WITHDRAWN: Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease.

BACKGROUND: Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial. OBJECTIVES: To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC. SEARCH METHODS: 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 June 2006. SELECTION CRITERIA: Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-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). MAIN RESULTS: Sixty-five trials (13601 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 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97). AUTHORS' CONCLUSIONS: 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.

Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease.

BACKGROUND: Randomized trials have demonstrated that adding a drug to a single-agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial. OBJECTIVES: To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC. SEARCH STRATEGY: 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 June 2006. SELECTION CRITERIA: Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-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). MAIN RESULTS: Sixty-five trials (13601 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 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97). AUTHORS' CONCLUSIONS: 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.

Meta-analysis when only the median survival times are known: a comparison with individual patient data results.

BACKGROUND: The hazard ratio (HR) is the most appropriate measure for time to event outcomes such as survival. In systematic reviews, HRs can be calculated either from the raw trial data obtained as part of an individual patient data (IPD) meta-analysis or from the appropriate trial-level summary statistics. However, the information required for the latter are seldom reported in sufficient detail to allow reviewers to calculate HRs. In contrast, the median survival and survival rates at specific time points are frequently presented. We aimed to evaluate retrospectively the performance of meta-analyses using median survival times and survival rates by comparing them with meta-analyses using IPD to calculate HRs. METHODS: IPD from thirteen published meta-analyses (MAs) in cancers with high mortality rates were used. Median survival and survival rates were calculated from the IPD rather than taken from publications so that the same trials, patients, and extended follow-up are used in each analysis. RESULTS AND CONCLUSIONS: We show that using median survival times or survival rates at a particular point in time are not reasonable surrogate measures for meta-analyses of survival outcomes and that, wherever possible, HRs should be calculated. Individual trial publications reporting on time to event outcomes, therefore, should provide more detailed statistical information, preferably logHRs and their variances, or their estimators.

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.

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.

Adjusting for patient selection suggests the addition of docetaxel to 5-fluorouracil-cisplatin induction therapy may offer survival benefit in squamous cell cancer of the head and neck.

When induction chemotherapy is used in locally advanced squamous cell cancer of the head and neck (SCCHN), patients often receive cisplatin-5-fluorouracil (PF) followed by radical loco-regional therapy. Phase II studies of docetaxel-cisplatin-5-fluorouracil (TPF) induction therapy, with or without leucovorin (L), have achieved high survival rates versus those reported in phase III PF trials. However, the distribution of prognostic factors may vary between phase II and phase III study populations, making the extrapolation of phase II TPF/L results to phase III PF populations difficult. This study used a patient selection standardization method and Cox model to adjust for potential selection bias. Thus, the survival benefit from adding docetaxel into PF induction regimens in SCCHN could be more accurately assessed. The TPF/L dataset comprised 195 patients from six phase II trials. The PF dataset of 585 patients was derived from five large randomized trials included in the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) database. TPF/L and PF datasets differed significantly concerning the distribution of several prognostic factors. Adjusting for these differences, the relative risk of death in the PF versus TPF/L datasets was 1.85 (95% confidence interval 1.37-2.49), corresponding to a 20% 2-year survival benefit (p < 0.0001). Sensitivity analyses confirmed that this improved 2-year survival rate of TPF/L over PF was robust, irrespective of the distribution of studied prognostic factors between treatment datasets. We conclude that this improved survival might be due either to docetaxel's pharmacologic effect or to uncontrolled prognostic factors.