Locoregional combined systemic therapies for unresectable hepatocellular carcinoma in the era of immunotherapy: a narrative review

Most patients with hepatocellular carcinoma (HCC) present at intermediate or advanced stages. Current guidelines generally recommend transarterial chemoembolization (TACE) for intermediate-stage disease and systemic therapy for advanced-stage disease. Whether combining locoregional therapy (e.g., TACE) with systemic treatment confers additional benefit remains debated. Immunotherapy combinations may have a synergistic effect with locoregional treatments. Four recent trials conducted mainly in intermediate-stage populations showed that adding an immunotherapy combination to TACE increased response rates and prolonged progression-free survival, but did not clearly improve overall survival (OS) and, at best, suggested a trend toward OS benefit. These mixed results have fueled ongoing controversy about how best to integrate locoregional and systemic treatments. In the present narrative review, based on the current evidence, attempts were made to stratify intermediate-stage HCC into resectable, potentially resectable, and unresectable disease. Advanced HCC was stratified into potentially resectable and unresectable disease. Resectable intermediate-stage HCC should undergo surgical resection, with consideration of perioperative immunotherapy combinations. Patients with potentially resectable intermediate or advanced disease should receive potent systemic therapy, with or without locoregional treatment, to facilitate conversion to resection. Unresectable intermediate-stage HCC can be further categorized by tumor burden, small, intermediate, or large, guiding treatment selection toward TACE, TACE plus systemic therapy, or systemic therapy, respectively. Unresectable advanced-stage HCC should be managed with systemic therapy, adding locoregional treatment as appropriate based on response. The aim for this framework is to inform clinical decision-making on the integration of locoregional and systemic therapies for unresectable HCC.