Pan Arab Journal of Oncology - Arab Medical Association Against ...

Pan Arab Journal of Oncology 

ISSN: 2070-254X 

Official Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 4; issue 1 | March 2011 

Original Articles 

• Pathologist’s role in Modern Oncology 

Practice 

• Chroidal Metastases from Breast 

carcinoma 

No winter lasts forever; no spring skips its turn. 

~Hal Borland 

• Hypofractionated vs. Conventional 

RT in Glioblastoma Multiforme

Aranesp ® (darbepoetin alfa) SureClick Brief Prescribing Information. Please refer to the 

Summary of Product Characteristics before prescribing Aranesp ® . Pharmaceutical Form: 

Solution for injection presented in prefilled pens containing 150, 300, and 500 micrograms of 

darbepoetin alfa, for single-dose use only. Indication: Treatment of symptomatic anaemia in adult 

cancer patients with non-myeloid malignancies receiving chemotherapy. Dosage and 

Administration: Cancer patients: Aranesp ® should be administered by the subcutaneous route to 

patients with anaemia (e.g. haemoglobin concentration ≤10 g/dL (6.2 mmol/l)) in order to increase 

haemoglobin to not greater than 12 g/dL (7.5 mmol/l). Anaemia symptoms and sequelae may vary 

with age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’s 

clinical course and condition is necessary. Due to intra-patient variability, occasional individual 

haemoglobin values for a patient above and below the desired haemoglobin level may be 

observed. Haemoglobin variability should be addressed through dose management, with 

consideration for the haemoglobin target range of 10 g/dL (6.2 mmol/l) to 12 g/dL (7.5 mmol/l). A 

sustained haemoglobin level of greater than 12 g/dL (7.5 mmol/l) should be avoided; guidance for 

appropriate dose adjustments for when haemoglobin values exceeding 12 g/dL (7.5 mmol/l) are 

observed are described below. The recommended initial dose is 500 μg (6.75 μg/kg) given once 

every three weeks, or once weekly dosing can be given at 2.25 μg/kg body weight. If the clinical 

response of the patient (fatigue, haemoglobin response) is inadequate after nine weeks, further 

therapy may not be effective. Aranesp ® therapy should be discontinued approximately four weeks 

after the end of chemotherapy. Once the therapeutic objective for an individual patient has been 

achieved, the dose should be reduced by 25 to 50% in order to ensure that the lowest approved 

dose of Aranesp ® is used to maintain haemoglobin at a level that controls the symptoms of 

anaemia. Appropriate dose titration between 500 μg, 300 μg, and 150 μg should be considered. 

Patients should be monitored closely, if the haemoglobin exceeds 12 g/dL (7.5 mmol/l), the dose 

should be reduced by approximately 25 to 50%. Treatment with Aranesp ® should be temporarily 

discontinued if haemoglobin levels exceed 13 g/dL (8.1 mmol/l). Therapy should be reinitiated at 

approximately 25% lower than the previous dose after haemoglobin levels fall to 12 g/dL (7.5 

mmol/l) or below. If the rise in haemoglobin is greater than 2 g/dL (1.25 mmol/l) in 4 weeks, the 

dose should be reduced by 25 to 50%. Contraindications: Hypersensitivity to darbepoetin alfa, 

r-HuEPO or any of the excipients. Poorly controlled hypertension. Special Warnings and 

Precautions: General: blood pressure should be monitored in all patients, particularly during 

initiation of Aranesp ® therapy. If blood pressure is difficult to control by initiation of appropriate 

measures, the haemoglobin may be reduced by decreasing or withholding the dose of Aranesp ® . 

Iron status should be evaluated for all patients prior to and during treatment and supplementary 

iron therapy may be necessary. Non-response to therapy with Aranesp ® should prompt a search 

for causative factors. Deficiencies of iron, folic acid or vitamin B12 reduce the effectiveness of 

erythropoiesis-stimulating agents and should therefore be corrected. Intercurrent infections, 

inflammatory or traumatic episodes, occult blood loss, haemolysis, severe aluminium toxicity, 

underlying haematologic diseases, or bone marrow fibrosis may also compromise the 

erythropoietic response. A reticulocyte count should be considered as part of the evaluation. If 

typical causes of non-response are excluded, and the patient has reticulocytopenia, an 

examination of the bone marrow should be considered. If the bone marrow is consistent with 

PRCA, testing for anti-erythropoietin antibodies should be performed. Pure red cell aplasia caused 

by neutralising anti-erythropoietin antibodies has been reported in association with erythropoiesisstimulating 

agents (ESAs), including darbepoetin alfa. This has been predominantly reported in 

Give them the energy 

to keep up with life 

Aranesp ® offers convenient and tailored treatment 

as the only ESA licensed for QW and Q3W 1-3 

patients with CRF treated subcutaneously. Cases have also been reported in patients with hepatitis 

C treated with interferon and ribavirin, when epoetins are used concomitantly (ESAs are not 

indicated for use in this patient population). These antibodies have been shown to cross-react with 

all erythropoietic proteins, and patients suspected or confirmed to have neutralising antibodies to 

erythropoietin should not be switched to darbepoetin alfa. Active liver disease was an exclusion 

criteria in all studies of Aranesp ® , therefore no data are available from patients with impaired liver 

function. Since the liver is thought to be the principal route of elimination of Aranesp ® and 

r-HuEPO, Aranesp ® should be used with caution in patients with liver disease. Aranesp ® should 

also be used with caution in those patients with sickle cell anaemia or epilepsy. Convulsions have 

been reported in patients receiving Aranesp ® . Misuse of Aranesp ® by healthy persons may lead to 

an excessive increase in packed cell volume. This may be associated with life-threatening 

complications of the cardiovascular system. The needle cover of the pre-filled syringe contains dry 

natural rubber (a derivative of latex), which may cause allergic reactions. In patients with chronic 

renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the 

target haemoglobin concentration. In clinical studies, an increased risk of death, serious 

cardiovascular events and vascular access thrombosis was observed when ESAs were 

administered to target a haemoglobin of greater than 12 g/dL (7.5 mmol/l). Controlled clinical trials 

have not shown significant benefits attributable to the administration of epoetins when 

haemoglobin concentration is increased beyond the level necessary to control symptoms of 

anaemia and to avoid blood transfusion. Cancer patients: Effect on tumour growth. Epoetins are 

growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be 

expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern 

that epoetins could stimulate the growth of tumours. In several controlled studies, epoetins have 

not been shown to improve overall survival or decrease the risk of tumour progression in patients 

with anaemia associated with cancer. In controlled clinical studies, use of Aranesp ® and other 

ESAs have shown: shortened time to tumour progression in patients with advanced head and neck 

cancer receiving radiation therapy when administered to target a haemoglobin of greater than 14 

g/dL (8.7 mmol/l) (ESAs are not indicated for use in this patient population); shortened overall 

survival and increased deaths attributed to disease progression at 4 months in patients with 

metastatic breast cancer receiving chemotherapy when administered to target a haemoglobin of 

12-14 g/dL (7.5-8.7 mmol/l); increased risk of death when administered to target a haemoglobin 

of 12 g/dL (7.5 mmol/l) in patients with active malignant disease receiving neither chemotherapy 

nor radiation therapy (ESAs are not indicated for use in this patient population). In view of the 

above, in some clinical situations blood transfusion should be the preferred treatment for the 

management of anaemia in patients with cancer. The decision to administer recombinant 

erythropoietins should be based on a benefit-risk assessment with the participation of the 

individual patient, which should take into account the specific clinical context. Factors that should 

be considered in this assessment should include the type of tumour and its stage; the degree of 

anaemia; life-expectancy; the environment in which the patient is being treated; and patient 

preference. In patients with solid tumours or lymphoproliferative malignancies, if the haemoglobin 

value exceeds 12 g/dL (7.5 mmol/l), the dosage adaptation described in the Posology and Method 

of Administration section should be closely respected, in order to minimise the potential risk of 

thromboembolic events. Platelet counts and haemoglobin level should also be monitored at regular 

intervals. Pregnancy and Lactation: No adequate experience in human pregnancy and lactation. 

Exercise caution when prescribing Aranesp ® to pregnant women. Do not administer to women who 

are breastfeeding. When Aranesp ® therapy is absolutely indicated, breastfeeding must be 

discontinued. Undesirable Effects: General: There have been reports of serious allergic reactions 

including anaphylactic reaction, angioedema, allergic bronchospasm, skin rash and urticaria 

associated with darbepoetin alfa. Clinical Trial Experience - Cancer patients: Adverse reactions 

were determined based on pooled data from seven randomised, double-blind, placebo-controlled 

studies of Aranesp ® with a total of 2112 patients (Aranesp ® 1200, placebo 912). Patients with 

solid tumours (e.g., lung, breast, colon, ovarian cancers) and lymphoid malignancies (e.g., 

lymphoma, multiple myeloma) were enrolled in the clinical studies. Incidence of undesirable 

effects considered related to treatment with Aranesp ® from controlled clinical studies: Very 

common (≥1/10) Oedema; Common (≥1/100 to

editorial board < contents < 

º Editor-in-Chief 

Marwan Ghosn, MD, MHHM 

> mghosn.hdf@usj.edu.lb 

> marwan.ghosn@cmc.com.lb 

Lebanon 

º Deputy Editor 

Sami Khatib, MD 

> amaac.pajo@gmail.com 

Jordan 

º Associate Editors 

Khaled Al-Saleh, MD 

> gffccku@yahoo.com 

Kuwait 

Jamal Khader, MD 

> jkhader@khcc.jo 

Jordan 

Hussein Khaled, MD 

> khaled@internetegypt.com 

Egypt 

Nazar Makki, MD 

> ntmakki@yahoo.com 

Iraq 

Mohamad Jaloudi, MD 

> mjaloudi@tawamhospital.ae 

UAE 

º Design & Layout 

Zéna Khairallah 

> design@zenak.me 

º PAJO Editorial Board 

> editorinchief.pajo@yahoo.com 

ISSN: 2070-254X 

Pan Arab Publishing Company 

P. O. Box: 2509 

Amman 11953 - Jordan 

Beer Al Sabe’ St 

Shocair Medical Complex 

2nd Fl, office No. 201 

Phone + 962 6 566 78 53 

Fax + 962 6 562 38 53 

www.e-pamj.com 

AMAAC Introduction > 2 

International Advisory Board > 3 

Special Thanks > 4 - 5 


º Choroidal Metastases from Breast Carcinoma: Case series 

Mohammed Jaloudi et al. > 6 - 10 

º Multidrug Resistance- related Protein (MRP) and Lung 

Resistance Protein (LRP) mRNA Expression in Egyptian Patients 

with Acute Leukemia 

Amira Ahmed Hammam et al. > 12 - 16 

º Phase II pilot study of weekly Docetaxel as Neoadjuvant 

Chemotherapy for operable Breast Cancer 

Mahmoud Ellithy, et al. > 18 - 23 

º The Role of Pathologist in Modern Oncology Practice 

Abdul-Rahman Jazieh et al. > 24 - 26 

º Taxanes Versus Vinorelbine and 5-Fluorourocil as a First 

Therapy in Metastatic Breast Cancer 

Wessam Ali El-Sherief et al. > 28 - 33 

º Dose-Dense Chemotherapy in High-Risk Breast Cancer: 

Treatment Outcome and Toxicity 

Amr El-Kashif et al. > 34 - 39 

º Genomics views: Xenobiotic metabolizing enzymes 

and cancer risks 

Bechr Hamrita et al. > 40 - 46 

º Hypofractionated radiotherapy versus conventional radiotherapy 

in treatment of glioblastoma multiforme 

Mohamed Abdelgawad et al. > 48 - 52 

News from the Arab World > 54 - 61 

º Announcements 

º 11th Panarab Cancer Congress 

º 1st Annual Congress of the Arab Alliance for Medical Education 

º UAE Cancer Congress 2011 

º Hematology and Blood Transfusion 

º 3rd EASO Masterclass in Clinical Oncology 

º AORTIC 2011 

º 3rd Asian Breast Cancer Congress 

Cancer Awareness Calendar > 62 

Instructions for Authors > 63 - 66 

www.amaac.org Pan Arab Journal of Oncology | vol 4; issue 1 | March 2011 < 1

amaac < 

AMAAC Introduction 

The Arab Medical Association Against Cancer (AMAAC) is a medical body that was established in 2001 as part of the Arab Medical 

Association where its main office is located in Cairo - Egypt, and it is also a continuation of the Arab Council Against Cancer that 

was founded in 1995. The Executive Committee of (AMAAC) is represented by two members who are named officially by the 

Oncology Society of each Arab Country. 

The Arab Medical Association Against Cancer aims at strengthening relationships between members in different Arab Countries to 

raise the level of cooperation in the field of oncology on both scientific and practical aspects. Exchanging information and researches 

between members through Regional and Arab Conferences and Publications. Holding Public Awareness Campaigns in the field of 

oncology that are organized by Arab Countries. Participating in scientific activities with International Oncology Societies. Finally, 

encouraging researchers and doctors to meet and exchange experiences together with finding training opportunities in the field of 

oncology inside and outside the Arab World. 

> The Executive Board of AMAAC 

Sami Khatib, MD (Jordan) Secretary General 

Hussein Khaled, MD (Egypt) Associate Secretary General 

Maha Manachi, MD (Syria) Associate Secretary General 

Khaled Al-Saleh, MD (Kuwait) Associate Secretary General 

Brahim El Gueddary, MD (Morocco) Associate Secretary General 

Said Al-Natour, MD (Jordan) Associate Secretary General (for financial affairs) 

> The officially nominated members of AMAAC by the Oncology Societies of Each Country 

Algeria Adda Bounedjar, MD 

Kamel Bouzid, MD 

Bahrain Abdulla Ajami, MD 

Egypt Hussein Khaled, MD 

Sherif Omar, MD 

Iraq Abdul Mon’em Ahmed, MD 

Nezar Taha Maki, MD 

Jordan Sami Khatib, MD 

Said Al-Natour, MD 

Kuwait Khaled Al Khalidi, MD 

Khaled Al Saleh, MD 

Lebanon Marwan Ghosn, MD 

Nagi El-Saghir, MD 

Libya Hussein A Hashemi, MD 

Rammah Rumaihi, MD 

Mauritania Jiddou Abdou, MD 

El Issawi Salem Sidi Mohamed, MD 

Morocco Ashraki Abdel Kader, MD 

Brahim Khalil El Gueddari, MD 

Oman Bassim Bahrani, MD 

Palestine Fuad Sabatin, MD 

Abdel Razaq Salhab, MD 

Saudi Arabia Om Al Kheir Abu Al Kheir, MD 

Shawki Bazarbashi, MD 

Sudan Hussein Mohammad Hamad, MD 

Kamal Eldein l Hamad, MD 

Syria Wassma Achawi, MD 

Maha Manachi, MD 

Tunisia Hamouda Boussen, MD 

Khalid Rahhal, MD 

UAE Mohammed Jaloudi, MD 

Mohamad Abbas Alali, MD 

Yemen Arwa Awn, MD 

Afif Nabhi, MD 

2 > Pan Arab Journal of Oncology | vol 4; issue 1 | March 2011 www.amaac.org

international advisory board < 

Matti AAPRO, MD 

Director, Multidisciplinary Oncology Institute, Genolier, Switzerland 

Consultant to the Scientific Director, European Institute of Oncology, Milano, Italy 

Consultant, Division of Oncology, Geneva University Hospital 

Geneva - Switzerland 

Hoda ANTON-CULVER, PhD 

Professor & Chair 

Department of Epidemiology 

Professor, Department of Microbiology and molecular Genetics, 

School of Medicine 

Director, Genetic Epidemiology Research Institute 

University of California 

Irvine – USA 

Jean-Pierre ARMAND, MD 

Professor & General Director 

Centre de Lutte contre le Cancer 

Institut Claudius Regaud 

Toulouse – France 

Ahmad AWADA, MD 

Head of Medical Oncology Clinic 

Jules Bordet Cancer Institute 

Brussels - Belgium 

Patrice CARDE, MD 

Chairman Lymphoma Committee 

Gustave Roussy Institute 

Paris - France 

Franco CAVALLI, MD 

Professor & President UICC 

Director 

Oncology Institute of Southern Switzerland 

Bellinzona - Switzerland 

Joe CHANG, MD 

Assistant Professor of Radiation Oncology 

Clinical Service Chief, Thoracic Radiation Oncology 

MD Anderson Cancer Center 

Houston - USA 

William DALTON, MD 

President and Chief Executive Officer 

H.Lee Moffitt Cancer Center and Research Institute 

University of South Florida 

Florida - USA 

Jean-Pierre DROZ, MD 

Professor & Former Head of Oncology Department 

Centre de Lutte contre le Cancer Leon Berard 

Lyon - France 

Alexander EGGERMONT, MD, PhD 

Professor of Surgical Oncology 

Head of Department of Surgical Oncology 

Erasmus University Medical Center 

Daniel den Hoed Cancer Center 

Rotterdam - The Netherlands 

Jean-Pierre GERARD, MD 

Professor of Radiation Oncology 

General Director of Antoine-Lacassagne Cancer Center 

Lyon - France 

Joe HARFORD, MD 

Director of the Office of International Affairs 

National Institute of Health 

United States Department of Health and Human Services 

Bethesda - USA 

Alan HORWICH, MD 

Professor of Radiotherapy 

Section of Academic Radiotherapy and 

Department of Radiotherapy 

The Institute of Cancer Research 

London – United Kingdom 

Fritz JANICKE, MD 

Director Clinic & Polyclinic of Gynecology 

University Medical Center Hamburg-Eppendorf 

Hamburg – Germany 

Sima JEHA, MD 

Director of the Leukemia / Lymphoma Developmental Therapeutics 

Saint-Jude Children’s Research Hospital 

Memphis - USA 

Hagop KANTARJIAN, MD 

Professor of Medicine 

Chair of the Department of Leukemia 

The University of Texas - MD Anderson Cancer Center 

Houston - USA 

Fadlo R. Khuri, MD 

Professor and Chair, Department of Hematology and Medical Oncology 

Roberto C. Goizueta Distinguished Chair in Cancer Research 

Deputy Director, Clinical and Translational Research - Winship Cancer Institute 

Emory University School of Medicine 

Atlanta - USA 

Jean-Francois MORERE, MD 

Professor at University Paris XIII 

Head of the Department of Oncology 

Assistance Publique – Hôpitaux de Paris 

Paris - France 

Mack ROACH, MD 

Professor & Chairman 

Radiation Oncology & Professor of Urology 

University of California, Irvine 

California - USA 

Philippe ROUGIER, MD 

Professor of Medical Oncology 

Gastrointestinal Cancer 

Liver and Pancreas Tumors 

Ambroise-Pare Hospital 

Boulogne - France 

Youcef RUSTUM, PhD 

Chairman of the Department of Cancer Biology 

Roswell Park Cancer Institute 

Academic Research Professor 

Associate Vice Provost 

University at Buffalo 

New York - USA 

Sandra M. SWAIN, MD 

Medical Director, Washington Cancer Institute 

Washington Hospital Center 

Washington – USA 


special thanks < 

Thank you for all contributors, authors and reviewers of PAJO 


Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 1 | January 09 

Original Article 

Special Report 

Breast Cancer in Tunisia 

Highlights on the Speech and Language 

Pathologist’s role in Head and Neck Cancer 

Review 

Soft Tissue Sarcoma in Young Individuals MENA 2008 

BLOM Beirut Marathon 08 

new publication 


ISSN: 2070-254X 

Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 3 | December 09 

Special Report: COMO 8 | Nov 2009 | Beirut, Lebanon 


Effect of radiotherapy on malignant 

Proteomic approach for the detection of pleural mesothelioma in adjuvant, 

breast cancer biomarkers. 

radical or palliative basis. 



ISSN: 2070-254X 

Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 3; issue 3 | October 10 

Hope begins in the dark, the stubborn hope that if you just show 

up and try to do the right thing, the dawn will come. You wait and 

watch and work: You don’t give up. 

Anne Lamott 


• Infiltrating Ductal Carcinomas of the • Locally Advanced HNC: Cisplatin and 

Breast: Proteomic Analysis of Human Docetaxel plus Radiation Therapy 

plasma protein 

• Triple negative MBC: BRCA1 and EGFR 

• Gastric carcinoma: DCF vs ECF 

as prognostic biomarkers 


Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 1; issue 2 | June 08 

Health Economics Review Articles 

A cost-minimization analysis Present & Future of Radiation Oncology 

of 1st line polyCT regimens in Review of the Current Management of 

advanced NSCLC 

advanced prostate cancer 

4 > Pan Arab Journal of Oncology | vol 4; issue 1 | March 2011 www.amaac.org 



Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 2 | April 09 

Special Issue Including the Proceedings of PACC 2009 

9 TH PAN ARAB CANCER CONGRESS 

7 - 9 May 2009 - Cairo, Egypt 



ISSN: 2070-254X 

Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 3; issue 1 | March 10 

INITIATIVE TO IMPROVE CANCER CARE IN THE ARAB WORLD 

Proceedings of the Symposium 

March 23 - 25, 2010 | Riyadh, KSA 


ISSN: 2070-254X 

Official Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 3; issue 4 | December 10 

Screening and Early Detection Awareness 


• Report of preliminary experience of the • C/EBPα Expression in Egyptian patients with 

prone table stereotactic breast core biopsy Acute Myeloid Leukemia 

at the King Fahad National Guard Hospital • Treatment results of Stereotactic Radiosurgery 

for cerebral arteriovenous malformations 


Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 1; issue 3 | September 08 

Review 

Meeting Highlights 

Treatment of Acute Lymphoblastic Leukemia ASCO 2008 

UICC 2008 

Targeted Therapy Development 

Angiogenesis review 



ISSN: 2070-254X 

Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 2; issue 3 | September 09 


Low dose Gemcitabine and Cisplatin 

in Advanced NSCLC 

PRAME and WT1 Genes expression 

in CML Patients 

While there’s 

there’s 

life, 

hope. 

(Cicero, 106 - 43 BC) 

Meeting Highlights 

9th Pan Arab Oncology Congress 

Best of ASCO 2009 



ISSN: 2070-254X 

Official Publication of the Arab Medical Association Against Cancer | www.amaac.info | vol 3; issue 2 | June 10 

CANCER 

SURVIVOR 

MONTH 


• Receptor for hyaluronic acid-mediated 

• L’ approche immuno-ptoteomique motility(RHAMM/CD168)inAMLpatients 

SEPRA et Cancer du Sein (in French) 

• Egyptian experience of modified 

medical thoracoscopy 


ISSN: 2070-254X 

Official Publication of the Arab Medical Association Against Cancer | www.amaac.org | vol 4; issue 1 | March 2011 


• Pathologist’s role in Modern Oncology 

Practice 

• Chroidal Metastases from Breast 

carcinoma 

No winter lasts forever; no spring skips its turn. 

~Hal Borland 

• Hypofractionated vs. Conventional 

RT in Glioblastoma Multiforme

Gerard Abadjian, MD 

Hamdi Abdel Azim, MD 

Wafaa Abdel-Hadi, MD 

A. Abdelkefi, MD 

Abdel Rahman M., MD 

Fatma Aboulkasem, MD 

Omalkhair Abulkhair, MD 

Mohsen Abdel Mohsen, MD 

Arabi Abdessamad, MD 

Noha Abdou, MD 

Miguel Aboud, MD 

Philippe Aftimos, MD 

Salim Adib, MD 

B. Allani, MD 

Bekadja Mohamed Amine, MD 

Elie Attieh, MD 

Fadwa Attiga, MD 

Ahmad Awada, MD 

Amal Baccar, MD 

Jean-Marc Bachaud, MD 

Thouraya Baroudi, MD 

Ali Bazerbachi, MD 

Amel Ben Ammar Elgaaied, MD 

Khaled Ben Rhomdhane, MD 

Alain Bernard, MD 

Ghislaine Bernard, MD 

Nizar Bitar, MD 

H. Boussen, MD 

Karim Chahed, MD 

Georges Chahine, MD 

Anouar Chaieb, MD 

Nicolas Chemali, MD 

Lotfi Cherni, MD 

Lotfi Chouchane, MD 

Elizabeth Cohen, MD 

Michel Daher, MD 

Géraldine Dalmasso, MD 

Kamal El-Dein Hamed Mohamed, MD 

Dalia Darwish, MD 

Jean-Pierre Droz, MD 

Tayssir Eyada, MD 

Ahmad El-Ezzawy, MD 

Fadi Farhat, MD 

Nivine Gado, MD 

Marwan Ghosn, MD 

Heba Gouda, MD 

E. Gouider, MD 

Amin Haddad, MD 

Mohammad El-Hajj, MD 

Khaled Halahlah, MD 

Bechr Hamrita, MD 

Gregory Hangard, MD 

Colette Hanna, MD 

Mohamed A Hassan, MD 

Hassan A. Hatoum, MD 

Johan Hoebeke, MD 

Hesham El Hossieny, MD 

Ahmad Husari, MD 

Noha Ibrahim, MD 

Elias Jabbour, MD 

Sima Jeha, MD 

Maria Kabbage, MD 

Fadi El Karak, MD 

Joseph Kattan, MD 

M. Kefi, MD 

Jamal Khader, MD 

Hussein Khaled, MD 

Sami Khatib, MD 

Anne Laprie, MD 

Robert Launois, MD 

Katell Le Lay, MD 

Christelle Lemaitre-Guillier, MD 

Rami Mahfouz, MD 

Nazar Makki, MD 

Carole Massabeau, MD 

Andre Megarbane, MD 

Brahimi Mohamed, MD 

Mohsen Mokhtar, MD 

Walid Moukaddem, MD 

Jonathan Moyal, MD 

Elie Nasr, MD 

Fadi Nasr, MD 

Ghazi Nsouli, MD 

Ben Othman, MD 

Zaher Otrock, MD 

Martine Piccart, MD 

Shadi Qasem, MD 

Silvia Al Rabadi, MD 

Karim Rashid, MD 

Sami Remadi, MD 

Kamel Rouissi, MD 

Raya Saab, MD 

Ebtessam Saad El Deen, MD 

Laurence Ehret-Sabatier, MD 

Gamal Saied, MD 

Nagi El-Saghir, MD 

Ibrahim Saikali, MD 

Khaled El-Saleh, MD 

Ziad Salem, MD 

Lobna Sedky, MD 

Ali Shamseddine, MD 

Ahmad Shehadeh, MD 

Sana Al-Sukhun, MD 

Iyad Sultan, MD 

Ali Taher, MD 

Paul-Henri Torbey, MD 

Wafa Troudi, MD 

Virginie Vandenberghe, MD 

Alain Vergnenegre, MD 

Laure Vieillevigne, MD 

Besma Yacoubi-Loueslati, MD 

Mahmoud Yassein, MD 

Riad Younes, MD 


original article < 

Choroidal Metastases from Breast Carcinoma: Case series 

Jaloudi Mohammad, MD 1 , Sivatrakasam Karthiga, MD 2 , Al Qawasmeh Khaled, MD 1 , Kanbar Jihad, MD 1 , Kumar Pawan, MD 1 

(1) Department of Oncology, Tawam Hospital, Al-Ain, Abu Dhabi, UAE 

(2) Department of Radiotherapy, Tawam Hospital, Al-Ain, Abu Dhabi, UAE 

Corresponding Author: Dr. Mohammed Jaloudi, MD 

Department of Oncology, Tawam Hospital, Al-Ain, Abu Dhabi, UAE 

E-mail: mjaloudi@tawamhospital.ae 

Key words: Breast Cancer, Ocular, Metastases, Choroids, A-scan & B-scan Ultrasonography, Radiation Therapy. 

