Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data

NSCLC Meta-analyses Collaborative Group, R Arriagada, A Auperin, S Burdett, J P Higgins, D H Johnson, T Le Chevalier, C Le Pechoux, M K B Parmar, J P Pignon, R L Souhami, R J Stephens, L A Stewart, J F Tierney, H Tribodet, J van Meerbeeck, A Auperin, S Burdett, T Le Chevalier, C Le Pechoux, J-P Pignon, L A Stewart, J F Tierney, R J Stephens, S Burdett, J-P Pignon, J F Tierney, H Tribodet, S Burdett, J-P Pignon, J F Tierney, H Tribodet, S Burdett, J-P Pignon, H Tribodet, J F Tierney, A Auperin, T Le Chevalier, C Le Pechoux, J P Pignon, H Tribodet, S Burdett, L A Stewart, J F Tierney, R J Stephens, R Arriagada, J P Higgins, D H Johnson, J van Meerbeeck, M K B Parmar, R L Souhami, B Bergman, B Dautzenberg, J Y Douillard, A Dunant, C Endo, D J Girling, M Imaizumi, H Kato, S M Keller, H Kimura, A Knuuttila, K Kodama, R Komaki, M G Kris, T Lad, T Mineo, J H Park, S Piantadosi, S Pyrhönen, R Rosell, G V Scagliotti, L W Seymour, F A Shepherd, S G Spiro, G M Strauss, R Sylvester, H Tada, F Tanaka, V Torri, H Wada, D Waller, G C Xu, NSCLC Meta-analyses Collaborative Group, R Arriagada, A Auperin, S Burdett, J P Higgins, D H Johnson, T Le Chevalier, C Le Pechoux, M K B Parmar, J P Pignon, R L Souhami, R J Stephens, L A Stewart, J F Tierney, H Tribodet, J van Meerbeeck, A Auperin, S Burdett, T Le Chevalier, C Le Pechoux, J-P Pignon, L A Stewart, J F Tierney, R J Stephens, S Burdett, J-P Pignon, J F Tierney, H Tribodet, S Burdett, J-P Pignon, J F Tierney, H Tribodet, S Burdett, J-P Pignon, H Tribodet, J F Tierney, A Auperin, T Le Chevalier, C Le Pechoux, J P Pignon, H Tribodet, S Burdett, L A Stewart, J F Tierney, R J Stephens, R Arriagada, J P Higgins, D H Johnson, J van Meerbeeck, M K B Parmar, R L Souhami, B Bergman, B Dautzenberg, J Y Douillard, A Dunant, C Endo, D J Girling, M Imaizumi, H Kato, S M Keller, H Kimura, A Knuuttila, K Kodama, R Komaki, M G Kris, T Lad, T Mineo, J H Park, S Piantadosi, S Pyrhönen, R Rosell, G V Scagliotti, L W Seymour, F A Shepherd, S G Spiro, G M Strauss, R Sylvester, H Tada, F Tanaka, V Torri, H Wada, D Waller, G C Xu

Abstract

Background: Many randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy.

Methods: We included randomised trials, not confounded by additional therapeutic differences between the two groups and that started randomisation on or after Jan 1, 1965, which compared surgery plus adjuvant chemotherapy versus surgery alone, or surgery plus adjuvant radiotherapy and chemotherapy versus surgery plus adjuvant radiotherapy. Updated individual patient data were collected, checked, and included in meta-analyses stratified by trial. The primary endpoint was overall survival, defined as time from randomisation until death by any cause. All analyses were by intention to treat.

