The efficacy and safety of pemetrexed-based doublet therapy compared to pemetrexed alone for the second-line treatment of advanced non-small-cell lung cancer: an updated meta-analysis

BACKGROUND Pemetrexed is currently recommended as the second-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, it is unclear whether pemetrexed-based doublet therapy improves treatment efficacy and safety. Thus, this meta-analysis was performed to resolve this controversial question. METHODS Electronic databases, including PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant articles before April 2015. Hazard ratios (HRs) were used to estimate overall survival (OS) and progression-free survival (PFS), and odds ratios (ORs) were used to analyze the overall response rate (ORR) and grade ≥3 toxicities. Subgroup analysis, sensitivity analysis, and publication bias were also evaluated. RESULTS A total of 2,519 patients from ten randomized controlled trials were included. Compared to pemetrexed alone, PFS and ORR significantly improved in the pemetrexed-based doublet group (HR, 0.86; 95% CI [confidence interval], 0.75-0.99; P=0.038; and OR, 1.98; 95% CI, 1.25-3.12; P=0.003, respectively). However, no statistically significant differences in OS were observed between groups (HR, 0.92; 95% CI, 0.83-1.02; P=0.132). In addition, subgroup analyses indicated that improved OS was only observed in nonsquamous NSCLC patients who received the combination of pemetrexed and erlotinib. An increasing incidence of grade ≥3 neutropenia and thrombocytopenia was observed in the pemetrexed-based doublet group. CONCLUSION Among patients with advanced NSCLC, pemetrexed-based doublet treatment tended to be associated with improved PFS, ORR, and increased toxicity, but not OS.