JMIR Publications

ABSTRACT

Cholangiocarcinoma (CCA), a bile duct cancer with rising incidence and poor prognosis, is often diagnosed late due to nonspecific symptoms and diagnostic challenges. Surgical resection offers potential cure but is feasible in only 20-35% of cases; recurrence rates remain high. Current guidelines recommend adjuvant chemotherapy but do not endorse neoadjuvant therapy. Emerging immunotherapies and targeted treatments show promise, with ongoing studies exploring their use as neoadjuvant therapy. Given the limited prior research, largely from small retrospective studies, a systematic review and meta-analysis of the safety and efficacy of neoadjuvant therapy in CCA are warranted to inform treatment strategies and outcomes. The objective is to systematically evaluate the safety and efficacy of neoadjuvant therapy, including chemotherapy, chemoradiotherapy, immunotherapy, and targeted therapy, followed by curative-intent surgery, compared with upfront surgery in adult patients with cholangiocarcinoma, including those undergoing liver transplantation. This systematic review will include randomised controlled trials (RCTs) and non-randomised controlled cohort or observational studies comparing neoadjuvant therapy followed by surgery versus upfront surgery in adult patients (≥18 years) diagnosed with CCA eligible for curative intent surgery, including liver transplantation. Studies focusing solely on palliative or biliary drainage treatments will be excluded. Interventions encompass chemotherapy, targeted therapy, immunotherapy, or chemoradiotherapy as neoadjuvant treatments prior to surgery. Primary outcomes include overall survival and complete response rate. Secondary outcomes cover R0 resection rates, relapse-free survival, and postoperative complications. Comprehensive searches across multiple databases, with no language or publication status restrictions, will be conducted. Study selection and data extraction will be independently performed by two reviewers, with risk of bias assessed by Cochrane tools. Meta-analyses using random-effects models will pool data when appropriate; otherwise, narrative synthesis will be provided. Subgroup and sensitivity analyses will explore heterogeneity and assess robustness. We anticipate sufficient data to pool outcomes separately for resectable and non-resectable cholangiocarcinoma, including subgroups by anatomical location (intrahepatic and extrahepatic), stage, neoadjuvant regimen, surgical approach, and study design. This systematic review will generate a thorough methodological synthesis comparing neoadjuvant therapy followed by curative-intent surgery with upfront surgery in cholangiocarcinoma, filling key evidence gaps. The results are expected to clarify potential survival advantages, surgical outcomes, and post-operative complications, thereby informing therapeutic strategies for bile duct cancer. Systematic review registration: PROSPERO CRD420251111270 https://www.crd.york.ac.uk/PROSPERO/view/CRD420251111270