Biliary drainage plus hepatic arterial infusion chemotherapy versus biliary drainage plus best supportive care for advanced perihilar cholangiocarcinoma in China: a prospective multicentre non-randomised controlled study.

BACKGROUND: In most patients with advanced perihilar cholangiocarcinoma (pCCA), multi-branch biliary involvement results in inadequate jaundice relief despite biliary drainage. Together with recurrent cholangitis, persistent fever, impaired liver function, and poor performance status, these factors often preclude standard systemic treatment. We conducted a prospective, multicentre, non-randomised controlled study to evaluate whether a treatment pathway incorporating hepatic arterial infusion chemotherapy (HAIC) after biliary drainage was associated with clinical outcomes in this treatment-limited population.

METHODS: This prospective, multicentre, non-randomised controlled study enrolled systemic-treatment-naïve participants with pathologically confirmed advanced pCCA at five tertiary centres in China between November 1, 2021, and July 5, 2024. Key eligibility criteria included absence of distant metastases or N2 disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and Child-Pugh score ≤7; key exclusion criteria included prior systemic treatment, uncontrolled infection, and severe organ dysfunction. Participants received biliary drainage followed by HAIC (BD + HAIC) or biliary drainage plus best supportive care (BD + BSC). HAIC consisted of oxaliplatin 40 mg/m2 (0-2 h) and 5-fluorouracil 800 mg/m2 (2-24 h) on days 1-3, with intravenous leucovorin 200 mg/m2, repeated every 4 weeks. The primary outcome was overall survival (OS) in the intention-to-treat population, assessed throughout follow-up. Secondary endpoints included jaundice remission rate, duration of jaundice remission (DJR), and safety; safety was assessed in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05024513) on Aug 23, 2021.

FINDINGS: A total of 127 participants were enrolled (63 BD + HAIC; 64 BD + BSC). Median OS was 17.63 months in the BD + HAIC group and 6.10 months in the BD + BSC group (P < 0.0001). Jaundice remission occurred in 93.7% versus 46.9% of participants (P < 0.0001). Median DJR was 12.67 months versus 4.50 months (P < 0.0001). Adverse events were generally manageable; haematological and gastrointestinal events were more frequent with BD + HAIC, whereas elevated total bilirubin was more frequent with BD + BSC. Grade 3-4 events were uncommon, and no treatment-related deaths were observed.

INTERPRETATION: Biliary drainage followed by HAIC was associated with longer survival and more durable jaundice remission than biliary drainage plus best supportive care in a treatment-limited population with advanced pCCA. Given the non-randomised design, lack of a contemporary systemic-therapy control arm, and risk of selection bias and unmeasured confounding, these findings should be considered hypothesis-generating only and not evidence of a causal treatment effect. Randomised studies comparing BD + HAIC with appropriate contemporary systemic therapy are required to determine its clinical benefit in this setting.

FUNDING: This study was supported by the Beijing Natural Science Foundation, and the National Natural Science Foundation of China.