ISSN: 2070-254X 

Introduction 

Choroidal metastases were first reported in 1872 by Perls1 , who noted an 

intraocular metastatic lung carcinoma. Since then, choroidal metastases have 

become well established as the most common intraocular malignancy2 . Choroidal 

metastases have not been documented to be a frequent finding in disseminated 

breast cancer. Ocular symptomatology in a breast cancer patient should alert the 

physician to undertake a thorough examination of the eye. 

Background 

Breast cancer is one of the most common malignant diseases with a lifetime 

risk of approximately 10% in females and is also one of the major causes of 

cancer related mortality among women worldwide. Attempts to improve survival 

have targeted early diagnosis and development of adjuvant and neoadjuvant 

chemotherapy regimens. Breast cancer screening programs for early diagnosis 

have been incorporated in many international guidelines in the hopes of 

improving survival rates3 . 

Frequent or well described sites of metastases include bone, liver, lung, pleura, 

skin, brain and eye, but tumor manifestations have been reported in nearly 

all anatomic regions. Breast cancer possesses the highest incidence of ocular 

metastatic involvement and the choroids because of their high vascularity are 

the most common site for ocular metastases. This is followed by the anterior 

segment and the optic nerve among solid tumors (female patients with breast 

cancer and male patients with lung cancer). The metastatic involvement of 

ocular structures in breast cancer seems to be a rare clinical entity; nevertheless, 

histopathological inquiries propose that 10-37% of patients with breast cancer 

have detectable ocular or orbital metastases2 . 

In 12-31% of affected individuals, eye metastases were reported to be the 

first sign of malignant disease or metastatic spread2. Choroidal metastases in 

advanced asymptomatic breast cancer patients were determined to be 5% of 

ophthalmological screening. Risk factors included spread of disease to more than 

one organ and the coexistence of lung and brain metastases increased the risk to 

11% 4 . The median period from diagnosis of breast cancer to the development 

of choroidal metastases is reported to be 4 years with a median survival of 5 

to 17 months5 . A large survey of 520 eyes with uveal tract metastases revealed 

that 88% were located in the choroid, 9% in the iris, and 2% in the ciliary body. 

Due to recent advances in breast cancer treatment which has impacted on 

improved survival rates, clinicians should begin incorporating a complete 

ophthalmological examination for tumoral spread as part of a routine screening 

program, particularly in high risk patients or in the setting of disseminated 

disease. This thorough incorporation of an ophthalmologic exam and the 

improved life expectancy of patients with metastatic disease will make the 

diagnosis even more prevalent. 

Case reports 

Six cases of Choroidal metastases from breast cancer were detected at Tawam 

Hospital, Al-Ain, U.A.E., over a period of five years (2004-2008). 

These case reports are discussed in brief below. 

Case 1… A 50 y/o female with no known co-morbid conditions initially 

diagnosed with left breast carcinoma by FNA (fine needle aspiration). Later on 

she had a lumpectomy with axillary clearance followed by adjuvant radiotherapy 

(T1N0M0) in 1992. Histopathology revealed an infiltrating ductal carcinoma; 

grade II, ER/PR positive, Cerb2 negative. All lymph nodes were negative. 

She had no further hormonal therapy or chemotherapy. In February 2004, she 

had mediastinal lymphadenopathy and lung secondaries. Biopsy confirmed 

metastatic IDC, ER positive, PR negative and Cerb2+3. She received 2 cycles 

of chemotherapy with Docetaxel and Capecitabine. Due to poor tolerance, this 

was switched to Docetaxel and Gemcitabine. She completed six cycles with 

good response on CT scans. After 8 months she presented with progressive 

lymphadenopathy. She was again started on systemic chemotherapy with FEC 

(FEC = 5-FU, Epirubicin, Cyclophosphamide). After 4 days in the 2nd cycle, 

she began complaining of left eye pain and blurring of vision. Funduscopic 

evaluation by an ophthalmologist revealed whitish sub retinal exudates. Fundus 

fluorescein angiography (FFA) and B-scan were consistent with choroidal 

metastases. MRI brain and orbits showed normal orbits with small variable 

sized lesion in the left frontal, left post parietal, and right high parietal regions, 

suggestive of cerebral deposits. 

She commenced on whole brain radiotherapy including orbits after appropriate 


simulation using 6MV photon beams on LA on 11/07/05. A dose of 30 Gy in 10 

fractions was delivered using opposing lateral techniques, which was completed 

on 24/07/05. After radiotherapy completion; patient lost follow up. 

Case 2… A 49 y/o female with no known co morbid conditions was diagnosed 

with right breast infiltrating ductal carcinoma with FNA. This was followed by 

a right breast lumpectomy with axillary clearance. Histopathology revealed an 

infiltrating ductal carcinoma; grade III, Triple negative on 02/06/08. She received 

1st cycle of chemotherapy; FEC regimen. Post chemotherapy, she was admitted 

for febrile neutropenia. During the hospitalization, she began complaining of left 

eye diplopia. A CT scan of the orbits and brain was performed which revealed 

a normal brain with left sided retinal detachment, choroidal metastases and optic 

nerve involvement. 

The patient was evaluated by ophthalmology. On examination, right eye was 

normal, left eye disc margins were not clear, yellowish white mass over and 

around the disc and inferior part of retina. B-scan revealed retinal detachment 

with choroidal infiltration. She received radiotherapy to the left orbit at a dose of 

30 Gy in 10 fractions from 31/05/06 to 06/06/06; after radiotherapy completion; 

patient lost follow up. 

Case 3… An 80 y/o female patient with hypertension, acute renal failure, and 

hypercalcaemia was diagnosed with right breast carcinoma via core biopsy in 

April 2008. Histopathology was consistent with an infiltrating ductal carcinoma, 

ER positive, PR negative, and Cerb2 negative. A bone scan revealed extensive 

bone metastases. She was started on the aromatase inhibitor Letrozole. A few 

months later, she developed diplopia. A CT scan of the brain and orbits revealed a 

normal brain with a right orbital mass about 17.0x15.0x7.0 mm along the medial 

wall and causing compression of the optic nerve. The patient was evaluated 

by ophthalmology and later referred to radiotherapy. She received 20 Gy in 5 

fractions with conformal technique. Shortly thereafter, she was lost to follow-up. 

Case 4… A 49 y/o female with primary infertility was diagnosed with a 

triple negative infiltrating ductal carcinoma of the right breast on 27/05/2008. 

Metastatic workup revealed diffuse bone metastases, including the lumbar 

spine. She received 20 Gy in 5 fractions to the lumbar spine. She was then 

started on systemic chemotherapy, FEC regimen on 13/06/08. One week later, 

she presented with blurred vision in the left eye. An MRI of orbits confirmed 

choroidal metastases. Upon these findings, she received 30 Gy in 10 fractions 

to both orbits including optic nerves from 30/06/08 – 16/07/08. During 

radiotherapy, she developed a massive pulmonary embolism which was treated 

with anticoagulant. Upon stabilization, she was started on Epirubicin and 

Taxotere from 23/07/08 and completed a total of 6 cycles with a good PR. 

Three months later, she presented with new liver lesions and was started on 

Capecitabine and Bevacizumab. Up to last follow-up, she had received 4 cycles 

with improvement in her liver lesions. 

Case 5… A 62 y/o female was diagnosed with infiltrating ductal carcinoma of 

left breast in June 2005. The tumor was pT3 N2 M0, ER+, PR+, and HER- 

2 +. She received adjuvant chemotherapy with 4 FEC and 4 Taxotere with 

Trastuzumab. The patient also received radiotherapy to the chest wall and axilla 

and maintenance Trastuzumab. Hormonal therapy with an aromatase inhibitor 

was started after completion of the radiotherapy. In July 2006, she was admitted 

for loss of vision in the left eye and blurred vision in the right eye. An MRI 

revealed bilateral choroidal metastases. She received 40 Gy in 20 fractions to 

both eyes between July and August 2006. Hormonal therapy was changed to 

Tamoxifen. After radiotherapy, she was started on Capecitabine and Trastuzumab 

was recommenced. Unfortunately, she developed a right pathological hip 

fracture and expired after the first cycle due to deterioration of her condition. 

Case 6…. A 38 years old female was diagnosed with left breast cancer in August 

2002. She underwent a lumpectomy with axillary clearance. Pathology revealed 

invasive lobular carcinoma, grade 2, ER +, PR +, HER-2 positive. Adjuvant 

chemotherapy was given with 4 cycles of Vinorelbine and Epirubicin (part of 

a clinical trial) followed by 4 cycles of Paclitaxel. Adjuvant radiotherapy was 

given to the left breast and supra clavicular region for a total of 50 Gy in 25 

fractions; this was followed by an additional boost to the tumor bed giving 9 

Gy in 3 fractions making the total dose of radiation therapy given 59 Gy in 28 

fractions. Post radiotherapy, she was commenced on Tamoxifen. In September 

2004; biopsy proven lung metastases was present. She was restarted on 

Docetaxel and Trastuzumab. After 4 cycles and a good PR, a CT scan of the chest 

revealed progressive disease, so she was switched to Letrozole with Goserelin 

and Trastuzumab was continued. In February 2006, a CT scan revealed 

progression of the lung lesions, Trastuzumab was stopped and patient was 

started on Capecitabine and Bevacizumab. From February 2006 until May 2010 

patient had several lines of chemotherapy. In May 2010 patient presented with 

blurred vision in the left eye. MRI of the orbits revealed choroidal metastasis 

to the left eye. Radiotherapy was given for 25 Gy in 5 fractions to the left eye. 

In August 2010 patient was restarted on Trastuzumab, Lapatinib, and Caelyx. 

After 4 cycles of chemotherapy a CT scan to the chest and abdomen revealed 

a new metastatic lesion in the liver. In August 2010 patient was switched to 

Ixabepilone, Capecitabine, Lapatinib, and Trastuzumab. Another CT scan in 

December 2010 revealed stable disease. 

Pathophysiology 

Intraocular metastases arise when the neoplasm at the primary site spreads 

through the blood to the eye. Due to the high vascularity of the uveal and, 

specifically, the choroid - there is a greater likelihood that metastases will enter 

and remain there. Most choroidal metastases are carcinomas; they are seldom 

melanomas or sarcomas6 . 

Workup 

Workups for choroidal metastases include an MRI of the head to rule out brain 

metastases and to determine the extent of the tumor. Incidence of central nervous 

system (CNS) metastases increases from 6% to 28% after development of ocular 

metastases7 . Patients with an unknown primary site of origin should obtain a 

thorough physical examination and have a chest radiograph and mammogram. 

If the primary site is known, serum chemical analysis, plasma carcinoembryonic 

antigen (CEA), liver function tests, chest radiography, isotope bone scan, and CT 

scan of abdomen should be obtained8 . 

Treatment 

There are a wide variety of treatment options for patients with Choroidal 

metastases, the choice of which depends on many factors, including the 

patient’s systemic state, the presence of visual symptoms, tumor activity, tumor 

size, location, primary site, and whether the patient is concurrently receiving 

chemotherapy. The report by Shields et al. presented a breakdown of common 



treatment options and the percentage of patients who were receiving these 

corresponding therapies. They included: chemotherapy (8%), external beam 

radiation (39%), plaque radiation (7%), hormone therapy (1 %), resection (6%), 

observation (14%), and combination therapy (24%) 9 . 

In cases of regressed lesions or visually asymptomatic patients with advanced 

systemic disease, the judicious option is to observe6. For visually asymptomatic 

patients, many lesions will respond to systemic chemotherapy, hormone 

therapy, or immunotherapy. Brinkley10 used a five drug chemotherapy protocol 

for treatment of metastatic breast cancer and found that choroidal metastases 

responded to chemotherapy with the same sensitivity as metastases elsewhere 

in body11 . If the lesion is unresponsive to chemotherapy, the patient is visually 

symptomatic, or the patient is not able to tolerate chemotherapy, palliative 

radiation therapy may be implemented. There are two types of radiation: 

external beam radiation therapy (teletherapy) and episcleral plaque therapy 

(Brachytherapy). Both aim for tumor flattening and pigment proliferation. The 

decision on which option to choose depends on the size of the lesion and the 

patient’s life expectancy. 

Because choroidal metastases are radiosensitive, external beam radiation therapy 

(EBRT) is the most commonly used treatment for these lesions. This treatment is 

administered with the goal of saving the vision and the globe and provides quick 

tumor regression. The response rate is 80% but if untreated leads to blindness15 . 

In some studies chemotherapy was also as effective as radiotherapy16 . The 

procedure is performed in an outpatient setting. Radiation from a remote source 

is directed at the lesion, and is often performed with a block to limit the radiation 

to anterior ocular structures and to the contra lateral eye. Total doses of 30 to 40 

Gy are administered in daily doses of 2 Gy for 4 weeks. 

A study by Rudoler et al of 233 eyes with Choroidal metastases treated with EBRT 

found that EBRT led to tumor control in 90% of eyes, and globe preservation in 

98% of eyes. Weigel et found that the standardized treatment of 40 Gy (with 

daily doses of 2 Gy given 5 days a week) led to complete remission of the tumor 

in 38% of the patients, partial remission is 27%, minor remission in 18%, and no 

remission in 17%.Patients with breast cancer had a significantly increased rate 

of complete tumor remission, and all patients with combined chemotherapy and 

EBRT had complete remission. 

Higher dosages produce better tumor regression; however, the risk of radiation 

retinopathy or radiation- induced ocular complications is greater. Radiation can 

cause dry eye, cataract, hair loss, cutaneous erythema, and conjunctival irritation6 . 

Late side effects include cataract, glaucoma, and radiation retinopathy12 . Weigel 

found that using more than 40 Gy increased the risk of radiation retinopathy. 

In a retrospective study by Rosset et a112 of 58 patients treated with EBRT, 

patients treated with higher amounts of radiation had better resolution and 

acuities, but more complications. Of patients treated with more than 35.5 Gy, 

72% had complete resolution (CR) and 18% had partial resolution (PR). Of 

patients treated with less than 35.5 Gy, 33% had CR and 41% had PR12. Four 

of the five patients with complications were found in the group receiving more 

than 35.5 Gy. 

Episcleral plaque therapy is focal radiotherapy to the eye performed in an 

inpatient setting. The benefit is that treatment time is reduced to 3 days. This 

therapy is recommended for patients with solitary lesions, patients for whom 

other modes of treatment have been unsuccessful, or for patients whose life 

expectancy is short and who want to maximize their quality of life6 . Radioactive 

seeds such as Iodine-125 sit inside a gold shield, which is sutured to the globe so 

that there is a short distance to the target tissue. The plaque is surgically attached 

to the globe at the site of the lesion. A typical amount of 40 Gy of radiation is 

delivered to the apex of the tumor. Shields15 reported that most patients achieve 

tumor regression to half the original thickness and resorption of the sub retinal 

fluid within the first 3 months after treatment. Complications with plaque therapy 

parallel those of external beam radiation6 . 

Other techniques that are used include local resection, laser photocoagulation, 

transpupillary thermotherapy, and enucleation. Transpupillary thermotherapy is 

still in the early stages of its use in the realm of treating choroidal metastases; 

however, case reports in the literature have shown promising results13 . When the 

patient is in a great deal of pain or the choroidal metastases have grown out of the 

scope of treatment options, enucleation is the recommended treatment. Of note, 

a recent case report of a carcinoid tumor metastatic to the choroid treated with 

photodynamic therapy (PDT) showed tumor regression and an improvement in 

visual acuity14 . 

Survival time 

Prognosis is poor for patients diagnosed with choroidal metastases. Average 

survival time is 8 to 9 months after diagnosis6. The major determinant of 

prognosis for patients with uveal metastases is based on the primary tumor type. 

Cutaneous tumors have the worst prognosis (1 to 2 months survival time), and 

breast tumors have the best prognosis (7 to 31 months). Freedman and Folk7 found that patients with breast cancer had a median survival time of 314 days. 

They analyzed the patient population with regard to the stage of breast cancer. 

Patients with Stage 1 or 2 breast cancer with choroidal metastases had a median 

survival time of 873 days (29.1 months), and patients with Stage 3 or 4 breast 

cancer with Choroidal metastases had a median survival time of 139 days (4.6 

months) 7 . The overall median survival is better in stages I/II than stages III/IV17 . 

Conclusions 

Due to the earlier recognition of cancer and the progress of chemotherapeutic 

medications, the number of patients who manifest Choroidal metastases will 

continue to increase. It is essential for the practitioner to be able to recognize this 

disease process to institute proper treatment for metastatic disease and prevent 

visual loss. A thorough fundus examination, coupled with the use of A-scan and 

B-scan ultrasonography, will aid in the diagnosis of suspicious choroidal lesions. 

The goal of therapy is often palliative if the patient is already being treated 

systemically for cancer. 

References 

1. American Cancer Society. Cancer facts and figures 2003. Atlanta: American 

Cancer Society, 2003. 

2. Ferry AP, Font RL. Carcinoma metastatic to the eye and orbit: a 

clinicopathologic study of 227 cases. Arch Ophthalmol 1974; 92:276-86. 

3. Sheth D, C.A Wasen, D. Schroder, J.E. Boccaccio and L.R .Lloyd, 1999. The 

advanced breast biopsy instrumentation (ABBI) experience at a community 

hospital. Am. Surg., 65: 726-30. 

4. Wiegel T, K.M. Kreusel and N. Bon Feld et al, 1998. Frequency of 


asymptomatic Choroidal metastases in patient with disseminated breast 

cancer: results of a prospective screening programme. Br. J. Ophthalmol., 

22: 1159-61. 

5. Ratanatharathorn V, Powers WE, Grimm J, et al. eye metastases from 

carcinoma of breast: diagnosis, radiation treatment and results. Cancer treat 

rev 1991; 18:161-76. 

6. Shields CL. Plaque radiotherapy for management of uveal metastases. Curr 

Opin Ophthalmol 1998; 9:31-7. 

7. Freedman MI, Folk JC. Metastatic tumors of eye and orbit: patient survival 

and clinical characteristics. Arch Ophthalmol 1987; 105:1215-9. 

8. Demirci H, Shields CL, Chao A, et al. uveal metastases from breast cancer 

in 264 patients. Am J Ophthalmol 2003; 136:264-71. 

9. Shields CL, Shields JA, Gross N, et al. survey of 520 eyes with uveal 

metastases. Ophthalmology 1997; 104:1265-76. 

10. Brinkley JR Jr. Response of Choroidal metastases to multiple drug 

chemotherapy. Cancer 1980; 45:1538-39 

11. Wilson MW, Czechonska G, Finger PT, et al. chemotherapy for eye cancer. 

Surv Ophthalmol 2001; 45:416-44. 

12. Rosset A, Zografos L, Coucke P, et al. radiotherapy of Choroidal metastases. 

Radiotherapy Oncol 1998; 46:263-8. 

13. Puri P, Gupta M, Rundle PA, et al. Indocyanine green augmented 

transpupillary thermotherapy in the management of Choroidal metastases 

from breast cancer. Eye 2001; 15(Pt 4): 515-8. 

14. Harbour JW. Photodynamic therapy for Choroidal metastases from carcinoid 

tumor. Am J Ophthalmol 2004; 137:1143-45. 

15. Thatcher N, Thomas PR: Choroidal metastases from breast carcinoma: 

a survey of 42 patients and the use of radiation therapy. Clin Radiol 26: 

549–553, 1975. 

16. Letson AD, Davidorf FH, Bruce Jr RA: Chemotherapy for treatment of 

Choroidal metastases from breast carcinoma. Am J Opthalmol 93: 102–106, 

1982. 

17. Freedman MI, Folk JC: Metastatic tumors to the eye and orbit. Patient 

survival and clinical characteristics. Arch Opthalmol 105: 1215–1219, 1987 



Figures 

Fig. 1: C/EBPα subgroups and FAB subtypes in our study group. 

a b 

Fig. 2: Disease free survival (a) and overall survival (b) of AML patients based on C/EBPα expression levels. 


notes < 



Multidrug Resistance- related Protein (MRP) and Lung Resistance Protein (LRP) m 

RNA Expression in Egyptian Patients with Acute Leukemia 

Amira Ahmed Hammam, MD 1 , Mohsen Mokhtar, MD 2 

(1) Department of Clinical Pathology, Faculty of medicine, Beni Suef University 

(2) Department of Clinical Oncology , Faculty of medicine, Cairo University 

Corresponding Author: Amira Ahmed Hammam, MD 

Lecturer of clinical Pathology, Faculty of medicine Beni Suef university, Cairo-Egypt 

E-mail: amirahammam@gmail.com 

Key words: MDR, Multidrug Resistance-related Protein, Lung resistance protein, Prognosis, Acute leukemia. 

ISSN: 2070-254X 

Abstract 

Background and objectives: Clinical resistance to chemotherapy is a major 

obstacle in treatment and an important cause of death in Acute Leukemia.Such 

resistance is usually associated with the expression of multidrug resistance(MDR) 

genes. The significance of MDR genes expression is still controversial 

Aim of the work: We investigated whether multidrug resistance-related protein 

(MRP) and Lung resistance protein (LRP) m RNA expression are associated 

with outcomes ,clinical and laboratory findings in acute leukemia patients. 

Patients&methods: At diagnosis we examined MRP and LRP m RNA 

expression in peripheral blood samples from 50 Egyptian Acute Leukemia 

patients (25 myeloid& 25 lymphoblastic) using nested RT-PCR. Ten age matched 

normal individuals were included as control group. 

Results: m RNA of MRP and LRP genes were detected in 28/50 (56%) & 

22/50 (44%) respectively, while there was double expression of both genes in 

18/50 (36%) of acute leukemia patients. There was no statistically significant 

difference between MRP&LRP positive and negative patients as regards 

their clinical and laboratory data including age, sex , hemoglobin, platelets, 

hepatosplenomegally, lymphandenopathy and CNS involvement. As regards 

Total leucocytic count (TLC) the comparison between positive and negative 

cases showed high statistically significant difference (p

National Cancer Institute, Egypt. The median age of the patients was 28 years, 

with mean 25.3 years (range 2yr-75yr). Diagnosis and classification of acute 

leukemia was made according to the French-American-British (FAB) criteria 

and immunophenotype analyses. There were 25 acute myeloid leukemia (AML) 

and 25 acute lymphoblastic leukemia(ALL) patients. Among the 25 AML 

patients, two patients had AML M0, 7 M1, 8 M2, 2 M3, 3 M4, 2 M5, 1 M6. 

Among the 25 ALL patients, fifteen patients were B-lineage, 6 T-lineage and 4 

common ALL. 

Ten normal age matched individuals were included as control group 

Complete remission(CR) 

Complete remission was defined as normocellular bone marrow with less than 

5% blasts after induction chemotherapy, no Auer rods, and no evidence of 

extramedullary involvement(Marry et al;2007). Patients who relapsed or died 

within 28 days after CR were considered as not having achieved a CR. 

Sample collection and Nested RT-PCR assay 

Fifty peripheral blood samples collected in EDTA were obtained at the initial 

diagnosis. A COR-L23/R cell line was used as a positive control for LRP m 

RNA expression, and the HL60/Adr cell line for MRP m RNA expression. 

RNAase-free water was used as negative control, also ten age matched normal 

individuals were included as control group. Β actin m RNA amplification was 

used as an internal control. 

