 1678P, 

1703IN 

TAK-441: 449PD 

TAK-700: 918P 

TAK-733: 456P, 

Talactoferrin: 1363TiP, 

Tamoxifen: 14IN, 17IN, 196P, 249PD, 279P, 280P, 

295P, 311, 339P, 360P, 384, 1147, 1502P 

TAS-102: 126IN 

Tasquinimod: 919P 

T-DM1: 318O 

Temozolomide: 410O, 416PD, 424P, 426P, 436TiP, 

437TiP, 1126P, 1135P, 1368TiP, 1529P, 1676P, 

1686P, 1703IN 

Temsirolimus: 65IN, 68IN, 420PD, 450PD, 462P, 

717P, 793PD, 810P, 816P, 818P, 824P, 828P, 

839P, 845P, 846P, 852P, 875, 879, 1023PD, 

1107TiP 

Tesetaxel: 481P, 486P 

TH-302: 435TiP, 666O 

Thalidomide: 1088P 

Thiotepa: 789O 

Tigatuzumab (CS-1008): 662TiP 

Tipifarnib: 43IN 

Tivatinib: 738P, 739P, 1293P 

Tivozanib: 53IN, 795PD, 796PD, 892TiP 

TNFalpha: 1504P 

Tocilizumab: 153P 

Topotecan: 968O, 986P, 1529P 

Trabectedin: 984P, 986P, 1511P, 1517TiP 

Trastuzumab: 6IN, 7IN, 29IN, 44IN, 53IN, 57IN, 

103IN, 104IN, 115IN, 154P, 202P, 226P, 228P, 

243, 246O, 247O, 245PD, 255PD, 266P, 267P, 

268P, 270P, 271P, 272P, 273P, 274P, 275P, 276P, 

308, 309, 315TiP, 318O, 322PD, 325PD, 337P, 

343P, 344P, 346P, 373P, 380, 389, 391, 393, 396, 

404, 406TiP, 407TiP, 408TiP, 40TiP, 454P, 470P, 

476P, 496P, 677P, 699P, 761, 762, 786O, 

1232PD, 1373P, 1397P, 1398P, 1646PD, 1657P 

TSU-68: 732P 

U3-1287: 467P 

Uracil-tegafur (UFT): 542P, 552P, 575P, 576P, 

582P, 611P, 623, 625, 628, 681P 

Vandetanib: 7IN, 508, 804P 

Vedotin: 68IN, 1083P 

Veliparib: 428P 

Vemurafenib: 6IN, 28IN, 29IN, 227P, 242, 1124P, 

1125P, 1146 

Vinblastine: 799P, 802P, 807P, 860P, 1138P 

Vincristine: 1062O, 1063O, 1071P, 1073P, 1074P, 

1079P, 1080P, 1098, 1525P, 1529P 

Vindesine: 1062O, 1204P, 1234PD 

Vinflunine: 21IN, 787O, 804P 

Vinorelbine: 80IN, 106IN, 168O, 391, 392, 393, 

394, 399, 408TiP, 1058, 1183P, 1199P, 1201P, 

1202P, 1243P, 1247P, 1249P, 1272P, 1276P, 

1286P, 1297P, 1301P, 1304P, 1329, 1337, 1356, 

1357, 1502P, 1542TiP, 1645PD 

Vismodegib: 1111PD, 1112PD 

Volasertib: 804P 

Vorinostat: 68IN, 700P, 1273P, 

XL-147: 7IN 

XL-765: 7IN 

XL880: 1027P 

Y-27632: 947 

Y90 Iritumomab: 1073P, 

Y-DOTATOC: 75IN, 1703IN 

YS110: 498P 

YTTRIUM-90: 735P 

Zalypsis: 806P 

Zoledronic acid: 49IN, 937P, 945, 1108TiP, 1321, 

1580P, 1583P, 1584P, 1585P, 1633, 1641 

Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds479 | ix603 

drug index

translational 

research 

index 

translational research index 

3’-UTR: 1032P 

4EB-P1: 

5HT3: 129IN 

9F1: 562P 

A488G: 374P 

ABCA13: 1701 

ABCB1: 724P, 1667P, 1678P 

ABCG2: 215P, 64O, 724P 

ABL1: 1311P 

ACC: 618 

ACTN4: 1174P, 1186P, 1701 

Adiponectin: 190P 

AEG-1: 807P 

AFP: T33P, 790O, 866P, 994P, 1539P, 1693P 

AFR: 1211 

AKR1C: 928P, 1701 

AKT: 2IN, 7IN,52IN, 65IN, 76IN, 90IN, 102IN, 

107IN, 108IN, 119IN, 154P, 156P, 173O, 179P, 

180P, 185P, 214P, 318O, 343P, 347P, 350P, 

41PD, 442O, 450PD, 458P, 474P, 483P, 781TiP, 

807P, 812P, 80TiP, 917P, 1031P, 1196P, 1491P, 

1652P, 1659P, 1668P, 1675P, 1676P, 1685P, 

1690P 

ALCAM: 215P, 720P 

ALDH1: 149P, 216P, 375P 

ALDH2: 1701 

ALK: 6IN, 7IN, 62IN, 78IN, 81IN, 82IN, 83IN, 

108IN, 119IN, 138IN, 167O, 193P, 195P, 438O, 

439O, 440O, 441O, 1063O, 1176P, 1187P, 

1191PD, 1193P, 1195P, 1208, 1230PD, 1231PD, 

1248P, 1266P, 1267P, 1268P, 1274P, 1284P, 

1290P, 1312, 1324, 1497P, 1647PD, 1664P 

ALPHA-2A: 299 

ALPHA-6: 214P 

Amphiregulin: 526PD, 536P 

AMPK: 618 

Ang-1: 975PD 

Ang-2: 184P, 600P, 794PD, 975PD, 1648P 

Annexin A4: 

