First-line use of antiangiogenic agents in unresectable hepatocellular carcinoma: a double-edged sword?

Abstract

Treatment options for hepatocellular carcinoma (HCC), the most prevalent primary liver malignancy, have historically been limited, particularly in unresectable cases with underlying cirrhosis. Initial systemic therapy with antiangiogenic agents, notably vascular endothelial growth factor (VEGF) inhibitors such as sorafenib, showed modest survival gains but lacked durable responses. Subsequent trials with more potent VEGF pathway inhibitors failed to improve overall survival significantly, raising concerns about the long-term utility and potential hepatic and renal toxicities of prolonged VEGF blockade. The advent of immune checkpoint inhibitors (ICIs) marked a paradigm shift. Trial results demonstrating that dual-ICI regimens induced more durable responses and achieved higher long-term survival rates have challenged the prior VEGF-centric therapeutic approach and suggest that early use of dual ICIs may offer a more transformative effect on disease trajectory. Although anti-VEGF therapies remain valuable for initial tumor shrinkage, prolonged use may compromise liver regeneration and worsen portal hypertension. A refined treatment strategy emphasizing VEGF inhibition for a limited duration followed by or combined with ICIs may optimize both efficacy and safety. Future research should focus on identifying predictive biomarkers for ICI response and on developing regimens that maximize long-term survival in unresectable HCC.