The efficacy of adjuvant chemotherapy for curative resected biliary tract cancers: a systematic review and network meta-analysis of randomized clinical trials

Background: Despite complete resection, the recurrence rate of biliary tract cancer (BTC) remains high, leading to poor prognosis. Postoperative adjuvant chemotherapy (ACT) following radical resection may substantially reduce the recurrence risk by eradicating micrometastatic lesions. However, the benefits of postoperative ACT and the optimal ACT strategy are still unclear for BTC. The objectives of this study are to evaluate the prognostic value of ACT and compare the effectiveness of different ACTs among BTC patients after curative resection. Methods: A comprehensive literature search was conducted across PubMed, Cochrane Library, Web of Science, and EMBASE databases to identify randomized controlled trials (RCTs) comparing the benefits of ACT versus no intervention or other ACTs in BTC patients after curative resection. A random-effects network meta-analysis was performed to compare overall survival (OS) and relapse-free survival (RFS). The quality of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation framework. Results: Eight RCTs comprising 1803 patients were included in the meta-analysis. ACT was associated with significant improvements in 5-year all-cause mortality [four RCTs, hazard rate (HR) 0.93; 95% confidence interval (CI), 0.87-1.00, marginally significant; low-certainty evidence], RFS (five RCTs, HR 0.87; 95% CI, 0.78-0.98; moderate-certainty evidence), and OS (7 studies, HR 0.85; 95% CI, 0.75-0.96; low-certainty evidence) compared with observation. ACT had significantly better survival benefits on patients with negative margins (R0), lymph node-positive (N+), and tumor node metastasis classification (TNM) stage I/II ( P < 0.05). Further network meta-analysis demonstrated that fluorouracil-based ACT was significantly inferior to gemcitabine-based ACT (HR 1.20; 95% CI, 1.10-1.25) in improving RFS. However, both were superior to observation ( P < 0.05). No statistical difference in OS was observed between gemcitabine-based and fluorouracil-based chemotherapy (HR 1.00; 95% CI, 0.86-1.20). In subgroup analysis, fluorouracil-based ACT but not gemcitabine-based ACT achieved significantly better OS benefits on patients with N+ (HR 0.67; 95% CI, 0.52-0.86) and R0 (HR 0.69; 95% CI, 0.54-0.88). Conclusion: Compared with observation, ACT should be routinely recommended to improve survival outcomes in BTC patients after curative resection, especially for those with R0, N+, and TNM stage I/II. Gemcitabine-based ACT performed better than other chemotherapies in improving RFS. This network meta-analysis provides precise information for determining the best adjuvant treatment for resected BTC. Further thorough and high-quality RCTs are needed.