Mononuclear cells were separated from peripheral blood samples by density 

gradient centrifugation using Ficoll-Hypaque and preserved at -20ºC till use. 

Total cellular RNA was extracted from MNCs using a QIAamp RNA blood 

kit (Qiagen,Germany) . Complementary DNA (cDNA) was synthesized using 

Revert Aid First strand c DNA synthesis kit(Fermentas,K1621). The reaction 

was performed at 70ºC for 2 min and 42ºC for 60 min. MRP and LRP m RNA 

amplifications were performed after heating the reaction mixture to 99ºC for 5 

min. 

The first round of PCR reactions involved 30 cycles of: 1 min denaturing at 

94ºC, 1 min annealing at 64ºC and 2 min extension at 72ºC using a thermocycler. 

The PCR reactions were carried out in a final volume of 25µl containing 12.5 µl 

Dream Tag Green PCR Master Mix(Fermentas,K0171 which contains TaqDNA 

polymerase in reaction buffer MgCl2 and Dntps), 5/µl of 5pmol of each primer, 

2 µl c DNA, completed to the final volume with nuclease free water. The first 

round of PCR was followed by a second round of 20 cycles. Amplification of 

β-actin m RNA (20 cycle PCR) was performed and the data obtained used to 

normalize any variation in samples. PCR primer sequences are shown in Table 

1. PCR products were electrophoretically separated on 2% agarose gel and 

visualized using ethidium bromide staining. The sample was considered positive 

when a clear sharp band was observed at the specific molecular weight;420 bp 

for MRP, 239 bp for LRP and 166 bp for β actin. The gel was photographed with 

Polaroid film. 

Statistics 

Data were summarized and presented in the form of percentage, range , mean 

and median. Descriptive statistics and statistical comparisons were performed 

using the statistical soft ware program SPSS (version 14). A P value of < 0.05 

indicated a significant difference while a p value of > 0.05 indicated insignificant 

difference. 

Table 1: NestedRT-PCR primer sequences for MRP, LRP and β- actin m 

RNA amplification (1) 

www.amaac.org Pan Arab Journal of Oncology | vol 4; issue 1 | March 2011 < 13 

Results 

Expression rates of m RNA of MRP and LRP genes: 

By Nested RT-PCR, m RNA of MRP and LRP genes were detected in 28/50 

(56%) & 22/50 (44%) respectively, while there was double expression of both 

genes in 18/50 (36%) of acute leukemia patients. 

In terms of leukemia categories, MRP was expressed in 14/25 (56%) of AML 

patients and 14/25 (56%) of ALL patients; while LRP was expressed in 12/25 

(48%) of AML Patients and 10/25 (40%) of ALL patients. 

All normal controls didn’t express both genes. 

Comparison between MRP&LRP positive and negative patients regarding their 

clinical and laboratory data is presented in table (2). 

There was no statistically significant difference between MRP&LRP positive 

and negative patients as regards their clinical and laboratory data including age, 

sex , hemoglobin, platelets, hepatosplenomegally, lymphandenopathy and CNS 

involvement. 

As regards Total leucocytic count (TLC) the comparison between positive and 

negative cases showed high statistically significant difference (p


Table 2: Relationship between MRP&LRP genes expression and clinical 

and laboratory data of patients 

Acute leukemia 

(n=50) 

AML 

(n=25) 

ALL 

(n=25) 

Sex 

Male(n=24) 

Female(n=26) 

TLCx10³/cm³ 

(mean&range) 

Hemoglobin gm/dl 

(mean&range) 

Plateletsx10³/cm³ 

(mean&range) 

MRP 

positive negative 

28/50 22/50 

(56%) (44%) 

14/25 11/25 

(56%) (44%) 

14/25 11/25 

(56%) (44%) 

17/24 7/24 

(70.8%) (29.2%) 

12/26 14/26 

(46.2%) (53.8%) 

90.35* 40.3* 

(3-325) (1.35-115) 

8.1 7.6 

(4.4-11.6) (2.5-10) 

98.4 110.6 

(8-413) (6-765) 

Hepatosplenomegaly 10/28 8/22 

(35.7%) (36.4%) 

Lymphadenopathy 8/28 7/22 

(28.5%) (31.8%) 

CNS involvement 4/28 3/22 

(14.2%) (13.6%) 

Complete Remission 6/28* 15/22* 

(21.4%) (68.2%) 

*p value Pan Arab Journal of Oncology | vol 4; issue 1 | March 2011 www.amaac.org

RT-PCR the m RNA of two genes named MRP&LRP genes. Fifty patients (30 

males and 20 females) diagnosed with denovo acute leukemia between January 

2009 and December 2009 recruited from the National Cancer Institute, Egypt 

were included in this study. The median age of the patients was 28 years, with 

mean 25.3 years (range 2yr-75yr). Diagnosis and classification of acute leukemia 

was made according to the French-American-British (FAB) criteria and 

immunophenotype analyses. There were 25 acute myeloid leukemia (AML) and 

25 acute lymphoblastic leukemia(ALL) patients. Among the 25 AML patients, 

two patients had AML M0, 7 M1, 8 M2, 2 M3, 3 M4, 2 M5, 1 M6. 

Among the 25 ALL patients, fifteen patients were B-lineage, 6 T-lineage and 4 

common ALL. 

Ten normal age matched individuals were included in our study as control group. 

m RNA of MRP and LRP genes were detected in 28/50 (56%) & 22/50 (44%) 

respectively, while there was double expression of both genes in 18/50 (36%) of 

acute leukemia patients. 

In terms of leukemia categories, MRP was expressed in 14/25 (56%) of AML 

patients and 14/25 (56%) of ALL patients; while LRP was expressed in 12/25 

(48%) of AML Patients and 10/25 (40%) of ALL patients. 

All normal controls didn’t express both genes. 

There was no statistically significant difference between MRP&LRP positive 

and negative patients as regards their clinical and laboratory data including age, 

sex , hemoglobin, platelets, hepatosplenomegally, lymphandenopathy and CNS 

involvement. 

Mary M. et al (2007)(2) showed that the m RNA expression of resistance genes 

were not significantly associated with the age of patients. 

As regards Total leucocytic count (TLC) the comparison between positive and 

negative cases showed high statistically significant difference (p


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notes < 



Phase II pilot study of weekly Docetaxel as Neoadjuvant Chemotherapy for operable 

Breast Cancer 

El. Bassiouny M. Mohamed, MD 1 , Hesham El. Ghazaly, MD 1 , Mahmoud A. El. Lithy, MD 1 , Ramy R. Ghali, MD 1 , Moustafa 

Mahmoud, MD 2 , Gamal Fawzy MD and Osama Mahmoud MD, FRCS 3 

(1) Department of Radiation Oncology and Nuclear Medicine, Ain Shams University. 

(2) Department of Radiology, Ain Shams University. 

(3) Department of General Surgery, Ain Shams University. 

Corresponding Author: Mahmoud Ellithy, MD 

Address: Ebadelrahman city, Ring road. Omar Ebn Elkkattab st. No 58. 

E-mail: doctor_ellithy@yahoo.com 

Key words: Weekly, Docetaxel, Neoadjuvant, Breast cancer. 

ISSN: 2070-254X 

Abstract 

Purpose: In this study of weekly docetaxel in the neoadjuvant treatment of stage 

II breast cancer, we evaluated the efficacy and safety of docetaxel and analyzed 

the correlation between the response observed and the expression of c-erbB2, 

ER status. 

Patients and Methods: This study included patients with previously untreated, 

stage II & III breast cancer. Docetaxel was given as a 30-min i.v. infusion at 

a dose of 40 mg/m2 weekly for 6 weeks, followed by 2 weeks rest. Patients 

received two 8-week cycles of treatment. Patients achieving a CR or partial 

response or who had stable disease at the end of treatment proceeded directly 

to surgery. 

Results: A total of 40 patients were evaluated by intention-to-treat analysis 

for efficacy and safety. The overall clinical response rate was 65% (complete 

and partial response, 25 and 40%, respectively). Six patients (15%) achieved 

a pathological complete response. There was no correlation between response 

to docetaxel and the expression of molecular markers, however, the majority 

of the pathological complete responses were observed in patients with 

c-erbB2-negative tumors. Nonhematological toxicity was more common than 

hematological toxicity, with alopecia and asthenia were the most frequently 

reported adverse events. Severe hematological toxicity was rare. 

Conclusion: Weekly docetaxel appears to be very effective in the neoadjuvant 

setting. A high pathological response rate was achieved with tolerable toxicity. 

Introduction 

Breast cancer is the most common cancer in women and it is incurable when 

metastases are diagnosed. Taxanes, namely docetaxel and paclitaxel, are effective 

chemotherapeutic agents in the metastatic, neoadjuvant and adjuvant settings. 

HER-2 over expression is detected in 25–30% of breast cancer , it confers 

aggressive tumor behavior as well as resistance to some systemic treatments and 

has been associated with poor outcome, in both node-negative and node-positive 

early breast cancer [1-4]. In vitro, HER-2 overexpression confers increased 

resistance to paclitaxel in breast cancer cells, while HER-2 degradation increases 

docetaxel-induced apoptosis [5-7]. This is further supported by data from a phase 

III clinical trial showing that paclitaxel response rate was significantly improved 

in breast cancer patients when HER-2 was downregulated by the humanized anti- 

HER-2 antibody, trastuzumab [8]. 

Neoadjuvant therapy for breast cancer generally refers to the administration 

of chemotherapy prior to local treatment with surgery and/or radiation. The 

biological rationale for neoadjuvant therapy of breast cancer is based on the 

observation of accelerated metastatic growth following tumor resection.. 

Neoadjuvant chemotherapy minimize the emergence of chemo resistant clones 

,increasing tumor resectability by reducing the size of an unresectable tumor, 

improving local control and improving cosmesis by allowing breast-conserving 

treatment. It also offers an important test bed for novel therapies including new 

drugs and new combinations of drugs. More recently, neoadjuvant therapy has 

been studied as a way of testing the relevance of biological markers in predicting 

disease outcome. The expression of the proto-oncogenes c-erbB2 (her2/neu), 

bcl-2 and p53 have been evaluated as predictive markers in several trials without 

clearly defined results [9-12]. 

Observations from early studies, both single arm phase II studies and those 

randomizing pre-operative systemic therapy against post-operative adjuvant 

therapy, have confirmed that those women whose tumors have a pathological 

complete response to neo-adjuvant chemotherapy have the best long-term 

outcome, and this remains true after multivariate analysis [13]. It has even been 

suggested that regimens achieving a higher proportion of patients in pathological 

complete response should then be used in the adjuvant setting as they must give 

a survival improvement on older treatments [14]. 

The taxanes have emerged as critically important drugs in the treatment of 

patients with breast cancer. Taxanes were generally recognized as evidencebased 

components of therapy for metastatic breast cancer within a few short 

years of their initial phase II evaluations. In addition, the data in support of their 

use in the adjuvant and neoadjuvant settings continue to strengthen [15]. 

Docetaxel is a taxane prepared by semisysnthesis beginning with a precursor 

extracted from the needles of yew plant it binds to the ß-tubulin subunit causing 

inhibition of microtubule depolemerization [16], and several phase II and III 

trials reported a high activity in first- and second-line therapy of metastatic breast 

cancer, as well as in patients previously exposed or resistant to anthracycline [17- 


18]. When docetaxel was compared with doxorubicin, it produced statistically 

superior response rates compared with doxorubicin (48% versus 33%, P = 0.008) 

and longer time to treatment failure [17]. It has also been studied in patients who 

have progressed on anthracycline-containing chemotherapy and differences in 

progression-free survival have been found [18]. 

Weekly regimens of taxanes may enhance dose intensity by minimizing regrowth 

of cells between cycles of treatment and can also be combined with other new 

drugs such as biological agents directed against the tyrosine kinase I receptor 

c-erbB2 [19] . Experience with docetaxel as neoadjuvant chemotherapy has 

mainly been in combination with an anthracycline . The rates of pahological 

complete remission (pCR) reported in these trials are similar to those obtained 

with standard regimens, although the best regimen with docetaxel as neoadjuvant 

chemotherapy has not yet been defined. 

Based on indirect comparisons as well as the results of the recent randomized 

trial conducted in patients with metastatic breast cancer, docetaxel appears to 

be the more active taxane. In addition to its longer half-life, docetaxel also has a 

more rapid cellular uptake and longer intracellular retention than paclitaxel [20].. 

Docetaxel is highly active when given as a short, intermittent infusion. [21]. 

This study is a pilot phase II trial of single-agent docetaxel given on a weekly 

schedule as neoadjuvant treatment for patients with breast cancer. Our primary 

aim was to measure the overall objective clinical response rate to weekly 

docetaxel. Secondary objectives included assessing the safety of the regimen, 

measuring the pathological response rate to docetaxel, and evaluating the role 

of the c-erbB2 receptor and ER as potential predictive factors of response to 

single-agent docetaxel. 

Patients and Methods 

Patient Population 

Patients with previously untreated, histologically confirmed, operable breast 

cancer were included in the study. Infiltrating disease was confirmed before 

chemotherapy for all patients. Patients were required to have measurable 

disease by physical examination and diagnostic breast imaging (mammogram, 

ultrasound and Magnetic Resonant Image) with a primary tumor ≥ 2 cm. All 

patients were ≥ 18 years. Patients had to have Eastern Cooperative Oncology 

Group performance status < 2, hemoglobin ≥ 10 g/dl, neutrophils ≥ 2 × 109 / 

liter, and platelets ≥ 100 × 109 /liter, with adequate hepatic and renal function 

(including calculated creatinine clearance ≥ 60 ml/min). Cardiac function was 

evaluated by echocardiography and a left ventricular ejection fraction of ≥50% 

was required. Patients were excluded if they had bilateral tumor or metastatic 

disease as confirmed by chest radiography, liver ultrasound or computer 

tomography imaging and bone scintigraphy, or if they had any other severe or 

uncontrolled systemic disease. Fertile women had to have a negative pregnancy 

test and had to be using adequate, non hormonal contraception. 

Treatment 

Docetaxel was given as a 30-min i.v. infusion at a dose of 40 mg/m2 weekly 

for 6 weeks, followed by 2 weeks rest. Patients received two 8-week cycles of 

treatment. Patients achieving a CR or partial response or who had stable disease 

at the end of treatment proceeded directly to surgery. After surgery, adjuvant 

chemotherapy was delivered according to the standard regimen. 

Docetaxel administration was delayed for up to 1 week in the event of a neutrophil 

count < 1 × 109 /liter, platelet count 10% tumor cells; and score 3+, 

strong, complete membrane staining in >10% of tumor cells. Scores 0 and 1+ 

were considered negative, and scores 2+ and 3+ were considered positive for 

c-erbB2 overexpression. 

Statistical Analysis 

The sample size was calculated using with a type I error of 5% and a study power 

of 80%. The target enrollment was estimated to be 40 patients. All patients who 

fulfilled the inclusion criteria and received at least one infusion were evaluated 

for efficacy and safety on an intention-to-treat analysis. The statistical analysis 

was performed by SPSS version 17. All variables were analyzed by descriptive 

methods. Chi square test was used to assess the relation between response to 

Docetaxel (clinical and pathological response) with Her 2 neu expression and 

Hormonal receptors status. 



Results 

Patients 

• Forty patients were included in the trial. Characteristics of the 

patients are summarized in Table 1. All patients were evaluated for 

efficacy and safety on an intention-to-treat basis. Two patients were 

withdrawn with progressive disease during treatment. 

Efficacy 

Response rates is illustrated in table 2 .Before treatment, only 20 (50%) patients 

were eligible for lumpectomy, and no patient initially scheduled for lumpectomy 

subsequently required mastectomy. The precise surgical procedure carried out 

was decided upon by the surgeon on a case-by-case basis, with consent from the 

patient. A pCR, with no evidence of invasive tumor in breast and lymph nodes, 

was confirmed in 10 of 40 patients (25%), including 2 patients with residual 

carcinoma in situ only. 

Immunohistochemistry 

Tumor paraffin blocks were obtained from 40 patients before treatment. 

No correlation was seen between clinical or pathological response with the 

expression of any of the biological markers assessed, however, the majority of 

the pCRs were observed in patients with c-erbB2-negative tumors. (Table 3) 

Safety 

Toxicity was assessed in 40 patients (Table 4). 

Discussion 

In this study the overall response rate was slightly low (65%) compared with 

other recent studies , the pCR rate was very high with 10 patients (25%) showing 

no evidence of invasive tumor at definitive surgery. 

Most of the neoadjuvant trials reported to date with docetaxel are Phase II 

studies in combination with an anthracycline and no particular combination or 

regimen appears to be outstanding in terms of pathological and clinical response 

rates. Trial B-27 from the National Surgical Adjuvant Breast and Bowel Project 

(NSABP) demonstrated that the addition of four cycles of sequential, preoperative 

docetaxel to preoperative AC(Adriamycin /cyclophosphamide) chemotherapy in 

2411 patients produced a significantly superior outcome ( Overall response rate 

(ORR)=90.7% ,pCR=26.3%). relative to four cycles of AC alone (ORR=85.7% 

,pCR=12.9%). [24]. 

Some have criticized the design of the NSABP B-27 trial because the 

preoperative regimens were of different durations (four versus eight cycles) 

and suggested that the favorable results in the AC/docetaxel arm may be due to 

the delivery of additional cycles of chemotherapy rather than a distinct taxane 

benefit. However, the results of a study conducted at the University of Aberdeen, 

in which eight cycles of neoadjuvant CVAP (cyclophosphamide/vincristine/ 

doxorubicin/prednisolone) chemotherapy were compared with four cycles of 

CVAP followed by four cycles of docetaxel (eight cycles total) prior to surgery 

, suggested that the addition of the taxane is indeed beneficial (ORR=66% 

vs 94% ,pCR= 16% vs 34% respectively). [25]. In that trial, 162 patients with 

large or locally advanced breast cancer were randomized to the study regimens, 

and 145 patients completed eight cycles of neoadjuvant therapy.. The results 

were statistically significant in the primary analysis and in the intent-to-treat 

population. Furthermore, two patients who received eight cycles of CVAP 

developed progressive disease after initially responding to the first four cycles 

of CVAP, which suggests the development of acquired resistance to the regimen. 

This observation was not seen in the docetaxel group, and this finding supports 

the use of non-cross-resistant chemotherapy combinations such as anthracyclines 

plus taxanes. 

The NSABP B-27 data are corroborated by the results of the GEPARDUO trial 

conducted by the German Adjuvant Breast Cancer Group, which compared four 

cycles of dose-dense AT (doxorubicin/docetaxel) given concomitantly with a 

sequential regimen of four cycles of doxorubicin/cyclophosphamide followed 

by four cycles of docetaxel (AC-T) as neoadjuvant therapy in 913 patients with 

operable breast carcinoma [26]. In the primary analysis, AC-T was associated 

with a superior pCR rate and ORR, as well as a greater rate of breast-conserving 

surgery and higher incidence of pathologically negative axillary lymph nodes ( 

ORR=77.2% vs 86.8% ,pCR= 11.5% vs.22.4% respectively). 

Conversely, interim results of a phase III trial conducted by the Anglo-Celtic 

Cooperative Oncology Group showed that there was no benefit to using a 

concomitant docetaxel/doxorubicin regimen every 3 weeks, relative to AC, 

in the neoadjuvant setting [27]. A total of 363 women with locally advanced 

breast cancer were randomized in that trial. At the time of analysis, there was a 

trend toward a higher ORR with AT (72% versus 62%; p = 0.07), but there were 

no differences in rates of pCR, axillary lymph node involvement, relapse-free 

survival, or overall survival. 

In our study, using single-agent docetaxel in a weekly schedule, resulted in a 

high number of pathological responses and a favorable toxicity profile. The fact 

that the proportion of stage II patients included was high (85%), with a relatively 

small median tumor size (4.6 cm), may have favorably affected this pCR. 

Docetaxel was generally well tolerated. Apart from alopecia, asthenia was the 

most frequent side effect but did not result in patient withdrawal from the study. 

Nail disorders and acral erythema were frequent, although the number of patients 

with grade 3–4 events was low, and the symptoms were reversible. Grade 3–4 

myelosuppression was rare in our study, with only 2 cases of neutropenia and 

none of thrombocytopenia. 

In neoadjuvant trials, HER-2 positive was associated with an improved response 

to dose-dense paclitaxel in 15 of 21 stage T2–3 BC patients; clinical response 

was more than double in patients with HER2-positive tumors treated with 

paclitaxel (P < 0.05). Although this trial was prospective, it was not randomized, 

had a small number of patients and has been published only as an abstract [28]. 

Another small prospective study failed to demonstrate any correlation between 

HER-2 positivity and pathological complete response (pCR) in 29 patients with 

locally advanced breast cancer (LABC), T3 or T4, treated with doxorubicin 

followed by paclitaxel or paclitaxel followed by doxorubicin in a dose-dense 

regimen [29]. These negative results were also confirmed using FISH (Her-2/ 

CEP17 >2) in 71 patients treated with neoadjuvant paclitaxel or docetaxel given 

every 3 weeks [30]. Estévez et al. [31] also failed to demonstrate correlation 

between pathological or clinical response and HER-2 expression (P = 0.355 and 

P = 0.942, respectively) in 56 stage II–III breast cancer patients treated with 

weekly neoadjuvant docetaxel (ORR 68% and pCR 16%). However, all these 

three trials were non-randomized, had few patients and in two studies, HER-2 

status was not confirmed by FISH. 

Interesting findings from Modi et al. [32] showed that phosphorylated-activated 

HER-2 is associated with clinical resistance to taxanes in 126 patients enrolled in 

different trials with single-agent taxanes for metastatic and, perhaps, functional 

assessment of HER-2 status may provide unique predictive information not seen 

with conventional assessment. 

More recently, gene expression profiling techniques have been used for the 

development of a prediction model for response to docetaxel and paclitaxel. 


Chang et al. [33] have reported 92 genes that correlated with docetaxel response 

(P = 0.001) using microarray technology. Sensitive tumors had higher expression 

of genes involved in cell cycle, cytoskeleton, adhesion, protein transport, protein 

modification, transcription and stress or apoptosis; whereas resistant tumors 

showed increased expression of some transcriptional and signal transduction 

genes. However, this study was not designed to discover specific genes for 

docetaxel response or resistance, but rather to identify patterns of many genes 

that could be used as a predictive test in patients with breast cancer. [34].Ayers et 

al. [35] have examined the feasibility of developing a multigene predictor of pCR 

to sequential weekly paclitaxel and FAC (T/FAC) neoadjuvant CT for breast 

cancer. pCR was achieved in 13 patients (31%) out of 42 patients: 24 patients 

were used in the training set and 18 patients in the validation set. The authors 

could not identify any single marker that was sufficiently associated with pCR to 

be used as an individual predictor. [36]. 

In our study, we found no association between overexpression of c-erbB2 and 

the clinical and pathological response to neoadjuvant docetaxel. However, the 

majority of the pCRs were observed in patients with c-erbB2-negative tumors. 

The number of the patients in our study was low, and this trend should be 

studied in a larger trial. In addition, these data suggest that blocking c-erbB2 

overexpression using a monoclonal antibody such as trastuzumab (Herceptin) 

could enhance the response to docetaxel. 

This pilot phase II trial highlights the need to identify the best schedule for 

neoadjuvant docetaxel. In our study, single-agent docetaxel given on a weekly 

schedule appeared to be very effective and well tolerated as neoadjuvant 

chemotherapy, with a high documented pCR. 

Because at present there is no evidence that primary systemic therapy offers a 

disease-free survival or overall survival benefit over adjuvant systemic therapy, 

knowledgeable patients may choose to receive systemic therapy before surgical 

resection to take advantage of the response-assessment of the primary tumor 

before it is removed. 

Acknowledgment 

We are in debited to all the nursing staff, the residents and the patients who 

accepted to join this study in the Clinical Oncology Department, Faculty of 

Medicine, Ain ShamsUniversity. 

