early stage nsclc the role of chemotherapy
TRANSCRIPT
Early Stage NSCLC: The Role of Chemotherapy
Eric Vallieres, MD
Lung C ancerNSCLC 80%
SCLC 20%
> 60% / 5y
Stages IA / IBT1N0 / T2N0
10%17,20 0
30-50% / 5y
Stages IIA / IIBT1N1 / T2N1 & T3N0
20%34,40 0
10- 30 % / 5y
Stage IIIAT3N1, T1-3 N2
15%25,80 0
5% / 5 y
Stage IIIBT4, N3
15%25,80 0
Less than stage IV
<2% / 5y
Stage IVM1
40%68,80 0
Stage IV
172,000 new cases13 % / 5Y
Clinical IB, IIA, IIB diseasesClinical 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 RadiotherapyAdjuvant Radiotherapy
Adjuvant Radiotherapy
M RC Lung Cancer W orking Party
Observation Adjuvant RTx40 Gy / 15 fractions
T1-2 N1-2 NSCLCCom pletely resected (R0)
n = 308
N2 appeared to gain 1 month in survival...
MRC LCWP
Stephens et al, Br J Cancer 1996
Adjuvant RadiotherapyAdjuvant Radiotherapy
No improvement in survival
Improved loco-regional control with squamous histology (LCSG 773)
but
systemic failures lead to death...
Adjuvant ChemotherapyAdjuvant Chemotherapy
Adjuvant ChemotherapyAdjuvant Chemotherapy ALPI (Adjuvant Lung Project Italy) ALPI (Adjuvant Lung Project Italy)
O bserva tionn = 594
M V P *3n = 602
(C D D P 100 )
I ( .42 ), II ( .31 ), III ( .27 )NS C L C
R0 resec tions
Tonato, PASCO 2002 abstract 1157
Overall SurvivalOverall Survival
Events/Total
CT 278/548
Control 288/540
HR=0.96 (0.81 - 1.13) p=0.585
PROBABILITY
YEARS
Median f/up of 63 months
Adjuvant ChemotherapyAdjuvant 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 diseasesClinical 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/ paclitaxelre-imaged 4 weeks later
Pre Post
Scans not available
Induction ChemotherapyThe BLOT Phase II StudyThe BLOT Phase II Study
Additional carbo/ paclitaxel * 3
Surgery
Carboplatin AUC 6Paclitaxel 225
2 cycles
Clinical Stages IB, IIA, IIB, T3N1Negative M ediastinoscopy
Pisters K et al., J Thor CV Surg 2000; 119:429-439
The BLOT StudyThe 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 StudyThe BLOT Study
Progression during induction: 3/98 ( 3%)
Pisters K et al., J Thor CV Surg 2000; 119;429
The BLOT StudyThe BLOT Study
86/94 were explored77/ 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 ChemotherapyInduction ChemotherapyTheThe Depierre Phase IIIDepierre Phase III StudyStudy
Surgery
Additional M IP * 2 in responders
Surgery
Induction M IP * 2
Clinical T2N0, stage II and resectable IIIA373 patients38 centers
6 years
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 StudyThe Depierre Study
Depierre et al., J Clin Oncol 2001; 20: 247-53
Overall SurvivalOverall Survival
11 22 5533 YearsYears44
100100
8080
6060
4040
2020
p = 0.15p = 0.15
PCTPCT
PRSPRS
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Reference Reference date : date :
Nov 1, 2000Nov 1, 2000
PCT arm 179 138 105 87 6433 20
PRS arm 176 129 92 67 51 3221
00Patients Patients at risk 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 chemotherapyPerioperative 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 ChemotherapyThe Roth Phase III Study (MDACC)The Roth Phase III Study (MDACC)
S urgeryn = 32
S urgeryn = 28
InductionC yE P *3
(C D D P 100 )
Resec table c /p N2 and T 3N0-1
Roth J NCI May 1994
Induction ChemotherapyThe Rosell Phase III StudyThe Rosell Phase III Study
S urgeryn = 30
S urgery
Induction M IP *3n = 30
(C D D P 50 )
Resec table c /p N2 and T 3N0-1
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 chemotherapyOperative risks after induction chemotherapy
Chemo>Surgery (%) Surgery (%)
Mortality 1.3 5
Morbidity 44.7 51
Major Pulmonary 13.2 11.6
Tracheostomy 5.3 3.5
Empyema 0 1.2
BP Fistula 0 1.2
Transfusion 9.2 9.7
LOS, ICU admit, readmit same
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 TherapyInduction Therapy
(pre-operative)
Ongoing Studies
Early Stage DiseaseEarly Stage Disease
Phase III Trial INT S 9900Phase III Trial INT S 9900
cT2N0, T1N1, T2N1, T3N0, T3N1
Resection Induction carboplatin/ paclitaxel3 cycles
ResectionActivated 11.99
Accrual goal = 6001/24/03 = 279
Phase III Trial INT S 9900Phase III Trial INT S 9900
“Son of BLOT”
“ BLOT or KNOT”
• Through SWOG, NCCTG, ECOG, RTOG, ACOSOG, NCIC and the CTSU.
Resection
InductionCarboplatinPaclitaxel
*3
Resection
AdjuvantCarboplatinPaclitaxel
*3
Resection
Clinical StagesIA(T>2cm )
IIA-IIB, T3N1
Early Stage DiseaseEarly Stage DiseaseNATCH* NATCH* ( Neoadjuvant/ Adjuvant Taxol Carboplatin Hope)( Neoadjuvant/ Adjuvant Taxol Carboplatin Hope)
*Switzerland, Spain, Germany, Portugal, SwedenActivated 4.00
Accrual goal = 624
Early Stage DiseaseEarly Stage Disease
ChEST (Chemotherapy for Early Stage Tumor)ChEST (Chemotherapy for Early Stage Tumor)
cT2N0, T1N1, T2N1, T3N0, T3N1
Resection Induction gemcitabine/ cddp3 cycles
ResectionItaly
Accrual goal = 606-712
Early Stage DiseaseEarly Stage Disease
MRC Lu-22MRC Lu-22
cT1N0, T2N0, T1N1, T2N1, T3N0, T3N1
Resection Induction chemotherapy*3 cycles, Q 3weeks
ResectionUK + EORTC ( 6/02)
Activated Jan 1998Accrual goal = 450April 2002 = 239 *MVP, MIP, Cis-Vinorelbine, Cis-Gem
Will induction chemotherapy become Will induction chemotherapy become the standard of care for our patients the standard of care for our patients
with early stage disease ?with early stage disease ?
Only by completing the ongoing Only by completing the ongoing clinical trials in a timely fashion, will clinical trials in a timely fashion, will
we be able to answer this very we be able to answer this very important question.important question.