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MCO 2011 - Slide 28 - C. Faivre-Finn - SCLC

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MCO 2011 - Slide 28 - C. Faivre-Finn - SCLC

  1. 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. 2. <ul><li>‘ 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’ </li></ul>Gandara and Lara. J Clin Oncol 2008; 26: 4236-38
  3. 3. Facts <ul><li>Incidence of SCLC is declining-less than 10-15% of all lung cancer cases </li></ul><ul><li>Govindan JCO 2006 </li></ul><ul><li>One third present with limited stage disease </li></ul><ul><li>Excellent responses to CT and RT but few patients will be long term survivors </li></ul><ul><li>High risk of local relapse </li></ul><ul><li>High risk of distant spread (brain) </li></ul>
  4. 4. How do we stage SCLC? <ul><li>Veterans classification TNM classification </li></ul>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. 5. <ul><li>CHEMOTHERAPY </li></ul><ul><li>Platinum-etoposide </li></ul><ul><li>is the standard CT regime for the treatment of SCLC </li></ul>
  6. 6. Anthracyclines Sundstr øm et al. J Clin Oncol 2002; 20: 4665 - 4672 <ul><ul><li>436 patients with LS and ES </li></ul></ul><ul><ul><li> EP CEV </li></ul></ul><ul><li>Survival 10.2 7.8 p = 0.0004 </li></ul><ul><li>LS 14.5 9.7 p = 0.01 </li></ul><ul><li>ES 8.4 6.5 p = ns </li></ul>EP CEV CEV-cyclophosphamide/epirubicin/vincristine EP-etoposide/cisplatin
  7. 7. Platinum vs non-Platinum <ul><li>21 trials extensive stage SCLC </li></ul><ul><ul><li>cisplatin vs no cisplatin </li></ul></ul><ul><ul><li>median survival 9.5 vs 7.1 months, p = 0.002 </li></ul></ul><ul><ul><li>cisplatin based therapy independent predictor of survival p = 0.04 </li></ul></ul><ul><li>Chute et al, J Clin Oncol 1999 </li></ul><ul><li>Meta-analysis 19 trials 4054 pts </li></ul><ul><ul><li>cisplatin vs no cisplatin </li></ul></ul><ul><ul><li>Cisplatin - 4.4% survival benefit at 1 year </li></ul></ul><ul><ul><li>Pujol et al Br J Cancer 2000 </li></ul></ul><ul><li>Cochrane meta-analysis 2008 </li></ul><ul><ul><li>29 trials, 5530 patients </li></ul></ul><ul><ul><li>No difference in 6, 12 or 24 month survival </li></ul></ul><ul><ul><li>No difference OR rate </li></ul></ul><ul><ul><li>Higher CR rate for platinum </li></ul></ul><ul><ul><li>Higher toxicity rates with platinum </li></ul></ul><ul><ul><li>Amarasena et al. Cochrane Library 2009 </li></ul></ul>
  8. 8. Carboplatin <ul><li>A reasonable alternative to cisplatin in patients with poor prognostic factors </li></ul><ul><li>Less toxicity compared to cisplatin </li></ul><ul><li>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 </li></ul><ul><li>Skarlos et al. Ann Oncol 1994 </li></ul>
  9. 9. <ul><li>Cisplatin is the best radiosensitiser </li></ul><ul><li>Cisplatin plays a major role in the treatment of LS-SCLC </li></ul><ul><li>EP can be delivered at full dose with thoracic RT with an acceptable toxicity profile </li></ul>CTRT combinations
  10. 10. Pujol et al. J Clin Oncol, 1997. 15: 2082-9 <ul><li>125 patients with ES </li></ul><ul><li>PCDE q28 6# </li></ul><ul><li>1200/100/40/225 </li></ul><ul><li>vs </li></ul><ul><li>PCDE q28 4# with GCSF </li></ul><ul><li>1800/120/60/330 </li></ul><ul><li>No significant difference </li></ul><ul><li>Cumulative doses equivalent in </li></ul><ul><li>each arm except cisplatin dose </li></ul><ul><li>increased by 80% </li></ul>Dose intensity PCDE-cisplatin/CPM/epirubicin/etoposide