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Tables 

Table 1. Baseline characteristics of patients 

No. of patients (%) 

Total no. of patients 

Age (yr) 

40 (100) 

Mean 

53±SD19.7 

Range 

Tumor size (cm) 

28–73 

Mean 

4.4±SD1.7 

Range 

ECOG 

2–8.5 

a performance status 

0 

39 (97.5) 

1 

Menopausal status 

1 (2.5) 

Premenopausal 

18 (45) 

Perimenopausal 

2 (5) 

Postmenopausal 

Disease stage 

20 (50) 

IIA 

16 (40) 

T2N0M0 

16 (40) 

IIB 

18 (45) 

T3N0M0 

14 (35) 

T2N1M0 

4 (10) 

IIIA 

4 (10) 

T2N2M0 

2 (5) 

T3N1M0 

2 (5) 

IIIB 

2 (5) 

T3N2M0 

aEastern Cooperative Oncology Group 

2 (5) 

Table 2: Response rate to docetaxel on intention-to-treat basis 

No. of patients % 

CR 10 25 

Partial response 16 40 

Stable disease 12 30 

Progressive disease 2 5 

Response rate (95% 

confidence interval) 

26 65 (56–80)

Table 3 : Relation between biological markers and Response 

Her 2 neu 

positive 

Her 2 neu negative 

Pathological CR 2 4 6 

Non Pathological 

CR 

15 19 34 

Total 17 23 40 

P value 0.6 (Non Significant) 

Estrogen Receptor Estrogen Receptor 

positive 

negative 

Pathological CR 3 3 6 

Non Pathological 

CR 

23 11 34 

Total 26 14 40 


Her 2 neu 

positive 

Her 2 neu negative 

Clinical Response 12 14 26 

Non responders 5 9 14 

Total 17 23 40 


Estrogen Receptor Estrogen Receptor 

positive 

negative 

Clinical Response 15 11 26 

Non responders 9 3 16 

Total 26 14 40 


Table 4. Hematological and nonhematological adverse events (n = 40) 

Adverse event Grade 1 or 2 


Hematological 

Anemia 

Leucopenia 

Neutropenia 

Thrombocytopenia 

Nonhematological 

Alopecia 

Anxiety 

Asthenia 

Conjunctivitis 

Cutaneous 

Diarrhea 

Hypersensitivity 

Infection 

Nail disorder 

Nausea/Vomiting 

Paresthesia 

Peripheral edema 

Stomatitis 

2 (5) 

20 (50) 

20 (50) 

4 (10) 

40 (100) 

0 

24 (60) 

10 (25) 

20 (50) 

16 (40) 

4 (10) 

6 (15) 

22 (55) 

16 (40) 

21 (42.5) 

9 (22.5) 

14 (35) 

Grade 3 or 4 


1 (2.5) 

0 

2 (5) 

0 

1 (2.5) 

8 (20) 

2 (5) 

6 (15) 

2 (5) 

0 

1 (2.5) 

7 (17.5) 

0 

2 (5) 

0 

2 (5) 



The Role of Pathologist in Modern Oncology Practice 

Hanaa Bamefleh, MBchB, FRCPC 1 , Abdul-Rahman Jazieh, MD, MPH 2 

(1) Department of Pathology and Laboratory Medicine 

(2) Department of Oncology 

King Abdulaziz Medical City, Riyadh, KSA 

King Saud bin Adbulaziz University for Health Sciences, Riyadh, KSA 

Corresponding Author: Abdul-Rahman Jazieh, MD, MPH 

Chairman, Department of Oncology (Mail code 1777) 

King Abdulaziz Medical City, Kingdom of Saudi Arabia 

E-mail: jazieha@ngha.med.sa 

Keywords: Pathologist, Oncology, Cancer Diagnosis, Tumor Boards 

ISSN: 2070-254X 

Abstract 

Background: Pathologists are often viewed as the invisible members of 

oncology multidisciplinary teams, yet major decisions about patient care are 

totally dependent on their input. Making an accurate diagnosis is the first and 

most crucial step in managing cancer patients, which is the pathologist’s arena. 

Methods: Information about the topic was compiled from literature review, 

professional societies publications, colleagues input and personal experience. 

Results: The purpose of this manuscript is to illustrate and outline the 

comprehensive role that should be fulfilled by a competent pathologist in 

providing state of the art service to oncology practices and to encourage 

maximum utilization of this role. The pathologist’s role in oncology practices is 

becoming increasingly critical due to the accelerated rate of new diagnostic tools 

and tests used in clinical applications. The roles of pathologist’s include making 

accurate diagnoses, evaluating disease response, participating in tumor boards, 

educating staff and conducting research. 

Conclusion: The role of pathologist is central to modern oncology practice and 

the pathologist is an integral member of the oncology care team. 

Various medical specialties and subspecialties have emerged over the last few 

decades creating increasing complexities in functions and roles of various heath 

care professionals. To ensure best patient care, a strong cooperation among these 

subspecialties is crucial. 

Some specialties are essential for any tertiary health care center such as laboratory 

medicine and radiology, because all other services are dependent on them. For 

example, a surgeon may need the guidance of the pathologist preoperatively and 

intraoperatively for optimal completion of surgery. Similarly, an oncologist will 

not be able to treat a cancer patient appropriately without a proper diagnosis 

made by a pathologist. 

Since many of their activities are done away from the clinic or the patients, 

pathologists are considered by some as invisible members of oncology care team 

in spite of their critical role. 

The pathologist has multiple roles in the contemporary and future oncology 

practice that are presented and discussed in this manuscript. (Table 1) 

Making an accurate diagnosis 

To ensure that a pathologist carries this task effectively and efficiently to 

generate accurate specific diagnostic reports, he/she has to be updated on all 

issues relevant to tissue handling, evaluation and interpretation. The College of 

American Pathologists (CAP) offers anatomic pathology educational programs 

that are designed to improve the analytic and diagnostic skills of pathologists 

and technologists. 1 These skills and techniques have to be translated into a clear, 

accurate, surgical pathology report that indicates the diagnosis. 2 The Pathologists 

should know their limitations and capabilities and they should ask for help when 

needed. Inaccurate interpretation of pathology samples in any given patient may 

lead to providing erroneous management which must be avoided at all costs. 

Helping clinicians interpret the laboratory data to synthesize a clearer 

clinical picture 

How was the diagnosis reached should be highlighted by explaining all specific 

studies used to reach it, such as special stains, immunohistochemistry, molecular 

studies, electron microscopy and flowcytometry. 

How these studies correlate with the behavior or prognosis of the tumor has to 

be stated in the report. 

Correlation with any previous tissue or cytology samples taken from the patient 

has to be made to explain clearly whether they are the same pathology or two 

different pathologies. Furthermore, the updated pathologic staging, grading 

and status of resection margins are all essential information for any report 

on malignant lesion. A standardized reporting format has to be followed. 

References are available in many sites such as CAP or reference books. 3,4 

The need for more tissue should be mentioned in the report with explanation 

why it is needed. Is it for more studies essential for diagnosis, prognosis and 

management or because the tumor is very heterogeneous and different areas of 

the tumor may show different morphology such as in many sarcomas, or just 

simply because the first biopsy was insufficient. Another scenario for requiring 

more tissue is the presence of carcinoma insitu in a superficial biopsy, where the 

possibility of invasion cannot be ruled out and a deeper biopsy is needed. The 

pathologist opinion will influence the sequence of the patient workup and enable 


the clinician to select the best diagnostic procedure. Adequate tissue specimen is 

essential for securing a final and accurate diagnosis. 

The pathologist should be receptive for the treating physician input regarding 

any missing relevant data from the report thus monitoring completeness of the 

surgical pathology report. 

All available data has to be reported using clear, precise words, avoiding vague, 

equivocal, or ambiguous terminology; keeping in mind that every word may be 

utilized by the oncologist / clinician to tailor the treatment plan for the patient. 

Assessing response to treatment 

In cases of patients with solid tumors who have received neoadjuvant therapy and 

in those with hematologic malignancies who have received induction therapy, 

the pathologist should comment on presence, grade and percentage of viable 

tumor, if it exists. Furthermore, comparison of tumor grade and differentiation 

in the current tissue sample with the previous samples is very important to plan 

further management. 

Evaluating and assessing new diagnostic technology application and 

utilization in clinical practice 

The pathologist should evaluate all new technologies in the field and decide with 

the clinicians about acquiring it to their practice. 

The behavior and prognosis of many cancers are better elucidated by the 

recent advanced in the genomic and molecular field. Pathologists should not 

only specify tumor size, lymph node status but also should state expression of 

certain markers with prognostic or predictive values. Pathologists have become 

central in the development, validation, implementation and appropriate use of 

predictive testing to better treat patients with targeted therapy. 5 Examples of such 

targets include over expression and or amplification of HE-2 Neu Oncogen, the 

expression or activation of epidermal growth factor receptor – Tyrosine Kinase 

pathway and over expression of C-Kit in gastrointestinal stromal tumor and 

leukemia. 6 Regular update of the pathology department policy and procedure 

manual for the proper and state-of- the-art way of handling and reporting of each 

tissue type should be done and maintained in the department. The oncology 

clinical team members should be kept abreast about all these updates. 

By providing this diagnostic information and by characterizing the biologic 

behavior of the tumor, the pathologist plays a critical role in the oncology team 

and impacts tremendously the patient’s care. 

Role in multidisciplinary teams and tumor boards 

The contributions of pathologists in the multidisciplinary meetings and tumor 

boards are essential. The pathologist does not just present slides, discuss 

differential diagnosis and suggest further work up; but he/she also answers 

queries, explains reasons for incomplete report and reasons for requesting more 

tissue or second opinion. 

This integrated care through the multidisciplinary approach has been widely 

recognized by different specialties. A good example is the many multidisciplinary 

breast teams that have been established all over the world. 5 

Education 

The pathologist should contribute and participate in the education of the clinical 

care teams whether in form of didactic lectures, tumor boards, or individual 

encounters to discuss specific cases and update the group on the most recent 

advances in the field. 

Effective communication 

there are many ways to deliver the report to the clinician. However, direct 

communication is essential to clarify any ambiguous issues and to get critical 

points through. For cases with insufficient clinical information or ambiguous 

findings, additional information should be sought out. Some cases may require 

urgent intervention and therefore, personal communication will assure timely 

action. Documentation of this discussion has to appear in the final report, which 

can be sent via intranet to patient’s electronic file and to responsible physicians 

by email as well as by sending a hard copy to patients file or doctors office. 7,8 

In a survey done by Zarbo, the greatest opportunities for improvement of anatomic 

pathology service were determined to relate not to professional competence 

but to communication. 9 These include timeliness of reporting, communication 

of relevant information and the mandated notification of significant abnormal 

results. i.e critical value which requires immediate contact of the physician to 

rapidly initiate/modify treatment or to perform further required timely evaluation 

(Table 2 & 3). However, since there are no established critical value guidelines 

in surgical pathology, some situations may arise that require a common sense 

and personal experience of the pathologist to determine when an immediate 

communication with the clinician is needed. 8 

When communicating verbally with team members of the tumor board, 

pathologist should clearly explain all the terminology and descriptions used in the 

report and should correct any formatting problems to the reports during interface 

that might change the meanings. 2 This step is important to avoid misconstruction 

that can happen due to unawareness of some physicians to certain terminology 

used in surgical pathology practice. For example, some physicians think that 

metaplasia and dysplasia are a premalignant condition and the terms can be used 

interchangeably; while it is true for the later but not for the former term unless it 

becomes an atypical metaplasia. 

It is essential to deliver the diagnosis of unexpected malignancies, incomplete 

surgical resections, positive margins, unpredicted type of malignancy, frozen 

section results, discrepancies between frozen section and permanent section 

immediately and clearly to the clinicians, as these are critical findings that 

impact the management decisions. 7,8 

Any change of the final diagnosis for any reason such as obtaining more clinical 

information, getting more stains, more levels of the tissue blocks, more tissue 

from the same lesion should be delivered immediately to the oncologist and 

documented in the final amended report. The quality control officer of the 

laboratory should be informed and the reason for changing the report should be 

documented. 

Oncology research 

Well-structured research projects can be generated utilizing the data provided 

by the pathologists in the form of elaborate standardized reports that are well 

archived and easily retrievable. Correlative studies can be conducted for newly 

discovered tumor markers, molecular findings, and genetic alteration or of the 

different tumor types with response to different treatment modalities, behavior 



and prognosis. By putting together all these pathological data with the clinical 

details, brilliant research projects can be performed that will direct future 

diagnostic or management approaches and help more patients. 

The breakthroughs in molecular oncology led the pathologist to play a key-role 

in translational research for the identification of new targets in tissue specimens 

that may eventually lead to new therapeutics. 10 

Conclusion 

The pathologist roles in the modern oncology practice are complex and diverse 

but they are essential and critical for patient care, medical staff education and the 

advancement of medical knowledge and research. 

Acknowledgement 

The authors are indebted to Dr. Walid Khalbus for his critical review of this 

manuscript. 

References 

1. www.cap.org 

2. Valenstein PN. Formatting pathology reports. Applying four design 

principles to improve communication and patient safety. Arch pathol lab 

med 2008; 132(2):206-10. 

3. Rosai & Ackerman’s surgical pathology, Juan Rosai Mosby, Ninth Edition, 

2004. 

4. Susan C. Lester. Manual of surgical pathology, Susan C. Lester. Elsevier 

Churchil Livingstone, second edition, 2006. 

5. Masood S. The Expanding Role of Pathologists in the Diagnosis and 

Management of Breast cancer: worldwide Excellence in Breast Pathology 

Program. The Breast Journal 2003;9(2);s94-s97. 

6. Hartmann A. Role of predictive pathology in oncology-example of new 

therapies targeting EGFR. Verh Dtsch GCS Pathol 2006; 90:128 – 35. 

7. LiVolsi VA. Critical Values in Anatomic Pathology, How Do We 

Communicate? Am J Clin Pathol 2004; 122:171-172. 

8. Pereira TC, Liu Y, and Jan Silverman JF. Critical values in surgical 

pathology. Am J Clin Pathol 2004;122: 201-205. 

9. Zarbo RJ. Determining Customer Satisfaction in Anatomic Pathology. 

Arch Pathol Lab Med 2006; 130 (5): 645-649. 

10. Spatz A, Ruiter DJ, Busch C, Theodorovic I, Oosterhuis J.W, on behalf 

of the EORTC pathology group; The role of the EORTC pathologist in 

clinical trials: achievements and prospectives. European Journal of Cancer 

2002;28:S120-S24. 

Table 1: The Roles of the Pathologists in Oncology Practice 

1. Making an accurate diagnosis using all available tools including 

conventional and state-of-the-art methods 

2. Helping clinicians interpret the laboratory data to synthesize a clearer 

clinical picture. 

3. Helping in assessing and determining disease response. 

4. Evaluating and assessing new diagnostic technology application and 

utilization in clinical practice. 

5. Playing an active role in the multidisciplinary teams and tumor boards. 

6. Participating in the staff education. 

7. Maintaining communication with clinicians to provide critical 

information in a timely fashion. 

8. Participating actively in oncology research. 

Table 2: Critical values related to oncology patient 

1. Incomplete surgical resection 

2. Positive margins (margin involved by tumor) 

3. Discrepancy between frozen section & permanent section 

4. Change of a benign diagnosis to malignant 

5. Recurrence of tumor 

6. Unexpected malignancy (see table 3) 

7. Unpredicted type/grade or stage of malignancy 

8. Negative resection specimen 

9. Malignancy in superior vena cava syndrome 

10. Major change of final diagnosis for any reason 

11. Drug toxicity (e.g. lung, kidney, skin reaction) 

12. Organisms due to immuno suppression e.g. Mycobacterium 

tuberculosis, fungus, invasive aspergillosis, virus 

13. Neoplasm causing paralysis 

14. Large vessel in a core biopsy 

Table 3: Examples of unexpected malignancies 

1. Lymphoma in a gastric biopsy for Helicobacter 

2. Molar pregnancy in routine dilatation and curettage 

3. Lymphoma in fine needle aspiration of a lymph node suspected as 

tuberculosis 

4. Benign tumor with a focus of malignancy [table 4] 

5. Hematologic malignant neoplasms AML type M3, Burkitt’s lymphoma, 

and leukemia cutis. 8 

1. 

Table 4: Examples of Benign lesion /tumor with an unexpected 

focus of malignancy 

Carcinoma ex-pleomorphic adenoma 

2. Fibroadenoma with a focus of ductal carcinoma 

3. Mature cystic teratoma containing immature elements or carcinoma 

4. Benign prostatic hypertrophy with focal prostatic carcinoma 

5. Nodular goiter with microscopic focus of papillary carcinoma. 

6. Undescended tests with intratubular germ cell neoplasia and /or germ 

cell tumor. 

7. Umbilical hernia with metastatic adenocarcinoma 


notes < 



Taxanes Versus Vinorelbine and 5-Fluorourocil as a First Therapy in Metastatic 

Breast Cancer 

Ibtessam Saad El-Din, MD 1 , Wael Samir, MD 1 , Wessam El-Sherief, MD 1 , Yomna Khaiery, M.Sc 2 

(1) Kasr El-Aini Oncology Center (NEMROCK) 

(2) El-Salam Oncology Center 

Corresponding Author: Wessam Ali El-Sherief, MD 

E-mail: wessam_elsherief@yahoo.com 

Keywords: Metastatic Breast Cancer, Taxanes, Vinorelbine and 5-FU 

ISSN: 2070-254X 

Abstract 

Purpose: To compare the efficacy and tolerance of taxanes versus combination 

of vinorelbine and 5-FU in the treatment of MBC previously treated with 

anthracyclines and analyzing the effect of various prognostic factors. 

Material and methods: Between April 2005 and April 2007, sixty eligible 

MBC patients were randomized between 2 arms. Arm I received taxanes (either 

paclitaxel 175 mg/m2 D or Docetaxel 100 mg/m 1 2 D ) and arm II received 

1 

combination of vinorelbine 25 mg/m2 D and D , and 5- FU 600 mg/m 1 5 2 by 

continuous IV infusion D1 to D5. cycles of chemotherapy were repeated every 

21 to 28 days for a total of 6 cycles in both arms. 

Results: Three patients (10.3%) in arm I achieved complete remission versus 

one patient (3.4%) in arm I, while 13 patients (44.8%) in arm I versus 9 patients 

(31%) in arm II had partial remission. (P=0.383). Neurosensory changes and 

fluid retention were more evident is arm I while diarrhea and nail changes were 

more common in arm II (P=0.03). The mean overall survival was 27.7 months 

with taxanes and 26.5 months with vinorelbine and 5-FU (P = 0.79) while 

progression free survival was 15.7 months in patients treated in arm I versus 8.5 

months in arm II (P = 0.234). 

Conclusion: Both regimens are well tolerated and feasible, there treatment 

outcome and toxicity profile are comparable but cost effective issue may have an 

important impact on treatment selection. 

Introduction 

Breast cancer continuous to be the most common cancer in women world-wide. 

Metastatic breast cancer is usually considered as an incurable situation for which 

treatment chosen to control the disease should take into account the maintenance 

of a good quality of life. The clinical benefit which encompasses objective 

response and long standing stability of the disease has often become a goal in 

metastatic setting. (1) Also, improvement in time to progression and duration of 

response have been considered as primary goals of treatment. (2) 

Eventually, chemotherapy is considered for almost all patients with metastatic 

breast cancer. Several agents are now available offering expanded treatment 

options for many patients. (3) 

Combination regimens should be considered for patients with overwhelming 

symptoms or rapidly progressive or life threatening metastasis for which a 

combination regimen is more likely to result in a tumor response. (4) 

Response rates to initial therapy with anthracyclines, taxanes, capecitabine, 

vinorelbine, and gemecitaline range on average from 25% to 60% with median 

time to progression averaging approximately 6 months. (4) 

The aim of this study is to compare the efficacy and tolerance of taxanes versus 

combination of intravenous vinorelbine and 5-FU given by continuous infusion 

in the treatment of metastatic breast cancer patients previously treated with 

anthracyclines and analyzing the effect of various breast prognostic factors in 

both regimens. 


This study is a randomized prospective study that included 60 patients 

with metastatic breast cancer presented to Kasr El-Aini Oncology Center 

(NEMROCK) and El-Salam Oncology Center in the period from April 2005 to 

April 2007. 

Patient eligibility criteria: 

1. Patients age range from 18 to 70 years. 

2. WHO performance status of 0 to 2. 

3. Pathologically proved breast cancer with evidence of visceral, bone or 

locoregional metastasis. 

4. All patients should have been treated previously with an anthracycline as 

an adjuvant setting. 

Patients were randomized between two arms. Arm I received taxanes (either 

paclitaxel or docetaxel), and arm II received vinorelbine and 5-Flurouracil. 

Study design and treatment: 

Thirty patients were treated in arm I by a single agent, taxanes either docetaxal 

100 mg/m2 D 1 hour intravenous infusion or paclitxel 175 mg/m 1 2 D 3 hours 

1 

intravenous infusion, to be repeated from 3 to 4 weeks. Patients were given 

antiemetics, antihistaminecs and corticosteroids as premedications before 

receiving the taxane and continued two days after. 


Arm II included also 30 patients treated by a combination chemotherapy protocol 

consisting of vinorelbine (Navelbine) given intravenously in a dose of 25 mg/ 

m 2 D 1 and D5 together with 5-Fluorouracil 600 mg/m 2 by a continuous infusion 

from D1 to D5 of the cycle, cycles to be repeated 21 to 28 days provided clinical 

and hematological recovery. 

Actual body weight was used to calculate body surface area, and after an 

amendment to the study protocol the maximum body surface was limited to 2.0 

m 2 . Clinical, hematological and biochemical assessments were required before 

each cycle, including assessment of toxic effects according to the common 

toxicity criteria, version 1 of the National Cancer Institute. 

In both arms patients were re-evaluated by physical examination, radiological 

imaging and laboratory tests after completion of 3 cycles of the chemotherapy 

protocol to assess the response as well as the efficacy and toxicity of the 

treatment. 

Patients showing disease progression were planned to shift to another line of 

chemotherapy while those showing response or even stable disease continued on 

the same line of treatment to a total of 6 cycles in both arms of the study. 

Statistical Analysis 

Data were statistically described in terms of range, mean, standard deviation 

(± SD), median, frequencies (number of cases) and relative frequencies 

(percentages) when appropriate. Comparison of age between the study groups 

was done using Mann Whitney T-test for independent samples for comparing 

categorical data, Chi square (x2) test was; performed. Yates correction was 

used instead when the frequency is less than 10. Survival, analysis was done 

for the different outcome measures using Kaplan Mayer statistics with the 

corresponding survival graphs, A probability value (P-value) less than 0.05 was 

considered, statistically significant. All statistical calculations were done using 

computer programs. Microsoft Excel version 7 (Microsoft Corporation, NY, 

USA) and SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, 

IL, USA) statistical program. 

Results 

Patients characteristics: 

The characteristics of the 60 patients enrolled in the study are summarized in 

Table (1). 

Symptoms 

A variety of presenting symptoms were existing according to the different 

metastatic sites. 

The cardinal symptom was pain either in the right hypochondrium related to 

the liver metastasis of patients 9/30 (30%) in arm I and 5/30 (16.7%) in arm II 

(P- 0.22) or in bony metastatic sites 8/30(26.7%) in arm I and 12/30(40%) in 

arm II (P= 0.206). 

Chest symptoms (dyspnea, cough + expectoration) were found in 36.7 % (11/30) 

of patients in arm I and (30%) 9/30 in arm II (P = 0.392) 

Swelling (in the breast or lymph nodes) is 3/30 (10 %) of patients in arm I and 

4/30 (13.3%) in arm II (p-value0.5). Skin nodules in 12/30 (40%) of patients in 

arm I and 11/30(36.7) in arm II (P = 0.792). 

Number of metastasis: 

Number of metastatic sites in both arms are summerised in Table (2). 

Treatment related toxicity: 

Treatment related toxicities were measured from grade 0-4 according to the 

WHO recommendations as regard hematological toxicities (Table 3) and 

according to the EORTC classification and recommendation for grading of nonhematological 

toxicities (Table 4). 

Response: 

The assessment of response was carried out at the end of the treatment course. 

Patients who achieved complete response (CR) were 3/30 (10.3%) in arm I 

(received taxanes), versus 1/30 (3.4%) in arm II (received navelbine and 5-FU). 

Thirteen patients (44.8%) in arm I had partial remission (PR) versus 9 patients 

(31%) in arm II. 

While patients who developed disease progression were 3 patients (10.3%) in 

arm I versus 6 patients (31%) in arm II. 

Patients who had stationary disease (SD) were 11/30 (36.6%) in arm I versus 

14/30 (46%). 

The results of the response rate were statistically non significant between the two 

arms (P = 0.383). 

Survival: 

The mean overall survival (OAS) was 27.7 months in arm I versus 26.5 months 

in arm II (P = 0.79) (Fig. 1), while the progression free survival (PFS) for arm I 

was 15.7 months and 8.5 months for arm I (P = 0.234) (Fig. 2). 

Factors affecting response rate: 

Using umivariant analysis of different prognostic factors were studied in relation 

to response, time to progression and overall survival. 

Factors as age (>35 years), site of recurrence (local or bone) and number of 

metastatic sites (


Inspite adequate primary therapy in breast cancer, many patients with apparently 

localized disease harbor subclinical micrometastasis micrometastasis that may 

grow into clinically relevant macrometastases later on. (5) 

Metastatic breast cancer patients have a median survival of 2-3 years, this occurs 

despite the discovery of numerous new agents that can palliate the disease and 

more rarely increase the overall survival. (6) Therefore, for the majority of patients 

with metastatic breast cancer “cure” is not the goal of treatment ,instead, more 

conservative treatments are prefered to obtain maximum control of symptoms, 

prevent serious complications and prolong life with minimal toxicities and 

disruption of quality of life. (5) 

In the last decade the development of new cytotoxic drugs and combinations and 

the introduction of novel targeted agents have permitted to lenghthen patient’s 

survival and improve quality of life. (7) 

There is no single standard chemotherapy regimen for patients with MBC. 

In addition to the taxanes, various agents (e.g. capecitabine, gemcitabine and 

vinorelbine) used alone or in combination have emerged to be efficacious. 

In this retrospective study, we compared taxanes verus a combination of 

vinorelbine & fluorouracil in patients with metastatic cancer breast. Complete 

remission CR was 3/30 (10.3%) in arm I (received taxanes) vs 1/30 (3.4%) in 

arm II (received navelbine &5FU) with no statisticaly significant difference. 

However difference in partial response and progressive disease was slightly 

better in Taxane group with no statisticaly significant difference. 

Patient who attained partial remission PR was 13/30(44.8%) in arm I vs 9/30 

(31%) in arm II, while patient who developed progressive disease PD was 3/30 

(10.3%) in arm I vs 6/30 (20.0%) in arm II. The mean over all survival was 27.7 

months vs 26.5 months in arm II. 

