- Small cell lung cancer (SCLC) has seen little therapeutic advancement in over 20 years. Platinum-etoposide remains the standard chemotherapy regimen. - For limited-stage SCLC, concurrent chemoradiation is the standard of care and provides better outcomes than sequential treatment. Early twice-daily radiotherapy with prophylactic cranial irradiation improves survival. - For extensive-stage SCLC, prophylactic cranial irradiation after chemotherapy reduces the risk of brain metastases and improves survival compared to no cranial irradiation.

1. Small cell lung cancer Dr C Faivre-Finn Manchester Lung Cancer Group Manchester Radiation Related Research Group 10 th ESO-ESMO Masterclass 6 th April 2011 Manchester Lung Cancer Group

2. ‘ Progress in the therapy of SCLC has been painfully slow’. In fact you could argue that little or no therapeutic advances have been made for extensive- stage SCLC in more than 20 years’ Gandara and Lara. J Clin Oncol 2008; 26: 4236-38

3. Facts Incidence of SCLC is declining-less than 10-15% of all lung cancer cases Govindan JCO 2006 One third present with limited stage disease Excellent responses to CT and RT but few patients will be long term survivors High risk of local relapse High risk of distant spread (brain)

4. How do we stage SCLC? Veterans classification TNM classification 0 2 4 6 8 Survival (Years) 0% 20% 40% 60% 80% 100% IA IB IIA IIB IIIA IIIB IV 26 21 15 12 13 11 6 Median survival (months) 8008 patients

5. CHEMOTHERAPY Platinum-etoposide is the standard CT regime for the treatment of SCLC

6. Anthracyclines Sundstr øm et al. J Clin Oncol 2002; 20: 4665 - 4672 436 patients with LS and ES EP CEV Survival 10.2 7.8 p = 0.0004 LS 14.5 9.7 p = 0.01 ES 8.4 6.5 p = ns EP CEV CEV-cyclophosphamide/epirubicin/vincristine EP-etoposide/cisplatin

7. Platinum vs non-Platinum 21 trials extensive stage SCLC cisplatin vs no cisplatin median survival 9.5 vs 7.1 months, p = 0.002 cisplatin based therapy independent predictor of survival p = 0.04 Chute et al, J Clin Oncol 1999 Meta-analysis 19 trials 4054 pts cisplatin vs no cisplatin Cisplatin - 4.4% survival benefit at 1 year Pujol et al Br J Cancer 2000 Cochrane meta-analysis 2008 29 trials, 5530 patients No difference in 6, 12 or 24 month survival No difference OR rate Higher CR rate for platinum Higher toxicity rates with platinum Amarasena et al. Cochrane Library 2009

8. Carboplatin A reasonable alternative to cisplatin in patients with poor prognostic factors Less toxicity compared to cisplatin Median survival with cispatin-etoposide is comparable to with carboplatin-etoposide in ES patients. Toxicity was significantly less for carboplatin arm. Study not powered for equivalence Skarlos et al. Ann Oncol 1994

9. Cisplatin is the best radiosensitiser Cisplatin plays a major role in the treatment of LS-SCLC EP can be delivered at full dose with thoracic RT with an acceptable toxicity profile CTRT combinations

10. Pujol et al. J Clin Oncol, 1997. 15: 2082-9 125 patients with ES PCDE q28 6# 1200/100/40/225 vs PCDE q28 4# with GCSF 1800/120/60/330 No significant difference Cumulative doses equivalent in each arm except cisplatin dose increased by 80% Dose intensity PCDE-cisplatin/CPM/epirubicin/etoposide

11. ACE with primary prophylaxis Thatcher et al. J Clin Oncol, 2000. 18: 395-404 ACE with GCSF q14 (LS) ACE without GCSF q21 (LS) ACE with GCSF q14 (ES) ACE without GCSF q21 (ES) 1 yr survival - 47% G vs. 39% C 2 yr survival -13% G vs. 8% C

12. New Treatments… 47% Topotecan RR Phase II -2 nd line Single agent 52% Amrubicin 39% Pemetrexed 39% Irinotecan 26% Gemcitabine 34-41% Paclitaxel

