Multimodal Treatments for Resectable Gastric Cancer: A Systematic Review and Network Meta-Analysis

Abstract

Background: Based on specific regional evidences, different countries prefer particular types of multimodal treatments against resectable gastric cancer, such as perioperative chemotherapy in Europe, postoperative chemoradiotherapy in USA and postoperative chemotherapy in Asian world. However, irrespective of geographical differences, there is currently lacking of a comprehensive evidence to rank all recommended strategies simultaneously and hierarchically, which could facilitate clinical decision-making and future design of randomized trials. Therefore, we conducted the first systematic review and network meta-analysis on this field. Methods: Record retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, ASCO and ESMO meeting libraries from inception to September 2018. Regarding survival and tolerability, randomized controlled trials featuring comparisons between different preferred multimodal treatments against resectable gastric cancer were eligible. The Cochrane Risk of Bias Tool was applied to assess the methodological quality of included trials. Overall survival was primary endpoint, while recurrence-free survival, hematological and non-hematological adverse events were secondary endpoints. Network calculation was based on random-effects model and the relative ranking of each node was numerically indicated by P-score. Findings: A total of 11 studies were included into our systematic review, corresponding to 7235 patients. The demographic characteristics were comparable and the overall risk of bias was in low level. Regarding overall survival, PeriCT (FLOT) (perioperative 5-FU plus leucovorin plus oxaliplatin plus docetaxel chemotherapy) topped the hierarchy (HR 1.00, P-score=0.918), followed by PostCT (XP) (postoperative capecitabine plus platinum chemotherapy; HR 1.14, P-score=0.759) and PostCT (S-1) (postoperative S-1 monotherapy; HR 1.16, P-score=0.732). Among all subgroup analyses, PostCT (XP) became the top regimen for eastern population, D2 lymphadenectomy, less invasion depth and higher TNM stages, PeriCT (FLOT) was the optimal node for western population while PostCT (S-1) for gastric cases only, severer invasion depth and lower TNM stages. Concerning recurrence-free survival, PostCRT (XP) (postoperative capecitabine plus platinum chemoradiotherapy; HR 0.88, P-score=0.940) was the optimal node, slightly better than PeriCT (FLOT) (HR 1.00, P-score=0.895). Adverse events for major survival-beneficial regimens seemed to be comparable. Interpretation: Perioperative FLOT chemotherapy could potentially be the best multimodal treatment against resectable gastric cancer than other recommended strategies, including postoperative XELOX (capecitabine plus oxaliplatin) chemotherapy, postoperative S-1 monotherapy or postoperative FL (5-FU plus leucovorin) chemoradiotherapy. Therefore, a global D2-lymphadenectomy randomized controlled trial comparing perioperative FLOT chemotherapy with postoperative XELOX chemotherapy should be carried out. Funding Statement: Scientific Research Training Program for Young Talents (2017); National Natural Science Foundation of China (81572413) Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The protocol of this systematic review and network meta-analysis had been published in PROSPERO (CRD42018109147). The design, conduct and writing of this systematic review and network meta-analysis was strictly in accordance with the requirements from PRISMA Checklist for Network Meta-analysis and Cochrane Handbook 5.1. Each step was conducted by two investigators of our research group. Any discrepancy was judged and solved by the third investigator.