Factors affecting response were age, site of recurrence, number of metastasis all 

theses factors show statistically significant difference in both treatment groups, 

while other factors showed no statistically significant difference. 

These factors are performance status PS, menopausal status (MS), hormonal 

status (HS) as will as disease free survival (DPS). This response rate is 

comparaple to other study that use the same regimen like Bonneteterre et al. (8) 

who obtained response in 176 women with metastatic breast cancer who had 

failed anthracycline-based therapy The CR rate following Taxotere was 7%, 

compared to 4.4% following 5-FU and Navelbine. The PR rate was 36% for the 

Taxotere group and 34.4% for the combination group. Overall survival was 16 

months for the Taxotere group and 15 months for the combination group. 

Also in comparesion to other regimens used in MBC as vinorelbine and cispltin 

that reported by Vassilomanlakis et al. (9) , who obtaind response rate in 53 

patients with 4 patients (8%) in CR, 22 patients (41%) in PR, ORR (49%). In 

comparesion to Gunel et al. (10) who obtaind response rate25% in 24 patient and 

to Ray-Coquard et al. (1998) who obtaind response rate in 58 patients 2 patients 

(3%) in CR,22 patients (38%), ORR (43%) used the same regimen. 

There is wide range of variation between different studies using Chemotherapy 

in MBC even between studies using the same regimen, this might be due to 

selection bias where these studies are mostly non-randomized trial. 

Other important factor is the use of different dose schedules among different 

studies, not only the scheduled dose differ from study to study but more 

important the relative average dose intensity differ from study to study even if 

they have got same dose schedule. 

The number of patients needed hospitalization with blood transfusion and 

growth stimulating factor were 4 vs 5 for taxanes vs navelbine & 5-FU average 

hospital stay is four days, these adds to treatment cost. 

In comparison to Bonneterre et al. (8) who repoted the main grade III-IV toxicities 

were 82% vs 67%; stomatitis 5% vs 40%; febrile neutopenia 13%vs 22% and 

infection 2% vs 7% for docetaxel vs navelbine & 5-FU. There was one possible 

treatment-related death in docetaxel arm and five with navelbine & 5-FU. 

As regards cost effective outcome, the paclitaxel or docetaxel arm costs about 

35,000 L.E. and the navelbine &5-FU arm costs about 15,000 L.E. and this 

reflects the economical advantage of the vinorelbine & 5-flurouoracil. 

This economic advantage considered as a major advantage especially in favor of 

navelbine & 5-FU in developing countries. 

Clinical research in which more attention is paid to symptom control and quality 

of life and increased emphasis is placed on improving treatment individualization 

remains the only way for progress to be made in the management of MBC 

In conclusion, in a situation where treatment outcome as well as toxicity profile 

are comparable in both treatment arms, the cost effective issue should have an 

important impact on treatment selection. With the growing understanding of 

biology of breast cancer and the advent of new techniques such as genomics 

and proteomics, multiple new targets for anticancer therapy are identified every 

year. The challenge for clinicians will be to find the most appropriate niche for 

the new biologic therapies in breast cancer management, the hope being that the 

therapies will significantly improve the quality and the length of chemotherapy 

induced remissions and disease stabilization. 

References 

1. Orlando AS: Arm Oncol, 2007; 18 suppl 16: vi 74-6. 

2. Cathie TC & Robert WC: Goals and Objectives in the Management of 

Metastatic Breast Cancer. The Oncologist, December 2003; Vol. 8, No.6, 

514-520. 

3. Bernard-Marty, Fatima Cardoso, Martine J: Facts and Controversies in 

Systemic Treatment of Metastatic Breast Cancer The Oncologist, November 

2004; Vol. 9, No. 6, 617-632. 

4. Costanza ME, Weiss RB, Henderson IC: Safety and efficacy of using a 

single agent or a phase II agent before instituting standard combination 

chemotherapy in previously untreated metastatic breast cancer patients: 

report of a randomized study-Cancer and Leukemia Group B 8642. J Clin 

Oncol 1999; 17:1397. 

5. Colozza Mariantonie, Evandro De Azambuja, Nicola Personeni: 

Achievements in systemic therapies in the pregenomic era in MBC. The 

oncologist; March, 2007; 12, 253-270. 

6. Bontenbal M, Creemers GJ, Braun HJ: Phase II to III study comparing 

doxorubicin & docetaxel with 5-FU, doxorubicin & cyclophosphamide as first 

line chemotherapy in patients with MBCJ Clin Oncol, 2005; 23, 7081-7088. 


7. Adamo V, Franchina T, Adamo B, Ferraro G, Rossello R, Maugeri Sacca 

M, Scibilia C, Valerio MR & Russo A: Safety and activity of trastuzumab- 

containing therapies for the treatment of metastatic breast cancer: our long- 

term clinical experience (GOIM study) Annals of Oncology 18 (Supplement 

6): vill-vil5, 2007 doi: l0.10937 annonc/mdm217. 

8. Bonneterre J, Roche H, Monnier A: Docetaxel vs 5-fluorouracil plus 

vinorelbine in metastatic breast cancer after anthracycline therapy failure. 

British Journl of Cancer. 2002; 87:1210-1215. 

9. Vassilomanolakis M, Koumakis G, Barbounis V: First-line chemotherapy 

with docetaxel and cisplatin in metastatic breast cancer patients previously 

treated with anthracyclines.Ann oncol 2000; 11: 1155-1 1160. 

10. Gunel N, Akcail Z, Yamac D,Onuk E Yilmaz E, Bayram Tekin E, Coskun 

U et al.: Cisplatin plus vinorelbine as a salvage regimen in refractory breast 

cancer turners 2000 Jul -Aug; 86 (4) :283 -50. 

11. Ray-Coquard I, Biron P, Baachelot T et al.: Vinorelbine and cisplatin 

Figures 

(CIVIC regimen) for the treatment of metastatic breast carcinoma after 

failure of anthracycline and/or paclitaxl. co regimines 1998; 82: 134-40. 

Fig. 1: Overall survival 

Fig. 2: Progression free survival 



Tables 

Table 1: Patients characteristics 

Parameter 

Age in years < 35 

>35 

Performance status 0 

1 

2 

Menopausal status Pre 

Post 

Pathology IDC 

ILC 

Tumor grade II 

III 

ER group +ve 

-ve 

PR group +ve 

-ve 

Her 2neu +ve 

-ve 

Site of metastasis Visceral: 

Liver 

Lung 

Table 2: Number of metastatic sites in both arms 

Arm I Arm II 

Number Percent Number Percent 

5 

16.5% 

7 

23.3% 

25 

83% 

23 

76.6% 

5 

17.2% 

4 

14.8% 

18 

62.1% 

19 

66.7% 

6 

20.7% 

5 

18.5% 

10 

33.3% 

11 

37.9% 

20 

66.7% 

18 

62.1% 

26 

86.6% 

24 

80% 

4 

13.3% 

6 

19% 

20 

66.7% 

22 

73.3% 

10 

33.3% 

8 

26.7% 

18 

62.1% 

22 

73.3% 

11 

37.9% 

8 

26.7% 

17 

58.6% 

18 

60% 

12 

41.4% 

12 

40% 

3 

37.5% 

0 

0% 

5 

62.5% 

3 

100% 

12 

12 

40% 

40% 


8 

9 

26.7% 

30% 

P-value 

0.112 

0.581 

0.789 

0.551 

0.576 

0.412 

0.562 

0.339 

0.206 

0.294 

Loco 15 50% 14 46.7% 0.500 

Bone 9 30% 12 40% 0.294 

Number of metastatic sites 

No 

Arm I 

% No 

Arm II 

% 

One site 15 50 16 53.3 

Two sites 12 40 14 46.7 

Three sites 3 10 0 0 

Table 3: Hematological toxicities 

Parameter 

Neutropenia I, 

&III 

II 

Anaemia I, 

&III 

II 

Thrombo-cytopenia I, 

&III 

II 

P-value 

0.386 

No 

Arm I 

% No 

Arm II 

% 

P-value 

12 

40% 10 

33.3% 0.395 

0 

0 

4 

13.3% 3 

10% 0.690 

0 

0 

2 

6.7% 1 

3.3% 0.5 

0 

0

Table 4: Non-hematological toxicities 

Parameter Grade 

Number 

Arm I 

Percent 

Arm II 

Number Percent 

P-value 

Alopecia I ,II & III 6 

20% 2 

6.7% 0.12 

0 

0 

Fatigue I ,II & III 9 

30% 9 

30% 0.61 

0 

0 

Nausea I ,II & III 9 

30% 7 

23.3% 0.56 

0 

0 

Nail changes I ,II & III 0 

0% 4 

13.8% 0.03 

0 

0 

Fluid ret. > 3kg 8 26.7% 0 0 0.03 

Vomiting I ,II & III 7 

24.1% 12 

40% 0.196 

0 

0 

Diarrhea I ,II & III 0 

0 4 

13.3% 0.038 

0 

0 

Epiphora Positive 3 10% 2 6.9% 0.66 

Stomatitis I ,II & III 7 

23.3% 5 

16.7% 0.51 

0 

0 

Neurosens I ,II & III 7 

23.3% 1 

3.3% 0.02 

0 

0 

Neuromot I ,II & III 3 

10% 0 

0% 0.68 

0 

0 

Table 5 

Prognostic factor Response TTP OAS 

Age 0.014 0.034 0.001 

Site of recurrence 0.004 0.012 0.026 

No of metastatic sites 0.008 0.016 0.03 

Table 6 

Prognostic factor Response TTP OAS 

PS 0.794 0.727 0.317 

MS 0.544 0.118 0.119 

HS 0.452 0.969 0.668 

PS : Performance status MS: Menopausal status HS: Hormonal status 



Dose-Dense Chemotherapy in High-Risk Breast Cancer: Treatment Outcome and 

Toxicity 

Salah El-Mesidy, MD, Mohsen Mokhtar, MD, Amr El-Kashif, MD, Loay Kasem, M.Sc 

Department of Clinical Oncology, Faculty of Medicine, Cairo University. 

Corresponding Author: Dr. Amr El-Kashif, MD 

E-mail: amrelkashif@hotmail.com 

Keywords: Dose-Dense, Adjuvant Chemotherapy, Breast Cancer. 

ISSN: 2070-254X 

Abstract 

Purpose: To prospectively assess the treatment outcome of dose-dense adjuvant 

doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) in highrisk 

breast cancer patients (dose-dense arm) and to compare it with the available 

treatment results of the conventionally scheduled fluorouracil, doxorubicin, 

and cyclophosphamide (FAC) used to treat high-risk patients (control arm). 

Study endpoints included relapse-free survival (RFS), overall survival (OS) and 

toxicity. 

Patients and Methods: After mastectomy or breast conservative surgery, 

high-risk node-positive breast cancer 61 patients were assigned to receive 

adjuvant 4 cycles of doxorubicin/cyclophosphamide followed by 4 cycles of 

paclitaxel (AC/T) every 2 weeks. The treatment outcome of dose-dense AC/T 

was eventually compared with that of the conventionally treated high-risk 

patients using adjuvant 6 cycles of FAC combination chemotherapy scheduled 

every 3 weeks. The relevant data of 43 patients received FAC chemotherapy 

were obtained from the medical records. Both arms were balanced regarding 

age, menopausal status, number of positive axillary lymph nodes and hormonal 

status. 

Results: At a median follow up of 37 months (range 12 – 48 months), the 

3-year adjusted RFS rates for AC-T and FAC were 76% and 54.6%, respectively 

(P=0.042) and the mean disease-free interval was 40.6 ± 7.2 months (95% CI, 

37.7 - 43.6) for dose-dense AC/T arm Vs 36.9 ± 6.9 months (95% CI, 32.3 - 

41.5) for FAC arm, (P=0.040). The subgroup analysis revealed that dose-dense 

chemotherapy had a statistically significant positive effect on the 3-year RFS in 

premenopausal patients, patients with 10 or more (N3) positive axillary lymph 

nodes, positive ER status. There was no statistically significant difference in the 

3-year OS between the two regimens. The dose-dense arm was associated with 

more grade 3-4 toxicity compared to FAC arm, mainly neuropathy (36%. Vs 

2.3%, P=0.002), anemia (49%. Vs 13.9%, P=0.037) and granulocytopenia (57%. 

Vs 213%, P=0.04). No toxicity-related mortality was observed in both arms. 

Conclusion: Dose-dense AC/T significantly improved the relapse-free survival 

in patients with high-risk primary breast cancer and was less well tolerated 

compared with the conventionally scheduled FAC. The benefit was evident in 

premenopausal patients, extensive axillary nodal metastasis and positive ER 

status. 

Introduction 

The value of adjuvant chemotherapy has been convincingly demonstrated in 

breast cancer patients with involved axillary nodes. In the last three decades, 

incremental benefits in breast cancer disease-free survival (DFS) and overall 

survival (OS) have occurred with the introduction of anthracycline and taxane 

adjuvant chemotherapy regimens and with the exploration of higher doses (dose 

intense) and more frequent administration of these drugs (dose dense) (1-3). The 

importance of dose-intensity for adjuvant chemotherapy in patients with breast 

cancer has first described by Hryniuk et al.(4). Higher dose-intensity can be 

achieved by either increasing the single dose per cycle (i.e. higher dose) or by 

reducing the intervals between cycles (i.e. dose density) (5). 

The concept called log-cell kill postulated that a given dose of an antineoplastic 

compound would always kill a certain fraction of the tumor, regardless of the 

number of cells present. On the basis of that model, higher doses are supposed 

to be effective because the fraction of destroyed cancer cells will increase with 

intensification of the dose. However, the impact of therapy is not only associated 

with the tumor-cell kill by each dose but also with the rate of cancer regrowth 

between cycles (6). Gompertzian kinetics suggest that micrometastases in the 

adjuvant setting grow faster than established macrometastases; thus, there is 

likely a higher regrowth of micrometastases between the cycles. Therefore, the 

administration of cytotoxic drugs with a shortened interval between treatments 

would be an even more effective strategy for minimizing residual tumor burden 

than pure dose escalation (5). 

In the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) 

MA5 trial, 6 months of cyclophosphamide, epirubicin, and fluorouracil (CEF) 

improved 5-year DFS and OS compared with 6 months of cyclophosphamide, 

methotrexate, and fluorouracil (CMF) (7). Subsequently, CEF was compared 

with a 12-week regimen of epirubicin and cyclophosphamide (EC) administered 

with higher doses and more frequent dosing in locally advanced breast cancer. 

No difference was detected between regimens in progression-free survival at 34 

months (8). Incorporating taxanes into anthracycline-based schedules yielded, 

in most studies, an additional benefit in both DFS and OS and dose-dense 

anthracycline-based and paclitaxel-based regimens have shown to be more 

effective than the conventional dosing schedule (9-13). 


The aim of the current study was to prospectively assess the treatment outcome 

of dose-dense adjuvant doxorubicin and cyclophosphamide (AC) followed of 

paclitaxel (T) in high-risk breast cancer patients. Furthermore, the results of dosedense 

chemotherapy were compared with those of the conventionally scheduled 

combination chemotherapy of fluorouracil, doxorubicin, and cyclophosphamide 

(FAC) used to treat high-risk patients (control arm). Study endpoints included 

relapse-free survival (RFS), overall survival (OS) and toxicity. 


The current prospective study included female patients with histologically 

proven node-positive high-risk invasive early breast cancer referred to Kasr 

El–Aini Center of Radiation Oncology and Nuclear Medicine (NEMROCK) 

during the period between January 2006 and December 2009. The study had the 

institutional ethical review board approval. 

Patient population: Patients eligible to receive dose-dense AC/T chemotherapy 

had the following criteria: 

• Age 18 - 65 years old. 

• Performance Status (PS) of 0–2 according to The Eastern Cooperative 

Oncology Group (ECOG) scale. 

• Operable breast cancer: T1-3, N1-2 treated by either mastectomy or 

breast conservative surgery (BCS) and axillary nodal dissection with free 

surgical margins. 

• High-risk features: either 4 or more positive axillary lymph nodes or 1-3 

positive nodes with over expression of the human epidermal growth factor 

receptor 2 (HER2/neu). 

• No evidence of metastatic disease. 

• No prior chemotherapy or radiotherapy received. 

• Adequate organ functions and No evidence of significant illness or comorbidities. 

Pre chemotherapy investigations included; 1- Laboratory investigations: 

complete blood picture, kidney function tests, liver function tests, CA15-3. 

2- Radiological assessment: baseline chest radiograph, abdominal ultrasound, 

echocardiography 3- Isotopic bone scanning. 4- Estrogen and progesterone 

receptors (ER and PR) status. 5- HER2/neu expression by immunohistochemistry: 

a score of (3+) was considered positive (overexpressed) while scores of (0, 1+, 

or 2+) were considered negative. 

Treatment regimen: Eligible patients were assigned to receive dose-dense AC/T 

adjuvant chemotherapy which consisted of: 4 cycles of AC (doxorubicin 60 mg/ 

m2 and cyclophosphamide 600 mg/m2 administered IV on day 1) every 2 weeks 

followed by 4 cycles of T (paclitaxel 175 mg/m2 administered by IV infusion over 

3 hours on day 1) every 2 weeks. Prophylactic granulocyte colony-stimulating 

factor (G-CSF) was administered using filgrastim (5 ug/Kg/day subcutaneous 

injection) for 3 consecutive days 24-48 hours after chemotherapy. Treatmentinduced 

toxicity was evaluated according to the National Cancer Institute (NCI) 

Common Toxicity Criteria version 2.0 grading system (14). Patients who had an 

overexpressed HER2/neu did not receive adjuvant trastuzumab to exclude any 

positive effect on treatment outcome that may be attributed to its addition. 

After completion of chemotherapy, radiotherapy was given to the whole breast 

(after BCS) or chest wall ( after mastectomy) and peripheral lymphatics at a 

dose of 5040 cGy/28 fractions using linear accelerator 6 MV followed by a 

boost to the site of primary tumor(after BCS) at a dose of 1600-2000 cGy/8-10 

fractions by electron beam or photons. Premenopausal patients with ER and/or 

PR positive tumors were assigned to receive 5 years of adjuvant tamoxifen 20 

mg/day while postmenopausal women with positive receptors were assigned to 

receive 5 years of sequential aromatase inhibitor (AI) and tamoxifen. 

Follow-Up: After completion of chemotherapy and radiotherapy, patients were 

planned for follow up visits every 3 months during the first year, every 4 months 

in the second year, and every 6 months until the end of the fifth year. Patients were 

subjected to careful history-taking and physical examination. A mammogram 

and echocardiography were performed yearly whereas, chest X-ray, abdominal 

ultrasound or bone scan were requested if symptoms or laboratory abnormalities 

were present. 

Outcome Measures: The primary end point of this study was relapse-free 

survival (RFS) which was defined as the time from surgery to documented 

recurrence. Local breast recurrence, nodal recurrence, and metastatic disease 

were considered as a recurrence. Patients who had a contralateral breast cancer 

or a second malignancy were not considered to have a relapse. Secondary 

outcome measures included overall survival (OS) which was defined as the time 

from surgery to documented death due to any cause. Treatment-related toxicity 

is another secondary end point. 

AC/T versus FAC analysis: The treatment outcome of dose-dense AC/T was 

eventually compared with the available treatment results of the conventionally 

treated high-risk node-positive patients using adjuvant 6 cycles of FAC 

combination chemotherapy (5-flurouracil 600mg/m2 , doxorubicin 60 mg/m2 and 

cyclophosphamide 600 mg/m2 were administered IV on day 1) scheduled every 

3 weeks. Patients received FAC chemotherapy enrolled in the analysis had the 

same inclusion criteria and were treated during a defined period of time with a 

comparable follow-up period to assess the same outcome measures. The relevant 

data including the clinico-pathological characteristics, outcome parameters and 

treatment-related toxicity were obtained from the medical records. 

Statistical analysis: Data were statistically described in terms of range, mean ± 

standard deviation (± SD), frequencies (number of cases) and percentages when 

appropriate. Survival analysis was done for the different outcome measures 

using Kaplan Maier statistics calculating the mean and median survival time for 

each group with their 95% CI and the corresponding survival graphs. Factors 

examined as a stepwise adjusted Kaplan Meier were age at presentation ( 

35, 35 - 49 , 50 years), T status (T1, T2, T3, T4), N status (N1, N2, N3), 

menopausal status (postmenopausal or premenopausal), ER status (negative or 

positive), PR status (negative or positive), and HER2/neu status (negative or 

amplified). A plot of RFS and OS Vs the mentioned factors were calculated and 

compared between the two groups. A probability value (p value) less than 0.05 

was considered statistically significant. All statistical calculations were done 

using computer programs Microsoft Excel 2007 (Microsoft Corporation, NY, 

USA) and SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, 

IL, USA) version 17 for Microsoft Windows. 


Results 

A total of 61 patients were recruited to receive dose dense AC-T and were 

compared with 43 patients received standard FAC chemotherapy with respect 

to the clinico-epidemiological features, disease-related events and treatmentrelated 

events. The follow-up period ranged from 12 months to 48 months with a


median follow up of 37 months. Baseline characteristics were balanced between 

both treatment arms with no statistically significant differences. (Table 1) 

Table 1: Baseline patient and tumor characteristics 

FAC 

(no.=43) 

AC-T 

(no.=61) 

P 

value 

No. % No. % 

Age (years) 

35 3 7 8 13.1 

36-50 21 48.8 25 41 

50+ 19 44.2 28 45.9 0.53 

Median (range) 

Menopausal 

status 

47.5 (27 - 65) 47 (24 -63) 0.6 

Pre menop. 20 46.5 38 62.3 

Post menop. 

Grade 

23 53.5 23 37.7 0.81 

G1 2 4.65 2 3.3 

G2 39 90.70 54 91.5 

G3 

Type of surgery 

2 4.65 5 8.2 0.2 

MRM 32 74.5 54 88.5 

BCS 

T-stage 

11 25.5 7 11.5 0.16 

T1 5 11.6 8 13.1 

T2 26 60.4 39 63.9 

T3 5 11.6 10 16.4 

T4 

N-stage 

7 16.4 4 6.6 0.41 

N1 3 7 6 9.8 

N2 23 53.5 33 54.1 

N3 

Receptor status 

17 39.5 22 36.1 0.85 

ER +ve 35 81.4 44 72.1 

ER -ve 8 18.6 17 27.9 0.19 

PR +ve 33 76.7 41 67.2 

PR -ve 

HER2/neu 

10 23.3 20 32.8 0.22 

Negative 38 88.4 51 83.6 

Positive 5 11.6 10 16.4 0.76 

Fifty patients out of the 61 patients (81.9%) in the dose dense arm completed the 

8 cycles of chemotherapy within 110 days (planned time between the first and the 

last cycles). The delay in the majority of patients was mainly due to treatmentrelated 

toxicity (neuropathy, cytopenia and febrile neutropenia) and rarely 

patient non-compliance. Dose reduction due to grade 3-4 toxicity was employed 

in 8 patients (13.1%). On the other hand, 39 out of the 43 patients (90.6%) in the 

FAC arm completed the 6 cycles within 110 days and most of the treatment delay 

was due to febrile neutropenia. Dose reduction due to hematological toxicity was 

required only in one patient (2.8%). The mean chemotherapy duration was 123 

± 5.9 days in the dose dense AC/T arm compared to 117 ± 6.3 days in the FAC 

arm and (P= 0.05). 

The 3-year adjusted RFS rates for AC-T and FAC were 76 % and 54.6 % 

respectively (P=0.042) (Fig.1). The mean disease-free interval was 40.6 ± 7.2 

months (95% CI, 37.7 - 43.6) for dose-dense AC/T arm Vs 36.9 ± 6.9 months 

(95% CI, 32.3 - 41.5) for FAC arm, (P=0.040). Regarding the pattern of relapse, 

systemic relapse (metastatic disease) was the predominant pattern in both arms 

(87.8% for dose-dense AC/T arm and 78.6% for FAC arm). 

Fig. 1: Kaplan-Maier survival curve of relapse-free survival in both 

treatment arms 

The subgroup analysis revealed that dose-dense chemotherapy had a statistically 

significant positive effect on 3-year RFS in premenopausal patients (77.5% 

for AC/T arm Vs 54% for FAC arm, P=0.045), patients with 10 or more (N3) 

positive axillary lymph nodes (72% for AC/T arm Vs 26% for FAC arm, P=0.02) 

and positive ER status (83% for AC/T arm Vs 50% for FAC arm, P=0.017). 

HER2/neu status did not significantly affect the 3-year RFS in patients received 

dose-dense AC/T though there was a trend towards better outcome compared 

with FAC arm in HER2/neu positive patients (77% for AC/T arm Vs 57% for 

FAC arm, P=0.051), 

There was no statistically significant difference in the 3-year OS between the two 

regimens or subgroups (Fig. 2). Mean OS was 46.1 ± 5.6 months for FAC arm 

compared to 43 ± 6.0 months in the dose dense arm (P= 0.7). Two patients in the 

FAC arm and 3 patients in the AC/T arm died due to extensive metastatic disease 

(mainly pulmonary and liver metastases). 


