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

Abstract

Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the third most common cause of cancer-related deaths; the number of new cases per year is approaching 750,000.1 The magnitude of the incidence of HCC has discouraged any attempts to apply liver transplantation (LT) as the prevailing curative therapy for HCC worldwide because of the limited sources of donated organs (deceased and living donors) and the poor access to sophisticated health care systems in some geographical areas. If these limitations continue to prevail throughout the world, any attempt to significantly reduce HCC-related mortality rates through the application of LT will be delusional. International experiences have confirmed, however, the potential of LT to definitively cure HCC because it presents a unique opportunity to remove both the tumor (HCC is associated with 695,000 deaths per year1) and the underlying cirrhosis. Despite its limited access, LT has become the standard of care for patients with small HCCs and the main driving force for alternative strategies offered to patients with intermediate HCCs. In 1996, a prospective cohort study defined restrictive selection criteria that led to superior survival for transplant patients in comparison with any other previous experience with transplantation or other options for HCC.2 Since then, these selection criteria have become universally known as the Milan criteria (MC) in recognition of their origin. Ever since their adoption in clinical practice, the MC have helped doctors to single out early-stage HCC as a prognostic category of cancer presentation that is amenable to curative treatments. After their implementation, the favorable posttransplant outcomes that were observed in cohort series were so convincing that the MC immediately became the standard of care for early HCC, and further validation by randomized controlled trials (RCTs) was prevented. After the passage of approximately a decade, researchers began to challenge the MC with other proposals designed to capture those patients not meeting the MC who could achieve similar posttransplant survival rates through the expansion of the accepted tumor limits for transplant eligibility. None of these expanded criteria have become the new reference standard for selecting LT candidates with HCC; any broadening of the selection criteria for transplantation is inevitably hampered by severe restrictions in donor availability. Consequently, the MC remain the benchmark for any transplant strategy involving patients with HCC and the cornerstone for decision making for other patients at any stage. Surprisingly, no systematic review of the available experiences with the MC has been published yet; the suboptimal quality of the literature and the poor application of evidence-based principles has prevented this exercise. The aim of this study was to fill the gap through a systematic review of the available evidence on the MC and the related issue of the position of LT in the treatment algorithm for HCC. AFP, alpha-fetoprotein; CI, confidence interval; df, degrees of freedom; HCC, hepatocellular carcinoma; LT, liver transplantation; MC, Milan criteria; MELD, Model for End-Stage Liver Disease; mVI, microvascular invasion; NA, not applicable; n/n, number of studies/number of patients; NOS, Newcastle-Ottawa scale; RCT, randomized controlled trial; TACE, transarterial chemoembolization. For the literature review, analysis, and discussion, the MC were defined as follows: a single HCC nodule with a maximum size of 5 cm or as many as 3 nodules with the largest not exceeding 3 cm and no macrovascular invasion.2 Is the posttransplant survival of patients influenced by the MC when they are assessed at the time of the explant pathology examination? Do the boundaries of the MC correlate with a reduced likelihood of detecting 2 pathology surrogates of tumor behavior: microvascular invasion (mVI) and poor differentiation (grade 3)? In addition, we also probed the literature to answer less stringent questions (eg, the role of pretransplant treatments in patients meeting or not meeting the MC at the time of wait listing). A review of the literature in English was performed with various search terms. A PubMed-, Embase-, and Scopus-based search strategy was used that combined text, keywords, and Medical Subject Headings terms for titles and abstracts. Manual cross-referencing was also used to find more relevant articles. This part of the search strategy was not restricted by date. The following search terms were used in various combinations: Milan criteria, primary liver cancer, primary liver tumor, hepatoma, hepatocellular carcinoma, HCC, BCLC A, T1-T2, tumor size, tumor number, tumor burden, metastatic disease and metastases of HCC, transplantation, liver transplantation, liver substitution, orthotopic liver transplantation, OLT, LT, living donor liver transplantation, deceased donor liver transplantation, survival, overall survival, recur