ANP: 1682P 

ANXA: 1701 

APC: 7IN, 92IN, 675P 

APOA1: 232 

Apoptosis: 66IN, 81IN, 109IN, 148P, 149P, 156P, 

158P, 165, 173O, 177PD, 179P, 236, 482P, 539P, 

575P, 769, 806P, 988P, 1122P, 1677P, 1682P 

AR: 20IN, 48IN, 257P, 325PD, 899PD, 900PD, 

922P, 924P, 925P, 1680P, 1689P 

ASL: 1660P 

ASS1: 1660P 

ATM: 7IN, 156P, 186P 

ATP: 159P, 166, 444PD, 458P, 495P 

ATRX: 12IN 

AURKA: 93IN 

Aurora-A kinase: 376, 461P, 489P, 921P 

AXL: 1027P 

B-actin: 1170P 

Bad: 156P, 405TiP 

BALP: 805P, 945, 1122P 

BAP1: 1300P 

Bax: 628, 1122P 

Bcl-2: 65IN, 156P, 249PD, 482P, 1075P 

Bcl-xl: 769, 1075P 

BCR-ABL: 1093P, 1481PD, 1102, 1105 

BDNF: 188P, 1464P 

Beclin-1: 1679P 

BETA: 179P, 214P, 299 

Beta-catenin: 675P, 703P, 1700 

beta-CTX: 805P, 945 

bFGF: 152P, 842P, 1236PD, 1657P 

BHCG: 790O, 865P, 994P 

BHR: 66IN 

BIM: 154P, 185P 

BIP/GRP78: 66IN 

Bmi1: 144PD 

BMP4: 720P 

BNIP3: 1033P 

BNP: 1682P 

BRAF: 6IN, 7IN, 19IN, 28IN, 29IN, 50IN, 70IN, 

78IN, 83IN, 102IN, 108IN, 119IN, 180P, 208P, 

212P, 227P, 237, 456P, 475P, 521O, 525PD, 

526PD, 532P, 535P, 536P, 537P, 548P, 557P, 

574P, 580P, 593P, 608P, 629, 631, 641, 656, 

696P, 1017O, 1118PD, 1123P, 1124P, 1125P, 

1135P, 1145, 1146, 1147, 1173, 1187P, 1349, 

1491P, 1647PD, 1649P, 1652P, 1664P 

BRCA: 55IN, 220P 

BRCA1: 7IN, 17IN, 20IN,33IN, 35IN, 36IN, 187P, 

294P, 511PD, 512PD, 513PD, 514P, 515P, 686P, 

720P, 807P, 969PD, 972PD, 1170P, 1300P, 

1449P, 1542TiP, 1655P, 1661P, 1662P 

BRCA2: 33IN, 35IN, 36IN, 294P, 371P, 511PD, 

512PD, 513PD, 514P, 515P, 720P, 969PD, 

972PD, 1449P, 1662P 

BRM: 186P 

BTK: 65IN, 68IN 

BXPC3: 1697P 

C26: 477P 

C3: 232 

C4: 232 

CA 72-4: 679P 

CA: 786O, 1167P 

CA125: 147P, 972PD, 978P, 983P, 987P, 1012, 

1013, 1203P 

CA15-3: 302, 339P, 376, 388 

CA19-9: 645, 666O, 679P, 713P, 721P 

CA9: 1033P 

CACO-2: 229P 

CADM1: 221P 

CAF: 833P 

CA-IX: 185P, 435TiP, 562P, 794PD, 835P, 1695P 

CALR: 1701 

Calreticulin: 495P 

Calretinin: 1533P 

Cancer stem cells: 375P, 385, 418PD, 463P 

Caspase-3: 443PD 

CBFB: 102IN 

CCL2: 838P 

CCNA2: 215P 

CCNB1: 24PD 

CCND: 180P, 1031P 

CCNE: 180P 

CD10: 287P, 1106 

CD105: 169O 

CD117: 1067PD, 1106 

CD11b: 480P, 1314 

CD127: 1138P, 1314 

CD13: 1314 

CD133: 149P, 159P, 418PD, 431, 604P 

CD135: 1067PD 

CD138: 66IN 

CD14: 1314 

CD144: 227P 

CD15: 480P, 676P, 1314 

CD154: 813P 

CD163: 1681P 

CD16b: 480P 

CD19: 1106 

CD2: 1106 

CD20: 64IN, 157P, 216P, 1079P 

CD22: 1106 

CD24: 720P 

CD25: 1138P, 1314 

CD26: 498P 


Annals Of Oncology 23 (Supplement 9): ix604–ix608, 2012 


CD3: 495P, 939P, 1106, 1314, 1644PD 

CD30: 861P, 1063O, 1083P 

CD31: 443PD, 501 

CD33: 480P, 1106, 1314 

CD34: 751, 1083P, 1085P, 1489P, 1106, 1624 

CD39: 1314 

CD4: 436TiP, 480P, 495P, 622, 915P, 939P, 1106, 

1110O, 1117PD, 1138P, 1314, 

CD40: 1645P 

CD44: 720P, 1685P 

CD44+/CD24-: 149P, 164, 215P, 300, 375P, 1696P 

CD45: 227P, 480P, 1067PD, 1175P, 1512, 1650P 

CD45RO: 622, 1314 

CD46: 1677P 

CD49f: 1685P 

CD5: 1106 

CD54: 942P 

CD56: 480P, 1543TiP, 1644PD 

CD68: 1681P 

CD7: 1106 

CD74: 195P 

CD8: 436TiP, 495P, 503, 915P, 939P, 1110O, 

1114PD, 1117PD, 1314 

CD80: 510TiP, 813P 

CD83: 510TiP, 1672P 

