Triplet vs doublet adjuvant chemotherapy for gastric cancer: A systematic review and meta-analysis

Abstract

BACKGROUND

Gastric cancer (GC) remains a major cause of cancer-related mortality worldwide. For patients undergoing curative gastrectomy, postoperative adjuvant chemotherapy is an established strategy to eradicate micrometastatic disease, reduce recurrence, and improve long-term survival. Platinum-fluoropyrimidine doublet regimens are widely used; however, the potential benefit and safety of intensified taxane-platinum-fluoropyrimidine triplet regimens in the adjuvant setting remain uncertain.

AIM

To systematically compare the efficacy and safety of taxane-platinum-fluoropyrimidine triplet chemotherapy vs platinum-fluoropyrimidine doublet chemotherapy as postoperative adjuvant treatment for GC.

METHODS

PubMed, EMBASE, and the Cochrane Library were searched from inception to December 31, 2025. Randomized controlled trials (RCTs) comparing taxane-platinum-fluoropyrimidine triplet chemotherapy with platinum-fluoropyrimidine doublet chemotherapy in patients receiving postoperative adjuvant treatment after curative gastrectomy for histopathologically confirmed GC were included. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included objective response rate (ORR), disease control rate (DCR), and grade 3-4 adverse events (AEs) when reported. Study quality was assessed using the Cochrane Risk of Bias tool. Meta-analysis was performed using RevMan 5.4. Random-effects models were applied when substantial heterogeneity was present, defined as I² ≥ 50% or P < 0.10. Risk ratios (RRs) were calculated for dichotomous outcomes, and hazard ratios were calculated for survival outcomes, both with 95% confidence intervals (95%CIs).

RESULTS

Twelve RCTs involving 11126 patients were included. Triplet chemotherapy was associated with a significantly higher ORR than doublet chemotherapy (RR = 1.73, 95%CI: 1.64-1.82, P < 0.0001), with substantial heterogeneity (I² = 84%). Triplet chemotherapy also achieved a higher DCR (RR = 1.22, 95%CI: 1.15-1.28, P < 0.0001; I² = 61%). However, neither OS [hazard ratio (HR) = 1.24, 95%CI: 0.90-1.72, P = 0.19; I² = 96%] nor PFS (HR = 1.52, 95%CI: 0.93-2.50, P = 0.09; I² = 94%) differed significantly between treatment groups. Grade 3-4 AE events, including leukopenia, neutropenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, fatigue, and anorexia, were not significantly different between triplet and doublet regimens. Publication bias was suggested for ORR and DCR.

CONCLUSION

In this meta-analysis, taxane-platinum-fluoropyrimidine triplet chemotherapy did not demonstrate a clear OS or PFS advantage over platinum-fluoropyrimidine doublet chemotherapy in the postoperative adjuvant setting. Although intensified regimens may be feasible in selected high-risk patients, treatment selection should be individualized according to pathological stage, recurrence risk, postoperative recovery, performance status, and tolerability.

Keywords: Gastric cancer; Adjuvant chemotherapy; Postoperative chemotherapy; Triplet chemotherapy; Doublet chemotherapy; Meta-analysis

Core Tip: This comprehensive meta-analysis of 12 randomized controlled trials encompassing 11126 patients demonstrates that taxane-platinum-fluoropyrimidine triplet chemotherapy significantly improves objective response rate (1.73-fold increase) and disease control rate (1.22-fold increase) compared to platinum-fluoropyrimidine doublet regimens in neoadjuvant treatment of gastric cancer. Despite superior tumor response, no significant survival benefits were observed. Importantly, safety profiles were comparable between regimens. These findings support individualized treatment selection, with triplet regimens preferred for maximal tumor downstaging when surgical resectability is borderline.