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Early Stage Nsclc The Role Of Chemotherapy

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Information about Early Stage Nsclc The Role Of Chemotherapy
Health & Medicine

Published on March 6, 2009

Author: fovak

Source: slideshare.net

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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

Resection by lobectomy or more if cardiopulmonary reserves

5-y Survival = 20-40 %

Adjuvant Therapy ?

Induction Therapy ?

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%

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

Resection by lobectomy or more if cardiopulmonary reserves

5-y Survival = 20-40 %

Adjuvant Therapy = NO

Induction Therapy ?

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

30 day operative mortality

MIP> S n=179 7.8%

S n=176 4.5%

NS

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

30 day operative morbidity

MIP> S 39 in 33 pts

S 27 in 25 pts

NS

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

BPF/ empyemas

MIP> S 10* ( 8 early + 2 late)

S 5

NS

* 8/10 in N2 pts, 9/10 after pneumonectomy

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

Pulmonary infections

MIP> S 10

S 11

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 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

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

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

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

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

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

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 ...

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.

“ 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.

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