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Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374:379-86. [2] Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386:1049-56. [3] Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:2181-90. [4] Collaud S, Fadel E, Schirren J, Yokomise H, Bolukbas S, Dartevelle P, et al. En Bloc Resection of Pulmonary Sulcus Non-small Cell Lung Cancer Invading the Spine: A Systematic Literature Review and Pooled Data Analysis. Ann Surg. 2015;262:184-8. [5] Rusch VW. Management of Pancoast tumours. Lancet Oncol. 2006;7:997-1005. [6] De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014;45:787-98. [7] Friedel G, Budach W, Dippon J, Spengler W, Eschmann SM, Pfannenberg C, et al. Phase II trial of a trimodality regimen for stage III non-small-cell lung cancer using chemotherapy as induction treatment with concurrent hyperfractionated chemoradiation with carboplatin and paclitaxel followed by subsequent resection: a single-center study. J Clin Oncol. 2010;28:942-8. [8] Hancock J, Rosen J, Moreno A, Kim AW, Detterbeck FC, Boffa DJ. Management of clinical stage IIIA primary lung cancers in the National Cancer Database. Ann Thorac Surg. 2014;98:424-32; discussion 32. Keywords: non small cell lung cancer, stage III, induction therapy ED10: LOCALLY ADVANCED NSCLC: STATE-OF-THE-ART TREATMENT TUESDAY, DECEMBER 6, 2016 - 16:00-17:30 ED10.03 NEW DEVELOPMENTS IN RADIOTHERAPY OF STAGE III NSCLC Jacek Jassem Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk/ Poland NSCLC accounts for 80-85% of all lung cancers, and stage III disease constitutes about 40% of the total cases. The main treatment modality in these patients is radiotherapy, usually combined with concurrent chemotherapy. Five-year overall survival in stage III disease is merely 10-15%. Radiotherapy of thoracic tumors poses several challenges, such as tissue heterogeneity, tumor and organ motion and changing anatomy over the treatment course. Main approaches addressing these problems include dose intensification, altered fractionation and advanced radiotherapy techniques. Until recently, dose escalation was considered the main means to increase radiotherapy efficacy. Despite encouraging results of phase I–II studies, the results of recent RTOG trial 0617 were disappointing (1). This study compared high-dose radiotherapy (74 Gy/37 fractions) to a standarddose (60 Gy/30 fractions) concurrently with weekly paclitaxel/carboplatin, with or without cetuximab. Surprisingly, median overall survival in the high-dose arms was significantly shorter (20 months vs. 29 months in the standard-dose arms; p=0.004) (1). It was speculated that the inefficacy of high-dose radiotherapy could be due to long overall treatment time and accelerated tumor repopulation. Shortening treatment time may be accomplished by accelerated radiotherapy. A phase III study investigating continuous hyperfractionated accelerated radiotherapy (CHART; 54 Gy/36 fractions of 1.5 Gy delivered 3 times daily over 12 consecutive days) showed increased efficacy compared to conventional fractionation (2). A CHARTWEL study, using the same fractionation but with weekend breaks, was not superior to conventional fractionation (3). A meta-analysis of 10 trials (2000 patients) demonstrated an absolute 5-year survival benefit of 2.5% with hyperfractionated and/or accelerated radiotherapy over conventional fractionation, at the expense of significantly increased grade 3–4 acute esophagitis (4). Important developments in lung radiotherapy represent new imaging techniques. PET-CT, currently a routine procedure, allows better patient selection for radical radiotherapy and facilitates selective irradiation of involved volumes (5). Image guided radiation therapy (IGRT), such as daily volumetric kilovoltage cone-beam computed tomography (CBCT), provides actual positional information, allowing for online repositioning and more precise tumor localization. Image-guided adaptive radiotherapy (IGART) additionally accounts for changes and deformations occurring during the radiotherapy course, thus allowing treatment re-planning (6). Currently, dose delivery in NSCLC is commonly accomplished by intensity modulated radiotherapy (IMRT). This technique improves the conformality of radiotherapy by modulating the radiation beam intensity profile, and allows decreasing the mean lung dose, particularly in patients with larger tumor volumes (7). The problem of intrafraction motion in thoracic malignancies has been traditionally managed by extension of treatment margins, leading to excessive radiation to normal tissues. Currently, tumor motion may be managed individually by respiratory-correlated 4-dimensional CT (4DCT) based on the acquisition of organ and tumor imaging data at extreme phases of the breathing cycle. An innovative option allowing for safe dose intensification is isotoxic therapy (8). This approach includes dose prescription defined by the maximal doses achievable to normal tissues. More recently, several clinical studies investigated the role of proton beam therapy in NSCLC. A dosimetric advantage of proton- over conventional photon radiotherapy is mediated by its unique properties: low doses upon tissue penetration, maximal dose deposition towards the end of the beam’s path (Bragg peak) and finite range with minimal dose beyond the tumor. Retrospective data and phase II studies suggested promising survival rates, and reduced pulmonary and esophageal toxicity with protons. However, the results of recent phase III trial did not confirm the superiority of this method over IMRT (9). In summary, recent diagnostic and therapeutic advances the use of radiation in stage III NSCLC allow for more accurate treatment planning, more precise dose delivery and managing tumor and organ motion. Some of these developments have been adopted in clinical practice, despite relatively few evidence of their advantages in terms of better local control and survival. The paucity of phase III trials testing new radiotherapy approaches is partly due to relying on better dose distribution and reduced exposure of normal tissues, making comparisons with less advanced techniques an ethical dilemma (10).References 1. