Early Stage Nsclc The Role Of Chemotherapy

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


Progression during induction: 3/98 ( 3%)



86/94 were explored77/ 94 had a R0 resection ( 82%)

One postoperative death

Operative morbidity comparable to historical series of Surgery alone


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

|||||

_

_

_

_

_

_

_

_

_

_

66|

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


The Depierre Study

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


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


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 (-ed)

Induction chemotherapy:

carboplatin/ paclitaxel in 93% of pts


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



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.



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


MSKCC (-ed)

297 lobectomies ( 9 sleeves, 26 bilobectomies )

97 pneumonectomies ( 20%)

18 lesser resections, 58 O&C

22% were extended resections



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



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.



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


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


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.

Early Stage Nsclc The Role Of Chemotherapy

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