Serum Tumor Markers Provide Refined Prognostication in Selecting Liver Transplantation Candidate for Hepatocellular Carcinoma Patients Beyond the Milan Criteria

Objective:To develop and validate a model to predict tumor recurrence after living donor liver transplantation (LDLT) (MoRAL) for hepatocellular carcinoma (HCC) beyond the Milan criteria (MC).Background:Some subgroups of HCC exceeding the MC experience substantial benefit from LDLT.Methods:This multicenter study included a total of 566 consecutive patients who underwent LDLT in Korea: the beyond-MC cohort (n = 205, the derivation [n = 92] and validation [n = 113] sets) and the within-MC cohort (n = 361). The primary endpoint was time-to-recurrence.Results:Using multivariate Cox proportional hazard model, we derived the MoRAL score using serum levels of protein induced by vitamin K absence-II and alpha-fetoprotein, which provided a good discriminant function on time-to-recurrence (concordance index = 0.88). Concordance index was maintained similarly on both internal and external validations (mean 0.87 and 0.84, respectively). At cut off of 314.8 (75th percentile value), a low MoRAL score (314.8) was associated with significantly longer recurrence-free (versus > 314.8, HR = 5.29, P < 0.001) and overall survivals (HR = 2.59, P = 0.001) in the beyond-MC cohort. The 5-year recurrence-free and overall survival rates of beyond-MC patients with a low MoRAL score were as high as 66.3% and 82.6%, respectively. The within-MC patients with a high MoRAL score showed a higher risk of recurrence than beyond-MC patients with a low MoRAL score (HR = 2.56, P = 0.035). The MoRAL score was significantly correlated with explant histology.Conclusions:This new model using protein induced by vitamin K absence-II and alpha-fetoprotein provides refined prognostication. Among beyond-MC HCC patients, those with a MoRAL score 314.8 and without extrahepatic metastasis might be potential candidates for LDLT.