CD86: 510TiP, 1673P 

CDH1: 225P, 511PD 

CDH13: 221P, 548P 

CDK4: 70IN, 92IN, 93IN 

CDKN2A: 7IN, 12IN, 180P, 720P, 1118PD 

CDS: 1032P 

CDX2: 675P 

CEA: 339P, 388, 505, 518O, 579P, 583P, 622, 627, 

637, 644, 645, 647, 653, 659, 679P, 911P, 1203P, 

1313 

CEBPA: 93IN 

CFDNA: 219P 

CHFR: 221P 

CHK1: 20IN, 61IN, 1677P 

CHR: 615 

Chromogranin A: 911P, 912P 

Circulating endothelial cells: 209P, 567P, 1240P 

Circulating endothelial progenitors: 1240P 

Circulating tumor cells (CTCs): 171O, 217P, 

218P, 223P, 227P, 230P, 255PD, 304, 582P, 767, 

897O, 900PD, 910P, 911P, 922P, 961, 963TiP, 

965TiP, 1029P, 1175P, 1240P, 1313, 1512, 1650P 

CIT: 229P 

CKB: 1701 

Class III beta tubulin: 187P, 291P 

Clec14: 178P 

CMCS: 21P, 227P 

c-MET: 7IN, 51IN, 70IN, 78IN, 83IN, 102IN, 

119IN, 143PD, 179P, 205P, 443PD, 444PD, 

445PD, 471P, 492P, 493P, 669PD, 687P, 720P, 

738P, 739P, 897O, 1027P, 1191PD, 1198P, 

1290P, 1291P, 1219P, 1293P, 1309P, 1322, 

1365TiP, 1532P 

COL1A1: 215P 

COX-2: 538P, 720P, 1026P, 1502P, 1652P 

Cparp: 154P 

C-RAF: 1349 

CSF1R: 102IN 

CTC: 223P 

CTDNEP1: 25IN 

CTGF: 1682P 

CTLA4: 22IN, 46IN, 53IN, 71IN, 175PD, 915P, 

1149 

CTNNB1: 7IN, 12IN, 25IN 

CXCL1: 228P 

CXCL10: 865P 

CXCL12: 1688PD

Annals Of Oncology translational research index 

CXCL14: 925P 

CXCL3: 228P 

CXCL9: 865P 

CXCR4: 1033P 

CXCR7: 1688PD 

Cyclin D1: 165, 483P, 1026P, 1027P, 1031P, 

1118PD, 1700 

Cyclin dependent kinases: 543P, 769 

Cyclin E1: 769 

Cycline H: 527PD 

CYFRA 21-1: 1310P 

CYFRA: 505, 1203P 

Cyp P450 2D6: 1034P 

CYP1: 17IN 

CYP11A1: 928P 

CYP17: 325PD, 925P, 927P, 946 

CYP17A1: 48IN 

CYP1A1: 374P, 724P 

CYP1A2: 850P 

CYP2C19: 1293P 

CYP2C9: 850P, 1667P 

CYP2D6: 17IN, 129IN, 189P, 196P, 295P 

CYP3A: 1678P 

CYP3A4: 291P, 1293P, 1578P, 1667P 

CYP3A5: 724P, 1667P 

Cytochrome P450: 506, 873, 1618P 

D2: 129IN 

DAPK1: 221P 

DAXX: 12IN 

DDR: 61IN, 81IN, 102IN, 119IN 

DDX3X: 25IN, 159P 

DEPDC1: 1671P 

DHEA: 277P 

DHFR: 1211 

DHH: 720P 

DLC1: 221P, 1701 

DLD30: 245O 

DLL4: 642 

DNA: 2IN, 10IN, 11IN, 20IN, 42IN, 5OIN, 61IN, 

86IN, 96IN, 116IN, 149P, 150P, 156P, 161P, 

168O, 171O, 185P, 22OP, 221P, 225P, 240, 

245O, 293P, 376, 397, 428P, 435TiP, 484P, 516P, 

518O, 527PD, 537P, 543P, 544P, 548P, 549P, 

613P, 656, 666O, 686P, 703P, 699P, 806P, 812P, 

813P, 85OP, 920P, 964TiP, 968O, 971PD, 988P, 

1025P, 1028P, 1032P, 1052, 1118PD, 1119PD, 

1121P, 1122P, 1123P, 1135P, 1139P, 1145, 1147, 

1192PD, 1242P, 1244P, 1266P, 1273P, 1315, 

1316, 1339, 1393P, 1649P, 1651P, 1662P, 1664P, 

1677P, 1679P, 1686P 

DPD: 550P, 1211 

DPYSL: 1701 

DR5: 662TiP 

D-SER: 483P 

DTX2: 215P 

DWS: 1032P 

Dysadherin: 838P 

E1: 277P 

E2: 277P 

E6: 62IN 

E7: 62IN 

EBER: 1026P 

EC: 861P 

E-cadherin: 145P, 483P, 511PD, 548P, 675P, 838P, 

1026P, 1693P, 1695P, 1700 

ECSCR: 178P 

EGF: 536P, 544P, 742P, 1464P, 1652P, 1668P 

EGFR: 6IN, 7IN, 19IN, 24IN, 28IN, 29IN, 58IN, 


85IN, 90IN, 105IN, 106IN, 119IN, 138IN, 

143PD, 158P, 170O, 179P, 180P, 182P, 183P, 

190P, 194P, 211P, 213P, 218P, 232, 234, 237, 

257P, 343P, 347P, 353P, 412O, 438O, 439O, 

467P, 509TiP, 525PD, 526PD, 533P, 535P, 536P, 

537P, 544P, 549P, 558P, 563P, 570P, 578P, 597P, 