Fig. 2: Kaplan-Maier survival curve of overall survival in both treatment 

arms 

Hematologic toxicity was more pronounced in the dose dense arm. The difference 

was highly significant (P=0.01) with respect to anemia, granulocytopenia and 

thrombocytopenia. In the AC/T arm, the incidence of hematological toxicity 

was more evident during treatment with paclitaxel rather than AC. All patients 

had full recovery of their peripheral-blood counts at the end of treatment. No 

toxicity-related mortality was observed in both arms. Non hematologic toxicity 

occurred significantly more often in the dose dense arm. For example, peripheral 

sensory neuropathy grade 3-4 was more evident in patients received AC/T 36% 

Vs 2.3% in FAC arm (P=0.002) (Table 2). After a median follow-up period of 

more than 3 years, only 2% of the patients received dose-dense chemotherapy 

had persistent grade 1 or 2 neurotoxicity compared with none in the FAC arm. 

In both arms, none of the patients developed clinically evident congestive heart 

failure or significant reduction in the ejection fraction. Furthermore, there 

were no recorded cases of secondary malignancy, leukemia or myelodysplastic 

syndrome (MDS) 

Table 2: Treatment-related toxicity (G III/IV) in both arms 

Toxicity FAC arm AC-T arm 

No. % No. % 

Nausea 25 58 50 81 

Vomiting 17 39.5 36 59 

Granulocytopenia 9 20.9 35 57 

Thrombocytopenia 4 9.3 3 5 

Anemia 6 13.9 30 49 

Neuropathy 1 2.3 22 36 

Febrile neutropenia 1 2.3 3 5 

Cardiotoxicity 0 0 0 0 

Fatigue 15 34.8 15 24.5 

Bony pains 2 4.6 3 4.9 

Discussion 

The outcomes of women with early breast cancer have improved incrementally 

through trials that have evaluated new chemotherapy drugs and different doses 

and schedules of drugs postoperatively. Although much progress has been made, 

women still develop recurrences (15). Dose-dense chemotherapy has become 

one of the possible standards of adjuvant chemotherapy (16). The hypothesis that 

such a strategy is effective was based, in part, on theories developed by Skipper 

and by Norton and Simon (17-19). In their experimental models, a given dose of 

drug always kills a certain fraction, rather than a certain number, of exponentially 

growing cancer cells. However, breast cancer cells proliferate by nonexponential 

gompertzian kinetics, and the rate of cancer cell proliferation between treatment 

cycles is more rapid than that used in exponential models (19). 

The current study was designed to assess the treatment outcome of adjuvant 

dose-dense AC/T in high-risk breast cancer patients and to identify the possible 

subgroup of patients that had a significant improvement of their survival 

parameters. Due to the growing evidence from recent clinical trials that 

showed improvement of treatment outcome in favor of dose-dense compared 

to conventionally scheduled chemotherapy, prospective data of AC/T were 

compared with the available data of the classic FAC regimen used to be the 

standard adjuvant treatment for high-risk patients. Baseline characteristics were 

balanced between both treatment arms with no statistically significant differences. 

The results of the current study revealed that dose-dense AC/T was superior to 

conventional FAC in terms of RFS. The benefit was evident in premenopausal 

patients, patients with 10 or more (N3) positive axillary lymph nodes and 

positive ER status, whereas the benefit was not affected by the HER2/neu status. 

There was no statistically significant difference in the 3-year OS between the two 

regimens. Several clinical trials have confirmed the importance of dose density 

and dose intensity in the adjuvant treatment of early breast cancer, especially in 

women with positive nodal status. 

The Cancer and Leukemia Group B (CALGB) trial C9741 compared 4 cycles of 

AC followed by 4 cycles of paclitaxel in dose-dense intervals with conventional 

3-week intervals in 1,973 node-positive patients and found that the dosedense 

regimen produced significantly better DFS (HR=0.74; P=.010) and OS 

(HR=0.69; p=.013). Severe neutropenia was observed less frequently in patients 

receiving G-CSF support with the dose-dense chemotherapy schedule, and the 

regimen was otherwise well tolerated (12). This finding was recently challenged 

by an extensive retrospective analysis of this and two other CALGB trials, in 

which patients who were estrogen or progesterone receptor positive and received 

tamoxifen after chemotherapy experienced a markedly smaller effect of dosedense 

delivery of chemotherapy, with a minimal reduction in the relative risk for 

recurrence and no reduction in the risk for death (20). 

The German Arbeitsgemeinschaft Gastrointestinal Onkologie (AGO) trial 

examined 1,284 patients with more than four positive lymph nodes using 

treatment with a dose-dense, dose-intense regimen of epirubicin, paclitaxel, and 

cyclophosphamide (E-T-C) administered sequentially on a 2-week schedule with 

GCSF support. These very high risk patients achieved 2- year RFS rates of 85%, 

versus 82% for conventionally dosed EC + T (p = .046, two-tailed test). Survival 

benefits were observed irrespective of hormone receptor status or HER-2 

expression, but were particularly impressive in women with 10 or more positive 

lymph nodes. That trial used epirubicin doses of 150 mg/m2 every 2 weeks for a 

cumulative epirubicin dose of 450 mg/m2 in the dose-dense arm (21). 



Many studies have suggested that the benefit of taxane-based or dose-dense 

chemotherapy may be restricted to patients with HER2-positive or steroid 

hormone receptor– negative disease (22, 23). The current study failed to 

demonstrate such benefit as the dose-dense regimen had a positive effect in 

patients with estrogen receptor–positive breast cancer with no effect of HER2/ 

neu status. The possible explanation could be the higher frequency of N3 disease 

(36%) among patients received AC/T, which may have minimized the effect of 

biological predictors of response (HER2/neu status) and maximized the effect of 

clinico-pathological factors (nodal status). 

However, not all adjuvant dose-dense trial data were viewed as positive. The 

GONO-MIG (Gruppo Oncologico Nord Ovest- Mammella InterGruppo) 

trial compared FU, epirubicin, and cyclophosphamide administered every 3 

weeks versus the same regimen given every 2 weeks with granulocyte colonystimulating 

factor support. As in the CALGB study, the chemotherapy dose 

per cycle and total number of cycles were held constant, and only the interval 

between cycles varied. The difference between these two arms did not reach 

statistical significance for either recurrence or death (24). These negative results 

may be explained by the study design. The GONO-MIG trial applied a suboptimal 

version of the FEC regimen (ie, FU at 600 mg/m2, epirubicin at 60 mg/m2, and 

cyclophosphamide at 600 mg/m2_six cycles). The total dose of epirubicin in 

both arms was 360 mg/m2, which corresponded to only 50% of the total 

dose in the highly effective Canadian CEF regimen (ie, cyclophosphamide 75 

mg/m2 orally days 1 through 14, epirubicin 60 mg/m2 days 1 and 8, and FU 

500mg/m2 intravenously day 1and 8 for six cycles) or to only 60% of the total 

dose in the French FE100C regimen (FU500mg/m2, epirubicin 100mg/m2, and 

cyclophosphamide 500 mg/m2 for six cycles) (25, 26). 

Hematologic and non hematologic toxicities were more pronounced in the 

dose-dense AC/T. However, all patients had full recovery of their peripheralblood 

counts at the end of treatment and only 2% of the patients had persistent 

grade 1 or 2 neurotoxicity. At a median follow up of 37 months, there were 

no recorded cases of secondary malignancy, leukemia or MDS and this finding 

does not correspond to published data of anthracycline and cyclophosphamide 

adjuvant regimens. In the randomized, phase III trial, conducted by Moebus et al, 

1,284 patients with four or more involved axillary lymph nodes were randomly 

assigned to receive intense dose-dense (IDD) sequential epirubicin, paclitaxel, 

and cyclophosphamide (IDD-ETC) every 2 weeks or conventionally scheduled 

epirubicin/cyclophosphamide followed by paclitaxel every three weeks. Four 

occurrences (0.6% of patients) of secondary leukemia/MDS were reported with 

the 5-year follow-up data in the IDD-ETC arm only (16). 

With 10 years of follow-up, 5 occurrences (1.4% of patients) of secondary 

leukemia/MDS were reported for patients receiving the Canadian CEF 

regimen (25). Praga et al, reviewed 19 adjuvant trials with epirubicin and 

cyclophosphamide in 2005. Depending on the total dose of both epirubicin and 

cyclophosphamide, patients had a 8-year cumulative probability of secondary 

leukemia/MDS ranging between 0.37% and 4.97% (27). The absence of 

secondary leukemia/MDS in the current study may be explained by the relatively 

short follow- up interval and low total anthracycline dose (240 mg/m2 in the 

dose dense arm and 360 mg/m2 in the conventional arm). 

In conclusion, dose dense AC/T is a highly effective, feasible, and safe regimen 

with manageable toxicity for adjuvant treatment of node-positive high-risk 

breast cancer patients. Future research should focus on predictive factors for 

different chemotherapeutic regimens and on combining targeted therapies with 

dose-dense regimens to continue the incremental advance in the outcomes of 

women with early breast cancer. 

Conclusion 

Dose-dense AC/T significantly improved the relapse-free survival in patients 

with high-risk primary breast cancer and was less well tolerated compared with 

the conventionally scheduled FAC. The benefit was evident in premenopausal 

patients, extensive axillary nodal metastasis and positive ER status. 

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Genomics views: Xenobiotic metabolizing enzymes and cancer risks 

Kamel Rouissi, MD* 1 , Bechr Hamrita, MD* 1 , Slah Ouerhani, MD 2 , Amel Benammar Elgaaied, MD 1 

(1) Laboratory of Genetic, Immunology and Human Pathology, Faculty of Sciences of Tunis, University of El Manar I. 2092, 

Tunis, Tunisia 

(2) Laboratory of Molecular and Cellular Hematology, Institut Pasteur de Tunis, Tunisia 

* Both authors contributed equally to the study. 

Corresponding Author: Correspondence to: Dr. Bechr Hamrita, MD 

Laboratory of Genetics, Immunology and Human Pathology, Faculty of sciences of Tunis 

University of El Manar I, 2092, Tunis, Tunisia. 

E-mai: bechrhamrita@yahoo.fr 

Keywords: Cytochrome P450, N-acetyltransferase, Glutathione S-transferase, Cancer, Polymorphisms, Xenobiotic enzymes. 

ISSN: 2070-254X 

Abstract 

Epidemiological studies have estimated that approximately 80% of all cancers 

are related to environmental factors. Individual cancer susceptibility can be 

the result of several host factors, including differences in metabolism, DNA 

repair, altered expression of tumor suppressor genes and proto-oncogenes, and 

nutritional status. In fact, xenobiotic metabolism is the principal mechanism 

for maintaining homeostasis during the body’s exposure to xenobiotics. Most 

xenobiotics that enter in the body are subjected to metabolism that functions 

primarily to facilitate their elimination. Metabolism of certain xenobiotics 

can also result in the production of electrophilic derivatives that can cause 

cell toxicity and transformation. The balance of xenobiotic absorption and 

elimination rates in metabolism can be important in the prevention of DNA 

damage by chemical carcinogens. Thus the ability to metabolize and eliminate 

xenobiotics can be considered one of the body’s first protective mechanisms. 

However, there are marked species differences in the way mammals respond to 

xenobiotics, which are due in large part to molecular differences in xenobioticmetabolizing 

enzymes and has been related to the enzymatic polymorphisms 

involved in activation and detoxification of chemical carcinogens and 

that can impact drug therapy and cancer susceptibility. This paper focus 

the member of the cytochrome P450 family of enzymes (Cyp2D6), glutathione 

S-transferases (GSTT1 and GSTM1 ) and N-acetyltransferases (NAT1 and 

NAT2) on genetic polymorphisms involved in the metabolism of endocrine 

disruptors potentially related to cancer development. 

Introduction 

Xenobiotics are natural or artificial chemical substances that are alien to the body, 

such as drugs, industrial products, pollutants, alkaloids, and toxins produced 

by fungi, plants, and animals, many of them acting as endocrine disruptors. 

In their natural or bio-transformed state, xenobiotics can affect DNA integrity, 

leading to cancer if exposure persists (1). Accumulated DNA damage, added 

to spontaneous replication errors not corrected by the repair system, can cause 

irreversible mutations which in turn can lead to the development of tumors and/ 

or progression of cancer. Epidemiological studies show that 80 % of all cancers 

are related to environmental factors like smoking and occupational and dietary 

exposures (2). Thus, the individual capacity to bio-transform toxic into non-toxic 

xenobiotics can be considered the first line of defense in the process characterized 

by successive stages of transformation of potentially toxic chemical substances 

as a pathway towards their subsequent elimination. The enzymes involved are 

frequently the ones that determine the intensity and duration of drug action and 

other xenobiotics, hence their importance in chemical and carcinogenic toxicity. 

Bio-transformation of xenobiotics involves the modification of their physical 

properties, generally from lipophilic to hydrophilic, facilitating their excretion. 

Otherwise, many lipophilic xenobiotics would be excreted so slowly that they 

would eventually accumulate, destroying the organism by making it biologically 

nonviable (1). Bio-transformation involves two stages: phase I, mainly 

involving enzymatic activity of the cytochrome P450 (CYP) family; and phase 

II, catalyzed by conjugation enzymes like glutathione S-transferase (GST), and 

N-acetyltransferase (NAT). 

Most carcinogenic chemical products are not toxic and require metabolic 

activation before interacting with cellular macro-molecules. Phase I enzymes 

promote the activation of drugs and pro-carcinogens for the genotoxic 

electrophilic intermediaries. Meanwhile, phase II enzymes generally act 

as inactivating enzymes, that is, they catalyze the binding of intermediary 

metabolites to cofactors, transforming them into more hydrophilic products, 

thus facilitating their elimination (3). Therefore, the coordinated expression 

and regulation of xenobiotic metabolizing enzymes (XMEs) in both phase I 

and phase II and their metabolic equilibrium in the cells of target organs can be 

important factors in determining susceptibility to cancer as related to exposure 

to carcinogens (4). Mutations in these genes can produce partially defective 

enzymes or ones with altered specificities to the substrates, and thus there may or 

may not be the production of functional proteins or even enzymes with different 

levels of activities. The combination of the alleles from these genes can cause an 

increase or decrease in the susceptibility to certain toxic agents or environmental 

carcinogens. 

There are marked inter-individual and inter-ethnic differences in the capacity 

to metabolize drugs and other xenobiotics. This variation is due to the 

polymorphisms in the corresponding genes and to physiological, pathological, 

and environmental factors (5). Inter-individual variability in xenobiotic 

metabolism has been associated with greater or lesser susceptibility to toxicity or 

cancer risk in response to the same exposure to a given environmental pollutant. 

Thus, individuals incapable of adequately detoxifying a metabolic carcinogen 


or toxic agent due to reduced enzymatic activity would undergo more DNA 

and cell damage with the formation of adducts, or chemical elements bound to 

the DNA and protein macromolecules, genomic instability, and consequently 

would have a greater risk of developing toxicity or cancer (3). Increasing 

attention has been focused on our knowledge of variations in susceptibility to 

diseases within a population and the identification of risk factors so as to orient 

preventive policies. The literature has shown that variability in the expression 

of genes for XMEs (xenobiotic metabolizing enzymes) suggests an influence 

on the biological response to carcinogens. Despite displaying weak indication 

of risk at the individual level due to association with various other factors, 

gene polymorphisms (principally those influencing the metabolic activation or 

detoxification of carcinogenic chemical products) can be important factors for 

susceptibility at the population level (6). Molecular epidemiology has made great 

progress in detecting many human gene polymorphisms in XMEs, and some 

have shown to be correlated to increased risk of cancer. This paper focuses on 

just a few genetic polymorphisms that have been investigated more extensively 

due to their association with cancer, such as genes encoding cytochrome P450 

(CYP2D6), glutathione S-transferase (GSTM1 and GSTT1) families and the 

N-acetyltransferases (NAT1 and NAT2). 

Cytochrome P450 (CYPs) 

The human cytochrome P450 superfamily comprises at least ten known and 

characterized families and numerous sub-families (7). During bio-transformation, 

cytochrome P450 mediates the phase I reactions in which xenobiotics are 

detoxified or activated to reactive intermediate substances. The highest 

concentration of these enzymes has been observed in the liver endoplasmic 

reticulum, but they are present in all tissues in a tissue-specific manner. In the 

liver, they determine the intensity and duration of drug action and promote the 

detoxification of xenobiotics. They also catalyze the activation of xenobiotics to 

toxic and/or carcinogenic metabolites. The contribution of each P450 enzyme to 

the activation of carcinogens has been extensively evaluated, and this research 

has shown that most environmental carcinogens are activated principally by a 

limited number of them, including the following: CYP1A1, CYP1A2, CYP2E1, 

CYP2C19, CYP2D6, and CYP3A (8). Many are polymorphic, displaying 

different metabolic activities, reflected in adverse toxic effects, including 

carcinogenesis induced by endogenous chemical substances (9). 

CYP2D6 

The CYP2D6 gene belongs to the CYP2 family and was mapped in human 

chromosome 22, band 22q13.1 (10). Enzyme CYP2D6 (debrisoquine-4hydroxylase) 

metabolizes debrisoquine and many other drugs, like antidepressants, 

neuroleptics, many anti-arrhythmics, and lipophilic b-blockers (9). 

In addition to these substrates, CYP2D6 also acts on the carcinogen nitrosamine 

NNK (4-methylnitrosamino-1(3-pyridyl)-1-butanone), a component of cigarette 

smoke (11). The absence of debrisoquine-4-hydroxylase activity can have 

serious clinical consequences and even lead to death, since usual doses can 

cause high plasma levels of the drug, leading to side effects (12). Debrisoquine 

is a drug used for treating hypertension, and a wide variation has been observed 

in the hypotensive response. A clinical consequence of slow metabolism is the 

great sensitivity to the anti-hypertensive effects of debrisoquine (13). Although, 

extensive metabolizers display less risk of the effects of overdoses from 

debrisoquine and related drugs, they show an increased risk of developing cancer 

of the liver, gastro-intestinal tract, and lung as compared to slow metabolizers (14). 

Most individuals (80-90%) have at least one wild allele (CYP2D6*1) for the 

CYP2D6 gene and are classified functionally as extensive metabolizers. There are 

two other groups of individuals: one with intermediate metabolic activity, known 

as intermediate metabolizers, and the other known as ultra-rapid metabolizers. 

The first phenotype is attributed to a mutation in the wild allele (CYP2D6*1) and 

the second to an amplification of either the wild allele or an active mutant allele. 

Finally, there is a small group (5-10% of Caucasians, 2% of African Americans, 

and 1% of Orientals) who are poor metabolizers and identified by loss of gene 

function and absence of protein (15). 

An updated review of this complex polymorphism is provided by Sachse et al, 

(16). According to these authors, different alleles for the CYP2D6 gene consist 

mainly of point mutations, conversions, gene duplications, and complete gene 

deletion. Some 15 alleles have been recorded and associated with low activity 

(CYP2D6*2, *9, *10) and with its absence (CYP2D6*3, *4, *5, *6, *7, *8, *11, 

*12, *13, *14, *15, *16). The combination of all these alleles provides a wide 

range of possible phenotypes in relation to CYP2D6 activity. Given the nature 

of the substances metabolized by these enzymes, this polymorphism is used 

principally to identify poor metabolizers with anomalous responses to given 

drugs. In ultra-rapid metabolizers, the usual doses of given drugs fail to produce 

the desired pharmacological effect. Determination of CYP2D6 expression 

serves to detect therapeutic problems due to metabolism and can contribute 

to individualization of the dose regimen, reaching optimum drug therapeutic 

levels and reducing both cost and possible adverse effects (17). An association 

was observed between this gene and lung cancer (18) and oral cancer (19). 

Increased CYP2D6 activity has been related to some malignant processes. In 

bladder cancer, Anwar et al, (20) have demonstrated that genetic polymorphism 

in CYP2D6 could play an important role as host risk factors for development of 

urinary cancer among Egyptians (20). In north Tunisia, a previous work revealed 

that CYP2D6*4 allele did not appear to influence bladder cancer susceptibility 

(p > 0.05). A similar result was obtained when he stratified cases group according 

to tobacco status (21). However, in other work on a cohort from the middle 

centre of Tunisia a significant association was found between CYP2D6 (G/G) 

wild type and breast carcinoma risk only in postmenopausal patients (p = 0.04) 

(22). The data suggest that the increased metabolism of one or more agents in 

the diet or other environmental agents, mediated by CYP2D6, forms reactive 

intermediaries that influence the initiation or promotion of cancer in various 

tissues (23). The reduced CYP2D6 activity has been related also to greater risk 

of oral cancer (17). 

Other studies demonstrate that patients with lung cancer have shown a greater 

frequency of extensive metabolizers (EM) genotype. This association is supported 

by the discovery that CYP2D6 can activate nitrosamine 4-(methylnitrosamino)- 

1-(3-piridyl)-1-butanone, specific to tobacco for reactive metabolites (11). Kato 

et al, (24) observed that the levels of DNA adducts in the lung were increased 

as a function of CYP2D6 activity, a result consistent with activation of tobacco 

mediated by this enzyme (24). 

CYP2E1 

Many studies have investigated the association between the CYP2E1 5’-flanking 

region (RsaI/PstI) polymorphism and head and neck cancer susceptibility, but 

the results were conflicting. Using the fixed effects model, Lu et al, (25) have 

found significant association between PstI/RsaI polymorphism and head and 

neck cancer risk. 

Significant results were also found in East Asians and Mix populations when 

stratified by ethnicity. However, no significant associations were found for 

Caucasians in all genetic models. Stratified analyses according to source of 

controls, significant associations were found only in hospital base controls. 



In the subgroup analyses by tumor types, significant association was detected 

only in oral cancer group, while no significant associations among laryngeal- or 

pharyngeal- cancer subgroup. In Egypt, Anwar et al, (20) have demonstrated 

any differences in the distribution of CYP2E1 polymorphism between bladder 

cancer patients and controls as detected by PstI restriction fragment length 

polymorphism (RFLP) analysis (20). These previous findings are in accordance 

with other work which demonstrates the absence of any association between 

CYP2E1 gene polymorphisms and breast cancer (22). 

CYP2C19 

CYP2C19 is one of the enzymes involved in the metabolism of tamoxifen into 

active metabolites. In patients on tamoxifen, CYP2C19*2 and *3 variants, 

known for their lack of enzyme activity, were associated with a significantly 

longer breast cancer survival rate than patients with the wild-type (26). In 

Japanese population, a genetic polymorphism of CYP2C19 was associated with 

susceptibility to biliary tract cancer (27). 

Regarding hormone-associated tumors such as ovarian, cervical or prostate 

cancers, many conflicting data have been found. In this field, numerous studies 

conducted on different populations and ethnic groups have indicated the 

absence of a major impact of the CYP2D6, CYP2C19 and CYP2E1 genes in 

cancer risk (28). These previous findings are in accordance with ours which 

demonstrate the absence of any association between CYP2C19 and CYP2E1 

gene polymorphisms with breast cancer. In addition, when compared with the 

allele frequencies of the CYP2D6, CYP2C19 and the CYP2E1 genes in Italian, 

Portuguese and Egyptian populations, we found similar frequencies in healthy 

Tunisian individuals (29-31) . 

Glutathione S-transferase (GST) 

The glutathione S-transferases (GSTs) are key phase II metabolic reaction 

enzymes, and they play critical roles in protection against products of oxidative 

stress and electrophiles. (32). These conjugation reactions facilitate the excretion 

of many xenobiotics, including carcinogens, toxins, and drugs in the form of 

mercapturic acids. Different GST isozymes have been identified in human 

populations, some with tissue-specific expression (33). In mammals they are 

expressed at a higher level in the liver, constituting more than 4% of total soluble 

protein (34). At least five related gene families, mu, alpha, pi, theta and sigma, 

have been identified, and genetic polymorphisms have been reported for GSTM1 

and GSTT1, resulting in either decreased or altered enzyme activity (35). 

GSTM1 

Five mu class genes (M1-M5) on chromosome 1p13 have been identified (36). 

Inter-individual differences in GSTM1 are due either to gene deletion (the null 

genotype) or allelic variation, resulting in production of a catalytic active protein 

with closely similar catalytic activities which differ by a single base pair in exon 

7, introducing a restriction site for Hae II in the gene sequence (37). GSTM1 

is expressed at a high level in the liver. Epidemiological studies suggest that 

individuals, who are homozygous null, have an increased risk for cancer at a 

number of sites, lung, bladder, colon, breast (38). The risk of lung cancer in 

association with GSTM1 null genotype is dependent on the extent of tobacco 

smoke exposure, the frequency of GSTM1 null being significantly higher in the 

high exposure group. It may suggest that at low exposure level the genotype 

of the GSTM1 is less important, and that other detoxification pathways could 

handle low doses. Tobacco smoke is considered a risk factor in larynx cancer, 

and the GSTM1 null genotype was associated with an increased risk, but only 

among smokers that smoke 20 g tobacco/day or less (39). 

GSTT1 

Two genes have been identified in the theta class: GSTT1 and GSTT2, located 

in chromosome 22, in the same region (22q11.2) (40). The null polymorphism 

at the GSTT1 shows large variation and occurs at a frequency of 16%-40%. The 

biological consequences of this polymorphism are fairly difficult to predict, as 

the enzyme is involved in both detoxification and activation reactions. Lack of 

GSTT1 enzyme activity was observed among 19% of Caucasians (41). Many 

studies have reported that the GSTT1 null genotype (GSTT1*0) was associated 

with increased risk for bladder and lung cancers (42). However, some studies 

reported that the risk of cancer was increased only among those with the GSTT1 

positive (wild-type) genotype (43). 

