ADJUVANT CHEMOTHERAPY IN RESECTED LUNG CANCER

ADJUVANT CHEMOTHERAPY IN RESECTED LUNG CANCER

Pınar Çelik

10th Annual Congress of Turkish Thoracic SocietyApril 25th – 29th 2007, Antalya

Presentation Scheme

Adjuvant CT trials in early stage resected lung cancer

cases

Second and third generation regimens

Adjuvant CT trials in early stage NSCLC

Targeted agents in adjuvant therapy

Molecular studies

Survival in early stage NSCLC

5-year survival(%)

IA 67

IB 57

IIA 55

IIB (T2 N1) 39

IIB (T3N0) 38

IIIA (T3 N1) 25

IIIA (T1-3 N2) 23

Mountain. Chest 1997

Recurrence in early stage NSCLC

Local (%) Distant (%)

IA 10 15

IB 10 30

II 12 40

IIIA 15 60

Pisters KMV, Le Chevalier T. J Clin Oncol 2005

Adjuvant CT Advantages

Early treatment of distant metastasis

Adjuvant CT trials in early stage (Resected

Cases)

LCSG Trials

LCSG 772 BCG+levamisole vs CT(CAP)

LCSG 791 RT vs CT+RT

LCSG 801 CT vs Observation

LCSG 853 CT vs Observation

Results are controversially

Holmes E, Gail M. J Clin Oncol 1986Lad T et al. J Clin Oncol 1988

Feld R et al. J Natl Cancer Ins 1993Figlin R et al. Chest 1994.

The non-small Cell Lung Cancer Collaborative Group (Meta-analysis)

9387 resected NSCLC

52 randomised trial

Between 1965-1991

CT vs Observation trials in resected cases

Results

3 % decrease in death risk, 5 % improvement in 5-year survival

CT with an alkylating agents: Death risk HR: 1.15

Platinum-based CT:

Death risk HR: 0.87, 13 % improvement in 5-year survival

Non-small Cell Cancer Colloborative Group BMJ 1995

Second and third generation regimens

The Adjuvant Lung Project Italy (ALPI)

1209 cases

Stage I-IIIA Resected NSCLC

Randomisation 587 Observation

592 CTx3(mitomycin,vindesine, cisplatin)

CT toxicity 30 % grade 3

18 % grade 4

RT optional

Median observation: 63

months

526 death, 1076 patients

HR: 0.94 overall survival

HR: 0.89 PFS

Scagliotti GV et al. J Natl Cancer Ins 2003

The Big Lung Trial (BLT)

381 cases

Stage I-IIIA Resected NSCLC

Randomisation Observation

CT+Surgery or Surgery+CT

4 CT protocols Cisplatin-vinorelbin

Cisplatin-vindesin

Mitomycin-ifosfamid-cisplatin

Mitomycin-vinblastin-cisplatin

Two groups were well-

balanced for risk factors

CT toxicity 30 % grade 3 or greater

No improvement in overall

and disease-free survival

rates.

Waller D et al. Eur J Cardiothorac Surg 2004

International Adjuvant Lung Trial (IALT)

Stage I-II-III NSCLC

Between 18-75 year-old

Postop.30-60 days later

randomisation

Primary objective: Overall survival

Secondary objective: Disease-free

survival, secondary cancer, toxicity

It is planned to include 3300 cases

Cisplatin doses 80mg/m2x4

100mg/m2x3-4

120 mg/m2x3

Combination Vindesin (%5)

Vinblastin (%10)

Vinorelbin (%25)

Etoposid (%55)

RT optional

Arriagada R et al. N Engl J Med 2004

IALT

1867 casesRandomisation

Observation CTN=935 N=932

148 center, 33 country, between1995-2000 years

Arriagada R et al. N Engl J Med 2004

IALT

RT CT: 70.4 % Control: 84.2 %

CT 73.8 % 240 mg/m2 cisplatin 7.8 % did not receive CT

Arriagada R et al. N Engl J Med 2004

IALT

Overall survival: 50.6 month vs 44.4 month

5-year survival: % 44.5 vs % 40.4

HR= 0.86 (0.76-0.98); p<0.03

Arriagada R et al. N Engl J Med 2004

Studies of Adjuvant Tegafur

Phase III, Japan 978 Stage I Adenocarcinoma Oral agent uracil-tegafur (UFT), up to 2 years HR: 0.71 (p=0.04)

Meta-analysis (6 studies) Stage I (95%) HR: 0.74 (p=0.001)

Kato H et al. J Clin Oncol 2004Hamada C et al. J Thorac Cardiovasc Surg 2004

Adjuvant CT Trials in Early Stage NSCLC

CALGB 9633

NSCLC T2N0M0(Stage IB)

344 Complete Resection

(4-8 week)

4 Cycles CT( Pacl-Carbo)Observation

Strauss GM et al. J Clin Oncol 2004

CALGB 9633

Both groups were well-balanced Prognostic factors; age, gender, race, ethnicity, histology, tm

differentiation, resection type

Toxicity: 36 % grade 3-4 neutropenia

Overall survival: Longer in CT arm (p=0.028); 12 % improvement in 4-year survival

Strauss GM et al. J Clin Oncol 2004

NCIC-CTG BR10

NSCLCStage IB and II (excluding T3N0M0)

482 Randomisation (Ras±; N0/1)

4 Cycles CT( Vinorelbin-Cis) Observation

Winton TL et al. J Clin Oncol 2004

NCIC-CTG BR10

Well-balanced for prognostic factors

No benefit in stage IB

Median survival was longer CT arm (94 months-73 months) (p=0.011);