  11. 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. 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. 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. 14. Meta-analysis Irinotecan /Platinum and Etoposide /Platinum in ES Jiang et al J Thor Oncol 2010 Irinotecan + Platinum not inferior to EP <ul><li>p=0.044 </li></ul><ul><li>p=0.163 </li></ul>
  15. 15. Pemetrexed <ul><li>Phase III (GALES trial) </li></ul><ul><li>1822 patients (stopped early - 733 patients) </li></ul><ul><li>Extensive stage </li></ul><ul><li>Carbo- Etop vs Carbo-Pem </li></ul><ul><li>Median survival </li></ul><ul><li>9.6 months CE vs 7.3 months CP </li></ul>Socinski, M. A. et al. J Clin Oncol 2009
  16. 16. Topotecan – 2nd line <ul><li>Von Pawel et al JCO 1999 </li></ul><ul><li>Ph III (ES) 2nd line CAV vs T </li></ul><ul><li>Less neutropenia but more thrombocytopenia with T </li></ul><ul><li>Less SOB/ fatigue /loss of appetite </li></ul><ul><li>O’Brien et al JCO 2006 </li></ul><ul><li>2 nd line oral T vs BSC </li></ul><ul><li>6 months survival 49% vs 26% </li></ul><ul><li>Eckhart et al JCO 2007 </li></ul><ul><li>2 nd line T (o) vs T (iv) </li></ul><ul><li>Equivalent </li></ul>
  17. 17. Amrubicin <ul><li>Two phase II second line studies have demontrated encouraging survival rates </li></ul><ul><li>A number of phase III studies are ongoing to evaluate this treatment in the first and second line setting </li></ul>
  18. 18. EORTC 08062 First Line <ul><li>Extensive Stage </li></ul><ul><li>No prior chemotherapy regimen </li></ul><ul><li>ECOG performance status 0-2 </li></ul><ul><li>Measurable disease </li></ul><ul><li>99 Pts </li></ul>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. 19. Maintenance or Consolidation Therapy Rossi et al Lung Cancer 2010 <ul><li>N = 3688 </li></ul><ul><li>All (n=21) HR 0.93 (0.87-1.00) p=0.05 </li></ul><ul><li>CT (n=11) HR 0.89 (0.81 0.98) p=0.02 </li></ul><ul><li>IFN α (n=4) HR 0.78 (0.64-0.96) p=0.02 </li></ul>‘ Clinical impact of maintenance chemotherapy needs to be confirmed by further studies’
  20. 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. 21. Conclusions <ul><li>High RR with chemotherapy </li></ul><ul><li>BUT high rates of local and distant relapses </li></ul><ul><li>Many newer combinations as good, but none convincingly better </li></ul><ul><li>PE is the standard treatment in SCLC </li></ul><ul><li>Disappointing results so far with targeted therapies </li></ul><ul><li>The way forward - a better understanding of the biology of the disease in order to develop more effective therapies </li></ul>
  22. 22. RADIOTHERAPY
  23. 23. Limited-stage SCLC
  24. 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. 25. Treatment options <ul><li>Sequential CTRT </li></ul><ul><li>Pros: reduction in tumour volume, reduced toxicity </li></ul><ul><li>Cons: delayed RT -> repopulation ->poorer outcome </li></ul><ul><li>Concurrent CTRT </li></ul><ul><li>Pros: radiosensitisation, early RT, short overall TT, better outcome </li></ul><ul><li>Cons: for selected patients only, toxicity </li></ul>RT CT CT CT CT CT RT CT (CT)
  26. 26. Concurrent CTRT <ul><li>Selection Crit eria </li></ul><ul><li>PS </li></ul><ul><li>Comorbidities </li></ul><ul><li>Tumour volume </li></ul><ul><li>Lung volume </li></ul><ul><li>Dose normal tissues </li></ul><ul><li>(age) </li></ul><ul><li>(lung function) </li></ul>
  27. 27. Sequential CTRT
