The Landmark Series: Perioperative Management of Hepatocellular Carcinoma

Background Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with an increasing burden of metabolic dysfunction-associated steatotic liver disease-associated HCC in Western populations. In treating HCC, recurrence after curative-intent therapy remains common, creating a compelling rationale for perioperative systemic therapy. Methods This Landmark Series review examines the pivotal studies that have shaped the surgical and perioperative management of HCC, tracing the evolution from principles of resectability to contemporary adjuvant and neoadjuvant immune-based strategies. Results The development of perioperative therapy has been defined by both landmark negative trials and emerging evidence of efficacy. The STORM trial demonstrated that sorafenib's activity in advanced HCC did not translate into benefit after resection or ablation. The IMbrave050 trial subsequently demonstrated an early recurrence-free survival advantage with adjuvant atezolizumab plus bevacizumab that was not sustained with longer follow-up evaluation, whereas the KEYNOTE-937 trial failed to demonstrate benefit with adjuvant pembrolizumab. In contrast, early-phase neoadjuvant immune checkpoint inhibitor-based studies have demonstrated feasibility and meaningful pathologic responses, and the CARES-009 trial provided the first randomized phase III evidence of improved event-free survival with a perioperative immune checkpoint inhibitor–antiangiogenic strategy. Conclusions Perioperative management of HCC is evolving toward an integrated, multidisciplinary treatment paradigm. Although no broadly applicable adjuvant systemic therapy has been established, emerging perioperative strategies provide proof of concept that systemic therapy may improve outcomes for selected patients. Future progress will depend on biomarker-driven patient selection, molecular residual disease assessment, standardized pathologic response criteria, and clinical trials identifying which patients require perioperative therapy and when treatment should be delivered.