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16:187- 99. 2. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in nonsmall-cell lung cancer: a randomised multicentre trial. Lancet 1997;350:161–5. 3. Baumann M, Herrmann T, Koch R, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97–1) comparing hyperfractionatedaccelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol 2011;100:76–85. 4. Mauguen A, Le Pe´choux C, Saunders MI, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol 2012;30:2788–97. 5. Chang JY, Dong L, Liu H, et al. Image-guided radiation therapy for non-small cell lung cancer. J Thorac Oncol 2008;3:177–86. 6. Sonke JJ, Belderbos J. Adaptive radiotherapy for lung cancer. Semin Radiat Oncol 2010;20:94-106. 7. Bezjak A, Rumble RB, Rodrigues G, and al. Intensity-modulated radiotherapy in the treatment of lung cancer. Clin Oncol 2012;24:508–20. 8. De Ruysscher D, van Baardwijk A, Steevens J, et al. Individualised isotoxic accelerated radiotherapy and chemotherapy are associated with improved long term survival of patients in stage III NSCLC: a prospective population-based study. Radither Oncol 2012;102:228-233. 9. ZX Liao, J. JJ Lee, R Komaki, et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer. J Clin Oncol 2016;34(15S):435s. 10. Dziadziuszko R, Jassem J. Randomized clinical trials using new technologies in radiation oncology: ethical dilemma for medicine and science. J Thor Oncol 2007;7:3-4. ED10: LOCALLY ADVANCED NSCLC: STATE-OF-THE-ART TREATMENT TUESDAY, DECEMBER 6, 2016 - 16:00-17:30 ED10.04 NEW DEVELOPMENTS FOR SYSTEMIC THERAPIES IN STAGE III NSCLC Everett Vokes Medicine, University of Chicago, Chicago/IL/United States of America Concomitant chemoradiotherapy is currently the most widely accepted standard of care for patients with locoregionally advanced NSCLC. Induction chemotherapy represents an evidence-based alternative and is a particular attractive prior to surgery in patients with marginally resectable disease (1). Over the past two decades, the regimens of cisplatin and etoposide and carboplatin and paclitaxel with concurrent radiotherapy, respectively have been most widely used, with cisplatin and vinorelbine with radiotherapy as possible alternative. More recently interest in the cisplatin/pemetrexed/ radiotherapy combination has gained interest based on the superior toxicity and efficacy profile of this regimen in the stage IV setting for patients with non-squamous cell malignancies (2). In addition, it is possible to administer this combination of drugs at systemic doses together with radiotherapy (3). In the randomized phase III PROCLAIM study, this regimen was directly compared with etoposide and cisplatin. The goal of this trial was to establish superiority of this regimen. The trial was closed prior to full enrollment with approximately 300 patients per arm evaluated, due to futility for superiority. Median survival for both study groups was very similar at 26.8 and 25.0 months, respectively and better than statistically assumed (4). Additional chemoradiotherapy regiments of current interest include the addition of the PARP inhibitor veliparib to chemoradiotherapy as recently presented (5). Over the last decade, systemic therapy for patients with metastatic lung cancer has been transformed through the use of tumor mutation analyses and targeted therapies as well as the emergence of immune-oncology. However, application of these strategies to the stage III setting has been slow and no definitive data exist currently to support these strategies in the curative intent setting. The addition of cetuximab to chemoradiotherapy did not result S24 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 in a survival benefit in RTOG 0612 (6). There are, however several ongoing trials that will be described, including RTOG 1306-Alliance 31101. In this trial patients with EGFR mutation or an alk translocation are randomized to either induction chemotherapy with the appropriate targeted agent (erlotinib and crizotinib, respectively) followed by concurrent chemoradiotherapy or concurrent chemoradiotherapy alone. This trial is actively accruing patients. Regarding immune-oncology, a trial evaluating a liposome-based MUC vaccine (tecemotide) has been completed. MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly glycosylated in NSCLC and a vaccination strategy was supported by preclinical studies as well as clinical data in a stage III subgroup analysis of an earlier exploratory trial. Butts et al (7) reported on a randomized trial in which patients completing locoregional sequential or concurrent therapy were randomized to placebo versus tecemotide vaccination therapy reporting a trend for improved overall survival that was statistically significant in the subset analysis of patients receiving concurrent radiotherapy as their primary therapy. Further investigations of this agent however were halted following emergence of additional negative data from a Japanese phase II trial that remains