605P, 606P, 630, 631, 641, 664TIP, 665TIP, 

667PD, 720P, 868, 970PD, 1016O, 1017O, 

1021PD, 1026P, 1027P, 1029P, 1031P, 1036P, 

1145, 1176P, 1187P, 1190P, 1193P, 1197P, 

1198P, 1209, 1211, 1218, 1226O, 1227O, 1228O, 

1229PD, 1232PD, 1251P, 1252P, 1254P, 1255P, 

1257P, 1258P, 1259P, 1260P, 1261P, 

1262P,1263P, 1264P, 1265P, 1266P, 1269P, 

1270P, 1271P, 1272P, 1273P, 1274P, 1277P, 

1280P, 1282P, 1283P, 1284P, 1286P, 1288P, 

1289P, 1291P, 1292P, 1293P, 1295P, 1300P, 

1302P, 1309P, 1310P, 1311P, 1313, 1315, 1316, 

1318, 1323, 1325, 1328, 1330, 1331, 1333,1336, 

1338, 1339, 1340, 1342, 1343, 1344, 1345, 1346, 

1347, 1348, 1362TiP, 1366TiP, 1367TiP, 1396P, 

1530P, 1644PD, 1649P, 1651P, 1652P, 1655P, 

1659P, 1662P, 1666P, 1668P, 1690P, 1692P, 1701 

ELAM-1: 732P 

EML4: 81IN, 108IN, 119IN, 195P, 1187P, 1193P, 

1195P, 1208, 1324 

EOMES: 71IN 

EP4: 1033P 

EPAS-1: 354P 

EpCAM: 217P, 472P, 495P, 911P, 1175P, 1313, 

1512, 1650P, 1696P 

EPHA4: 1691P 

Epiregulin: 526PD, 536P, 1027P 

ER: 14IN, 15IN, 19IN, 21IN, 151P, 172O, 176PD, 

197P, 199P, 201P, 205P, 206P, 216P, 245O, 

247O, 248O, 249PD, 252PD, 257P, 258P, 259P, 

264P, 265P, 266P, 278P, 279P, 283P, 284P, 288P, 

289P, 291P, 294P, 298P, 299, 301, 302, 305, 308, 

309, 323PD, 325PD, 336P, 340P, 343P, 345P, 

347P, 350P, 353P, 362P, 368P, 370P, 372P, 373P, 

376, 377, 378, 381, 384, 386, 397, 399, 406TIP, 

414PD, 513PD, 923P, 11090P, 1397P, 1398P, 

1656P, 1702 

ERCC1: 7IN, 77IN, 187P, 207P, 524P, 527PD, 

613P, 628, 803P, 990P, 1026P, 1052, 1170P, 

1193P, 1211, 1226O, 1244P, 1645PD 

Erk: 108IN, 119IN, 153P, 456P, 475P, 483P, 1075P, 

1349, 1491P, 1647PD, 1652P, 1668P 

ERP29: 1032P, 1119P 

E-selectin: 791PD, 833P, 1236PD, 1657P 

ESR1: 17IN 

ESR2: 17IN 

ETPA: 1701 

EWS/FLI1: 92IN 

EXE: 324PD 

EZH2: 208P, 1066PD 

F3: 906P 

FAK: 179P, 384, 1027P, 1659P 

FASCIN-1: 1026P 

FC: 64IN 

FCGR: 237 

FCyR: 472P, 495P 

FGF: 20IN, 52IN, 319O, 822P, 966O 

FGFR: 7IN, 50IN, 81IN, 119IN, 181P, 319O, 

417PD, 446PD, 737P, 744P, 814P, 81TIP 

FHIT: 675P 

FLAGS: 668PD 

FLR-B/FOX: 629 

FLT: 115IN, 1066PD,1067PD, 1194P, 1479PD 

FOXA1: 23P 

FOXL2: 993P 

FOXO3a: 185P 

FOXP3: 939P, 1314 

FPGH: 1211 

FPGS: 1211 

FRAP1: 812P 

FYC: 102IN 

GARFT: 1211 

Gata3:71IN, 102IN 

G-CSF: 246O, 1085P 

GDNF: 225P 

GGH: 542P 

GHRL2: 223P, 465P 

GLI1: 1309P, 1663P, 1693P 

GLUT1: 166, 562P, 1033P, 1180PD 

GLUT2: 166 

GM-CSF: 723P, 813P, 943P, 1672P 

GNAS: 12IN, 227P 

GRIN2A: 11IN 

GRM3: 11IN 

GSK-3: 156P, 1026P 

GSTM1: 1078P 

GSTT1: 1078P 

H2AX: 435TIP 

H3: 442O 

H-cadherin: 548P 

HDI: 150P 

Hedgehog: 62IN, 63IN, 449PD, 463P, 720P, 

1111PD, 1112PD, 1309P, 1663P, 1694P 

HENT1: 709P 

HER2: 7 IN, 15IN, 19IN, 21IN, 28IN, 44IN, 50IN, 


108IN, 119IN, 121IN, 172O, 180P,197P, 199P, 

201P, 202P, 205P, 206P, 216P, 217P, 228P, 231P, 

241, 243, 245O, 246O, 248O, 252PD, 254PD, 

255PD, 257P, 258P, 259P, 264P, 265P, 266P, 

267P, 268P, 269P, 270P, 271P, 272P, 274P, 275P, 

276P, 278P, 279P, 283P, 284P, 286P, 288P, 289P, 

291P, 292P, 294P, 298P, 299, 300, 301, 303, 304, 

308, 309, 315TIP, 316TIP, 317O, 318O, 319O, 

320PD, 321PD, 322PD, 323PD, 324PD, 325PD, 

336P, 342P, 343P, 344P, 345P, 346P, 347P, 352P, 

