Abstract
BACKGROUND: Systemic therapy, including immune checkpoint inhibitors, has improved survival in advanced hepatocellular carcinoma (HCC); however, its efficacy remains limited in patients with macroscopic vascular invasion (MVI), a subgroup with an extremely poor prognosis. Although combining immunotherapy with local treatments such as hepatic arterial infusion chemotherapy (HAIC) and radiation therapy (RT) is considered a promising approach, robust supportive evidence from routine clinical practice is lacking. OBJECTIVE: This study aims to evaluate the safety and therapeutic effectiveness of a multidisciplinary treatment strategy involving RT after HAIC, followed by immunotherapy, in patients with MVI-positive HCC, using real-world clinical data from Japan. METHODS: This is a prospective, multicenter registry study conducted at 3 hospitals in Hiroshima Prefecture, Japan. Eligible patients will have unresectable MVI-positive HCC confirmed by dynamic computed tomography. The treatment protocol follows a standardized sequence: 1 session of HAIC (cisplatin), RT targeting the MVI site (25 Gy in 5 fractions), and subsequent systemic immunotherapy. The primary end point is safety, which will be evaluated using the Common Terminology Criteria for Adverse Events (version 5.0). The secondary end points include progression-free survival at 12 and 24 weeks, tumor response, median progression-free survival, overall survival, and objective response rate at 12 and 24 weeks, assessed according to the Response Evaluation Criteria in Solid Tumors criteria. Data will be collected prospectively and analyzed according to the intention-to-treat principle. RESULTS: Patient enrollment began in March 2025, and data collection and analysis are ongoing as participants continue to be followed. CONCLUSIONS: This prospective registry study will generate real-world evidence on the safety and effectiveness of a multidisciplinary strategy combining HAIC, RT, and immunotherapy in patients with MVI-positive HCC. Given that all components are covered under Japan's national health insurance, this approach could be readily implemented in clinical practice and may inform future treatment guidelines for MVI-positive HCC.