Efficacy and Safety of Hepatic Arterial Infusion Chemotherapy (HAIC) Versus Systemic Therapy in Unresectable Intrahepatic Cholangiocarcinoma: A Systematic Review and Meta-Analysis

Background The optimal treatment for unresectable intrahepatic cholangiocarcinoma (iCCA) remains uncertain. Hepatic arterial infusion chemotherapy (HAIC) aims to increase local drug concentration and tumor response. Methods Following PRISMA 2020 guidelines and PROSPERO registration (CRD420251128740), we searched major databases up to March 2025. Included: observational comparative studies of HAIC (alone or with immunotherapy) vs. systemic therapy in unresectable iCCA. Outcomes: OS, PFS, ORR/DCR, grade 3–4 AEs. Pooled estimates used random-effects REML with Hartung–Knapp adjustment. Results Thirteen observational studies (~1,200 patients; no RCTs) were included. HAIC significantly improved tumor response (ORR/DCR RR 2.74 and 1.25, 95% CIs 1.91–3.92 and 1.04–1.50) with non-significant trends favoring HAIC for survival (OS HR 0.66, 95% CI 0.28–1.54; PFS HR 0.59, 95% CI 0.30–1.15). Severe toxicity was comparable (RR 0.79, 95% CI 0.10–6.20; exploratory, k=2). Heterogeneity low (I² ≤1%). Conclusions This observational meta-analysis suggests HAIC is associated with superior tumor response and non-significant survival trends without excess severe toxicity versus systemic therapy in unresectable iCCA. These hypothesis-generating findings require confirmation by randomized trials.