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Early Stage NSCLC:  The Role of Chemotherapy Eric Vallieres, MD
 
Clinical IB, IIA, IIB diseases <ul><li>Resection by lobectomy or more if cardiopulmonary reserves </li></ul><ul><li>5-y Su...
Adjuvant Radiotherapy
Adjuvant Radiotherapy N2 appeared to gain 1 month in survival...
MRC LCWP Stephens et al, Br J Cancer 1996
Adjuvant Radiotherapy No improvement in survival  Improved loco-regional control with squamous histology (LCSG 773) but sy...
Adjuvant Chemotherapy
Adjuvant Chemotherapy  ALPI (Adjuvant Lung Project Italy)  Tonato,  PASCO 2002 abstract 1157
Overall Survival PROBABILITY YEARS Median f/up  of 63 months     Events/Total CT  278/548 Control   288/540  HR=0.96 (0.81...
Adjuvant Chemotherapy <ul><li>Over the last 30 years, on trial, the delivery of the intended chemotherapy has been consist...
Clinical IB, IIA, IIB diseases <ul><li>Resection by lobectomy or more if cardiopulmonary reserves </li></ul><ul><li>5-y Su...
3 cycles carboplatin/ paclitaxel re-imaged 4 weeks later   Pre Post Scans not available
Induction Chemotherapy The BLOT Phase II Study Pisters K et al., J Thor CV Surg 2000; 119:429-439
The BLOT Study 94 patients 98% completed induction chemo as planned Clinical major RR: 53/90 ( 58.9%) Pisters K et al., J ...
The BLOT Study Progression during induction:  3/98 ( 3%) Pisters K et al., J Thor CV Surg 2000; 119;429
The BLOT Study 86/94 were explored 77/ 94 had a R0 resection ( 82%) One postoperative death Operative morbidity comparable...
The BLOT Study Induction carboplatin/ paclitaxel chemotherapy is safe and feasible prior to resection of clinical early NS...
Induction Chemotherapy The   Depierre Phase III   Study Depierre et al.,  Proc ASCO 1999, abstract 1792 Adjuvant RT for pT...
OP  MIP>OP Median survival (months)  26  p=0.11  36  Survival @ 1 y  (%)  73  NS  77 @ 2y  (%)  52  NS  59 @ 3y  (%)  41  ...
Overall Survival 1 2 5 3 Years 4 100 80 60 40 20 p = 0.15 PCT PRS | | | | | _ _ _ _ _ _ _ _ _ _ 6 | Reference date :  Nov ...
Vanderbilt Historical comparison   Induction PC  Surgery alone  N  34  67 Stages  2.52  <0.001  1.55 age, PFT, comorbid.  ...
The Depierre Study <ul><li>30 day operative mortality </li></ul><ul><li>MIP> S  n=179  7.8% </li></ul><ul><li>S  n=176  4....
The Depierre Study <ul><li>30 day operative morbidity </li></ul><ul><li>MIP> S  39 in 33 pts </li></ul><ul><li>S  27 in 25...
The Depierre Study <ul><li>BPF/ empyemas </li></ul><ul><li>MIP> S  10* ( 8 early + 2 late) </li></ul><ul><li>S  5 </li></u...
The Depierre Study <ul><li>Pulmonary infections </li></ul><ul><li>MIP> S  10 </li></ul><ul><li>S  11 </li></ul><ul><li>NS ...
Does induction chemotherapy ( without radiation )  really increase the morbidity and mortality of lung resection ?
Randomized Data  Stage III Experience
RESECTABLE  N2  DISEASE Pre chemotherapy Post chemotherapy Scans not available
Induction Chemotherapy The Roth Phase III Study (MDACC) Roth  J NCI May  1994
Induction Chemotherapy The Rosell Phase III Study Rosell  NEJM Jan 1994 Adjuvant mediastinal RTx 50 Gy
Operative risks after induction chemotherapy <ul><li>Phase III data   OPERATIVE MORTALITY </li></ul><ul><li>Pass   1992  C...
Retrospective Data
Operative risks after induction chemotherapy <ul><li>MDACC  </li></ul><ul><li>Aug 1996 to Apr 1999 </li></ul><ul><li>335 c...
Operative risks after induction chemotherapy MDACC (-ed) Induction chemotherapy: carboplatin/ paclitaxel in 93% of pts Sie...
Operative risks after induction chemotherapy Siegenthaler et al., Ann Thor Surg 71:1105, 2001
Operative risks after induction chemotherapy MDACC (-ed) Stage specific analysis : no difference in morbidity of CS vs. S ...
Operative risks after induction chemotherapy MSKCC  Jan 1993 to Dec 1999 412 pulmonary resections after induction therapy ...
