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A Meta-analysis

Catherine Delbaldo, MD; Stefan Michiels, MSc; Nathalie Syz, MSc; Jean-Charles Soria, MD, PhD; Thierry Le Chevalier, MD; Jean-Pierre Pignon, MD, PhD

JAMA. 2004;292:470-484.

Context  Randomized trials have demonstrated that adding a drug to a single-agent or to a 2-agent regimen increased the tumor response rate in patients with advanced non–small-cell lung cancer (NSCLC), although its impact on survival remains controversial.

Objective  To evaluate the clinical benefit of adding a drug to a single-agent or 2-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC.

Data Sources and Study Selection  Data from all randomized controlled trials performed between 1980 and 2001 (published between January 1980 and October 2003) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non–small-cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and October 2003.

Data Extraction  Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, 1-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (<1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen).

Data Synthesis  Sixty-five trials (13 601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR, 0.42; 95% confidence interval [CI], 0.37-0.47; P<.001) and 1-year survival (OR, 0.80; 95% CI, 0.70-0.91; P<.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI, 0.79-0.89; P<.001). An increase also was observed in the tumor response rate (OR, 0.66; 95% CI, 0.58-0.75; P<.001) in favor of the triplet regimen, but not for 1-year survival (OR, 1.01; 95% CI, 0.85-1.21; P = .88). The median survival ratio was 1.00 (95% CI, 0.94-1.06; P = .97).

Conclusion  Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.

Author Affiliations: Departments of Medecine (Drs Delbaldo, Soria, Le Chevalier) and Biostatistics and Epidemiology (Mr Michiels, Ms Syz, and Dr Pignon), Institut Gustave-Roussy, Villejuif Cedex, France.

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