Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience

This is the first systematic review assessing the valueof the MC as an independent prognostic factor affectingthe outcomes of LT for the treatment of HCC. A comprehensive search of the literature based on stringentselection criteria produced a list of 90 studies ofsufficient quality from 1864 references. In addition, ameta-analysis of 25 sufficiently powered studiesallowed the extraction of hazard ratios that significantlyproved the prognostic power of the MC andtheir ability to capture HCCs still retaining favorablebiological characteristics.The chosen methodology has allowed the prognosticimplications of MC to emerge with a lower grade ofevidence in comparison with pure RCTs. RCTs wereprevented for HCC by the striking differences in theposttransplant survival rates observed since theimplementation of MC and those of historicalcontrols.HCCs meeting the MC have been confirmed to be aseparate prognostic category associated with goodoutcomes after LT (a 5-year survival rate of at least70%). This has prompted the integration of the MCinto staging systems, transplant indications, and prioritizationpolicies worldwide.Although the lack of homogeneity and the presenceof noncomparative, retrospective studies hamper anyfirm conclusions, this review has translated objectiveMC data into assumptions of significant evidence:1. The MC are major determinants of the prognosisof patients undergoing LT for HCC. Patientsmeeting the MC achieve survival benefits similarto those of patients with nonmalignant diagnoses.The results of LT for patients meeting theMC should be the benchmark for any proposal ofexpanded criteria, which are associated with anincreased risk of adverse outcomes in comparisonwith conventional indications (Fig. 2).2. The MC identify a subset of patients with a significantlylower risk of tumor grades higher than2 and mVI (Fig. 3). Until more precise predictorsof prognosis using molecular techniques are validated,the MC in combination with the determinationof AFP levels remain a reliable andnoninvasive instrument for selecting patientswith less aggressive HCCs more suitable for LT.3. Locoregional treatment strategies for patientswith HCCs within the MC who are listed for LT(bridging therapies) are justified for the specificendpoint of reducing the dropout of patientsfrom the transplant waiting list. Conversely, theeffect of bridging therapies on post-LT survival isnot known.4. Arbitrary treatment plans lacking prospectivedesigns and predetermined endpoints do notfacilitate indications beyond the MC and shouldnot be recommended.