Advancing the frontiers of hepatocellular carcinoma treatment: a comprehensive review of past, ongoing, and future clinical trials.

Abstract

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths worldwide. The therapeutic landscape continues to evolve rapidly, with growing evidence supporting a range of treatment options across all disease stages. Notably, advancements in systemic therapies in advanced HCC have shifted first-line treatment preferences toward immune checkpoint inhibitor-based regimens, often combined with anti-angiogenic agents. These regimens have demonstrated meaningful improvements in overall survival, progression-free survival, and quality of life compared with historical standards such as sorafenib. At the same time, locoregional therapies (LRTs), including transarterial chemoembolization (TACE), transarterial radioembolization (TARE), ablation techniques, and external beam radiation, continue to play a central role in the management of intermediate and selected early or advanced-stage disease. Increasing understanding of tumor biology and treatment-related immunomodulation has prompted renewed interest in the synergistic potential of combining LRTs with systemic immunotherapy. Early-phase and ongoing later-phase trials suggest that these combined approaches may enhance antitumor immune activation, improve local tumor control, and potentially extend survival in carefully selected patients. This review summarizes the clinical trial evidence to date, emphasizing locoregional image-guided interventional therapies, systemic treatments, and emerging combination strategies. It highlights key findings from past and current clinical trials, discussing evolving treatment paradigms, and outlines future directions that may shape the next generation of multimodal therapy for patients with HCC.