• Vincenzo Mazzaferro, Josep M Llovet, Rosalba Miceli, Sherrie Bhoori, Marcello Schiavo, Luigi Mariani, Tiziana Camerini, Sasan Roayaie, Myron E Schwartz, Gian Luca Grazi, René Adam, Peter Neuhaus, Mauro Salizzoni, Jordi Bruix, Alejandro Forner, Luciano De Carlis, Umberto Cillo, Andrew K Burroughs, Roberto Troisi, Massimo Rossi, Giorgio E Gerunda, Jan Lerut, Jacques Belghiti, Ilka Boin, Jean Gugenheim, Fedja Rochling, Bart Van Hoek, Pietro Majno, and Metroticket Investigator Study Group.
• National Cancer Institute, Milan, Italy.
• Lancet Oncol. 2009 Jan 1; 10 (1): 35-43.

BackgroundPatients undergoing liver transplantation for hepatocellular carcinoma within the Milan criteria (single tumour MethodsData on patients who underwent transplantation for hepatocellular carcinoma despite exceeding Milan criteria at different centres were recorded via a web-based survey completed by specialists from each centre. The survival of these patients was correlated retrospectively with the size of the largest tumour nodule, number of nodules, and presence or absence of microvascular invasion detected at pathology. Contoured multivariable regression Cox models produced survival estimates by means of different combinations of the covariates. The primary aim of this study was to derive a prognostic model of overall survival based on tumour characteristics, according to the main parameters used in the Tumour Node Metastasis classification. The secondary aim was the identification of a subgroup of patients with hepatocellular carcinoma exceeding the Milan criteria, who achieved a 5-year overall survival of at least 70%-ie, similar to the outcome expected for patients who meet the Milan criteria.FindingsOver a 10-month period, between June 25, 2006, and April 3, 2007, data for 1556 patients who underwent transplantation for hepatocellular carcinoma were entered on the database by 36 centres. 1112 patients had hepatocellular carcinoma exceeding Milan criteria and 444 patients had hepatocellular carcinoma shown not to exceed Milan criteria at post-transplant pathology review. In the group of patients with hepatocellular carcinomas exceeding the criteria, the median size of the largest nodule was 40 mm (range 4-200) and the median number of nodules was four (1-20). 454 of 1112 patients (41%) had microvascular invasion and, for those transplanted outside the Milan criteria, 5-year overall survival was 53.6% (95% CI 50.1-57.0), compared with 73.3% (68.2-77.7) for those that met the criteria. Hazard ratios (HR) associated with increasing values of size and number were 1.34 (1.25-1.44) and 1.51 (1.21-1.88), respectively. The effect was linear for size, whereas for number of tumours, the effect tended to plateau above three tumours. The effect of tumour size and number on survival was mediated by recurrence (b=0.08, SE=0.12, p=0.476). The presence of microvascular invasion doubled HRs in all scenarios. The 283 patients without microvascular invasion, but who fell within the Up-to-seven criteria (hepatocellular carcinomas with seven as the sum of the size of the largest tumour [in cm] and the number of tumours) achieved a 5-year overall survival of 71.2% (64.3-77.0).InterpretationMore patients with hepatocellular carcinoma could be candidates for transplantation if the current dual (yes/no) approach to candidacy, based on the strict Milan criteria, were replaced with a more precise estimation of survival contouring individual tumour characteristics and use of the up-to-seven criteria.

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