1. Early Stage NSCLC: The Role of Chemotherapy Eric Vallieres, MD

2. USA 2003

3. Clinical IB, IIA, IIB diseases Resection by lobectomy or more if cardiopulmonary reserves 5-y Survival = 20-40 % Adjuvant Therapy ? Induction Therapy ? cT2N0 RUL NSCLC

4. Adjuvant Radiotherapy

5. N2 appeared to gain 1 month in survival...

6. MRC LCWP Stephens et al, Br J Cancer 1996

7. Adjuvant Radiotherapy No improvement in survival Improved loco-regional control with squamous histology (LCSG 773) but systemic failures lead to death...

8. Adjuvant Chemotherapy

9. Adjuvant Chemotherapy ALPI (Adjuvant Lung Project Italy) Tonato, PASCO 2002 abstract 1157

10. Overall Survival Events/Total CT 278/548 Control 288/540 HR=0.96 (0.81 - 1.13) p=0.585 PROBABILITYPROBABILITY YEARS Median f/up of 63 months

11. Adjuvant Chemotherapy Over the last 30 years, on trial, the delivery of the intended chemotherapy has been consistently poor: LCSG 801 (CAP * 4) = 53% JCOG 8601 (C Vd *3) = 68% ALPI (MVdP * 3) = 70%

12. Clinical IB, IIA, IIB diseases Resection by lobectomy or more if cardiopulmonary reserves 5-y Survival = 20-40 % Adjuvant Therapy = NO Induction Therapy ? cT2N0 RUL NSCLC Scan not available

13. 3 cycles carboplatin/ paclitaxel re-imaged 4 weeks later PrePost Scans not available

14. The BLOT Phase II Study Induction Chemotherapy The BLOT Phase II Study Pisters K et al., J Thor CV Surg 2000; 119:429-439

15. The BLOT Study 94 patients 98% completed induction chemo as planned Clinical major RR: 53/90 ( 58.9%) Pisters K et al., J Thor CV Surg 2000; 119;429

16. The BLOT Study Progression during induction: 3/98 ( 3%) Pisters K et al., J Thor CV Surg 2000; 119;429

17. The BLOT Study 86/94 were explored 77/ 94 had a R0 resection ( 82%) One postoperative death Operative morbidity comparable to historical series of Surgery alone Pisters K et al., J Thor CV Surg 2000; 119;429

18. The BLOT Study Induction carboplatin/ paclitaxel chemotherapy is safe and feasible prior to resection of clinical early NSCLC Pisters K et al., J Thor CV Surg 2000; 119:429-439

19. Induction Chemotherapy The Depierre Phase III Study Depierre et al., Proc ASCO 1999, abstract 1792 Adjuvant RT for pT3 and pN2

20. OP MIP>OP Median survival (months) 26 p=0.11 36 Survival @ 1 y (%) 73 NS 77 @ 2y (%) 52 NS 59 @ 3y (%) 41 NS 49 Operative mortality 4.5% NS 7.8% The Depierre Study Depierre et al., J Clin Oncol 2001; 20: 247-53

21. Overall Survival 1253 Years Years4 100 80 60 40 20 p = 0.15 PCTPRS ||||| _ _ _ _ _ _ _ _ _ _ 6 | Reference date : Nov 1, 2000 PCT arm 179 138 105 87643320 PRS arm 176 129 92 67513221 0 Patients at risk

22. Vanderbilt Historical comparison Induction PC Surgery alone N 34 67 Stages 2.52 <0.001 1.55 age, PFT, comorbid. = Life Threat. Comp. (%) 27% 0.0036 6% Reintubation 17.6% 0.0093 3% Tracheostomy 12% 0.0042 -- Mortality 5.6% 0.045 -- Induction chemotherapy Perioperative complications ? Roberts et al., Ann Thorac Surg 2001; 72: 885-8

23. The Depierre Study 30 day operative mortality MIP> S n=179 7.8% S n=176 4.5% NS Breton JP et al., Proc ASCO 2001, abstract 1239

24. The Depierre Study 30 day operative morbidity MIP> S 39 in 33 pts S 27 in 25 pts NS Breton JP et al., Proc ASCO 2001, abstract 1239

25. The Depierre Study BPF/ empyemas MIP> S 10* ( 8 early + 2 late) S 5 NS * 8/10 in N2 pts, 9/10 after pneumonectomy Breton JP et al., Proc ASCO 2001, abstract 1239

26. The Depierre Study Pulmonary infections MIP> S 10 S 11 NS Breton JP et al., Proc ASCO 2001, abstract 1239

27. Does induction chemotherapy (without radiation) really increase the morbidity and mortality of lung resection ?

28. Randomized Data Stage III Experience

29. RESECTABLE N2 DISEASE Pre chemotherapy Post chemotherapy Scans not available

30. The Roth Phase III Study (MDACC) Induction Chemotherapy The Roth Phase III Study (MDACC) Roth J NCI May 1994

31. The Rosell Phase III Study Induction Chemotherapy The Rosell Phase III Study Rosell NEJM Jan 1994 Adjuvant mediastinal RTx 50 Gy

