title: Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.
abstract: BACKGROUND
  Patients undergoing liver transplantation for hepatocellular carcinoma within the Milan criteria (single tumour </=5 cm in size or </=3 tumours each </=3 cm in size, and no macrovascular invasion) have an excellent outcome. However, survival for patients with cancers that exceed these criteria remains unpredictable and access to transplantation is a balance of maximising patients' chances of cure and organ availability. The aim of this study was to explore the survival of patients with tumours that exceed the Milan criteria, to assess whether the criteria could be less restrictive, enabling more patients to qualify as transplant candidates, and to derive a prognostic model based on objective tumour characteristics, to see whether the Milan criteria could be expanded.
  
  
  METHODS
  Data 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.
  
  
  RESULTS
  Over 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).
  
  
  CONCLUSIONS
  More 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.
authors.affiliation: National Cancer Institute, Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
authors.forename: Rosalba
authors.initials: R
authors.lastname: Miceli
authors.forename: Sherrie
authors.initials: S
authors.lastname: Bhoori
authors.forename: Marcello
authors.initials: M
authors.lastname: Schiavo
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.forename: Tiziana
authors.initials: T
authors.lastname: Camerini
authors.forename: Sasan
authors.initials: S
authors.lastname: Roayaie
authors.forename: Myron E
authors.initials: ME
authors.lastname: Schwartz
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Grazi
authors.forename: René
authors.initials: R
authors.lastname: Adam
authors.forename: Peter
authors.initials: P
authors.lastname: Neuhaus
authors.forename: Mauro
authors.initials: M
authors.lastname: Salizzoni
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruix
authors.forename: Alejandro
authors.initials: A
authors.lastname: Forner
authors.forename: Luciano
authors.initials: L
authors.lastname: De Carlis
authors.forename: Umberto
authors.initials: U
authors.lastname: Cillo
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Burroughs
authors.forename: Roberto
authors.initials: R
authors.lastname: Troisi
authors.forename: Massimo
authors.initials: M
authors.lastname: Rossi
authors.forename: Giorgio E
authors.initials: GE
authors.lastname: Gerunda
authors.forename: Jan
authors.initials: J
authors.lastname: Lerut
authors.forename: Jacques
authors.initials: J
authors.lastname: Belghiti
authors.forename: Ilka
authors.initials: I
authors.lastname: Boin
authors.forename: Jean
authors.initials: J
authors.lastname: Gugenheim
authors.forename: Fedja
authors.initials: F
authors.lastname: Rochling
authors.forename: Bart
authors.initials: B
authors.lastname: Van Hoek
authors.forename: Pietro
authors.initials: P
authors.lastname: Majno
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000601:surgery*; D002648:Child; D006801:Humans; D008113:Liver Neoplasms / Q000401:mortality / Q000601:surgery*; D016031:Liver Transplantation; D008875:Middle Aged; D012189:Retrospective Studies