unpublished. Regarding PD-1 or PD-L1 inhibitors, trials have recently been activated investigating the addition of such agents in the consolidation setting following primary treatment of patients with unresectable SCLC. For example, in the ‘Pacific’ trial patients are randomized in a 2-1 fashion to durvalumab for up to 12 months or placebo. In the Alliance, a trial looking at induction chemotherapy with atezolizumab is currently in the process of activation. Here patients will receive induction chemotherapy with atezolizumab for up to four cycles followed by concurrent chemoradiotherapy and additional adjuvant immune therapy. These strategies are well supported by preclinical data showing irradiation upregulating PD1 expression on myeloid and tumor cells and synergistic amplification of radiation antitumor effects by PD-L1 blockade (8). Updated information on these trials and relevant preclinical data will be presented. References: 1. Schild SE, Vokes EE. Pathways to improving combined modality therapy for stage III nonsmall-cell lung cancer. Ann Oncol 2016 Apr;27(4):590- 9. 2. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-smallcell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. 3. Govindan R, Bogart J, Stinchcombe T, Wang X, Hodgson L, Kratzke R, Garst J, Brotherton T, Vokes EE. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol. 2011 Aug 10;29(23):3120-5. 4. Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. 5. Cristea MC, Miao, J, Argiris A, Chen AM, Daly ME, Decker RH, Garland LL, Wang D, Koczywas M, Moon J, Kelly K, Gandara DR. SWOG S1206: A dose-finding study of veliparib added to chemoradiotherapy with carboplatin and paclitaxel for unresectable stage III non-small cell lung cancer. J Clin Oncol. 2016 34:(suppl; abstr 8537). 6. Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015 Feb;16(2):187-99. 7. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, Nawrocki S, Ciuleanu TE, Bosquée L, Trigo JM, Spira A, Tremblay L, Nyman J, Ramlau R, Wickart-Johansson G, Ellis P, Gladkov O, Pereira JR, Eberhardt WE, Helwig C, Schröder A, Shepherd FA; START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jan;15(1):59-68. 8. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu YX. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014 Feb;124(2):687-95. David R. Gandara1, Sanjay Popat 2 , Barbara Melosky 3 1 UC Davis Comprehensive Cancer Center/USA 2 Royal Marsden Hospital, London/UK; 3 Department of Medical Oncology, BC Cancer Agency Vancouver Centre, Vancouver/ Canada Oncogene-driven lung cancer remains the embodiment of personalized medicine. Since the first description of EGFR activating mutations found in patients with what was then called bronchiolalveolar carcinoma of the lung (BAC) in 2004, the topic of oncogene-driven lung cancer has grown rapidly and expanded to now encompass a number of additional mutation- and fusion-related entities. Recent updates to molecular testing guidelines, such as those of IASLC, have added several new oncogenes to the initial EGFR and ALK recommendations, including ROS1 and RET fusions, MET amplification or mutation, and HER2 mutations (1,2,3). Although the efficacy of tyrosine kinase inhibitors (TKI) in the treatment of some of these disease subsets is well established, the treatment decision-making process at the time of each relapse is becoming more complex as our knowledge of resistance pathways grows and more treatment options become available, with 2 nd and 3rd generation drugs now in play. Subtping of progressive disease (PD) in oncogene-driven lung cancer into systemic PD versus oligo-PD or CNSsantuary PD can assist in determining the most appropriate therapeutic approach, as shown in Figure 1 below(4). Further, the methods by which we assess tumor at the time of initial or re-biopsy are also rapidly evolving, from single gene or multiplexed gene panels to highly sensitive and specific next generation sequencing (NGS). Lastly, we and others (4,5) have proposed algorithms for possible substitution of plasma cell free DNA by NGS platforms for tissue re-biopsy or for serial monitoring in plasma, as demonstrated in Figure 2. In this presentation we will present a step-wise approach to molecular testing and personalizing treatment for patients with oncogene-driven NSCLC, focusing on EGFR-mutated and ALK-rearranged subsets, since the treatment paradigms are most well established. We will emphasize some of the real world challenges faced by treating physicians. Decision criteria for selecting the best first-line therapy will be reviewed, the importance of re-biopsy upon disease progression to determine the most appropriate next-line therapy highlighted, and third line therapy and beyond discussed. The emerging role of liquid biopsy for assessment of plasma cell free DNA will be discussed, as well as a rationale for substituting liquid biopsy for initial or repeat tumor biopsy in some clinical settings. Algorithms designed to facilitate treatment decision-making will be presented. Two examples in EGFR-mutated lung cancer are shown below. Figure 1: Algorithm for management by Progressive Disease Subtyping EGFR-mutated NSCLC Figure 2: Algorithm for Re-Biopsy and/or Plasma cf DNA Analysis In EGFR-mutated NSCLC Keywords: radiation sensitization, Stage III NSCLC, concurrent chemoradiotherapy SESSION ED11: ADVANCED NSCLC: STATE-OF-THE-ART TREATMENT WEDNESDAY, DECEMBER 7, 2016 - 11:00-12:30 ED11.01 SYSTEMIC THERAPY FOR ADVANCED ONCOGENE-DRIVEN NSCLC Copyright © 2016 by the International Association for the Study of Lung Cancer S25
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