Comprehensive insights into systemic therapy for the whole-course management of hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is a lethal malignancy. For many years, chemotherapeutic regimens have served as the foundation of systemic therapies for advanced HCC despite their limited efficacy and significant adverse effects. In recent decades, novel systemic therapies such as immunotherapy and targeted therapy have profoundly transformed HCC management. Although some patients with advanced HCC exhibit dramatically improved outcomes, the efficacy of immunotherapy and targeted therapy, either as monotherapy or in combination, remains limited. Numerous trials have indicated that locoregional therapies, including transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and transarterial radioembolization (TARE), may synergize with systemic therapies to enhance advanced HCC treatment. However, further studies are required to optimize these combination regimens. In contrast, curative treatments, such as surgical resection, liver transplantation, or local ablation, are typically recommended for patients with early-stage HCC. Although these treatments have achieved an impressive median overall survival (OS) exceeding 60 months, more than half of the patients experience recurrence within 5 years. Consequently, the development of effective perioperative neoadjuvant or adjuvant therapies is urgently needed to reduce the incidence of recurrence and metastasis. It provides a comprehensive overview of recent advances in systemic therapies for advanced HCC, as well as adjuvant or neoadjuvant immunotherapies for early HCC. Additionally, emerging clinical trials and trial designs for future investigations into systemic therapies for HCC management are critically analyzed.