Simple SummaryUnresectable biliary tract cancer has a poor prognosis, with insufficient response rates from the standard treatment. We developed a new combination therapy regimen of intra-arterial chemotherapy plus radiation therapy based on a retrospective study, and we found its high effectiveness in cases of some unresectable biliary tract cancers. Then, we conducted this prospective study, which demonstrated the benefits for some patients with unresectable biliary tract cancer, resulting in high clinical response and disease control rates of 71.4% and 100%, respectively. Furthermore, two patients converted to surgery, indicating its high potential as a preoperative therapeutic strategy to achieve a long-term prognosis. This treatment was considered tolerated due to the absence of treatment-related deaths. This prospective pilot study is an important step toward determining the usefulness and safety of intra-arterial chemotherapy plus radiation therapy, as well as its potential future utility.AbstractThe standard treatment of unresectable biliary tract cancer (BTC) has shown an insufficient response rate (RR). Our retrospective setting revealed that a combination therapy consisting of intra-arterial chemotherapy plus radiation therapy (IAC + RT) provided a high RR and long-term survival benefits in unresectable BTC. This prospective study aimed to test the effectiveness and safety of IAC + RT as the first-line therapy. The regimen included one-shot IAC with cisplatin, 3–6 months of reservoir IAC (5-FU and cisplatin, q/week), and 50.4 Gy of external radiation. The primary endpoints include the RR, disease control rate, and adverse event rate. This study included seven patients with unresectable BTC without distant metastasis, with five cases classified as stage 4. RT was completed in all cases, and the median number of reservoir IAC sessions was 16. The RR was 57.1% for imaging and 71.4% for clinical assessment, and the disease control rate was 100%, indicating a high antitumor efficacy, which allowed two cases to be transferred to surgery. Five cases of leukopenia and neutropenia; four cases of thrombocytopenia; and two cases of hemoglobin depletion, pancreatic enzyme elevation, and cholangitis were observed, but with no treatment-related deaths. This study revealed a very high antitumor effect with IAC + RT for some unresectable BTC, and it could be useful for conversion therapy.