Background: Cholangiocarcinoma is an aggressive biliary tract malignancy with poor long-term survival and high recurrence rates even after apparently curative surgery. Although postoperative systemic therapy is incorporated into contemporary management, the role of neoadjuvant therapy remains uncertain because the available evidence is heterogeneous and largely observational and often mixes initially resectable and initially unresectable disease.
Objective: This protocol describes a systematic review and meta-analysis that will evaluate the safety and efficacy of neoadjuvant therapy followed by curative-intent surgery or liver transplantation in adults with cholangiocarcinoma. The review will address 2 clinically distinct pathways: initially resectable disease, in which neoadjuvant therapy is intended to improve oncological outcomes, and initially unresectable disease, in which treatment is intended to downstage disease or bridge patients to potentially curative surgery or transplantation.
Methods: The protocol has been prepared in accordance with the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols) 2015 statement and registered in PROSPERO. We will include randomized controlled trials and comparative nonrandomized studies evaluating neoadjuvant chemotherapy, chemoradiotherapy, immunotherapy, targeted therapy, or other preoperative antitumor therapy followed by curative-intent surgery or transplantation vs upfront surgery without preoperative systemic therapy. Single-arm studies, case reports, case series, and purely palliative cohorts will be excluded. The primary outcome will be overall survival analyzed as a time-to-event outcome using hazard ratios. Secondary outcomes will include recurrence-free survival, R0 resection, pathologic or radiologic complete response, conversion to operability among initially unresectable cohorts, and postoperative morbidity and mortality. Two reviewers will independently screen studies, extract data, and assess risk of bias using version 2 of the Cochrane risk-of-bias tool for randomized trials and the Risk of Bias in Nonrandomized Studies of Interventions tool for nonrandomized comparative studies. Random-effects meta-analysis; subgroup analyses; sensitivity analyses; assessment of reporting bias; and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) certainty assessment will be undertaken where appropriate.
Results: Database searches were completed on February 27, 2026. Title and abstract screening and full-text eligibility assessment were completed in March 2026. Data extraction commenced in April 2026. Meta-analysis is scheduled for May 2026, risk-of-bias and GRADE assessments are scheduled for June 2026, final manuscript preparation is scheduled for August 2026, and submission of the completed systematic review manuscript is scheduled for September 2026.
Conclusions: This review will provide a methodologically explicit synthesis of comparative evidence on neoadjuvant therapy in cholangiocarcinoma while prespecifying separate analyses for initially resectable and initially unresectable disease. The findings are expected to inform future trial design, interpretation of emerging comparative evidence, and clinical decision-making in a setting where treatment intent varies substantially by resectability status.
Trial Registration: PROSPERO CRD420251111270; https://www.crd.york.ac.uk/PROSPERO/view/CRD420251111270
International Registered Report Identifier (IRRID): PRR1-10.2196/84912
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)