Meta-analysis of randomized trials: Evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer

Background: Single-agent gemcitabine ( GEM) is a standard treatment for advanced and metastatic pancreatic cancer. This study examines the question whether GEM-based combination chemotherapy can further improve treatment efficacy. Methods: A meta-analysis was performed to evaluate randomized trials comparing GEM versus GEM+X ( X = cytotoxic agent). Fifteen trials including 4465 patients were eligible for an analysis of overall survival, the primary end-point of this investigation. Results: The meta-analysis revealed a significant survival benefit for GEM+X with a pooled hazard ratio ( HR) of 0.91 ( 95% CI: 0.85 - 0.97, p = 0.004). The overall test for heterogeneity resulted in p = 0.82 ( I-2 = 0%). The analysis of platinum-based combinations indicated a HR of 0.85 ( 95% CI: 0.76 - 0.96, p = 0.010), while for fluoropyrimidine-based combinations the HR was 0.90 ( 95% CI: 0.81 - 0.99, p = 0.030). No risk reduction was observed in the group of trials combining GEM with irinotecan, exatecan or pemetrexed ( HR = 0.99). A meta-analysis of the trials with adequate information on baseline performance status ( PS) was performed in five trials with 1682 patients. This analysis indicated that patients with a good PS had a marked survival benefit when receiving combination chemotherapy ( HR = 0.76; 95% CI: 0.67 - 0.87; p < 0.0001). By contrast, application of combination chemotherapy to patients with an initially poor PS appeared to be ineffective ( HR = 1.08; 95% CI: 0.90 - 1.29, p = 0.40). Conclusion: The meta-analysis of randomized trials indicated a significant survival benefit when GEM was either combined with platinum analogs or fluoropyrimidines. Based on a preliminary subgroup analysis ( representing 38% of all patients included in this meta-analysis), pancreatic cancer patients with a good PS appear to benefit from GEM-based cytotoxic combinations, whereas patients with a poor PS seem to have no survival benefit from combination chemotherapy.