  28. 28. Current evidence <ul><li>Concurrent CTRT >sequential CTRT (Takada) </li></ul><ul><li>Early RT >late RT (Fried , Cochrane review) </li></ul><ul><li>Best survival results achieved with early BD concurrent CTRT (Turrisi, Jeremic) </li></ul><ul><li>RT doses up to 70 Gy can be safely delivered </li></ul><ul><li>concurrently with CT (CALGB 39808 and 30002) </li></ul>
  29. 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. 30. Standard of care in LS-SCLC <ul><li>Early twice daily concurrent CTRT </li></ul><ul><li>Turrisi trial </li></ul><ul><li>PE remains the standard CT </li></ul><ul><ul><li>Irinotecan trials </li></ul></ul><ul><ul><li>Pemetrexed trial </li></ul></ul><ul><li>PCI </li></ul>
  31. 31. <ul><li>Establish a standard regimen in LS-SCLC </li></ul><ul><li>Toxicity and outcome data with </li></ul><ul><li>modern RT techniques </li></ul><ul><li>Importance of </li></ul><ul><ul><li>the RT dose ? </li></ul></ul><ul><ul><li>the overall treatment time ? </li></ul></ul><ul><li>Translational research </li></ul>Why CONVERT
  32. 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. 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. 34. Prophylactic cranial irradiation <ul><li>Why? </li></ul><ul><ul><li>Major risk of spread to brain-50 to 60% </li></ul></ul><ul><ul><li>Eradicates micrometastatic disease </li></ul></ul><ul><ul><li>PCI can reduce the risk of spread by 50% </li></ul></ul><ul><ul><li>PCI improves survival (6% @ 3 years) </li></ul></ul><ul><ul><li>Auperin N Engl J Med 1999 </li></ul></ul><ul><li>When? </li></ul><ul><ul><li>After concurrent CTRT </li></ul></ul><ul><ul><li>With consolidation thoracic RT if sequential CTRT is given </li></ul></ul><ul><li>Toxicity </li></ul><ul><ul><li>Acute </li></ul></ul><ul><ul><ul><li>lethargy </li></ul></ul></ul><ul><ul><ul><li>raised ICP ->steroids </li></ul></ul></ul><ul><ul><ul><li>scalp reaction, hair growth will be delayed </li></ul></ul></ul><ul><ul><li>No reports of increased long term neurological sequalae in RCTs compared to control </li></ul></ul>
  35. 35. PCI 99-01 EORTC 22003-08004 - RTOG 0212 <ul><ul><ul><li> </li></ul></ul></ul>Le Pechoux et al. Lancet Oncol 2009 <ul><li>Multicentre randomised phase III </li></ul><ul><li>standard dose 25 Gy/10  /12 days </li></ul><ul><li>high dose 36 Gy in 18  /24 days or 24#/16 days </li></ul><ul><li>720 patients in CR were randomised (146 from RTOG institutions) </li></ul><ul><li>Immediate toxicity was equivalent in both arms </li></ul>0.05 1.20 (1.00-1.44) 37% (32%-42%) 42% (37%-48%) Survival <ul><ul><ul><li>0.18 </li></ul></ul></ul>0.80 (0.57-1.11) 23% (18%-29%) 29% (24%-35%) Incidence BM <ul><ul><ul><li>p </li></ul></ul></ul>HR 36Gy/18  25 Gy/10  2 years
  36. 36. Extensive stage SCLC
  37. 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. 38. Prophylactic cranial irradiation in ES-SCLC EORTC 08993-22993
  39. 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. 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. 41. Conclusions <ul><li>Major progress in both LS-SCLC and ES-SCLC in the last two decades with RT </li></ul><ul><li>Progress translating into improvements in both local control and survival </li></ul><ul><li>Future directions </li></ul><ul><ul><li>New agents combined with RT </li></ul></ul><ul><ul><li>Thoracic RT in ES-SCLC? </li></ul></ul><ul><ul><li>Translational research </li></ul></ul>

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