GSTT1, GSTM1 and susceptibility to cancer 

Most of the studies on the role of GST polymorphisms in the development of 

cancer have focused on GSTM1 and GSTT1. In relation to lung cancer, Seidegard 

et al, (44) showed that smokers deficient in GSTM1, that is, homozygotes for the 

null allele, showed increased risk for this type of cancer (44). The presence of the 

whole gene appeared to protect against chemically-induced cytogenetic damage 

and DNA adducts in the lung (45). In the same way, Ryberg et al, (46) showed 

that the level of DNA adducts in the lungs of male smokers was influenced more 

by GSTP1 than by GSTM1 (46). 

According to these authors, smokers with at least one mutant allele for GSTP1 

showed significantly higher levels of DNA adducts than controls, while the 

GSTM1 null genotype did not show higher levels. When they combined the 

two polymorphisms GSTM1 and GSTP1 they observed that patients with the 

GSTM1 null genotype and the GSTP1 genotype with at least one mutant allele 

had significantly higher levels of adducts than other combinations (46). 

To-Figueras et al, (47) did not observe a significantly greater frequency of the 

GSTM1 null genotype in lung cancer cases in a Caucasian population, which 

agrees with data from Nyberg et al, (48) (47-48). The frequency of the other 

genotypes GSTM1 A, GSTM1 B, and GSTM1 A/B did not differ between cases 

and controls (Nyberg et al, 1998), unlike the results of other studies on bladder 

tumors, larynx, and skin, in which a protective role was proposed for GSTM1*A 

(49-50) and GSTM1*A/GSTM1*B (51). 

Various others authors have described family clustering in oral cancer and the 

proposed explanation involves gene polymorphisms for drug-metabolizing 

enzymes (52). Jourenkova et al, (53) studied the effect of GSTM1 and GSTT1 

genotypes on the risk of cancer of the larynx and observed an increased risk related 

to the GSTM1 null genotype and greater risk for GSTT1 null (53). Individuals 

lacking both genes GSTM1 and GSTT1 had a two-fold risk, although not 

significant, as compared to those with at least one of the genes, and a three-fold 

risk as compared to those with both genes. In addition, a statistically significant 

interaction was observed between the GSTM1 genotypes and levels of tobacco 

consumption. However, Park et al, (54) failed to find an association between 

the GSTM1 null allele and oral cancer (54). Meanwhile, Matthias et al, (55), 

studying cancer of the upper aero-digestive tract (oral, laryngeal, and pharyngeal 

squamous cell carcinoma), did not observe differences in the frequency of the 

GSTT1 null genotype between cases and controls, but did observe that the 

frequency of genotype GSTM1 was significantly lower in patients with oral, 

laryngeal, and pharyngeal squamous cell carcinoma, suggesting a protective 

effect (55). 


Recent epidemiological studies on GSTs and breast cancer have been illustrated. 

Some studies suggest an association between the GSTM1 null genotype and 

breast cancer in postmenopausal women (56). More recently, Park et al, (54) 

observed that the GSTM1 null genotype showed a statistically significant 

association with breast cancer, increasing the risk in premenopausal but not in 

postmenopausal women, while the GSTT1 null genotype showed similar risk 

levels in all the groups analyzed (54). When they combined these two genotypes, 

they observed that the presence of both null alleles significantly increased the 

risk of this cancer, especially in premenopausal women and those who consumed 

alcohol, suggesting a gene-environment interaction in individual susceptibility 

to breast cancer (54). These results disagree with those of Curran et al, (57) 

who failed to find any association between polymorphisms GSTM1, GSTT1 and 

breast cancer in an Australian sample (57). Other independent studies on various 

types of cancer have also shown this positive association between these genes 

and lung cancer (58), bladder cancer (20), colorectal cancer (59), breast cancer 

(60), esophageal cancer (61), oral cancer (62), and leukemia (63). 

In North Tunisia, we have conducted a case control study to assess the role of 

smoking, slow NAT2 variants, GSTM1 and GSTT1 null genotypes in bladder 

cancer development. In all groups of patients, we have shown that GSTM1 and 

GSTT1 null genotypes did not appear to be a factor affecting bladder cancer 

susceptibility. Furthermore, we found that NAT2 slow acetylator individuals 

temporarily carrying wild-type GSTT1 or GSTM1 null genotypes have a strong 

increased risk of bladder cancer (OR=26 and 22.17, respectively) (64). 

N-acetyltransferase (NAT) 

The NAT locus on human chromosome 8 encodes three distinct NAT genes, the 

two active NAT genes, NAT1 and NAT2, separated by an inactive pseudogene. 

NAT2 and NAT1 genes are polymorphically expressed, and variation at the 

NAT2 locus is responsible for the classic acetylation polymorphism. 

NATs catalyze the acetylation of carcinogens and other xenobiotics. Arylamines, 

hydrazines and hydrazides are metabolized by NAT-mediated N-acetylation. 

A majority of N-acetylation requires acetyl-CoA as a cofactor; however, some 

NATs can also utilize N-arylhydroxamic acid as acetyl donors. NATs are 

cytosolic enzymes and are found in a large number of tissues. The ubiquitous 

expression profile of the NATs suggests a fundamental role in protection against 

reactive metabolites. N-acetylation is usually considered a detoxification 

process because it renders the nitrogen atom less susceptible to oxidation, an 

oxidative process mediated mainly by CYP1A2. NATs can also catalyze the 

bioactivation of arylhydroxylamines and arylhydroxamic acids by either an 

acetyl CoA-dependent O-acetylation or by intramolecular N, O-acetylation 

producing reactive N-acetoxyarylamine intermediates. These metabolites are 

considered the ultimate carcinogens, because they are able to react with DNA 

to form covalent adducts. As a consequence, these enzymes play a role in the 

carcinogenesis process initiated by aromatic amines and in arylamine-induced 

toxicities. O-acetylation is catalyzed by both NAT1 and NAT2. 

Early epidemiological studies have shown that slow acetylators have an 

increased risk of bladder cancer compared with rapid acetylators (38), especially 

in workers occupationally exposed to aromatic amines. However, the NAT2 

phenotype did not influence bladder risk among Chinese workers exposed to 

benzidine, suggesting that NAT2 N-acetylation is not a critical detoxification 

pathway for benzidine. It has been found that mono-functional acetylation is 

activation rather than a detoxification pathway for benzidine (65). 

NAT2 activity is expressed in human liver and intestinal tissues. The most 

studied NAT2 polymorphisms are due to point mutations in the coding region. 

Slow acetylators, who possess NAT2 mutant alleles, produce proteins that are 

either poorly expressed, unstable, or have partially reduced catalytic activity. 

There are at least 15 different NAT2 allelic variants, of which the NAT2*4 is 

the most predominant and confers a fast acetylating phenotype. Of all the NAT2 

allelic variants identified, three (NAT2*5, NAT2*6 and NAT2*7) were shown to 

account for most of the slow acetylators. 

NAT1 protein is found in many human tissues, including the liver and bladder. 

NAT1 seems to be primarily responsible for the NAT and O-acetyltransferase 

activities in bladder and colon tissues. NAT1 activity in urinary bladder 

mucosa represents a major bioactivation step that converts urinary N-hydroxyarylamines 

to reactive N-acetoxy esters to form DNA adducts. The activity 

of NAT1 is significantly correlated with putative aromatic amine adducts. 

Individuals classified as slow NAT2 and fast NAT1 would be at the highest risk. 

These individuals do also have a higher level of carcinogen–DNA adducts in 

bladder DNA than people carrying other genotype combinations (66-67). There 

are at least 8 identified allelic variants of human NAT1. Certain NAT1 variants, 

NAT1*10 and NAT1*17, have an elevated N- or O-acetylation compared with 

the more common NAT1*4 variant. 

A significant association between the NAT1 genotype and lung cancer risk was 

observed in smokers, with the slow acetylators having a significantly higher 

risk, whereas no association between lung cancer risk and NAT2 was observed 

(Bouchardy et al, 1998). However, in a Swedish study, an increased risk for lung 

cancer was observed, but only in never-smokers (48). 

A slightly increased risk of breast cancer was observed in smoking women 

classified as NAT2 slow, and this increased risk correlated with a higher 

mammary gland DNA adduct level. In contrast, NAT1 did not have any influence 

on the adduct level (68). 

In case of bladder cancer, smokers with the NAT1*10 allele had an increased 

risk. There was evidence of a gene-dosage effect, as individuals homozygous 

for the NAT1*10 alleles had the highest risk. The NAT2 genotype alone did not 

significantly influence the bladder cancer risk, but the cancer risk from smoking 

exposure was particularly high in those with NAT2 slow alleles in combination 

with one or two copies of the NAT1*10 allele (69). In Tunisia, For the NAT2 

slow acetylator genotype, the NAT2*5/*7 diplotype was found to have a 7-fold 

increased risk of bladder cancer (OR=7.14) (64). Mechanistically it is assumed 

that if an individual is NAT2 slow, arylamines may be rapidly detoxified in the 

liver, so that the activated hydroxylated arylamine may never reach the bladder 

epithelium, where NAT1 could act upon it. 

Occurrence or specific types of mutations in oncogenes or tumor suppressor 

genes may partially be determined by the NAT2 activity. In bladder cancer, 7 out 

of 25 acquired mutations in the p53 cancer suppressor gene were transversions, 

and 6 out of these 7 mutations were in individuals having two slow NAT2 alleles 

(70). Differences in metabolic activity play a role in the mutational pattern and 

hence the pathobiology of the disease. In contrast, no significant association 

between p53 gene mutations and NAT2 polymorphisms was observed in patients 

with non-small-cell lung cancer, although slow acetylators had an increased risk 

compared to fast acetylators (71). Information about the role of NAT enzymes 

as a risk factor in colorectal cancer is ambiguous (72). In the support of NAT as 

a risk factor, a Japanese study suggests that people classified as rapid acetylators 



are more likely to have a point mutation in the K-ras than people classified as 

low or intermediate. This suggests that aromatic amines do play a role in the 

etiology of colon cancer. 

Conclusion 

Many cancers are caused by various forms of environmental and viral exposure 

suggests that such causes could be avoided through preventive measures. In 

addition, metabolism of carcinogens under genetic control as an important 

factor in modulating individual susceptibility to cancer is a plausible hypothesis. 

Information on susceptibility to cancer is valuable for identifying high-risk 

individuals, allowing for early diagnosis and reduction of risk exposure to 

carcinogens, some of them possibly acting as endocrine disruptors. Recent 

knowledge on the basic genetics of metabolic variation has provided new 

possibilities for the study of individual susceptibility to cancer induced by the 

environmental factors. With the advent of techniques based on the polymerase 

chain reaction (PCR), it is now possible to identify the genotype of an individual 

with a series of enzymatic polymorphisms involved in the metabolism of 

xenobiotics, some of which are potent carcinogens. New molecular biology 

techniques have allowed for much more direct correlations between a particular 

genotype and the incidence of cancer and other chemically-induced diseases. 

Given the number of polymorphisms, the variability in the expression of XMEs, 

and the complexity of chemical exposure, determination of a single polymorphic 

enzyme may not be sufficient, and it appears to be necessary to establish a risk 

profile for each individual or sub-group. The conflictive results observed in the 

literature show the still present difficulty to evaluate this complex phenomenon. 

Cohorts used for major studies and the number of genes responsible for 

determining risk are still insufficient and not clear. Some individuals are 

more sensitive towards xenobiotics than others, and this may in part be due to 

differences in metabolic capacity. A genetic high risk profile cannot be made 

at the present time, as the profile will depend not only on the compound under 

investigation but also on the adverse health effect. Studies combining various 

XME genotypes from phases I and II of metabolism may be provide more 

information than the analysis of individual genes, since if genetic susceptibility 

is partially mediated by polymorphic variation, the risk associated with only one 

locus is probably small, due to the multiplicative interaction model probably at 

play. One of the futture challenges in molecular epidemiology may be resides in 

the ability to evaluate different scenarios in which interactions among several 

genetic polymorphisms, and among gene/s and environmental carcinogens yield 

different susceptibility levels on cancer etiology. 

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notes < 



Hypofractionated radiotherapy versus conventional radiotherapy in treatment of 

glioblastoma multiforme 

Mohamed Abdelgawad, MD 1 , Eman Ismail MD 1 , Nashwa Nawar, MD 1 

(1) Clinical oncology department, Faculty of Medicine, Zagazig University, Egypt 

Corresponding author: Mohamed Abdelgawad, MD 

Clinical oncology department, Faculty of Medicine, Zagazig University, Egypt 

E-mail: gawad2@yahoo.com 

ISSN: 2070-254X 

Abstract 

Purpose : This study was planned to evaluate the safety and efficacy of 

hypofractionated radiotherapy(HRT) in treatment of glioblastoma multiforme 

(GM). 

Patients and methods : Twenty adult patients with (GM) were prospectively 

treated with (HRT) after surgical excision. HRT was given 3 days a week with a 

tumor dose of 3Gy/fraction. There were two phases of treatment, the first phase 

was 12 fractions, and the second phase was three fractions with smaller field 

size. The total dose was 50 Gy/15 fraction. The results were compared with a 

control group retrospectively treated with conventional radiotherapy. 

Results : Twenty patients with GM were treated. Excisional biopsy was done in 

15% of cases , 25% of cases underwent subtotal excision while 60% of cases 

were operated with total excision. As regard historical group 20% of cases 

underwent excisional biopsy ,subtotal excision in 30% and total excision in 50% 

of cases . The study revealed that median overall survival 6.5 months and 6 

months for (HRT) and conventional group respectively. The progression free 

survival was 6 months and 5 months for the (HRT) and conyentional group 

respectively. Treatment was well tolerated with minimal acute toxicities. 

Conclusion: Although HRT didn’t improve overall survival or progression free 

survival in GM compared with conventional group but the treatment duration 

was reduced which may be of palliative benefit in such group of patients. Further 

studies could be useful to determine the optimal fraction size for GM when HRT 

is used as an adjuvant treatment. 

Introduction 

Glioblastoma multiforme is one of the most common primary brain tumors in 

adults(1). Half of the brain tumors in adults are GM(2). The incidence of this 

disease increases after the age of forty (3). 

Although brain tumors are uncommon in comparison with other cancers such 

as breast or lung cancer. They exert a tremendous toll upon the patients, their 

spouses and families because of the sever neurologic disability they produce. 

The incidence and mortality from primary brain tumors appears to be rising, 

particularly amongst the elderly(4). 

High grade primary brain tumors such as anaplastic astrocytoma and glioblastoma 

are feard because of their aggressive course. In spite of intensive therapy with 

surgical resection, radiotherapy and chemotherapy the prognosis for malignant 

gliomas remains poor, with median survival of one year(5).The improvement in 

diagnostic and treatment modalities in the last years doesn’t affect the overall 

prognosis and natural course of GM(1). 

Although GM carries a fatal prognosis, postoperative radiotherapy has been 

shown to increase the median survival compared with that for patients treated 

with surgery alone(6) . 

The standard dose of radiation given after surgical resection is 60 Gy delivered 

in 1.8 – 2.0 Gy / fration. Dose escalation through standard fractionation to 70 – 

90 Gy has recently been attempted with conformal techniques, although changes 

in the pattern of failure have been observed, survival improvement hasn’t been 

achieved(7) . 

Hyperfractionation (giving a smaller fraction size twice daily) to a total dose 72 

Gy has shown no specific benefit for GM(8) . 

From the radiobiologic standpoint, late responding tissues such as neural tissue 

should be more responsive to fewer, but larger dose fractions of radiation, 

therefore to control CNS tumors such as GM adequately, it is likely that the 

radiation dose given must exceed the tolerance of the surrounding brain tissue, 

resulting in an unacceptable side effect profile. However, this basic problem may 

be overcome if the tumor alone is treated to these higher doses, and the normal 

tissue is spared(9). 

Several prospective trials have been performed using hypofractionated radiation 

dosing for the treatment of primary GM(9). A randomized study from Maria 

Slodowska – Curie Memorial Center, Poland evaluated 44 patients with GM 

who were treated with three split courses of hypofrationated radiotherapy to a 

total dose of 50 Gy and such study gave a statistically significant 2-year survival 

benefit compared with conventional therapy(10). 

In Royal Marsden Hospital, a phase I – II study had been performed using 

5-Gy fractions of stereotactic RT to 20 – 50 Gy proved to be efficacious and 

tolerable(11). 


In 1997 Arslan and his colleagues designed a prospective study to evaluate the 

safty and efficacy of postoperative HRT in GM patients in terms of overall and 

progression – free survival, treatment was well tolerated, acute toxicity was 

minimal and the study supported that HRT could be used instead of conventional 

and hyperfractionated radiotherapy(12). 

A non randomized study involved 30 patients treated with a hypofractionated 

course of 42 Gy in 14 fractions. The median survival and toxicity were 

comparable to that after standard fractionation(13). 

Although the methods of such trials varied as regard fraction size, total dose, 

and the overall treatment time, all were shown to have an acceptable toxicity and 

encouraging results. 

The aim of this study was to evaluate the safety and efficacy of adjuvant 

hypofractionated radiotherapy for patients with GM 


From December 2007 to January 2009,twenty adult patients diagnosed 

histologically as GM were referred to clinical oncology department Zagazige 

University Hospitals. These cases were enrolled in group A which were treated 

with hypofractionated radiotherapy and were compared with a historical 

control group treated with conventional radiotherapy. Table(1)shows patient 

characteristics . 

The types of operation which were performed for the study group and the control 

group ,respectively, were : total tumor excision 12 (60%) and 10 (50%); subtotal 

excision 5 (25%) and 6 (30%); biopsy 3 (15%) and 4 (20%) . 

The diagnosis was confirmed to be GM by the pathologic examination of the 

surgical specimen. After wound healing; on the average 3 weeks postoperatively; 

HRT was delivered with linear accelerators . The irradiated volume was 

determined by preoperative compeutrized tomography or the magnetic resonance 

imaging. The gross target volume (GTV) for both the initial volume (GTV1) and 

the conedown volume(GTV2) is obtained from the MRI. GTV1 includes the 

contrast enhancing lesion, the surgical resection cavity and surrounding edema; a 

2.0-cm margin is added to form PTV1. GTV2 for the conedown treatment should 

include the contrast enhancing lesion (without edema) plus a 2.5-cm margin to 

form PTV2. In the first phase of treatment, the tumor and edema around were 

irradiated with 2-3cm margin from the normal brain tissue. In the second phase 

the tumor region only was irradiated. 

The HRT was applied 3 days a week with a tumor dose 3.33 Gy per fraction. At 

the first phase of treatment 12 fractions and at the second phase 3 fractions with 

smaller fields were delivered. The total dose was 50 Gy/15 fraction 15 weeks. 

The histortical control group were treated with conventional radiotherapy with 

total dose 60 Gy in 30 fractions over 6 weeks one year overall survival and 

progression free survival times were calculated from date of operation using the 

Kaplan meier method. 

Daily dexamethasone 16 mg I.V was given as a brain dehydrating 

measure to all patients during HRT. After HRT 50% of patients continued 

maintenance dexamethasons 4 mg daily for about 6 weeks with gradual 

discontinuation also antiepileptic treatment was given continuously. 

After Radiotherapy completed, patients were evaluated monthly by physical 

examination, neurologic examination and determination of performance status. 

Radiological examination by C.T or MRI were done every three months. 


Results 

Twenty patients were included in the study group, 12 males (60%) and 8 

females (40%) the mean age was 55 years (rang 40 – 72). All patients had an 

initial Karnofsky performance status > 70 . 75% of the study group had tumor 

dimension 4 cm or less all patients had supratentorial tumor. Sixteen patients 

(80%) presented with symptoms of increased intracranial tension i.e headache, 

nausea, vomiting, mental changes and blurring of vision. Forty percent of the 

patients had hemiparesis–hypoesthesia and 30% had seizures.The mean duration 

of illness was 10 weeks (range 2 – 72). 

The patients of the study group were irradiated with HRT after the operation. 

Treatment was well tolerate and acute toxicities were mild, serious acute side 

affect were not observed. In all cases, radiation necrosis as identified on MRI 

appeared to be within the high does area which determined during treatment 

planning. 

All twenty patients were followed up regularly until death the overall survival 

and time to disease progression were measured from the day of radiotherapy 

completion. 

The median overall survival of the study group was 6.5 months (range1-14) and 

the median of progression free survival was 6 months (range 1-15). 

As regard the historical conventional group the median overall survival was 6 

months (range 2-18) while the progression free survival was 5 months (range 

2-14) Table(2) fig 1,2. 

Discussion 

Although prognosis of GM is ominous, some characteristics of the patients, 

tumor and treatment can affect the natural course of this neoplasm. Known 

and reported prognostic factors related to patients and tumor characteristics are 

patients age, performance status before operation, tumor size, tumor localization 

and symptoms of their duration.The treatment of glioblastoma is a serious 

clinical problem. If no adjuvant treatment is given after operation, the median 

survival time is about 4 months(1). Surgery plus post operative radiotherapy is 

standard and optimal treatment (14). 

With respect to survival duration, the optimum dose of radiation defined in 

randomized studies is 60 Gy in 30 fractions given over 6 weeks (15). The dose 

per fraction is between 1.8 – 2 Gy (14) . 

A meaningful improvement in survival from doses above 60 Gy has not been 

demonstrated (16). Postoperative HRT has been tested from the radiobiologic 

stand point, GM are relatively radioresistant and respond more like neural tissue, 

which is a late responding tissue the a/B ratio is small for late responding tissues 

this implies that a late responding tissue should be more sensitive to fewer, 

higher dose fractions (HRT) (9).Postoperative HRT has been tested in some trials 

(12). Hypofractionated radiotherapy has three advantages over standard therapy.


First, fewer overall treatment session are needed and the total treatment time is 

shorter. With a uniformly fatal disease such as GM this is an important concern 

in terms of quality of life owing to the significant time commitment required 

to undergo RT. This regimen offers a treatment course that is completed in 2, 

instead of 6 weeks which may be preferable in certain subsets of patients such 

as those with poor performance status unresectable disease when palliation is 

the primary treatment goal. Second, the reduced number of treatment sessions 

confers a cost advantage over standard therapy. Finally radiobiologic advantage 

to hypofractionation with GM my exist (9). The general consensus is that 

conventional intensive treatment which carries morbidity may not be appropriate 

for patients with adverse prognostic features who may have a limited gain in 

life expectancy. These patients tend to be offered either supportive care alone or 

short palliative radiotherapy with the aim of avoiding both prolonged treatment 

which would take up a large part of remaining life and prolonged side effects of 

intensive radiotherapy (17). 

Slotman etal (18) treated thirty patients with HRT in the form of 42 Gy given 

in 3 weeks (5 daily fractions of 3 Gy each per week) the median follow up time 

was 24 months and 80% of patients recurred after 6.5 months, Age performance 

status and type of operation were found as prognostic factors. 

Such study reported that the results of HRT were similar with conventional 

radiotherapy. None of the patients experienced sever acute or late complications. 

Glinski et al (10) compared 44 patients treated with HRT or conventional 

radiotherapy in their randomized prospective trial. Two – year survival was 10% 

in the conventional arm and 23% in the HRT arm. Treatment in both arms was 

well tolerated. 

Lang et al (19) treated 38 patients, diagnosed as glioblastoma multiforme with 

HRT where 3.5 Gy per fraction were given with 5 fractions per week up to total 

dose of 42 Gy. Median survival was 11.5 months (45.7 weeks; rang 29.6 – 63.6). 

There were no serious acute or late radiation toxicities and this regmine was 

found as effective as the conventional arm. 

Arslan et al (12) designed a study to evaluate the effectiveness of tumor control 

with HRT in cases of GM and compare them with group previously treated 

with conventional radiotherapy concluded that no survival difference was seen 

between the two fractionation regimens. Survival in HRT arm was better but not 

statistically significant. Overall survival and progression free survival were 13.5 

and 11.3 months for HRT arm while it was 6.8 and 6.5 months for conventional 

arm. 

Phillips et al (20) had performed the first randomized comparison of conventional 

fractionated radiotherapy with short course of hypofrectionated treatment in GM 

and AA A statistically significant survival difference between the two arms could 

not be demonstracted and they recommented further studies to support this result. 

Mc Aleese, et al (17) had treated two groups of poor prognosis malignant glioma 

patients one group with HRT 5 Gy/fraction biweekly up to 30 Gy the other group 

was treated with conventional RTH they concluded that HRT offered reasonable, 

but lesser survival benefit than that would obtained with conventional RTH. 

In the randomized trial conducted at sites in seven European countries, 

researchers recruited 342 patients with newly diagnosed glioblastoma. 

Patients were assigned standard 60 Gy radiotherapy delivered in 2 Gy fractions 

for 6 weeks (n=100), hypofractionated 34 Gy radiotherapy delivered in 3,4 Gy 

fractions for 2 weeks (n=123), or 200 mg/m2 temozolomide daily on days 1 to 

5 every 4 weeks for 6 cycles (n=119). 

Median survival was 8.3 months for temozolomide, 7.5 months for 

hypofractionated radiation 34 Gy and 6 months for standard radiation. There 

was no significant difference in survival for patients treated with temozolomide 

or 34 Gy radiation. 

“These results indicate that standard 60 Gy radiation could replaced by HRT or 

temozolomide in patients with glioblastoma(21) 

In our study, we compare HRT with conventional radiotherapy in treatment of 

GM patients. No survival difference was seen between both group but it was 

noticed that survival was slightly better in HRT group and of no statistical 

significance. Overall survival and progression free survival were 6.5 and 6 

months ,and 6 and 5 months for HRT and conventional radiotherapy groups 

respectively, and these results greatly coincide with the results of most trials 

which were mentioned in the literature. 

