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First-Line Systemic Therapy for Advanced Gastric Cancer: A Systematic Review and Network Meta-Analysis of 118 Randomized Controlled Trials
66 Pages Posted: 29 Aug 2018
More...Abstract
Background: Systemic therapy is the standard treatment against advanced gastric cancer. Although two-drug fluoropyrimidine and platinum-based regimens have been recommended as the preferred first-line strategy, other regimens also display potentially comparable efficacies. However, despite of several previously published systematic reviews, there is still lacking of a comprehensive and hierarchical evidence that compares all eligible literatures simultaneously, including chemotherapies and targeted medications. Hence, we performed a systematic review as well as network meta-analysis in order to summarize and analyze all potential knowledge on this field, including both survival and tolerability analysis.
Methods: Record retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, ASCO and ESMO meeting abstract library from inception to June 21st of 2018. Regarding survival and tolerability, randomized controlled trials featuring comparisons between different first-line systemic treatments against locally inoperable, recurrent or metastatic gastric cancer were eligible for our systematic review. Overall survival (OS) was utilized as primary endpoint, while progression-free survival, objective response rate, hematological and non-hematological adverse events were selected as secondary endpoints. Hazard ratio (HR) and risk ratio (RR) with their 95% confidence interval were used for time-to-event survival and dichotomous variables respectively. Pairwise and network calculation were based on random-effects model and the relative ranking of each regimen was numerically indicated by P-score. Furthermore, sensitivity analyses were also performed to detect the stability of outcomes. All procedures were conducted according to Cochrane Handbook 5.1 and PRISMA for Network Meta-analysis. The protocol of our systematic review was published in PROSPERO (CRD42018084951).
Findings: Chronologically ranging from 1979 to 2018, a total of 118 studies were included into our systematic review. The demographic characteristics were comparable across the studies and the overall risk of bias was in low level. Concerning general analysis, "Fluoropyrimidine plus platinum-based quadruplet (FP4)" was the best ranking regimen irrespective of overall survival (HR 0.89 (0.77-1.02), P-score=0.921), progression-free survival (HR 0.80 (0.66-0.97), P-score=0.971) and objective response rate (RR 1.45 (1.22-1.73), P-score=0.964), displaying potentially significant survival superiority against "Fluoropyrimidine plus platinum doublet (FP2)". More specifically, "Capecitabine plus cisplatin-based quadruplet (XC4)" topped the hierarchy among all fluoropyrimidine plus platinum-based regimens in additional analysis, demonstrating significant advantages against "5-FU plus cisplatin doublet (FC2)" (HR 0.63 (0.41-0.97)) while was statistically comparable to "Capecitabine plus cisplatin doublet (XC2)" with slight superior tendency (HR 0.73 (0.49-1.08)). Moreover, compared to "FP2" and "FC2" or "XC2", "FP4" and "XC4" were respectively statistically comparable in terms of hematological adverse events (P=0.09, 0.14, 0.40 respectively) while potentially significantly inferior regarding non-hematological adverse events (P=0.03, 0.03, 0.05 respectively).
Interpretation: Fluoropyrimidine plus platinum-based quadruplet, especially capecitabine plus cisplatin-based quadruplet displays potential survival superiority against fluoropyrimidine plus cisplatin doublet. However, in fear of higher risk of toxicity, whether it could be an alternative regimen for advanced gastric cancer requires the design and conclusion of parallel large-scale randomized trials against fluoropyrimidine plus cisplatin doublet, in terms of both efficacy and tolerability assessment.
Funding Statement: The meta-analysis was funded by Scientific Research Training Program for Young Talents (Union Hospital, Tongji Medical College, Huazhong University of Science and Technology) to Ji Cheng and National Natural Science Foundation of China (81572413) to Kaixiong Tao.
Declaration of Interests: The authors declare no competing interests.
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