Operative risks after induction chemotherapy MSKCC (-ed) 297 lobectomies ( 9 sleeves, 26 bilobectomies ) 97 pneumonectomie...
Operative risks after induction chemotherapy <ul><li>MSKCC (-ed) </li></ul><ul><li>Operative mortality </li></ul><ul><li>O...
Operative risks after induction chemotherapy MSKCC (conclusion) Major morbidity 26.6% , mainly respiratory Multivariate an...
Operative risks after induction chemotherapy <ul><li>Does induction chemotherapy without radiationtherapy  really increase...
Induction Therapy ( pre-operative ) Ongoing Studies
Early Stage Disease Phase III Trial  INT S 9900   cT2N0, T1N1, T2N1, T3N0, T3N1 Resection Induction carboplatin/ paclitaxe...
Phase III Trial INT S 9900 <ul><li>“ Son of BLOT”  </li></ul><ul><li>“  BLOT or KNOT” </li></ul><ul><li>Through SWOG, NCCT...
Early Stage Disease NATCH*  ( Neoadjuvant/ Adjuvant Taxol Carboplatin Hope) * Switzerland, Spain, Germany, Portugal, Swede...
Early Stage Disease ChEST (Chemotherapy for Early Stage Tumor)   cT2N0, T1N1, T2N1, T3N0, T3N1 Resection Induction gemcita...
Early Stage Disease MRC Lu-22   cT1N0, T2N0, T1N1, T2N1, T3N0, T3N1 Resection Induction chemotherapy* 3 cycles, Q 3weeks R...
Will induction chemotherapy become the standard of care for our patients with early stage disease ? Only by completing the...
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Early Stage Nsclc The Role Of Chemotherapy

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Transcript of "Early Stage Nsclc The Role Of Chemotherapy"

  1. 1. Early Stage NSCLC: The Role of Chemotherapy Eric Vallieres, MD
  2. 3. Clinical IB, IIA, IIB diseases <ul><li>Resection by lobectomy or more if cardiopulmonary reserves </li></ul><ul><li>5-y Survival = 20-40 % </li></ul><ul><li>Adjuvant Therapy ? </li></ul><ul><li>Induction Therapy ? </li></ul>cT2N0 RUL NSCLC
  3. 4. Adjuvant Radiotherapy
  4. 5. Adjuvant Radiotherapy N2 appeared to gain 1 month in survival...
  5. 6. MRC LCWP Stephens et al, Br J Cancer 1996
  6. 7. Adjuvant Radiotherapy No improvement in survival Improved loco-regional control with squamous histology (LCSG 773) but systemic failures lead to death...
  7. 8. Adjuvant Chemotherapy
  8. 9. Adjuvant Chemotherapy ALPI (Adjuvant Lung Project Italy) Tonato, PASCO 2002 abstract 1157
  9. 10. Overall Survival PROBABILITY YEARS Median f/up of 63 months Events/Total CT 278/548 Control 288/540 HR=0.96 (0.81 - 1.13) p=0.585
  10. 11. Adjuvant Chemotherapy <ul><li>Over the last 30 years, on trial, the delivery of the intended chemotherapy has been consistently poor: </li></ul><ul><li>LCSG 801 (CAP * 4) = 53% </li></ul><ul><li>JCOG 8601 (C Vd *3) = 68% </li></ul><ul><li>ALPI (MVdP * 3) = 70% </li></ul>
  11. 12. Clinical IB, IIA, IIB diseases <ul><li>Resection by lobectomy or more if cardiopulmonary reserves </li></ul><ul><li>5-y Survival = 20-40 % </li></ul><ul><li>Adjuvant Therapy = NO </li></ul><ul><li>Induction Therapy ? </li></ul>cT2N0 RUL NSCLC Scan not available
  12. 13. 3 cycles carboplatin/ paclitaxel re-imaged 4 weeks later Pre Post Scans not available
  13. 14. Induction Chemotherapy The BLOT Phase II Study Pisters K et al., J Thor CV Surg 2000; 119:429-439
  14. 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
  15. 16. The BLOT Study Progression during induction: 3/98 ( 3%) Pisters K et al., J Thor CV Surg 2000; 119;429
  16. 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
  17. 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
  18. 19. Induction Chemotherapy The Depierre Phase III Study Depierre et al., Proc ASCO 1999, abstract 1792 Adjuvant RT for pT3 and pN2
  19. 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
  20. 21. Overall Survival 1 2 5 3 Years 4 100 80 60 40 20 p = 0.15 PCT PRS | | | | | _ _ _ _ _ _ _ _ _ _ 6 | Reference date : Nov 1, 2000 PCT arm 179 138 105 87 64 33 20 PRS arm 176 129 92 67 51 32 21 0 Patients at risk
  21. 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
  22. 23. The Depierre Study <ul><li>30 day operative mortality </li></ul><ul><li>MIP> S n=179 7.8% </li></ul><ul><li>S n=176 4.5% </li></ul><ul><li>NS </li></ul>Breton JP et al., Proc ASCO 2001, abstract 1239
  23. 24. The Depierre Study <ul><li>30 day operative morbidity </li></ul><ul><li>MIP> S 39 in 33 pts </li></ul><ul><li>S 27 in 25 pts </li></ul><ul><li>NS </li></ul>Breton JP et al., Proc ASCO 2001, abstract 1239
  24. 25. The Depierre Study <ul><li>BPF/ empyemas </li></ul><ul><li>MIP> S 10* ( 8 early + 2 late) </li></ul><ul><li>S 5 </li></ul><ul><li>NS </li></ul><ul><li>* 8/10 in N2 pts, 9/10 after pneumonectomy </li></ul>Breton JP et al., Proc ASCO 2001, abstract 1239
  25. 26. The Depierre Study <ul><li>Pulmonary infections </li></ul><ul><li>MIP> S 10 </li></ul><ul><li>S 11 </li></ul><ul><li>NS </li></ul>Breton JP et al., Proc ASCO 2001, abstract 1239
  26. 27. Does induction chemotherapy ( without radiation ) really increase the morbidity and mortality of lung resection ?
