First-line systemic therapy for advanced gastric cancer: a systematic review and network meta-analysis

Background: Systemic therapy is the standard treatment against advanced gastric cancer. Fluoropyrimidine plus platinum doublet has been recommended as the preferred first-line strategy. However, there is still a lack of a comprehensive and hierarchical evidence that compares all eligible literature simultaneously. Methods: Record retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, ASCO, and ESMO meeting library from inception to October 2018. Randomized controlled trials featuring comparisons between different first-line systemic treatments against advanced gastric cancer were eligible. Overall survival was utilized as the primary endpoint. Pairwise and network calculations were based on a random-effects model and the hierarchical ranking was numerically indicated by P-score. All procedures were conducted according to Cochrane Handbook 5.1 and PRISMA for Network Meta-analysis (Registration identifier: CRD42018084951). Results: A total of 119 studies were eligible for our pooled analysis. Concerning general analysis, 'fluoropyrimidine plus platinum-based triplet' topped the overall survival hierarchy (HR 0.91 [0.83-0.99], P-score = 0.903, p = 0.04) while it ranked in second place for progression-free survival and objective response rate. However, it displayed worse tolerability against 'fluoropyrimidine plus platinum doublet'. More specifically, 'Capecitabine plus cisplatin-based triplet plus targeted medication' topped the ranking among all fluoropyrimidine plus platinum-based regimens in additional analysis. Nevertheless, it did not reach statistical advantage against fluoropyrimidine plus oxaliplatin doublet in terms of survival benefits, while still displaying significantly worse safety profile. Conclusions: Taken together, fluoropyrimidine plus oxaliplatin doublet (especially capecitabine or S-1) should still be considered as the preferred first-line regimen owing to its comparable survival benefits and lower toxicity.