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ADJUVANT CHEMOTHERAPY IN RESECTED LUNG CANCER

ADJUVANT CHEMOTHERAPY IN RESECTED LUNG CANCER. Pınar Çelik 10 th Annual Congress of Turkish Thoracic Society April 25 th – 29 th 2007, Antalya. Presentation Scheme. Adjuvant CT trials in early stage resected lung cancer cases Second and third generation regimens

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ADJUVANT CHEMOTHERAPY IN RESECTED LUNG CANCER

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  1. ADJUVANT CHEMOTHERAPY IN RESECTED LUNG CANCER Pınar Çelik 10th Annual Congress of Turkish Thoracic Society April 25th – 29th 2007, Antalya

  2. Presentation Scheme • Adjuvant CT trials in early stage resected lung cancer cases • Second and third generation regimens • Adjuvant CT trials in early stage NSCLC • Targeted agents in adjuvant therapy • Molecular studies

  3. Survival in early stage NSCLC Mountain. Chest 1997

  4. Recurrence in early stage NSCLC Pisters KMV, Le Chevalier T. J Clin Oncol 2005

  5. Adjuvant CT Advantages • Early treatment of distant metastasis

  6. Adjuvant CT trials in early stage (Resected Cases)

  7. LCSG Trials • LCSG 772 BCG+levamisole vs CT(CAP) • LCSG 791 RT vs CT+RT • LCSG 801 CT vs Observation • LCSG 853 CT vs Observation • Results are controversially Holmes E, Gail M. J Clin Oncol 1986 Lad T et al. J Clin Oncol 1988 Feld R et al. J Natl Cancer Ins 1993 Figlin R et al. Chest 1994.

  8. The non-small Cell Lung Cancer Collaborative Group (Meta-analysis) • 9387 resected NSCLC • 52 randomised trial • Between 1965-1991 • CT vs Observation trials in resected cases • Results • 3% decrease in death risk, 5 % improvement in 5-year survival CT with an alkylating agents: • Death risk HR: 1.15 • Platinum-based CT: • Death risk HR: 0.87, 13 % improvement in 5-year survival Non-small Cell Cancer Colloborative Group BMJ 1995

  9. Second and third generation regimens

  10. 1209 cases Stage I-IIIA Resected NSCLC Randomisation 587 Observation 592 CTx3(mitomycin,vindesine, cisplatin) CT toxicity 30 % grade 3 18 % grade 4 RT optional Median observation: 63 months 526 death, 1076 patients HR: 0.94overall survival HR: 0.89 PFS The Adjuvant Lung Project Italy (ALPI) Scagliotti GV et al. J Natl Cancer Ins 2003

  11. 381 cases Stage I-IIIA Resected NSCLC Randomisation Observation CT+Surgery or Surgery+CT 4 CT protocols Cisplatin-vinorelbin Cisplatin-vindesin Mitomycin-ifosfamid-cisplatin Mitomycin-vinblastin-cisplatin Two groups were well-balanced for risk factors CT toxicity 30 % grade 3 or greater No improvement in overall and disease-free survival rates. The Big Lung Trial (BLT) Waller D et al. Eur J Cardiothorac Surg 2004

  12. Stage I-II-III NSCLC Between 18-75 year-old Postop.30-60 days later randomisation Primary objective: Overall survival Secondary objective: Disease-free survival, secondary cancer, toxicity It is planned to include 3300 cases Cisplatin doses 80mg/m2x4 100mg/m2x3-4 120 mg/m2x3 Combination Vindesin (%5) Vinblastin (%10) Vinorelbin (%25) Etoposid (%55) RT optional International Adjuvant Lung Trial (IALT) Arriagada R et al. N Engl J Med 2004

  13. IALT 1867 cases Randomisation Observation CT N=935 N=932 148 center, 33 country, between1995-2000 years Arriagada R et al. N Engl J Med 2004

  14. IALT • RT • CT: 70.4 % • Control: 84.2 % • CT • 73.8 % 240 mg/m2 cisplatin • 7.8 % did not receive CT Arriagada R et al. N Engl J Med 2004

  15. IALT • Overall survival: 50.6 month vs 44.4 month • 5-year survival: % 44.5vs% 40.4 • HR= 0.86 (0.76-0.98); p<0.03 Arriagada R et al. N Engl J Med 2004

  16. Studies of Adjuvant Tegafur • Phase III, Japan • 978 Stage I Adenocarcinoma • Oral agent uracil-tegafur (UFT), up to 2 years • HR: 0.71 (p=0.04) • Meta-analysis (6 studies) • Stage I (95%) • HR: 0.74 (p=0.001) Kato H et al. J Clin Oncol 2004 Hamada C et al. J Thorac Cardiovasc Surg 2004

  17. Adjuvant CT Trials in Early Stage NSCLC

  18. CALGB 9633 NSCLC T2N0M0(Stage IB) 344 Complete Resection (4-8 week) 4 Cycles CT( Pacl-Carbo) Observation Strauss GM et al. J Clin Oncol 2004

  19. CALGB 9633 • Both groups were well-balanced • Prognostic factors; age, gender, race, ethnicity, histology, tm differentiation, resection type • Toxicity: 36 % grade 3-4 neutropenia • Overall survival: Longer in CT arm (p=0.028); • 12% improvement in 4-year survival Strauss GM et al. J Clin Oncol 2004

  20. NCIC-CTG BR10 NSCLC Stage IB and II (excluding T3N0M0) 482 Randomisation (Ras±; N0/1) 4 Cycles CT( Vinorelbin-Cis) Observation Winton TL et al. J Clin Oncol 2004

