Pathological Complete Response after Systemic Therapy and Curative Resection in Initially Unresectable Hepatocellular Carcinoma: Feasibility of a Tumor-Free with Drug-Free Strategy.

Introduction: The outcomes and optimal postoperative management of patients with initially unresectable hepatocellular carcinoma (uHCC) who achieve pathological complete response (pCR) after systemic therapy and curative resection remain undefined. Methods: This multicenter retrospective cohort study included consecutive patients with initially uHCC who received systemic therapy followed by curative resection at three tertiary centers in China between January 2020 and December 2023. The primary outcome was overall survival (OS); secondary endpoints included recurrence-free survival (RFS) and incidence of treatment-related adverse events (AEs). Results: Of the 2,212 patients who underwent conversion surgery, 1,623 (73.4%) received systemic therapy-based regimens; among them, 257 (15.8%) patients achieved pCR and were included in the analysis. The median tumor diameter was 9.0 cm; 39.7% had multifocal tumors, 55.6% presented with macrovascular invasion, and 70.4% were AFP-positive. Most patients (87.2%) received combination regimens based on immune checkpoint inhibitors. Postoperative adjuvant therapy was administered in 88 (34.2%) patients for a median duration of 6.05 months. After a median follow-up of 32.7 months, the 1-, 3-, and 5-year RFS rates were 81.7%, 60.3%, and 58.3%, and OS rates were 98.0%, 91.1%, and 85.5%, respectively. No significant differences in RFS or OS were observed between the adjuvant and active surveillance groups, though AEs occurred more frequent in the adjuvant group. Subgroup analyses failed to identify any population with clear benefit from adjuvant therapy. On multivariate analysis, postoperative alpha-fetoprotein (AFP) positivity was independently associated with inferior RFS and OS. Conclusions: Patients with uHCC who achieve pCR after systemic therapy and curative resection exhibit favorable long-term outcomes. Active surveillance yields comparable survival to adjuvant therapy with reduced toxicity. A "Tumor-Free with Drug-Free" strategy may be feasible in patients with normalized postoperative AFP levels, while those with persistent AFP positivity may represent a high-risk subgroup requiring individualized postoperative management.