Adjuvant chemotherapy for resectable biliary tract cancers: Current evidence and future directions – A systematic review and network meta-analysis

A BSTRACT Objectives: This study aims to address the uncertainty regarding the optimal adjuvant chemotherapy regimen for resectable biliary tract cancers (BTCs), which remain challenging to treat due to high recurrence rates, especially in patients with high-risk features such as R1 resection or lymph node positivity. By conducting a network meta-analysis (NMA), we evaluate the efficacy of various adjuvant chemotherapy regimens in improving overall survival (OS) and relapse-free survival (RFS) to provide evidence-based insights for clinical decision-making. Materials and Methods: A NMA was conducted by systematically searching PubMed, Cochrane Library, and Embase on November 18, 2024, to evaluate the efficacy of adjuvant chemotherapy regimens for resectable BTCs. A comprehensive search identified randomized controlled trials (RCTs) reporting OS and RFS. Hazard ratios (HRs) were estimated using random-effects models under a frequentist framework. Heterogeneity was assessed through τ 2 and I 2 , and inconsistency was evaluated using the netsplit method. The risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Results: The NMA included 5 RCT studies with 10 treatment arms, including 1449 patients, were analyzed. No regimen demonstrated statistically significant OS or RFS benefits compared to observation. Gemcitabine showed the most favorable trends for OS (HR: 0.72, 95% confidence interval CI: 0.27–1.97) and RFS (HR: 0.79, 95% CI: 0.47–1.31), while capecitabine demonstrated comparable trends for OS (HR: 0.84, 95% CI: 0.26–2.72) and RFS (HR: 0.81, 95% CI: 0.47–1.39). S-1 exhibited region-specific efficacy, particularly in Asian populations, with an OS HR of 0.96 (95% CI: 0.35–2.61). Gemcitabine and oxaliplatin (GEMOX) did not show notable benefits for OS (HR: 1.08, 95% CI: 0.32–3.69). Substantial heterogeneity ( I 2 = 82.3% for OS) and the absence of individual patient data restricted subgroup analyses. Based on P -score rankings, gemcitabine ranked highest for OS (0.68) and RFS (0.67), while GEMOX ranked last for OS (0.40) and observation ranked last for RFS (0.28). Conclusion: This study underscores the challenges of optimizing adjuvant chemotherapy for resectable BTCs, with no regimen demonstrating statistically significant survival benefits compared to observation. Gemcitabine and capecitabine showed comparable trends toward improved overall and RFS, while S-1 exhibited region-specific efficacy, particularly in Asian populations. These findings highlight substantial heterogeneity across studies and the need for large-scale, harmonized RCTs to evaluate high-risk subgroups (e.g., R1 resections and lymph node-positive patients), incorporate molecular stratification, and address quality-of-life and toxicity outcomes. By providing a comprehensive synthesis of the available evidence, this study advances the understanding of adjuvant therapy in BTCs and informs future research directions.