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

Potential conflict of interest: Nothing to report. See Article on Page 369 For patients with hepatocellular carcinoma (HCC) exceeding the Milan criteria, survival after liver transplantation (LT) incrementally decreases with increasing tumor size and number.1 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.2 Wait‐list dropout rates remain substantial even for HCC within Milan criteria in long wait‐time regions.3 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).4 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.5 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.6 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 Child‐Pugh 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, 5‐ and 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 (1 tumor > 5 cm but ≤ 8 cm, 2‐3 tumors at least 1 tumor > 3 cm but ≤ 5 cm with total tumor diameter ≤8 cm, or 4‐5 tumors ≤ 3 cm and total tumor diameter ≤8 cm).7 The 10 patients in the BCLC study who achieved downstaging to within Milan criteria by preoperative radiographic assessment had a significantly better 5‐ and 10‐year survival of 90% when compared with that in the other 12 patients who did not receive LRT or did not achieve downstaging (70% and 52%, respectively). These observations thus provide further support of downstaging as a selection tool,7 but the small sample size precludes drawing firm conclusions. When compared with the proposed BCLC extended criteria, more liberal upper limits in tumor size and number for LDLT have been advocated by other groups predominantly from Asia.5 Some of these proposed criteria have incorporated additional assessments of tumor aggressiveness (histology or biomarkers) beyond tumor size and number in candidate selection. Alpha‐fetoprotein (AFP) is a well‐established biomarker for discriminating prognosis after LT for HCC.1 An AFP > 1000 ng/mL is associated with particularly poor post‐LT outcomes and has been implemented as an exclusion criterion in the priority system of organ allocation in the United States (unless AFP decreases to <500 ng/mL with LRT).9 None of the patients in the BCLC study had AFP > 1000 ng/mL and only 1 had an AFP > 100 ng/mL before LDLT. The extended Toronto criteria10 pose no restrictions in tumor size and number but require biopsy of the largest tumor to exclude poorly differentiated tumor grade. With this approach, the 5‐year post‐LT survival of 69% was similar to that for HCC within Milan criteria.10 The National Cancer Center Korea criteria include total tumor diameter <10 cm and negative [18F]fludeoxyglucose positron emission tomography. In LDLT recipients meeting these criteria preoperatively, the 5‐year survival was 84% versus 54% in those exceeding these criteria.11 Des‐gamma‐carboxyprothrombin (DCP) has been incorporated into the Kyoto criteria. Those with <10 tumors, largest tumor <5 cm, and DCP of <400 mAU/mL had a 5‐year survival of 88% after LDLT, versus only 42% in those exceeding these criteria.12 Although these liberal criteria have produced surprisingly good 5‐year survival after LDLT, they require independent validation. In summary, the results of this pilot study by the BCLC group6 highlight a cautious approach to expanding HCC indications for LDLT, with 5‐ and 10‐year survival rates comparable to that in patients receiving a cadaveric graft. The small number of patients represents a major limitation, and the results therefore require confirmation in a larger cohort. This study also suggests superior outcome with downstaging to Milan that may prove to be the preferred approach over expanded criteria for LDLT. A large, prospective multicenter study applying uniform expanded criteria with and without downstaging and incorporating biomarkers of tumor aggressiveness in candidate selection will take us 1 step closer to developing a consensus approach to LDLT for HCC.

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