353P, 356P, 357P, 362P, 364P, 365P, 366P, 368P, 

370P, 373P, 377, 378, 379, 380, 381, 386, 387, 

389, 391, 392, 395, 396, 397, 399, 402, 404, 

406TIP, 407TIP, 408TIP, 409TIP, 414PD, 

446PD, 454P, 458P, 464P, 467P, 470P, 476P, 

494P, 496P, 509TiP, 513PD, 515P, 675P, 677P, 

678P, 699P, 703P, 720P, 750, 762, 768O, 970PD, 

974PD, 1142P, 1185P, 1228O, 1232PD, 1252P, 

1288P, 1290P, 1311P, 1313, 1322, 1397P, 1398P, 

1450P, 1646PD, 1647PD, 1656P, 1657P, 1659P, 

1664P, 1675P, 1698P, 1702 

HER3: 7IN, 202P, 214P, 226P, 231P, 343P, 467P, 

496P, 720P, 970PD, 974PD, 1185P, 1690P 

HER4: 7IN, 11IN, 50TiP, 970PD, 1185P, 1228O, 

1252P 

HGF: 70IN, 143PD, 205P, 222P, 443PD, 444PD, 

669PD, 687P, 720P, 791PD, 833P, 1291P, 

1365TIP 

HIF: 109IN, 156P, 354P, 532P, 751, 794PD, 830P, 

832P, 835P, 869, 1033P, 1170P, 1180PD, 1685P 

HIPEC: 774 

HK II: 166, 1033P 

HLA-A24: 460P 

HLA-A2402: 1671P 

HLA-DR: 197P 

HMGB1: 495P 

HMOX-1: 971PD 

HOX: 147P, 223P 

HRAS: 1311P 

HSP27: 900PD 

HSP90: 7IN, 57IN, 61IN, 66IN, 156P, 215P, 347P, 

438O, 922P, 1332, 1679P 

HXR3: 988P 

ICAM: 431, 1236PD, 1657P 

ICOS: 71IN 


translational 

research 

index

translational 

research 

index 


IDH: 23IN, 421P, 1701 

IFI16: 1701 

IFN alpha: 224P 

IFN gama: 163P, 622, 865P 

IFN: 503 

IGF: 90IN, 202P, 776TIP 

IGFBP3: 92IN, 411O, 906P, 1030P 

IGFR: 13IN, 90IN, 217P, 301, 606P, 776TIP, 830P, 

917P, 1030P, 1319, 1322, 1497P, 1668P, 1703IN 

IGluR: 11IN 

IHH: 720P 

IKBA: 148P 

IKBKAP: 1032P, 1119P 

IL-10: 190P, 1464P, 1672P 

IL-12: 17IN, 163P, 222P, 1672P 

IL-13: 480P 

IL-17: 17IN, 71IN, 150P, 480P 

IL-1B: 473P, 480P 

IL-2: 224P, 723P 

IL-22: 480P 

IL-23: 150P 

IL-2RA: 865P 

IL-4: 480P, 510TiP, 1314, 1672P 

IL-5: 480P 

IL-6: 153P, 165, 222P, 228P, 354P, 476P, 720P, 

791PD, 833P, 1088P, 1464P, 1693P 

IL-7: 813P 

IL-8: 52IN, 190P, 222P, 354P, 732P, 791PD, 1194P, 

1464P, 1657P 

ILKAP: 1701 

IL-RB2: 17IN 

INI1: 92IN 

Integrin b1: 179P 

IPO8: 1701 

IRF4: 66IN, 

JAK: 102IN, 483P 

KDM6A: 25IN 

KDR: 7IN, 266P 

Ki-67: 13IN, 15IN, 19IN, 71IN, 73IN, 102IN, 

191P, 200P, 201P, 233, 268P, 270P, 276P, 281P, 

284P, 303, 305, 306, 343P, 364P, 366P, 406TiP, 

442O, 443PD, 457P, 538P, 562P, 575P, 1026P, 

1158P, 1160P, 1164P, 1167P, 1695P 

KIF22: 1701 

KIF5B: 119IN 

KIT: 19IN, 92IN, 94IN, 102IN, 174O, 222P, 227P, 

244, 385, 417PD, 705P, 706P, 707P, 708P, 737P, 

814P, 880, 1067PD, 1118PD, 1123P, 1157O, 

1478O, 1479PD, 1486PD, 1489P, 1491P, 1516, 

1541, 1679P 

KIAA0664: 1701 

KLC1: 119IN 

KLF7: 225P 

KLK: 223P 

KOC1: 460P, 1671P 

KRAS: 6IN, 7IN, 12IN, 28IN, 78IN, 83IN, 119IN, 

143PD, 170O, 180P, 207P, 208P, 21OP, 211P, 

214P, 218P, 237, 438O, 442O, 475P, 520O, 

525PD, 526PD, 532P, 533P, 535P, 536P, 537P, 

543P, 548P, 549P, 555P, 557P, 558P, 561P, 564P, 

565P, 568P, 570P, 574P, 580P, 582P, 587P, 593P, 

594P, 597P, 598P, 605P, 606P, 608P, 629, 630, 

631, 641,643, 647, 649, 651, 653, 665TiP, 

667PD, 696P, 703P, 720P, 1017O, 1187P, 1190P, 

1193P, 1226O, 1233PD, 1248P, 1266P, 1282P, 

1302P, 1307P, 1311P, 1315, 1316, 1322, 1339, 

1349, 1362TiP, 1366TiP, 1647PD, 1649P, 1652P, 

1654P, 1664P, 1701 

KYNU: 1701 

LAP3: 1701 

LDHA: 1033P 