  27. 28. Randomized Data Stage III Experience
  28. 29. RESECTABLE N2 DISEASE Pre chemotherapy Post chemotherapy Scans not available
  29. 30. Induction Chemotherapy The Roth Phase III Study (MDACC) Roth J NCI May 1994
  30. 31. Induction Chemotherapy The Rosell Phase III Study Rosell NEJM Jan 1994 Adjuvant mediastinal RTx 50 Gy
  31. 32. Operative risks after induction chemotherapy <ul><li>Phase III data OPERATIVE MORTALITY </li></ul><ul><li>Pass 1992 CS(EP)>S> RT (n=13) 0% </li></ul><ul><li> S>RT (n=14) 0% </li></ul><ul><li>Rosell 1994 CS(MIP)>S > RT (n=30) 2/30 6.67% </li></ul><ul><li>S > RT (n=30) 2/30 6.67% </li></ul><ul><li>[ all 4 deaths (2+2) were respiratory ] </li></ul><ul><li>Roth 1994 CS(CyEP)>S (n=28) 0* </li></ul><ul><li>S alone (n=32) 6 </li></ul><ul><li>* had 3 treatment related deaths </li></ul>Pass, Ann Thor Surg 1992; Rosell, NEJM 1994; Roth, J NCI 1994
  32. 33. Retrospective Data
  33. 34. Operative risks after induction chemotherapy <ul><li>MDACC </li></ul><ul><li>Aug 1996 to Apr 1999 </li></ul><ul><li>335 consecutive “lobectomies or more” for NSCLC </li></ul><ul><li>76 after induction chemotherapy </li></ul><ul><li>259 surgery alone </li></ul><ul><li>Prospective data collection of peri-operative events </li></ul>Siegenthaler et al., Ann Thor Surg 71:1105, 2001
  34. 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
  35. 36. Operative risks after induction chemotherapy Siegenthaler et al., Ann Thor Surg 71:1105, 2001
  36. 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
  37. 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
  38. 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
  39. 40. Operative risks after induction chemotherapy <ul><li>MSKCC (-ed) </li></ul><ul><li>Operative mortality </li></ul><ul><li>Overall 3.8% </li></ul><ul><li>Lobectomy 2.4% </li></ul><ul><li>Left Pneumonectomy 0% </li></ul><ul><li>Right Pneumonectomy 23.9% </li></ul><ul><li>Multivariate analysis: right pneumonectomy was the only predictor of mortality </li></ul>Martin J et al., Ann Thorac Surg 2001; 72: 1149-54
  40. 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
  41. 42. Operative risks after induction chemotherapy <ul><li>Does induction chemotherapy without radiationtherapy really increase the morbidity and mortality of lung resection ? </li></ul><ul><li>Probably not… but most of the data published so far is either retrospective and/or comparing to historical controls ... </li></ul>
  42. 43. Induction Therapy ( pre-operative ) Ongoing Studies
  43. 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
  44. 45. Phase III Trial INT S 9900 <ul><li>“ Son of BLOT” </li></ul><ul><li>“ BLOT or KNOT” </li></ul><ul><li>Through SWOG, NCCTG, ECOG, RTOG, ACOSOG, NCIC and the CTSU. </li></ul>
  45. 46. Early Stage Disease NATCH* ( Neoadjuvant/ Adjuvant Taxol Carboplatin Hope) * Switzerland, Spain, Germany, Portugal, Sweden Activated 4.00 Accrual goal = 624
  46. 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
  47. 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
  48. 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.
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