We concluded that HRT could be an option in treatment of GM patients where 

most of such patients are with poor performance status and the lesser number 

of fraction with HRT could be more suitable for them. Mostly HRT could be 

received three times a week or five times a week in the above mentioned studies 

a further studies is recommended to compare between both and choose the most 

effective. So studies with greater number of patients are advised to evaluate if 

HRT is an effective alternative treatment in GM and to determine the optimal 

fraction size when HRT is used as an adjuvant treatment of GM. 

References 

1. Saleman M. Glioblastoma multiforme and anaplatic astrocytoma. In: Kaye 

AH, Laws ER (eds) : Brain Tumors : An encyclopedic approach Lnhurchill 

Livingstone, 2001, PP 493 – 523 . 

2. Schoenberg BS, Schoenberg DC, Christine BW. The epidemiology of 

primary intracranial neoplasms of childhood : A population study. Mayo 

Clin proc 1976; 51 : 51 -56 . 

3. Chadha M, Cpala J, Cderre JA, et al. Boron – neutron – capture therapy for 

glioblastoma multiforme using the epithermal neutron beam at Brook haven 

National laboratory. Int J Radiat oncol Biol Phys 1998; 40 : 929 – 834 . 

4. Bakhemuka M; Massey E; Schoenberg B International mortality from 

primary nervous system neoplasms distribution and trends. Int, J Epidem 

1988; 17 : 33 – 38 . 

5. Lederman G; Arbit E, Odaimi M, et al., Fractionated stereotactic 

radiosurgery and concurrent taxol in recurrent glioblastoma multiforme : A 

preliminary report. Int. J. Radiat. Oncol Biol Phys 1998; 40 (3) : 661 – 666 . 

6. Walker MD. Green SB, Byar DP, et al Randomized comparisons of 

radiotherapy and nitrosoureas for the treatment of malignant glioma after 

surgery : BTSG 22 – 01. N Engl J Med 1980; 303 : 1323 – 1327 . 

7. Nakagawa K, Aoki Y, Fujimaki T, et al. High-dose conformal radiotherapy 

influenced the pattern of failure but did not improve survival in glioblastoma 

multiforme. Int J Radiat Oncol Biol Phys 1998; 40 : 1141 – 1149 . 

8. Nelson DF, Cuman WJ, Scott C, et al. Hyperfractionated radiation therapy 

and bis-chloroethyl nitrosourea in the treatment of malignant glioma – 

Possible advantage observed at 72 Gy on 1.2 BID fractions : Report of the 

RTOG protocol 8302 . Int J Radiat Oncol Biol Phys 1993; 25 : 193 – 207 . 


9. Nathan SF, Shiao YW, Bin ST, et al. Hypofractionated intensity – modulated 

radiotherapy for primary glioblastoma multiforme. No 3, PP 721 – 726 . 

10. Glinski B. Postoperative hypofractionated radiotherapy versus 

conventionally fractionated radiotherapy in malignant gliomas : A 

preliminary report on a randomized trial J Neuro Oncol 1993; 16 : 167 – 

172 . 

11. Shepherd SF, Laing RW, Cosgrove VP, etal. Hypofractionated stercotactic 

radiotherapy in the management of recurrent glioma. Int J Radiat Oncol Biol 

Phys 1997; 37 : 393 – 398 . 

12. Arslan AN, Karadeniz G, Guveli MF. Postoperative hypofractionated 

radiotherapy in glioblastoma multiforme. Journal of BUON 2006; 11 : 39 

– 42 . 

13. Slotman BJ, Kralendonk JH, Van Alphen HA, et al. Hypofractionated 

radiation therapy in patents with glioblastoma multiforme : Results of 

treatment and impact of prognostic factors. Int J Radiat Oncol Biol Phys 

1996; 34 : 895 – 898 . 

14. Laperrieve N, Zuraw L, Cairncross G et al. Radiotherapy for newly 

diagnosed malignant glioma in adults : A systematic review. Radiother. 

Oncol 2002; 64 : 259 – 273 . 

15. MRC Brain Tumor Working Party, A medical research council trial 

astrocytoma. Br J Cancer 1991; 64 (4) : 769 – 774 . 

16. Chan JL, Lee SW, Fraass BA et al. Survival and failure of high grade 

gliomas after three dimensional conformal radiotherapy. J Clin Oncol 2002; 

20 : 1635 – 42 . 

17. McALeese JJ, Stenning SP, Ashley S et al. Hypofractionated radiotherapy 

for poor prognosis malignant glioma : matched pair survival analysis with 

MRC controls. Radiotherapy α Oncology 67 (2003) 177 – 182. 

18. Slotman B J, Kralendonk JH, van Alphen HAM et al. Hypofractionated 

radiation therapy in patients with glioblastome multiform : Results of 

treatment and impact of prognostic factors. Int J Radiat Oncal Bid Phys 

1996; 34 : 895 – 898 . 

19. Lang O, liebermeister E, Liesegang J, et al. Radiotherapy of glioblastoma 

multiforme : Feasibility of increased fraction size and shortened overall 

treatment. Strahlenther Onkol 1998; 174 : 629 – 632 . 

20. Phillips C, Guiney M, Smith J, et al. A randomized trial comparing 35 Gy in 

ten fractions of cerebral irradiation for glioblastoma multiforme and older 

patients with anaplastic astrocytoma. Radio therapy α oncology 68 (2003) 

23 – 26 . 

21. A Malmstrom, B. H. Grønberg, R. Stupp, C. Marosi, D. Frappaz et al 

glioblastoma (GBM) in elderly patients: A randomized phase III trial 

comparing survival in patients treated with 6-week radiotherapy (RT) 

versus hypofractionated RT over 2 weeks versus temozolomide single-agent 

chemotherapy (TMZ) J Clin Oncol 28:18s, 2010 (suppl; abstr LBA2002) 

Characteristics 

Age 

50 

Sex 

male 

female 

ECOG 

Duration of 

symptoms 

10week 

Increase ICT 

Present 

absent 

Surgery 

Complete 

Subtotal 

Biopsy 

Table 1 shows patient characteristics 

Hypofractionated 

Conventional 


NO 

9 

11 

12 

8 

7 

13 

14 

6 

16 

4 

12 

5 

3 

Table 2: Difference between the study group and control groups were non 

significant statistically 

Survival 

Median – over all survival 

Progression free survival 

% 

45 

55 

60 

40 

35 

65 

70 

30 

80 

20 

60 

25 

15 

Hypofractionated 

6.5 month 

6 month 

NO 

6 

14 

13 

7 

11 

9 

12 

8 

17 

3 

10 

6 

4 

Conventional 

6 month 

5 month 

% 

30 

70 

65 

35 

55 

45 

60 

40 

85 

15 

50 

30 

20 

P – value 

0.509 

0.967


Percent survival 

Fig 1: over all survival 

Percent survival 

100 

75 

50 

25 

100 

Fig 2: Progression free survival 

Overall Survival 

0 

0 5 10 

Time (months) 

15 20 

75 

50 

25 

Progression free survival 

0 

0 6 12 

Time 

Hypofractiontion 

Conventional 

Hypofractiontion 

Conventional 


N

New 

vinflunine 

The 1 st and only registered chemotherapy 

after failure of a platinum-containing regimen 

in advanced or metastatic TCCU 

www.amaac.org Pierre Fabre Oncology Middle East - Riad El Solh - P.O.Box 11 - 2131 Beirut - Lebanon Pan Arab Fax : Journal 00 961 of 1 98 Oncology 98 42 | vol 4; issue 1 | March 2011 < 53 

Full Prescribing information is available upon request 

Æ

news from the arab world < 

Announcements 

Dear all, 

We would like to announce the creation of the 

Junior Oncologists (JAMAAC) 

gathering all over the Arab world under the umbrella of Arab 

Medical Association Against Cancer and includes every young 

doctor working against cancer (medical, surgical,radiation, 

basic sciences, etc...) 

We have established this group to serve YOU and invest 

in YOU. Building capacities and facilitating mobility and 

research grants to all of YOU either through AMAAC 

fellowships or other internationally available grants that we 

will keep on announcing. Also, we will organize a number of 

educational and scientific activities to be announced soon. We 

look forward for your active participation. 

This group is totally endorsed by AMAAC board and 

Secretary General Prof. Sami Khatib. 

So i would like all of you who have facebook accounts to 

add Dr. Sami Khatib with the user name of Sami Khatib on 

Facebook for all the social activities. 

And to join the group of JAMAAC on Facebook with the 

user name of : ناطرسلا ةحفاكلم برعلا ءابطلأا بابش ةطبار - Junior 

AMAAC (JAMAAC). 

Waiting to see all of you members of this important group. 

Thanks, Majd Alkhatib 

Dear colleagues, 

The Abstract Submission Deadline for the 8th International AORTIC conference 

is upon us and is scheduled to close on the 15th May 2011. For those still busy 

with research, Late Breaking Abstracts will be accepted between 1 – 15 October 

2011. 

As indicated in our previous communiqué, we have been monitoring the 

situation in Egypt closely and taking everything into consideration we would 

like to reiterate that the conference will still be going ahead in Cairo , Egypt , 

as scheduled. 

We are also pleased to inform you that the development of Program is going 

well and is at an advanced stage, to date over 300 Abstracts have been received. 

Therefore the content and program promises to be highly interesting and 

informative.The conference promises to be excellent on all counts, if you have 

not registered yet, we urge you to register now. 

Please do not hesitate to contact us should you require any further information. 

Kind Regards 

AORTIC Conference Secretariat 

Global Conferences Africa - P O Box 6761, Roggebaai, Cape Town, South Africa 

Tel.: +27 21 408 9988 

Fax: +27 21 408 9956 

E-mail: aortic@globalconf.co.za 


Under the high patronage of his excellence 

Zine El Abidine Ben Ali, president of the republic of Tunisia, 

Arab Medical Association Against Cancer(AMAAC) 

organizes in Tunisia, in Hammamet (Hotels Russelior and Royal) 

from April 29th to May 1st 2011, 

the 11th Panarab Cancer Congress 

The topic concern: breast, lung, urologic and gynecologic 

cancers, hematologic malignancies and palliative care within 

lectures done by Arab and international recognized experts in 

the field. 

Posters sessions are programmed. 

Abstracts dealdline is fixed to the end of february 

You may fastly have all the informations via the website 

www.amaactunisia.com 







FLYER MCO_RV (7 Feb).qxp 21-04-2011 15:46 Pagina 3 

EURO-ARAB SCHOOL OF ONCOLOGY MASTERCLASS 

3 R D E A S O M A ST E RCLASS IN 

C L I N I CAL ONCOLO GY 

Jointly organised with the 

Arab Medical Association 

Ag a i n st Cancer (AMAAC) 

27-29 October 2011 

Amman, J o rd a n 

Chair: N. Pavlidis, GR - H. Khaled, EG 

Scientific coordinators: S. Khatib, JO - A. Costa, IT 




3rd ASIAN 

Breast Cancer Congress 

Interdisciplinary Integration 

3 - 4 MARCH, 2012 / BANGALORE, INDIA 

Supported By 

adding life to years 


cancer awareness calendar < 

january 

february 

march 

april 

may 

june 

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october 

november 

december 

Cervical Cancer Awareness Month 

Screening and Early Detection Awareness Month 

Colorectal Cancer Awareness Month 

Cancer Fatigue Awareness Month 

Melanoma and Skin Cancer Awareness Month 

National Cancer Survivors Day 

Sarcoma Awareness Month 

Pain Medicine and Palliative Care 

Gynecologic Cancer Awareness Month 

Prostate Cancer Awareness Month 

Leukemia and Lymphoma Awareness Month 

Breast Cancer Awareness Month 

Lung Cancer Awareness Month 

Smoking Cessation 

5 A Day Awareness Month 


objectives & scope of the PAJO < 

The Pan Arab Journal of Oncology (PAJO) is the official Journal of the Arab Medical Association Against Cancer (AMAAC). It is a 

quarterly publication targeting health professionals interested in the oncology field. It is a multidisciplinary peer-reviewed journal that 

publishes articles addressing medical oncology, malignant hematology, surgery, radiotherapy, pediatric oncology, geriatric oncology, 

basic research and the comprehensive management of patients with malignant diseases in addition to international oncology activities, 

congresses & news. 

The journal will be addressed, as a first step, mainly to the professionals in the hematology & oncology field in the Middle East 

region and North Africa. The goal is to share local & regional research activities news and to be updated with international activities. 

We hope, with your support, to achieve our following objectives: 

1. Promote and encourage research activities in the Arab World. 

2. Disseminate & analyze epidemiological local, regional and international data. 

3. Update health professionals with the most recent advances, news & developments in the field of oncology. 

4. Improve the level of scientific publications arising form the Arab World. 

5. Keep health professionals connected and exposed to the activities of different Arab cancer societies. 

6. Share with our immigrant compatriots their activities & feedback in this field. 

7. Involve all health professionals interested in the field of Oncology within the multidisciplinary scope of the Journal. 

8. Encourage post graduates students to submit their research work. 

instructions for authors < 

1. Manuscript Categories 

1.1. Clinical trials 

The Editor-in-Chief and an Associate Editor generally review 

Reports from clinical trials. Selected manuscripts are also reviewed 

by at least two external peer reviewers. Comments offered by 

reviewers are returned to the author(s) for consideration. 

Manuscript acceptance is based on many factors, including the 

importance of the research to the field of oncology & the quality 

of the study. Authors should focus on accuracy, clarity, and brevity 

in their presentation, and should avoid lengthy introductions, 

repetition of data from tables and figures in the text, and unfocused 

discussions. Extended patient demographic data should be included 

in a table, not listed within the text. 

Reports from Clinical trials are limited to 3,000 words of body 

text, excluding the abstract, references, figures, and tables. They 

are limited to six total figures and tables. All abstracts are strictly 

limited to 250 words. Titles are to be descriptive, but succinct. 

Results of clinical studies should be supported by a clear 

description of the study design, conduct, and analysis methods 

used to obtain the results. 

Reports of phase II & III studies should include from the protocol 

a clear definition of the primary end point, the hypothesized value 

of the primary end point that justified the planned sample size, 

and a discussion of possible weaknesses, such as comparison to 

historical controls. 

Phase I studies will be well received if they have interesting clinical 

responses, unusual toxicity that pointed to mechanism of action of 

the agents, and important or novel correlative laboratory studies 

associated with the trials. 

1.2. Review Articles 

All reviews must be clinically oriented, ie, at least half the review 

must describe studies that detail human impact, marker effect on 

prognosis, or clinical trials. 

Review Articles should be prepared in accordance with the Journal’s 

Manuscript Preparation Guidelines, and will be reviewed in the 

same manner as Reports from Clinical Trials. Reviews are limited 

to 4,500 words of body text, excluding the abstract, references, 

figures, and tables. The editors also suggest a limit of 150 references. 

1.3. Editorials / Comments / Controversies 

The Editor-in-Chief may solicit an Editorial to accompany an 

accepted manuscript. Authors who wish to submit unsolicited 

Comments and Controversies should contact the Editor-in-Chief, 

before submission to determine the appropriateness of the topic 

for publication in the Journal. 

Editorials should be no more than four to five pages in length. 

1.4. Articles on Health Economics 

Articles about health economics (cost of disease, cost-effectiveness 

of drugs, etc) are highly encouraged. 

1.5. Case Reports / Correspondence / Special Articles 

Correspondence (letters to the Editor) may be in response to a 

published article, or a short, free-standing piece expressing an 

opinion, describing a unique case, or reporting an observation that 

would not qualify as an Original Report. If the Correspondence is 

in response to a published article, the Editor-in-Chief may choose 

to invite the article’s authors to write a Correspondence reply. 

Correspondence should be no longer than three pages in length. 

Special Articles present reports, news from international, regional 

societies as well as news from our compatriots. 


instructions for the authors < 

2. Manuscript submission procedure 

All manuscripts should be submitted in word and PDF format 

directly to the Editor-in-Chief by e-mail at the following e-mail: 

editorinchief.pajo@yahoo.com. 

The manuscript should adhere to the journal requirements. Upon 

manuscript submission, corresponding authors must provide 

unique e-mail addresses for all contributing authors. Receipt of 

manuscripts will be acknowledged via e-mail. Upon completion of 

editorial review, the corresponding author will receive notification 

of the Editor’s decision, along with the reviewers’ comments, as 

appropriate, via e-mail. 

3. Disclosures of Potential Conflicts of interest 

In compliance with standards established and implemented by 

ASCO’s Conflict of Interest Policy (J Clin Oncol 24:519–521, 

2006), it is the PAJO’s intent, as previously referred, to ensure 

balance, independence, objectivity, and scientific rigor in all of its 

editorial policies related to the Journal through the disclosure of 

financial interests, among other measures. All contributors to the 

Journal are required to disclose financial and other relationships 

with entities that have investment, licensing, or other commercial 

interests in the subject matter under consideration in their 

article. These disclosures should include, but are not limited to, 

relationships with pharmaceutical and biotechnology companies, 

device manufacturers, or other corporations whose products or 

services are related to the subject matter of the submission. 

Disclosures of financial interests or relationships involving the 

authors must be addressed on the Author Disclosure Declaration 

form. The corresponding author may complete the form on behalf 

of other authors, or authors may complete their own forms and 

forward them to the corresponding author. This information will 

be sent to the Editorial Board. Statements regarding financial 

support of the research must be made on the manuscript title page, 

and disclosed on the form. This form is available upon request 

from the Editorial Office. All disclosures will appear in print at 

the end of all published articles. 

The Journal requires all Editors and reviewers to make similar 

disclosures. Reviewers are asked to make disclosures when 

accepting a review. 

4. Manuscript Preparation Guidelines 

Title Page 

The first page of the manuscript must contain the following 

information: (1) title of the report, as succinct as possible; (2) 

author list of no more than 20 names (first name, last name); (3) 

names of the authors’ institutions and an indication of each author’s 

affiliation; (4) acknowledgments of research support; (5) name, 

address, telephone and fax numbers, and e-mail address of the 

corresponding author; (6) running head of no more than 80 characters 

(including spaces); (7) list of where and when the study has been 

presented in part elsewhere, if applicable; and (8) disclaimers, if any. 

Abstract 

Abstracts are limited to 250 words and must appear after the title 

page. Abstracts must be formatted according to the following 

headings: (1) Purpose, (2) Patients and methods (or materials and 

methods, similar heading), (3) Results, and (4) Conclusion. Authors 

may use design instead of Patients and methods in abstracts of 

Review Articles. Comments and Controversies, Editorials and 

Correspondence do not require abstracts. 

Text 

The body of the manuscript should be written as concisely as 

possible and must not exceed the manuscript category word 

limits described herein. All pages of a submission should be 

numbered and double-spaced. Helvetica and Arial at 12pt size 

are the recommended fonts for all text (see Figures section for 

acceptable fonts for figures). The Journal adheres to the style 

guidelines set forth by the International Committee of Medical 

Journal Editors. 

References 

References must be listed and numbered after the body text in the 

order in which they are cited in the text. They should be doublespaced 

and should appear under the heading “REFERENCES.” 

Abbreviations of medical periodicals should conform to those 

used in the latest edition of Index Medicus and on MEDLINE. 

The «List of Journals Indexed in Index Medicus» includes the 

latest abbreviations. Inclusive page numbers must be cited in 

the reference. When a reference is for an abstract or supplement, 

it must be identified as such in parentheses at the end of the 

reference. Abstract and supplement numbers should be provided, 

if applicable. When a reference is a personal communication, 

unpublished data, a manuscript in preparation, or a manuscript 

submitted but not in press, it should be included in parentheses in 

the body of the text, and not cited in the reference list. Published 

manuscripts and manuscripts that have been accepted and are 

pending publication should be cited in the reference list. 

Reference Style 

º Journal article with one, two, or three authors 

1. Dolan ME, Pegg AE: O6-Benzylguanine and its role in 

chemotherapy. Clin Cancer Res 8:837-847, 1997 

º Journal article with more than three authors 

2. Knox S, Hoppe RT, Maloney D, et al: Treatment of cutaneous 

T-cell lymphoma with chimeric anti-CD4 monoclonal antibody. 

Blood 87:893-899, 1996 

º Journal article in press (manuscript has been accepted for 

publication) 

3. Scadden DT, Schenkein DP, Bernstein Z, et al: Combined 

immunotoxin and chemotherapy for AIDS-related non-Hodgkin’s 

lymphoma. Cancer (in press) 

º Supplement 

4. Brusamolino E, Orlandi E, Morra E, et al: Analysis of long-term 


esults and prognostic factors among 138 patients with advanced 

Hodgkin’s disease treated with the alternating MOPP/ABVD 

chemotherapy. Ann Oncol 5:S53-S57, 1994 (suppl 2) 

º Book with a single author 

5. Woodruff R: Symptom Control in Advanced Cancer. Victoria, 

Australia, Asperula Pty Ltd, 1997, pp 65-69 

º Book with multiple authors 

6. Iverson C, Flanagin A, Fontanarosa PB, et al: American Medical 

Association Manual of Style (ed 9). Baltimore, MD, Williams & 

Wilkins, 1998 

º Chapter in a multiauthored book with editors 

7. Seykora JT, Elder DE: Common acquired nevi and dysplastic 

nevi as precursor lesions and risk markers of melanoma, in 

Kirkwood JM (ed): Molecular Diagnosis and Treatment of 

Melanoma. New York, NY, Marcel Dekker, 1998, pp 55-86 

º Abstract 

8. Bardia A, Wang AH, Hartmann LC, et al: Physical activity and 

risk of postmenopausal breast cancer defined by hormone receptor 

status and histology: A large prospective cohort study with 18 

years of follow up. J Clin Oncol 24:49s, 2006 (suppl; abstr 1002) 

9. Kaplan EH, Jones CM, Berger MS: A phase II, open-label, 

multicenter study of GW572016 in patients with trastuzumab 

refractory metastatic breast cancer. Proc Am Soc Clin Oncol 

22:245, 2003 (abstr 981) 

º Conference/meeting presentation 

10. Dupont E, Riviere M, Latreille J, et al: Neovastat: An 

inhibitor of angiogenesis with anti-cancer activity. Presented at 

the American Association of Cancer Research Special Conference 

on Angiogenesis and Cancer, Orlando, FL, January 24-28, 1998 

º Internet resource 

11. Health Care Financing Administration: Bureau of data 

management and strategy from the 100% MEDPAR inpatient 

hospital fiscal year 1994: All inpatients by diagnosis related groups, 

6/95 update. http://www.hcfa.gov/a1194drg.txt 

º Digital Object Identifier (DOI) 

12. Small EJ, Smith MR, Seaman JJ, et al: Combined analysis 

of two multicenter, randomized, placebo-controlled studies of 

pamidronate disodium for the palliation of bone pain in men with 

metastatic prostate cancer. J Clin Oncol 10.1200/JCO.2003.05.147 

º Government Announcement/Publication 

13. Miller BA, Ries CAG, Hankey BF, et al (eds): Cancer Statistics 

Review: 1973-1989. Bethesda, MD, National Cancer Institute, 

NIH publication No. 92-2789, 1992 

º ASCO Educational Book 

14. Benson AB 3rd: Present and future role of prognostic and 

predictive markers for patients with colorectal cancer. Am Soc 

Clin Oncol Ed Book 187-190, 2006 

Figures 

Figures must be cited in the order they appear in the text using 

Arabic numerals. Figures should be submitted in a seperate 

documen. Figure legends are required for all article types. Figure 

legends must not exceed 55 words per figure and should be written 

below the figure. 

Images may be embedded in word or Power Point files. 

Tables 

Tables must be cited in the order in which they appear in the 

text using Arabic numerals. The table’s legend may include any 

pertinent notes and must include definitions of all abbreviations 

and acronyms that have been used in the table. Tables submitted 

with multiple parts will be renumbered. Tables should be submitted 

in a seperate document. Legends must not exceed 55 words per 

table and should be written above the figure. 

Appendices/Acknowledgments 

Appendices and acknowledgments will appear in the print version 

of the article. 

Language: Appropriate use of the English language is encouraged 

for publication in the Journal. 

5. Post-acceptance Information 

Copyright Form 

Corresponding authors must provide unique e-mail address 

for each contributing author at manuscript submission. Upon 

acceptance of the manuscript, each author will receive an e-mail 

invitation to sign a statement confirming that the manuscript 

contains no material for which publication would violate any 

copyright or other personal or proprietary right of any person or 

entity. Manuscripts will not be published until each author has 

completed the form. 

Page Proofs 

Corresponding author will receive proofs and must carefully 

review them for data and typesetting errors. Corrections to proofs 

must be returned by e-mail, fax, or mail within 1 week. The 

corresponding author is responsible for collecting and submitting 

all author corrections into a single submission. Publication may 

be delayed if proofs are not returned by the publisher’s deadline. 

The Editor-in-Chief must approve all major alterations, which 

may delay publication of the manuscript. 


subscription to PAJO < 

subscribe to PAJO 

In case you are not receiving the PAJO or you would like to 

change your address, kindly to contact us by E-mail to: 

editorinchief.pajo@yahoo.com or by fax to: + 962 65 62 38 53 

and update us with the following information: 

Title 

First Name 

Family Name 

Country 

City 

Clinic or Hospital or Office’s Name 

Street 

Bldg 

Floor 

Land Phone 

Mobile Phone 

Fax 

E-mail 


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ns 

ria 

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16:16

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