Moving past “One Size (and Number) Fits All” in the selection of candidates with hepatocellular carcinoma for liver transplantation

Liver transplantation (LT) is a cornerstone in the management of early-stage hepatocellular carcinoma (HCC). Despite favorable overall posttransplant survival with the restrictive Milan criteria, HCC recurrence still occurs in 10% to 15% of these patients. On the other hand, some patients with tumors beyond the Milan criteria may achieve survival similar to the survival of patients with tumors within the Milan criteria. Consequently, there are clearly factors beyond tumor size and number that are associated with worse tumor biology and thus a greater risk of HCC recurrence after LT. Microvascular invasion has been consistently shown to predict a poor prognosis after LT, but the presence of microvascular invasion cannot be ascertained before LT. In our ongoing efforts to refine current selection criteria and to further improve outcomes after LT, we are still searching for pretransplant tumor characteristics beyond size and number that can serve as surrogates for tumor aggressiveness and predict the likelihood of HCC recurrence after LT. Although a serum tumor marker that reliably predicts the presence of microvascular invasion or a high risk of HCC recurrence after LT remains elusive, there is a growing body of evidence indicating that a high alpha-fetoprotein (AFP) level is associated with worse outcomes after LT. However, the optimal AFP cutoff for predicting an unfavorable outcome has not yet been elucidated. In recent years, there has also been growing interest in further defining the role of locoregional therapy (LRT) in the selection of candidates with HCC for LT. Preliminary studies have suggested that a response to LRT based on the Response Evaluation Criteria in Solid Tumors may serve as a selection criterion for patients with HCC within or beyond the Milan criteria. The same principle has been applied to the down-staging of tumors by LRT within acceptable criteria based on tumor size and number, with the goal of achieving post-transplant survival similar to the survival of patients not requiring down-staging before LT. In this issue of Liver Transplantation, Lai and colleagues from 6 centers throughout Europe further explore the impact of AFP and responses to LRT on outcomes after LT for patients with HCC within or beyond the Milan criteria. In this large, multicenter cohort of 422 patients, the majority (73%) had HCC initially meeting the Milan criteria according to preoperative imaging, and the remaining patients were down-staged within the University of California San Francisco (UCSF) criteria. When the modified Response Evaluation Criteria in Solid Tumors (mRECIST) were used to assess responses to LRT, 29% exhibited a complete response, and 7% had progressive disease. HCC recurrence was observed in 14% of the study population. In a multivariate analysis of the entire population, patients with progressive disease had a 3.5-fold higher risk of HCC recurrence in comparison with patients with a complete response. The only stronger predictor of HCC recurrence was an AFP slope > 15 ng/mL/month, which was associated with a 5.4-fold increased risk of HCC recurrence. A