Findings: The first meta-analysis of surgery plus chemotherapy versus surgery alone was based on 34 trial comparisons and 8447 patients (3323 deaths). We recorded a benefit of adding chemotherapy after surgery (hazard ratio [HR] 0.86, 95% CI 0.81-0.92, p<0.0001), with an absolute increase in survival of 4% (95% CI 3-6) at 5 years (from 60% to 64%). The second meta-analysis of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy was based on 13 trial comparisons and 2660 patients (1909 deaths). We recorded a benefit of adding chemotherapy to surgery plus radiotherapy (HR 0.88, 95% CI 0.81-0.97, p=0.009), representing an absolute improvement in survival of 4% (95% CI 1-8) at 5 years (from 29% to 33%). In both meta-analyses we noted little variation in effect according to the type of chemotherapy, other trial characteristics, or patient subgroup.

Interpretation: The addition of adjuvant chemotherapy after surgery for patients with operable non-small-cell lung cancer improves survival, irrespective of whether chemotherapy was adjuvant to surgery alone or adjuvant to surgery plus radiotherapy.

Funding: UK Medical Research Council, Institut Gustave-Roussy, Programme Hospitalier de Recherche Clinique (AOM 05 209), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Copyright 2010 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Effect of surgery (S) and chemotherapy (CT) versus surgery on survival, by type of chemotherapy Every trial is represented by a square, the center of which denotes the hazard ratio (HR) for that trial comparison with the horizontal lines showing the 95% and 99% CIs. The size of the square is directly proportional to the amount of information contributed by the trial. The open diamonds represent pooled HRs for the trial groups, with the centre denoting the HR and the extremities the 95% CI. The black diamond gives the pooled hazard ratio from the fixed effect model, without double counting the control groups of the three-grouped trials WJSG2 and ACTLC4. The centre of this diamond denotes the HR and the extremities the 95% CI. The control groups of the three-grouped trials WJSG2 and ACTLC4 are included only once in the total events and patients and in the overall analysis. O–E=observed minus expected. IPCR=Institute of Pulmonary Cancer Research, Chiba. JLCSSG=Japan Lung Cancer Surgical Study Group. ALPI=Adjuvant Lung Cancer Project. IALT=International Adjuvant Lung Trial. BLT=Big Lung Trial. JCOG=Japan Clinical Oncology Group. ANITA=Adjuvant Navelbine International Trialist Association. CALGB=Cancer and Leukemia Group B. LCSG=Lung Cancer Study Group. FLCSG=Finnish Lung Cancer Study Group. SGACLC=Study Group of Adjuvant Chemotherapy for Lung Cancer. OLCSG=Osaka Lung Cancer Study Group. WJSG=West Japan Study Group for Lung Cancer Surgery. ACTLC=Study Group of Adjuvant Chemotherapy for Lung Cancer. NJSGLCS=North-east Japan Study Group for Lung Cancer. JLCRG=Japan Lung Cancer Research Group.
Figure 2
Figure 2
Simple (non-stratified) Kaplan-Meier curves for trials of surgery (S) and chemotherapy (CT) versus surgery alone and for trials of surgery and chemotherapy and radiotherapy (RT) versus surgery and radiotherapy
Figure 3
Figure 3
Exploratory analyses of the effect of surgery (S) and chemotherapy (CT) versus surgery on survival, by use of tegafur plus uracil or tegafur and by stage and performance status HR=hazard ratio. O–E=observed minus expected. PS=performance status.
Figure 4
Figure 4
Effect of surgery (S) and radiotherapy (RT) and chemotherapy (CT) versus surgery and radiotherapy on survival by type of chemotherapy HR=hazard ratio. O–E=observed minus expected. MSKCC=Memorial Sloan Kettering Cancer Center. GETCB=Groupe d'Etude et de Traitement des Cancers Bronchiques. MDA DM=MD Anderson Department of Medicine. Int=Intergroup. ALPI=Adjuvant Lung Cancer Project Italy. IALT=International Adjuvant Lung Trial. BLT=Big Lung Trial. ANITA=Adjuvant Navelbine International Trialist Association. LCSG=Lung Cancer Study Group. FLCSG=Finnish Lung Cancer Study Group. OLCSG=Osaka Lung Cancer Study Group.

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