Lea: 619 

LEF1: 1032P 

Leptin: 190P, 473P, 483P, 1603P 

Lex: 619 

Ley: 619 

LGR5: 720P 

LINE1: 225P 

LKB1: 180B 

LMO4: 1655P 

LMP1: 221P, 1027P 

LRIG: 544P 

LRRK2: 51IN 

LTK: 102IN 

MA2K1: 1030P 

MAGE: 1182P 

Mamaglobin: 304 

MAP: 102IN, 154P 

MAP1B: 1701 

MAP2K4: 102IN 

MAP3K1: 102IN 

MAPK: 119IN, 143PD, 154P, 173O, 348P, 451P, 

475P, 483P, 483P, 869, 1026P, 1030P, 1075P, 

1039P, 1185P, 1659P, 1668P, 1674P, 1693P 

MAPT: 1026P 

Matrix metalloproteinases (MMPs): 384, 617 

MCC: 1032P 

MCL-1: 1027P 

MCM2: 240 

MCMs: 240 

MCPH1: 1662P 

MCT1: 1033P 

MDC1: 686P, 1661P, 1662P 

MDM2: 7IN, 92IN, 93IN, 156P, 1122P 

MDR1: 196P 

MEK: 11IN, 90IN, 108IN, 119IN, 143PD, 154P, 

173O, 451P, 456P, 475P, 609P, 147P, 1124P, 

1193P, 1197P, 1349, 1647PD, 1674P 

Merlin protein: 419PD 

MGMT: 23IN, 24IN, 416PD, 421P, 424P, 435TiP, 

548P, 830P, 1676P 

MICA: 160P, 1690P 

MINT: 225P, 543P 

MIP1: 224P, 865P 

miRNA: 60IN, 143PD, 145P, 148P, 149P, 150P, 

159P, 160P, 169O, 178P, 188P, 202P, 205P, 215P, 

223P, 226P, 250PD, 305, 385, 426P, 525P, 535P, 

542P, 615, 686P, 723P, 807P, 1025P, 1027P, 

1030P, 1031P, 1139P, 1170P, 1242P, 1243P, 

1309P, 1312, 1532P, 1646PD, 1653P, 1655P, 

1661P, 1672P, 1679P, 1682P, 1693P 

Mismatch repair deficiency (dMMR): 516P, 521O, 

524P, 703P 

MLH1: 516P, 543P, 703P, 720P, 1311P 

MLL2: 25IN, 102IN 

MMP-1: 287P 

MMP-2: 146P, 384, 794PD, 1682P 

MMP-3: 224P 

MMP-7: 1700 

MMP-8: 910P 

MMP-9: 146P, 384, 545P, 617 

MMSET: 686P, 1661P 

MPHOSPH1: 1671P 

MSH2: 7IN, 516P, 703P, 720P 

MSH3: 720P 

MSH6: 516P, 703P 

MSI-H: 656, 675P 

MSN: 1701 

MSP: 1532P 

MST1R: 1532P 

MST2: 1684P 

MT: 1203P 

MTHFR: 640, 1244P, 1326 


mTOR: 2IN,13IN, 52IN, 57IN, 65IN, 76IN, 83IN, 

90IN, 92IN, 107IN, 108IN, 130IN, 154P, 173O, 

185P, 236, 318O, 324PD, 350P, 352P, 405TiP, 

419PD, 420PD, 442O, 450PD, 452P, 454P, 462P, 

532P, 717P, 781TiP, 783O, 798PD, 812P, 814P, 

818P, 819P, 822P, 823P, 828P, 837P, 839P, 840P, 

841P, 845P, 846P, 849P, 852P, 869, 873, 879, 

881, 890TiP, 917P, 1017O, 1026P, 1031P, 

1154O, 1156O, 1157O, 1491P, 1107TiP, 1162P, 

1165P, 1685P, 1703IN 

MUC1: 619, 622, 723P 

MUC2: 619, 719P 

MUC5AC: 619 

MUC6: 720P 

MVD: 1236PD 

MYC: 102IN, 202P, 490P, 832P, 916P, 1185P, 1210, 

1700 

MYH9: 102IN 

MYST1: 215P 

NANOG: 149P, 604P 

N-cadherin: 1695P 

NeuGc-GM3: 1238PD 

Neurokinin receptor: 1550PD, 1575P 

NF1: 92IN 

NF2: 419PD 

NF-kB: 17IN, 66IN, 148P, 150P, 348P, 752, 807P, 

1531P, 1680P 

NGF-B: 865P 

NK-1: 129IN 

NKG2D: 160P 

NMP-52: 239 

NOS2: 1681P 

NOTCH1: 62IN, 216P, 448PD, 463P, 642, 720P, 

996P 

NOXA: 66IN 

NPRA: 748 

NQO1: 235 

NRAS: 7IN, 119IN, 227P, 574P, 1649P 

NRP1: 1236PD 

NRP1: 546P 

NRP2: 915P 

NSE: 886, 911P, 1203P 

NTX: 132O, 1321 

OCT-4: 149P, 720P 

OPN: 791PD, 833P 

Osteopontin: 833P 

p14: 543P, 1118PD 

p16: 86IN, 221P, 543P, 1018O, 1045P, 1118PD, 

1211 

p19: 150P 

P1NP: 805P, 945 

p21: 575P 

P38: 348P, 1075P 

P40: 150P, 181P 

P4EBP1: 457P 

P4HB: 1701 

p53: 7IN, 12IN, 20IN, 25IN, 50IN, 61IN, 62IN, 

92IN, 93IN, 102IN, 156P, 170O, 180P, 187P, 

291P, 575P, 615, 628, 675P, 686P, 703P, 979P, 

1026P, 1031P, 1068PD, 1122P, 1192PD, 1311P, 

1661P, 1662P 