32. Operative risks after induction chemotherapy Phase III data OPERATIVE MORTALITY Pass 1992 CS(EP)>S> RT (n=13) 0% S>RT (n=14) 0% Rosell 1994 CS(MIP)>S > RT (n=30) 2/30 6.67% S > RT (n=30) 2/30 6.67% [all 4 deaths (2+2) were respiratory] Roth 1994 CS(CyEP)>S (n=28) 0* S alone (n=32) 6 * had 3 treatment related deaths Pass, Ann Thor Surg 1992; Rosell, NEJM 1994; Roth, J NCI 1994

33. Retrospective Data

34. Operative risks after induction chemotherapy MDACC Aug 1996 to Apr 1999 335 consecutive “lobectomies or more” for NSCLC 76 after induction chemotherapy 259 surgery alone Prospective data collection of peri-operative events Siegenthaler et al., Ann Thor Surg 71:1105, 2001

35. Operative risks after induction chemotherapy MDACC (-ed) Induction chemotherapy: carboplatin/ paclitaxel in 93% of pts Siegenthaler et al., Ann Thor Surg 71:1105, 2001

36. Operative risks after induction chemotherapy Siegenthaler et al., Ann Thor Surg 71:1105, 2001

37. Operative risks after induction chemotherapy MDACC (-ed) Stage specific analysis : no difference in morbidity of CS vs. S alone Multivariate analysis: only CAD and pneumonectomy were independent risk factors for a major postoperative event. Siegenthaler et al., Ann Thor Surg 71:1105, 2001

38. Operative risks after induction chemotherapy MSKCC Jan 1993 to Dec 1999 412 pulmonary resections after induction therapy ( ages ranged 25-82) Preop chemotherapy: carboplatin/ paclitaxel 32% MVP 38% Preop radiotherapy as well : 18% Martin J et al., Ann Thorac Surg 2001; 72: 1149-54

39. Operative risks after induction chemotherapy MSKCC (-ed) 297 lobectomies ( 9 sleeves, 26 bilobectomies ) 97 pneumonectomies ( 20%) 18 lesser resections, 58 O&C 22% were extended resections Martin J et al., Ann Thorac Surg 2001; 72: 1149-54

40. Operative risks after induction chemotherapy MSKCC (-ed) Operative mortality Overall 3.8% Lobectomy 2.4% Left Pneumonectomy 0% Right Pneumonectomy 23.9% Multivariate analysis: right pneumonectomy was the only predictor of mortality Martin J et al., Ann Thorac Surg 2001; 72: 1149-54

41. Operative risks after induction chemotherapy MSKCC (conclusion) Major morbidity 26.6%, mainly respiratory Multivariate analysis: Increased operative blood loss, low FEV1 and right pneumonectomy were the only independent predictors of post- operative morbidity The type of induction regimen was not a risk factor. Martin J et al., Ann Thorac Surg 2001; 72: 1149-54

42. Operative risks after induction chemotherapy Does induction chemotherapy without radiationtherapy really increase the morbidity and mortality of lung resection ? Probably not… but most of the data published so far is either retrospective and/or comparing to historical controls...

43. Induction Therapy ( pre-operative ) Ongoing Studies

44. Early Stage Disease Phase III Trial INT S 9900 cT2N0, T1N1, T2N1, T3N0, T3N1 Resection Induction carboplatin/ paclitaxel 3 cycles Resection Activated 11.99 Accrual goal = 600 1/24/03 = 279

45. Phase III Trial INT S 9900 “Son of BLOT” “ BLOT or KNOT” Through SWOG, NCCTG, ECOG, RTOG, ACOSOG, NCIC and the CTSU.

46. Early Stage Disease NATCH* ( Neoadjuvant/ Adjuvant Taxol Carboplatin Hope) *Switzerland, Spain, Germany, Portugal, Sweden Activated 4.00 Accrual goal = 624

47. Early Stage Disease ChEST (Chemotherapy for Early Stage Tumor) cT2N0, T1N1, T2N1, T3N0, T3N1 Resection Induction gemcitabine/ cddp 3 cycles Resection Italy Accrual goal = 606-712

48. Early Stage Disease MRC Lu-22 cT1N0, T2N0, T1N1, T2N1, T3N0, T3N1 Resection Induction chemotherapy* 3 cycles, Q 3weeks Resection UK + EORTC ( 6/02) Activated Jan 1998 Accrual goal = 450 April 2002 = 239 *MVP, MIP, Cis-Vinorelbine, Cis-Gem

49. Will induction chemotherapy become the standard of care for our patients with early stage disease ? Only by completing the ongoing clinical trials in a timely fashion, will we be able to answer this very important question.