Adjuvant and Perioperative Systemic Therapy for Resectable Hepatocellular Carcinoma: Evidence, Biological Rationale, and Trial Design

Recurrence after curative-intent resection or ablation remains a major barrier to cure in hepatocellular carcinoma (HCC). Postoperative sorafenib was neutral in STORM, the initial recurrence-free survival signal with atezolizumab plus bevacizumab in IMbrave050 was not sustained with longer follow-up, and pembrolizumab was neutral in KEYNOTE-937. By contrast, perioperative camrelizumab plus rivoceranib improved event-free survival in CARES-009. This focused narrative review separates direct HCC clinical evidence from preclinical, cross-tumor, and translational evidence and addresses three development questions: how to test the intact-tumor antigen-source hypothesis, how to select patients biologically, and how to advance perioperative regimens without compromising curative surgery. The primary tumor and its draining lymphatic network may support antigen presentation and expansion of tumor-reactive lymphocytes during checkpoint blockade, but no randomized HCC trial has isolated treatment timing while holding regimen, exposure, population, and time origin constant. CARES-009 therefore validates one complete perioperative strategy rather than proving that neoadjuvant exposure caused benefit. Biological selection should proceed across the treatment pathway: pretreatment clinical risk and liver reserve establish eligibility; on-treatment safety and tissue response assess pharmacodynamic activity; and postoperative pathology, circulating tumor DNA, alpha-fetoprotein/des-gamma-carboxy prothrombin kinetics, and spatial immune features refine residual risk. These markers are prognostic, but none has demonstrated treatment-predictive utility in a randomized biomarker-guided trial. A stage-gated development program should establish agent-specific dose and washout, preserve operability, separate timing and treatment components in randomized phase II studies, and then confirm durable event-free and overall survival in globally representative phase III trials. Durable cure without loss of surgical opportunity, hepatic reserve, or quality of life should define success.