P63: 1026P 

p70S6K: 236, 420PD 

P85: 419PD 

P95: 243, 267P, 347P 

PAI: 615 

pAkt: 60IN, 154P, 343P, 405TiP, 406TiP, 442O, 

443PD, 457P, 474P, 1026P, 1031P, 1668P, 1676P 

PAL1: 249PD 

PAM50: 176PD 

PAP: 943P 

ix606 | translational research index Volume 23 | Supplement 9 | September 2012

Annals Of Oncology translational research index 

PARP: 7IN, 20IN, 21IN, 35IN, 36IN, 55IN, 61IN, 

66IN, 428, 972PD, 988P 

Paxillin: 1659P 

PBRM1: 51IN 

PC1/2: 236 

P-cadherin: 1026P 

PD-1: 22IN, 53IN, 71IN, 453P, 459P, 784O, 915P, 

1109O, 1237PD 

PDGF: 92IN, 102IN, 152P, 203P, 505, 507, 663TiP, 

732P, 814P, 835P, 865P, 1657P 

PDGFR: 92IN, 174O, 417PD, 446PD, 720P, 737P, 

744P, 880, 1027P, 1157O, 1349, 1478O, 1479PD, 

1486PD, 1494P, 1496P, 1516, 1687P 

PDK1: 185P 

PD-L1: 453P 

PDX1: 215P 

p-EGFR: 1668P 

p-ER: 534P 

p-ERK: 443PD, 451P, 475P 

PGD: 1701 

PGF: 720P 

PGK1: 1170P 

P-glycoprotein: 364P, 481P, 486P, 873, 1678P 

PI3K: 2IN, 7IN, 13IN, 20IN, 2IN, 62IN, 65IN, 

70IN, 76IN,78IN, 83IN, 107IN, 108IN, 119IN, 

148P, 154P, 173O, 185P, 204P, 214P, 237, 318O, 

343P, 347P, 350P, 405TiP, 419PD, 442O, 

450PD, 452P, 454P, 457P, 458P, 483P, 532P, 

664TiP, 781TiP, 807P, 812P, 890TiP, 917P, 

1017O, 1030P, 1491P, 1656P, 1668P, 1675P, 

1676P, 1685P, 1693P 

PIAS4: 686P, 1661P 

PIGF: 203P, 1154O 

PIK: 548P 

PIK3CA: 20IN, 50IN, 102IN, 108IN, 119IN, 180P, 

202P, 204P, 243, 406TiP, 442O, 452P, 457P, 

574P, 630, 667PD, 675P, 696P, 812P, 1017O, 

1030P, 1193P, 1649P, 1656P 

PIP3: 2IN 

PKM2: 1308P 

PLGF: 1236PD 

p-MAPK: 406TiP 

p-MEK: 475P 

p-MET: 443PD 

PMS1/2: 516P 

PNPO: 915P 

POSTN: 914P 

PPARγ: 590P 

PPP2R1B: 1701 

PR: 21IN, 197P, 199P, 201P, 205P, 248O, 249PD, 

257P, 258P, 259P, 264P, 265P, 266P, 278P, 279P, 

284P, 291P, 298P, 302, 323PD, 343P, 353P, 

357P, 370P, 376, 377, 378, 381, 386, 397, 

406TiP, 414PD, 513PD, 1398P, 1702 

PROM1: 720P 

PS6: 154P, 443PD, 457P 

PSA: 46IN, 87IN, 893O, 900PD, 901PD, 902P, 

905P, 906P, 907P, 908P, 911P, 912P, 914P, 917P, 

918P, 919P, 920P, 922P, 923P, 925P, 929P, 930P, 

934P, 935P, 938P, 940P, 950, 951, 952, 953, 961, 

962TiP, 963TiP, 964TiP 

PSF: 233 

PSMA: 915P 

pSTAT3: 501 

PTCH1: 25IN, 720P, 1032P, 1119P, 1121P, 1309P, 

1663P 

PTCH2: 720P 

PTEN: 7IN, 12IN, 20IN, 55IN, 107IN, 108IN, 

119IN, 173O, 202P, 204P, 343P, 406TiP, 457P, 

458P, 532P, 548P, 630, 890TiP, 917P, 922P, 

1026P, 1031P, 1656P 

PTGR1: 1701 

PTK7: 539P 

PTPN12: 20IN, 353P 

p-VHL: 835P 

Rad51: 1662P 

Raf: 92IN, 143PD, 173O, 475P, 874, 1349, 1647PD 

RANKL: 49IN, 316TiP, 348P, 1108TiP 

RAP1A: 1701 

RAP80: 807P 

RARB2: 293P, 1211 

Ras: 143PD, 173O, 242, 1146, 1349, 1491P, 

1647PD 

RASSF: 221P, 1211 

RB1: 7IN, 50IN 

RDH5: 928P 

RESISTIN: 190P, 

RET: 7IN, 81IN, 119IN, 417PD, 445PD, 737P, 

814P 

RFC: 1211 

RHO: 947 

RIZ1: 221P 

RNA: 2IN, 100IN, 145P, 147P, 159P, 177PD, 216P, 

223P, 245O, 426P, 769, 803P, 1025P, 1031P, 

1032P, 1393P, 1673P, 1684P 

RNF113: 1701 

RNF43: 12IN, 144PD, 460P 

Robo4: 178P 

RON: 471P, 492P, 1532P 

RORA: 225P 

ROS: 7IN, 78IN, 81IN, 82IN, 119IN, 195P, 

1119PD 

RPS3: 1701 

RPS5: 1701 

Rrca1: 290P 

RRM1: 77IN, 144PD, 187P, 1645PD 

RRM2: 187P 

RSK: 1674P 

