Early Stage Nsclc The Role Of Chemotherapy
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Early Stage Nsclc The Role Of Chemotherapy

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    Early Stage Nsclc The Role Of Chemotherapy Early Stage Nsclc The Role Of Chemotherapy Presentation Transcript

    • Early Stage NSCLC: The Role of Chemotherapy Eric Vallieres, MD
    •  
    • 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
    • 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 systemic failures lead to death...
    • 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 - 1.13) p=0.585
    • 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%
    • 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
    • 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 Thor CV Surg 2000; 119;429
    • 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 to historical series of Surgery alone Pisters K et al., J Thor CV Surg 2000; 119;429
    • 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
    • Induction Chemotherapy The Depierre Phase III Study Depierre et al., Proc ASCO 1999, abstract 1792 Adjuvant RT for pT3 and pN2
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • The Depierre Study
      • Pulmonary infections
      • MIP> S 10
      • S 11
      • NS
      Breton JP et al., Proc ASCO 2001, abstract 1239
    • 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
      • 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
    • Retrospective Data
    • 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
    • Operative risks after induction chemotherapy MDACC (-ed) Induction chemotherapy: carboplatin/ paclitaxel in 93% of pts Siegenthaler et al., Ann Thor Surg 71:1105, 2001
    • 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 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
    • 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
    • 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
    • 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
    • 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
    • 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 ...
    • Induction Therapy ( pre-operative ) Ongoing Studies
    • 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
    • Phase III Trial INT S 9900
      • “ Son of BLOT”
      • “ BLOT or KNOT”
      • Through SWOG, NCCTG, ECOG, RTOG, ACOSOG, NCIC and the CTSU.
    • Early Stage Disease NATCH* ( Neoadjuvant/ Adjuvant Taxol Carboplatin Hope) * Switzerland, Spain, Germany, Portugal, Sweden Activated 4.00 Accrual goal = 624
    • 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
    • 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
    • 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.