Living donor liver transplantation for hepatocellular carcinoma: To expand (beyond Milan) or downstage (to Milan)?

For patients with hepatocellular carcinoma (HCC) exceeding the Milan criteria, survival after liver transplantation (LT) incrementally decreases with increasing tumor size and number. The allocation system for deceased donors in the United States is largely restricted to HCC within Milan criteria and does not accommodate to even modest expansion of tumor size. Wait-list dropout rates remain substantial even for HCC within Milan criteria in long wait-time regions. Living donor liver transplantation (LDLT) has been performed for patients with HCC beyond Milan criteria adhering to the principle that the risk to the donor is justified by the expectation of an acceptable outcome for the recipient (double equipoise). However, the boundaries of tumor size and number to be considered for LDLT have varied widely among centers without a consensus based on reproducible data. Furthermore, the minimal acceptable survival threshold after LDLT has not been well defined. In this issue of Liver Transplantation, Llovet et al. from the Barcelona Clinic Liver Cancer (BCLC) group report their longterm results up to 10 years following LDLT for HCC beyond Milan criteria in a prospectively applied protocol. The study cohort met the proposed BCLC extended criteria (1 tumor> 5 cm but 7 cm, 2-3 tumors at least 1 tumor> 3 cm but 5 cm, or 4-5 tumors 3 cm) and other protocol eligibility requirements including Eastern Cooperative Oncology Group performance status 0 and ChildPugh class A/B. Out of 22 patients enrolled between 2001 and 2014, 5 were successfully downstaged with local-regional therapy (LRT) from beyond BCLC extended criteria to within Milan criteria. A total of 12 of the 22 patients received LRT, in whom 10 were downstaged to within Milan criteria prior to LDLT. This study was therefore composed of a heterogeneous group of patients who underwent LDLT either with extended criteria or after tumor downstaging—2 different approaches that should be considered separately. Explant tumor stage exceeded BCLC extended criteria in 50% (understaged) and within Milan criteria in 18% (downstaged). Poorly differentiated tumor grade and microvascular invasion were observed in 23% and 46%, respectively. Despite the frequency of unfavorable histopathologic characteristics, 5and 10-year survival rates after LDLT were excellent at 80% and 67%, respectively. The cumulative probability of HCC recurrence was 24% and 44% at 5 and 10 years, respectively. In all but 1 case, HCC recurrence occurred beyond 4 years after LDLT. The reason for the surprising predominance of late HCC recurrence is unknown. All 7 (32%) patients with HCC recurrence had recurrent hepatitis C after LDLT, including 5 with graft cirrhosis. Some of these cases might therefore represent de novo HCC development in a graft with advanced fibrosis rather than recurrent tumor. An intriguing question raised in the BCLC study is whether downstaging is preferable to expansion of criteria in LDLT. The proposed BCLC extended criteria are very similar to the University of California, San Francisco downstaging criteria, which also include an upper limit in the total tumor diameter Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; DCP, des-gamma-carboxyprothrombin; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; LRT, local-regional therapy; LT, liver transplantation.