RUNX1: 102IN 

RyR2: 1682P 

S100: 227P, 919P 

S1PR: 1651P 

S6: 1491P, 1674P 

S6K: 1491P 

Sca-1: 1685P 

SCC: 1203P, 

SCGF-B: 865P, 

SDF-1: 865P, 1033P 

SDH: 92IN 

SELENBP1: 910P 

SERCA2a: 1682P 

SF3B1: 102IN 

SHH: 720P 

SHP-1: 1075P 

shRNA: 30IN, 539P 

siRNA: 144PD, 145P, 169O, 185P, 188P, 205P, 

1659P, 1673P 

SKDR: 1194P 

SLC34A2: 195P 

SLC3A2: 1701 

SLC44A4: 963TiP 

SLCAM: 1194P 

SLCO1B1: 17IN 

SLD5: 233 

Slug: 145P 

SMAD: 12IN, 605, 720P 

SMARCA4: 25IN 

SMO: 720P, 1309P 

SMRP: 192P 

Snail: 145P 

SOCS: 153P, 1030P 

Somatostatin receptor: 1164P, 1703IN 

SOX-2: 149P, 216P 

SPARC: 720P 

SPHK1: 1651P 

sRAGE: 919P 

SRC: 44IN, 53IN, 501, 1481PD, 1659P, 1686P 

STAT: 150P, 153P, 483P 

STK11: 7IN, 180P, 22OP 

STNF-RS: 488P 

Survivin: 156P, 979P 

SWI-SNF: 51IN, 186P 

SYK: 65IN 

T2E: 922P 

T6235C: 374P 

TAK1: 348P 

Tau: 291P 

TCL1A: 17IN 

TGASE-2: 830P 

TGF beta: 169O, 197P, 865P, 919P, 1209, 1695P 

TGFBR1: 615 

TGF-α: 143PD, 1027P, 1209 

TGM2: 1701 

TIE-2: 471P, 492P, 975PD, 1027P, 1194P 

TIMP-1/2: 146P, 791PD, 833P 

TK1: 645 

TLG: 567P 

TLR: 719P, 813P 

Tn: 619 

TNFa: 163P, 190P, 476P, 480P 

TNFSF: 228P 

TOMM34: 460P 

Topoisomerase IIα: 202P, 245O, 291P, 406TiP, 

485P, 1170P 

TP: 542P, 550P 

TPS: 302 

TR4: 463P 

T-regulatory cells (TREG): 174O 

TRIK128: 1701 

TrkB: 188P 

TROLOX: 473P 

TS: 187P, 550P, 1211, 1242P, 1243P 

TSC1: 5OIN 

TSC2: 12IN 

TSP-1: 354P, 919P 

TSPYL5: 17IN 

TTF1: 181P 

TTK: 1671P 

Twist: 1693P 

TX: 313 

TXR: 1170P 

TYMS: 1170P 

UBA6: 1701 

UBC9: 686P, 1661P 

URLC10: 1671P 

USP5: 1701 

VCAM-1: 732P 

VEGF: 52IN, 54IN, 57IN, 91IN, 109IN, 152P,155P, 

156P, 174O, 184P, 194P, 197P, 203P, 222P, 

292P, 323PD, 354P, 377, 417PD, 435TiP, 

448PD, 493P, 501, 505, 507, 529PD, 532P, 578P, 

581P, 594P, 600P, 633, 642, 659, 663TiP, 696P, 

734P, 737P, 751, 752, 791PD, 796PD, 814P, 

822P, 829P, 831P, 835P, 837P, 840P, 841P, 842P, 

843P, 855P, 869, 876, 829TiP, 966O, 1080P, 

1154O, 1159P, 1160P, 1194P, 1245P, 1687 

VEGF-A: 155P, 198P, 241, 546P, 720P, 724P, 734P, 

794PD, 829P, 830P, 919P, 1026P, 1154O, 1194P, 

1236PD, 1239P, 1657P, 1687 

VEGF-B: 720P 

VEGF-C: 734P, 829P, 919P, 1026P, 1657P, 1687P 

VEGF-D: 1687P 

VEGFR: 91IN, 174O, 198P, 200P, 222P, 319O, 

347P, 354P, 417PD, 445PD, 446PD, 448PD, 

460P, 471P, 492P, 545P, 609P, 617, 659, 720P, 

724P, 734P, 737P, 740P, 744P, 794PD, 796PD, 


translational 

research 

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translational 

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index 


811P, 814P, 821P, 823P, 829P, 830P, 835P, 837P, 

841P, 842P, 875, 880, 897O, 1026P, 1027P, 

1115PD, 1154O, 1157O, 1194P, 1236PD, 1239P, 

1245P, 1287P, 1349, 1479PD, 1496P, 1648P, 

1652P, 1657P, 1687P 

VGLL3: 906P 

VHL: 52IN, 501, 794PD, 830P, 832P, 835P, 869 

ViViD: 163P 

WEE1: 20IN 

WIF1: 221P 

Wnt: 463P, 545P, 617, 720P, 1700 

WT1: 490P, 1533P 

XIAP: 156P 

XPD: 1244P 

XRCC: 527PD, 1052 

YEATS4: 93IN 

YPK-1: 723P 

ZEB-1/2: 145P, 1693P 

ZNF415: 1032P, 1119P 

αv integrins: 965TiP 


ix608 | translational research index Volume 23 | Supplement 9 | September 2012

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