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Benefits of Adding a Drug to a Single-Agent or a 2-Agent Chemotherapy Regimen in Advanced Non–Small-Cell Lung Cancer 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(4):470-484. doi:10.1001/jama.292.4.470.
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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.

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Figures

Figure 1. Selection of the Trials
Graphic Jump Location
Figure 2. Odds Ratio for the Tumor Response Rate With Doublet vs Single Agent Regimens
Graphic Jump Location
Asterisk indicates decreased doses of drug in the investigational arm; dagger, study 1; double dagger, study 2. P<.001 for treatment effect.
Figure 3. Median Ratio for Survival With Doublet vs Single-Agent Regimens
Graphic Jump Location
Asterisk indicates decreased doses of drug in the investigational arm. P<.001 for treatment effect.
Figure 4. Odds Ratio for the Tumor Response Rate With Triplet vs Doublet Regimens
Graphic Jump Location
Asterisk indicates decreased doses of drug in the investigational arm. P<.001 for treatment effect.
Figure 5. Median Ratio for Survival With Triplet vs Doublet Regimens
Graphic Jump Location
Asterisk indicates decreased doses of drug in the investigational arm. P = .97 for treatment effect.

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