13. Irinotecan Noda NEJM 2002 Hanna JCO 2006 MS 12.8 vs 9.4 months 1 yr S 58.4% vs 37.7% (p=0.002) MS 9.3 vs 10.2 months 1 yr S 35% vs 35.2% (p=0.074)

14. Meta-analysis Irinotecan /Platinum and Etoposide /Platinum in ES Jiang et al J Thor Oncol 2010 Irinotecan + Platinum not inferior to EP p=0.044 p=0.163

15. Pemetrexed Phase III (GALES trial) 1822 patients (stopped early - 733 patients) Extensive stage Carbo- Etop vs Carbo-Pem Median survival 9.6 months CE vs 7.3 months CP Socinski, M. A. et al. J Clin Oncol 2009

16. Topotecan – 2nd line Von Pawel et al JCO 1999 Ph III (ES) 2nd line CAV vs T Less neutropenia but more thrombocytopenia with T Less SOB/ fatigue /loss of appetite O’Brien et al JCO 2006 2 nd line oral T vs BSC 6 months survival 49% vs 26% Eckhart et al JCO 2007 2 nd line T (o) vs T (iv) Equivalent

17. Amrubicin Two phase II second line studies have demontrated encouraging survival rates A number of phase III studies are ongoing to evaluate this treatment in the first and second line setting

18. EORTC 08062 First Line Extensive Stage No prior chemotherapy regimen ECOG performance status 0-2 Measurable disease 99 Pts R A N D O M I S E O`Brien et al ASCO 2010 AMR AMR/Cis Cis/Etop OR 61% 77% 63% PFS mos 5.2 6.9 5.8 OS mos 11.7 11.1 10.0 ARM A Amrubicin 45 mg/m 2 d 1-3 ARM B Amrubicin 40 mg/m 2 d 1-3 + Cisplatin 60 mg/m 2 d 1 ARM C Cisplatin 75mg/m 2 ,d1 + Etoposide iv 100 mg/m 2 d1-3, iv 100 mg/m 2 d1 , po 200 mg/m 2 d2,3

19. Maintenance or Consolidation Therapy Rossi et al Lung Cancer 2010 N = 3688 All (n=21) HR 0.93 (0.87-1.00) p=0.05 CT (n=11) HR 0.89 (0.81 0.98) p=0.02 IFN α (n=4) HR 0.78 (0.64-0.96) p=0.02 ‘ Clinical impact of maintenance chemotherapy needs to be confirmed by further studies’

20. TARGETED THERAPIES FOR SMALL CELL LUNG CANCER The Hallmarks of Cancer : Hanahan and Weinberg, Cell 2000 ANGIOGENESIS INHIBITORS INHIBITORS OF GROWTH AND PROLIFERATION APOPTOSIS PROMOTERS

21. Conclusions High RR with chemotherapy BUT high rates of local and distant relapses Many newer combinations as good, but none convincingly better PE is the standard treatment in SCLC Disappointing results so far with targeted therapies The way forward - a better understanding of the biology of the disease in order to develop more effective therapies

22. RADIOTHERAPY

23. Limited-stage SCLC

24. Progress in LS-SCLC? CT alone Sequential CTRT Concurrent CTRT BD conc CTRT Komaki et al-BD Komaki et al-OD 0 10 20 30 5 year survival (%) <10 10-15 20-25 25-30 25 (32) 12 (19)

25. Treatment options Sequential CTRT Pros: reduction in tumour volume, reduced toxicity Cons: delayed RT -> repopulation ->poorer outcome Concurrent CTRT Pros: radiosensitisation, early RT, short overall TT, better outcome Cons: for selected patients only, toxicity RT CT CT CT CT CT RT CT (CT)

26. Concurrent CTRT Selection Crit eria PS Comorbidities Tumour volume Lung volume Dose normal tissues (age) (lung function)

