Radiation Therapy in SCLC. What is New? Prof. Dr. Hoda Abdel Baky El Bakry Cairo Cancer Institute Radiation Oncology Department

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1 Radiation Therapy in SCLC What is New? Prof. Dr. Hoda Abdel Baky El Bakry Cairo Cancer Institute Radiation Oncology Department

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3 Background Overview Small Cell Lung cancer constitute about 15 % of all newly diagnosed lung cancer More than 70% of the patients presented in advanced stage More than 70% of the ones at the advanced stage are presented with metastasis it is CT and RT sensitive and many patients get CR by treatment yet OS and DFS are very poor The SCLC is staged into Limited (LD) Extensive (ED)

4 SCLC: Classification LIMITED DISEASE (TNM stage: I IIIB) Tumour involving one hemithorax (can be irradiated using a single field): a) with or without homo or contralateral supraclavicular mediastinal lymph node involvement, b) with or without ipsilateral pleural effusion, c) with or without involvement of left laryngeal nerve or superior vena cava obstruction EXTESIVE DISEASE (TNM stage IV) Any disease further than limited disease including metastasis (Modifiied after Stahel R,. Lung Cancer, 1989)

5 SCLC: Proposed new classification Very limited I A-B T 1 N 0 T 2 N 0 IIA T 1 N 1 IIB T 2 N 1 T 3 N 0 AJCC-UICC STAGE IIIA T 3 N 1 T 1-3 N 2 (1 mediastinic station) Limited IIIA T 1-3 Bulky N 2 IIIB T 4 N 0-2 T 4 N 3 Extensive M 1

6 SCLC: Survival in relation to disease extent assessed according to TNM classification % 70% % 20-30% 10-20% 10% <5% 0 IA op. IB IIA IIB IIIA IIIB IV LIMITED DISEASE

7 Limited Disease Treatment Is mainly by CT and RT both TRT and PCI No marked change in the treatment in the last 3 decades except: PET scan for staging PET scat for delineation and planning Use of advanced techniques (3DCRT-IMRT) for TRT Surgery has a minor role in very limited disease which can be increased

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9 Extensive Disease Main treatment is by CT Radiotherapy was mainly to palliate metastasis This has been changed as regards Central disease Brain Irradiation (prophylactic or palliative) PCI TRT

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16 LD-SCLC what is the best timing of thoracic irradiation: results from selected randomized trials Author (yr) n. pts CT Dose Gy /FR Survival results RT timing wk ms 3 yr % Takada 228 EPx4 45/15 bid E= (2002) q 4 wks L= Skarlos 81 C-VP16x6 45/15 bid E= (2001) q 3 wks L= Murray 308 CAV-EPx3 40/2.67 daily E= (1993) q 4 wks L= Perry 270 CAVEx18 mos 50/2.0 daily E= ( ) q 3 wks L=

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18 The Japan Clinical Oncology Group Study : 231 patients were randomized EP chemotherapy x 4 cycles with TRT at cycle #1 vs. TRT after cycle # 4 PCI for CR pts at end of therapy ( Gy bid) 228 were eligible; Median follow-up: -- Early TRT Late TRT p OS (mo) S (5 yrs) 23.7% 18.3% 0.09 Brain rec 19% 27% 0.16 Takada M et al. J Clin Onc; 2002

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20 Prophylactic cranial irradiation (PCI)

21 PCI : Meta Analysis (Auperin 1999, Takada 2002 and others) Proved to significantly increase OS, PFS and 25% decrease in incidence of brain mets It is now used routinely with LD NCCN-2016 PCI + TRT for Extensive disease after CR or PR to CT

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32 Outline Effect of Thoracic RT Timing of Thoracic RT Volume, dose-fractionation of TRT Chemotherapy regimen Role of PCI The Guidelines

33 2014 ASCO Annual Meeting Randomized trial on thoracic radiotherapy (TRT) in extensive-stage small cell lung cancer. Author(s): Corinne Faivre-Finn, Harm van Tinteren, John Praag, Joost Knegjens, Sherif El Sharouni, Matthew Hatton, Astrid Keijser, Suresh Senan; VU University Medical Center, Amsterdam, Netherlands; The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom; Department of Statistics, The Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Radiation Oncology, Erasmus MC, Rotterdam, Netherlands; Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Radiation Oncology, UMC Utrecht, Utrecht, Netherlands; Department of Clinical Oncology, Weston Park Hospital, Sheffield, United Kingdom; IKNL Clinical Research Department, Amsterdam, Netherlands; Department of Radiation Oncology, VU University Medical Center, Amsterdam, Netherlands

34 Background: Prophylactic cranial irradiation (PCI) reduces the risk of brain metastases and improves survival in ES-SCLC after response to chemotherapy. As a majority of patients have intrathoracic disease after chemotherapy, this randomized study assesses the role of TRT in ES-SCLC

35 Methods: Patients (WHO 0-2) with confirmed ED- SCLC with a response after 4-6 cycles of standard chemotherapy were randomized to : TRT (30 Gy/10fx) or no TRT. All received PCI. Primary study endpoint was overall survival. Acute toxicity was graded using CTCAE v3.0.

36 Results: Between Feb 09 and Dec 12, 498 patients were enrolled (249 per arm) Median follow-up was 24 months. 88% had residual intrathoracic disease. Baseline characteristics were well balanced. Mean age was 63 year P.S. 89% had WHO 0-1; 11% WHO-2. Mean interval between start of chemotherapy and randomization was 16 weeks.

37 Results: At the time of analysis (Dec 13), 76 patients were still alive. Progression-free survival was longer in the TRT-arm (p=0.001). Curves for overall survival overlapped during the first 9 months and then diverged in favour of the TRT-arm. The survival difference at 1 year was not statistically significant (33% vs 28%; p=0.066). Survival at 2 years was 13% for the TRT and 3% for no TRT

38 Overall survival

39 Overall survival Analysis of interaction of factors with treatment Factor Sex Age (in groups) WHO performance score Basis for ES (distant, intrathoracic or both) Response after chemotherapy Presence of intrathoracic disease at randomization Sign. p=0.06 p=0.58 p=1.00 p=0.86 p=0.58 p=0.35 Presented by: Ben Slotman

40 Progression-free survival

41 Intrathoracic progression TRT Control p-value All 43.7% 79.8% p<0.001 As first site of relapse 41.7% 77.8% p<0.001 As only site of relapse 19.8% 46.0% p<0.001 Progression occurring at different organ sites within 30 days was considered as simultaneous progression.

42 Conclusions: TRT improves progression-free survival. Although TRT did not influence the risk of death in the first year, it led to a significant increase in 2-year survival. TRT should therefore be offered to all ED-SCLC patients with a response to initial chemotherapy.

43 Recommendations for LD Early thoracic radiation therapy starting with the first or second cycle of chemotherapy An optimal radiation schedule would be 45 Gy at 1.5 Gy bid over 3 weeks with an off-cord reduction at 30 Gy. If hyperfractionation is not practically feasible, conventional fractionation could be used to Gy at 2 Gy per fraction with an off-cord reduction at 44 Gy.

44 Recommendations for LD For patients starting on TRT with the second cycle, the post chemotherapy volume is used as the gross tumor volume (GTV) Patients with CR or near CR should receive prophylactic brain irradiation (PCI) to 25 Gy in 10 fractions or 30 Gy in 15 fractions.

45 Recommendations for ED NCCN-2016 PCI + TRT for Extensive disease after CR or PR to CT

46 Prof. Dr. Hoda Abdel Baky el Bakry