Prognostic Stratification after Successful Downstaging of Hepatocellular Carcinoma beyond the Milan Criteria: Potential Implications for Liver Transplant Candidate Selection

Background/Aims: Locoregional therapy (LRT) can downstage hepatocellular carcinoma from beyond to within the Milan criteria, enabling liver transplantation. However, whether all successfully downstaged patients benefit equally from liver transplantation remains unclear. Methods: We analyzed 1,043 treatment-naive patients with hepatocellular carcinoma beyond the Milan criteria, without extrahepatic metastasis or vascular invasion, and with Child-Pugh class A liver function, who underwent surgical resection or LRT. Among successfully downstaged LRT-treated patients, a Cox-based nomogram and simplified decision-tree model were developed. A 12-month landmark analysis addressed potential immortal-time bias. Results: The 5-year overall survival (OS) rate was 71% after resection (n=470) and 38% after LRT (n=573). Among LRT-treated patients, 376 (66%) achieved downstaging, with a 5-year OS of 50%, compared with 14% among those who did not achieve downstaging. Tumor viability on follow-up imaging, follow-up alpha-fetoprotein (AFP), and baseline albumin-bilirubin (ALBI) grade stratified prognosis. The 5-year OS rates were 25% for patients with a viable tumor and an AFP concentration ≥20 ng/mL, 46% for those with a viable tumor and an AFP concentration <20 ng/mL, 64% for those with no viable tumor and ALBI grade 2, and 81% for those with no viable tumor and ALBI grade 1. The nomogram showed modest discrimination (concordance index, 0.694). The survival gradient and prognostic associations remained consistent in a 12-month landmark analysis. Conclusions: Post-treatment tumor viability, liver functional reserve, and AFP response may support post-downstaging prognostic stratification and individualized discussions regarding transplant timing.