27. Sequential CTRT

28. Current evidence Concurrent CTRT >sequential CTRT (Takada) Early RT >late RT (Fried , Cochrane review) Best survival results achieved with early BD concurrent CTRT (Turrisi, Jeremic) RT doses up to 70 Gy can be safely delivered concurrently with CT (CALGB 39808 and 30002)

29. Timing of thoracic RT with chemotherapy J Clin Oncol. 2004;22:4837-45 7 RCTs Advantage of early (<9 weeks) radiotherapy 2 yr % NNT for benefit P All (1524) Platinum Platinum+ HART +5.2 [0.6-9.7] 20 0.03 +9.8 [3.8-15.9] 10 0.001 +16.7 [9.4-26] 6 0.001

30. Standard of care in LS-SCLC Early twice daily concurrent CTRT Turrisi trial PE remains the standard CT Irinotecan trials Pemetrexed trial PCI

31. Establish a standard regimen in LS-SCLC Toxicity and outcome data with modern RT techniques Importance of the RT dose ? the overall treatment time ? Translational research Why CONVERT

32. Once daily Thoracic Irradiation D1 D3 D22 D24 D43 D45 D64 D66 RT 66Gy/45D/33F Twice daily Thoracic Irradiation D1 D3 D22 D24 D43 D45 D64 D66 RT 45Gy/19D/30F Limited Stage Small Cell Lung Cancer SD, PR,CR  PCI If<SD  No PCI Registration Randomisation Restage Chemotherapy Radiotherapy CONVERT STUDY PS 0-2 No age limit Manchester Lung Cancer Group

33. Targeted agents and RT Spigel et al. J Clin Oncol 2010 Phase II -29 LS-SCLC patients recruited Early trial closure Two patients developed tracheoesophageal fistulae One patient died from an aerodigestive hemorrhage

34. Prophylactic cranial irradiation Why? Major risk of spread to brain-50 to 60% Eradicates micrometastatic disease PCI can reduce the risk of spread by 50% PCI improves survival (6% @ 3 years) Auperin N Engl J Med 1999 When? After concurrent CTRT With consolidation thoracic RT if sequential CTRT is given Toxicity Acute lethargy raised ICP ->steroids scalp reaction, hair growth will be delayed No reports of increased long term neurological sequalae in RCTs compared to control

35. PCI 99-01 EORTC 22003-08004 - RTOG 0212 Le Pechoux et al. Lancet Oncol 2009 Multicentre randomised phase III standard dose 25 Gy/10  /12 days high dose 36 Gy in 18  /24 days or 24#/16 days 720 patients in CR were randomised (146 from RTOG institutions) Immediate toxicity was equivalent in both arms 0.05 1.20 (1.00-1.44) 37% (32%-42%) 42% (37%-48%) Survival 0.18 0.80 (0.57-1.11) 23% (18%-29%) 29% (24%-35%) Incidence BM p HR 36Gy/18  25 Gy/10  2 years

36. Extensive stage SCLC

37. Prophylactic cranial irradiation in ES-SCLC (EORTC 08993-22993) PCI 20-30 Gy in 5-12 fractions No PCI Random Any response PS 0-2 Age  75 < 5 weeks 4-6 weeks No response Chemotherapy (4-6 cycles) Slotman et al. N Engl J Med 2007

38. Prophylactic cranial irradiation in ES-SCLC EORTC 08993-22993

39. Jeremic B. et al. J Clin Oncol 1999 100 50 57.5 115 Months p=0.041 Group 1-RT 2-no RT MST (months) 17 11 2yr 65 46 5yr 9.1 3.7 % Alive % Alive Thoracic RT for ES-SCLC?

40. Dutch-UK TRT EDSCLC Study Design PCI alone Random Any response PS 0-2 < 4 weeks 4-6 weeks No response Chemotherapy (4-6 cycles) PCI 20 Gy/5# or 30 Gy/10# TRT 30 Gy/10# +PCI

41. Conclusions Major progress in both LS-SCLC and ES-SCLC in the last two decades with RT Progress translating into improvements in both local control and survival Future directions New agents combined with RT Thoracic RT in ES-SCLC? Translational research