Systemic Treatment Strategies for Recurrent Hepatocellular Carcinoma Following Liver Transplantation: A 20-y Retrospective Analysis With Clinical Insights

BACKGROUND: Recurrent hepatocellular carcinoma (HCC) following liver transplantation (LT) represents a major clinical challenge. Optimal treatment strategies for posttransplant recurrence or metastasis remain undefined. METHODS: We retrospectively analyzed 136 LT cases with recurrent or metastatic HCC where systemic therapy was applied in a single high-volume LT center during 2002-2024. Progression-free survival (PFS) and overall survival were evaluated using Kaplan-Meier and Cox models, with additional strategies to address treatment-era effects, including drug-overlap era cohort, restricted targeted therapy-only subgroup, an 8-wk landmark analysis, and overlap-weighted Cox models. RESULTS: First-line therapy included sorafenib (n = 72) and lenvatinib (n = 64). Median PFS (95% confidence interval) was 3.5 mo (3.00-5.70 mo) with sorafenib versus 9.4 mo (6.17-16.07 mo) with lenvatinib (P < 0.001), while median overall survival was 12.1 mo (9.47-17.30 mo) versus 18.5 mo (12.73-25.70 mo; P = 0.120). After adjusting for treatment era and covariates, lenvatinib remained associated with longer PFS (hazard ratio [HR], 0.39; 95% confidence interval, 0.18-0.86; P = 0.02). The association persisted in sensitivity analyses (drug-overlap era: HR, 0.41; P = 0.046; targeted therapy-only subgroup: HR, 0.3; P = 0.076; and 8-wk landmark: HR, 0.38; P = 0.021). Grade ≥3 adverse events were less frequent with lenvatinib (1.6% versus 12.5%). Independent predictors of poorer PFS included recurrence within 1 y post-LT, alpha-fetoprotein >100 ng/mL, and modified albumin-bilirubin grade 2, but initial combination locoregional therapy is a protective predictor. CONCLUSIONS: Lenvatinib was associated with improved PFS and fewer severe adverse events compared with sorafenib in post-LT recurrent HCC. Prospective multicenter studies are warranted.