  21. NCIC-CTG BR10 • Well-balanced for prognostic factors • No benefit in stage IB • Median survival was longer CT arm (94 months-73 months) (p=0.011); • 15% improvement in 5-year survival Winton TL et al. J Clin Oncol 2004

  22. Comparison of Adjuvant CT in Early Stage Cancers Study Organ CT Risk of death p Winton et al. Lung Cis-vin 0.7 0.012 Strauss et al. Lung Carbo-Pac. 0.62 0.028 Sedrakyan et al. Lung Platinum-based ± UFT 0.87 <0.0001 Hotta et al. Lung Platinum-based ± UFT 0.87 0.001 Comets et al. Colon 5FU/FA 0.88 0.15 Gray et al. Over Plt 0.67 0.008

  23. POSTOPERATIVE RT • IALT • 572 cases were treated with RT • CT: compliance 70.4 %, Control: 84.2 % • No difference • PORT meta-analysis • No improvement in survival • Harmful effects in stage I/II • No adverse events in stage III • ECOG 3590 • 53 % cases were pN2 • No decrease in intrathoracic recurrence • No survival advantage in stage II/III Arriagada R et al. N Engl J Med 2004 PORT Metaanalysis Trialists Group. Lancet 1998 Keller SM et al. N eng J Med 2000

  24. Meta-analysis 2005 • Stage I-III NSCLC • 6 neoadjuvant and 19 adjuvant trial • Neoadjuvant HR: 0.66 • Adjuvant HR: 0.84 • Adjuvant Stage I-II HR: 0.88 • Adjuvant Stage III HR: 0.85 • Adjuvant CT is effective in stageI-II resected NSCLC Stage III ? Berghmans T et al. Lung Cancer 2005

  25. Adjuvant Navelbine International Trialist Association (ANITA) Stage IB and IIIA NSCLC 840 cases were randomised 4 Cycle CT( Vinorelbin-Cis) Observation • 5 and 7-year survival is in favor of CT • 5-year survival 51%vs43% p<0.03 • 7 year survival 45.2%vs36% p<0.03 • No benefit in Stage IB Douillard JY et al. Lancet Oncol 2006

  26. ANITA Douillard JY et al. Lancet Oncol 2006

  27. ANITA Douillard JY et al. Lancet Oncol 2006

  28. CALGB 9633 Update ASCO 2006 • 2004: 88 ex, median survival HR: 0.62 (p=0.01) • 2006: 137 ex, median survival HR: 0.80 (p=0.1) • Sampling population was small • Results had a weak power • Probability of having no adjuvant benefit in Stage I • Choosing carboplatin instead of cisplatin

  29. Lung Adjuvant Cisplatin Evaluation (LACE) Pignon JP et al. J Clin Oncol 2006

  30. Lung Adjuvant Cisplatin Evaluation (LACE) • A meta-analysis including largest Cisplatin-based 5 trails • 5-year survival advantage: 5.3 %(HR: 0.89) • Stage IA HR: 1.41 • Stage IB: HR: 0.92 • Stage II-III HR: 0.83 • CALBG 9633 trial • Tm>4 cm overall survival HR: 0.66 • Tm<4 cm overall survival HR: 1.02 • Cisplatin-vinorelbin is superior over other cisplatin CTs, however Pignon JP et al. J Clin Oncol 2006

  31. Cisplatin vs Carboplatin • CISCA meta-analysis ASCO 2006 • 2968 advanced stage NSCLC cases • 9 trials • Cisplatin is superior • Cisplatin-based regimens are standart as an adjuvant therapy in early stage resected NSCLC, if there is a contraindication carboplatin can be used Ardizzoni A et al. J Clin Oncol 2006

  32. Targeted Agents in Adjuvant Therapy

  33. JBR 19 Stage IB and IIIA NSCLC Randomisation (Stage, histology, CT, RT, gender) 250 mg/day gefitinib Observation

  34. E 1505 Stage IB(>4 cm)-IIIA 1500 Randomisation (Stage, histology, gender, CT regimen*) CTx4 CTx4 + bevacizumabx1year Primary end-point: overall survival *: Cisplatin-based 3 CT regimens

  35. RADIANT Stage I-IIIA (Resected) 945 Randomised (IHC/FISH and EGFR)(CT optional) Erlotinib 150 mg/dayx2years Observation • Histology • Gender • EGFR condition • Smoking • Adjuvant CT • If IHC or copying gene is + • Primary end-point: Disease-free survival

  36. Molecular Studies

  37. Positivity of ERCC1 enzyme • IALT investigators, retrospective analysis • ERCC1 nucleosid excision repair enzyme • ERCC1 negative tumours HR: 0.65 • ERCC1 positive tumours HR: 1.14 • This study is important for detecting cases who will benefit from cisplatin-based adjuvant CT Olaussen KA et al. N Engl J Med 2006

  38. CONCLUSION • Postoperative CT is effective in stage II and IIIA, but is it in stage IB? • Stage IB tm> 4cm more effective • Stage IA • Results of Japan trials with Tegafur is positive, but Tegafur is not available in Europe and America. • Results of USA and Europe trials are negative, adjuvant CT is contraindicated • Platinum-based CT in adjuvant therapy • Cisplatin(320 mg/m2) + vinorelbin ? • Cisplatin, is more effective than carboplatin ? • Results of studies with targeted agents? • Molecular studies ? • Comparison of adjuvant and neoadjuvant therapy ?

  39. thank you

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