15% improvement in 5-year survival

Winton TL et al. J Clin Oncol 2004

Study Organ CT Risk of death p

Winton et al. Lung Cis-vin 0.7 0.012

Strauss et al. Lung Carbo-Pac. 0.62 0.028

Sedrakyan et al. Lung Platinum-based ± UFT 0.87 <0.0001

Hotta et al. Lung Platinum-based ± UFT 0.87 0.001

Comets et al. Colon 5FU/FA 0.88 0.15

Gray et al. Over Plt 0.67 0.008

Comparison of Adjuvant CT in Early Stage Cancers

POSTOPERATIVE RT

IALT 572 cases were treated with RT

CT: compliance 70.4 %, Control: 84.2 %

No difference

PORT meta-analysis No improvement in survival

Harmful effects in stage I/II

No adverse events in stage III

ECOG 3590 53 % cases were pN2

No decrease in intrathoracic recurrence

No survival advantage in stage II/III

Arriagada R et al. N Engl J Med 2004PORT Metaanalysis Trialists Group. Lancet 1998

Keller SM et al. N eng J Med 2000

Meta-analysis 2005

Stage I-III NSCLC

6 neoadjuvant and 19 adjuvant trial Neoadjuvant HR: 0.66 Adjuvant HR: 0.84 Adjuvant Stage I-II HR: 0.88 Adjuvant Stage III HR: 0.85

Adjuvant CT is effective in stage I-II resected NSCLC

Stage III ?

Berghmans T et al. Lung Cancer 2005

Adjuvant Navelbine International Trialist Association (ANITA)

Stage IB and IIIA NSCLC840 cases were randomised

4 Cycle CT( Vinorelbin-Cis) Observation

5 and 7-year survival is in favor of CT 5-year survival 51 % vs 43 % p<0.03 7 year survival 45.2 % vs 36 % p<0.03 No benefit in Stage IB

Douillard JY et al. Lancet Oncol 2006

ANITA

Douillard JY et al. Lancet Oncol 2006

ANITA

Douillard JY et al. Lancet Oncol 2006

CALGB 9633 Update ASCO 2006

2004: 88 ex, median survival HR: 0.62 (p=0.01)

2006: 137 ex, median survival HR: 0.80 (p=0.1)

Sampling population was small Results had a weak power Probability of having no adjuvant benefit in Stage I Choosing carboplatin instead of cisplatin

Lung Adjuvant Cisplatin Evaluation (LACE)

Stage N CT HR p

IALT I-III 1867 Cis/vinca or etop

0.86 <0.03

JBR 10 IB-II 482 Cis/vino 0.7 0.012

ANITA I-IIIA 840 Cis/vino 0.79 0.013

ALPI I-IIIA 1209 Mit/vin/cis 0.94

BLT I-IIIA 381 4 different protocols

No difference

Pignon JP et al. J Clin Oncol 2006

Lung Adjuvant Cisplatin Evaluation (LACE)

A meta-analysis including largest Cisplatin-based 5 trails 5-year survival advantage: 5.3 %(HR: 0.89) Stage IA HR: 1.41 Stage IB: HR: 0.92 Stage II-III HR: 0.83

CALBG 9633 trial Tm>4 cm overall survival HR: 0.66 Tm<4 cm overall survival HR: 1.02

Cisplatin-vinorelbin is superior over other cisplatin CTs,

however

Pignon JP et al. J Clin Oncol 2006

Cisplatin vs Carboplatin

CISCA meta-analysis ASCO 2006 2968 advanced stage NSCLC cases 9 trials Cisplatin is superior

Cisplatin-based regimens are standart as an adjuvant

therapy in early stage resected NSCLC, if there is a

contraindication carboplatin can be used

Ardizzoni A et al. J Clin Oncol 2006

Targeted Agents in Adjuvant Therapy

JBR 19

Stage IB and IIIA NSCLCRandomisation (Stage, histology, CT, RT, gender)

250 mg/day gefitinib Observation

E 1505

Stage IB(>4 cm)-IIIA

1500 Randomisation (Stage, histology, gender, CT regimen*)

CTx4 CTx4 + bevacizumabx1year

Primary end-point: overall survival

*: Cisplatin-based 3 CT regimens

RADIANT

Stage I-IIIA (Resected)945 Randomised (IHC/FISH and EGFR)(CT optional)

Erlotinib 150 mg/dayx2years Observation

Histology Gender EGFR condition Smoking Adjuvant CT If IHC or copying gene is + Primary end-point: Disease-free survival

Molecular Studies

Positivity of ERCC1 enzyme

IALT investigators, retrospective analysis ERCC1 nucleosid excision repair enzyme ERCC1 negative tumours HR: 0.65 ERCC1 positive tumours HR: 1.14

This study is important for detecting cases who will

benefit from cisplatin-based adjuvant CT

Olaussen KA et al. N Engl J Med 2006

CONCLUSION Postoperative CT is effective in stage II and IIIA, but is it in stage IB?

Stage IB tm> 4cm more effective Stage IA

Results of Japan trials with Tegafur is positive, but Tegafur is not available

in Europe and America. Results of USA and Europe trials are negative, adjuvant CT is

contraindicated Platinum-based CT in adjuvant therapy

Cisplatin(320 mg/m2) + vinorelbin ? Cisplatin, is more effective than carboplatin ? Results of studies with targeted agents? Molecular studies ?

Comparison of adjuvant and neoadjuvant therapy ?

thank you