Elsevier

The Lancet Oncology

Volume 10, Issue 1, January 2009, Pages 35-43
The Lancet Oncology

Fast track — Articles
Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis

https://doi.org/10.1016/S1470-2045(08)70284-5Get rights and content

Summary

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.

Findings

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).

Interpretation

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.

Funding

Specific funding was not used to do this study.

Introduction

Early-stage hepatocellular carcinoma is recognised as an excellent indication for liver transplantation. The size of the tumour, the number of tumours, and the presence of vascular invasion have been incorporated into the so-called Milan criteria, which predicts a low incidence of recurrence (about 10%) for transplant patients with a single tumour of 5 cm or less in size or with many tumours (up to a maximum of three, each 3 cm or less in size), and no macroscopic vascular invasion. Since the first prospective series done more than 10 years ago,1, 2 these criteria have been validated in several centres around the world, adopted as a prioritisation tool in the United Network of Organ Sharing (UNOS), and incorporated in the Tumour Node Metastasis (TNM) and Barcelona Clinic Liver Cancer (BCLC) staging systems for hepatocellular carcinoma.3, 4, 5, 6

In recent years, several studies have reported a good outcome for some patients transplanted outside these conventional criteria and the dichotomous yes/no nature of these criteria has been challenged for being too strict, because they exclude specific subgroups with meaningful, albeit lower, chances to benefit from transplantation. Furthermore, some patients might be excluded from transplantation as a result of the improvement in the accuracy of imaging techniques that enable the identification of very small lesions (<1 cm), which were undetectable a decade ago. Most of the studies on patients exceeding Milan criteria, however, are retrospective, with only a small number of patients, disease of variable severity, and short follow-up.7, 8, 9, 10, 11, 12 Overall, no precise information can be extracted from these studies, other than the further the distance from conventional limits, the higher the price in terms of malignant recurrences.7

The aim of the current study was to explore the area outside the conventional criteria for liver transplantation in hepatocellular carcinoma, by use of morphological (size of the largest tumour and number of tumours) and histological (microscopic vascular invasion) parameters in a large cohort of patients with adequate follow-up. The working postulation was that beyond the conventional eligibility criteria for transplantation for patients with hepatocellular carcinoma, a continuum in outcome probabilities could be identified linked to characteristics assessed in the TNM classification.5

Section snippets

Study background and data collection

The study design was presented during the International Liver Transplantation Society meeting held in Milan, Italy, in 2006 and a web-based survey of patients who received liver transplantation for hepatocellular carcinoma exceeding the Milan criteria was proposed. The website on which the survey can be completed (www.hcc-olt-metroticket.org) was built at the Clinical Trial Office of the National Cancer Institute of Milan, supported only by grants for investigator-initiated studies. The website

Results

During the 10-month recruitment period, between June 25, 2006, and April 3, 2007, 36 liver-transplantation centres entered data on the website, with an overall data collection of 1556 patients who underwent liver transplantation for hepatocellular carcinoma: 1274 patients (81·9%) from 31 centres in Europe, 269 patients (17·3%) from four centres in America, and 13 patients (0·8%) from one centre in Asia. The study population included 1112 patients (71·5%) with hepatocellular carcinoma exceeding

Discussion

This study, based on an unprecedented sample size of 1112 patients with hepatocellular carcinomas that fell outside the conventional transplantation criteria, aimed to establish a model that is able to predict survival probabilities on the basis of objective tumour parameters—ie, size of the tumour, number of tumours, and microscopic vascular invasion. The model presented here represents the first large-scale attempt to stratify patients with hepatocellular carcinoma in a continuum of outcome

References (40)

  • Cancer staging handbook. TNM liver classification

  • HY Yoo et al.

    The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time

    J Clin Oncol

    (2003)
  • P Majno et al.

    Living donor liver transplantation for hepatocellular carcinoma exceeding conventional criteria: questions, answers and demands for a common language

    Liver Transpl

    (2006)
  • JM Llovet et al.

    Resection and liver transplantation for hepatocellular carcinoma

    Semin Liver Dis

    (2005)
  • M Schwartz et al.

    Strategies for the management of hepatocellular carcinoma

    Nat Clin Pract Oncol

    (2007)
  • JM Llovet et al.

    Intention to treat analysis for surgical treatment of hepatocellular carcinoma: resection vs transplantation

    Hepatology

    (1999)
  • Consensus conference: indications for liver transplantation, January 19 and 20, 2005, Lyon-Palais Des Congrès: text of recommendations (long version)

    Liver Transpl

    (2006)
  • JM Llovet et al.

    Design and endpoints of clinical trials in hepatocellular carcinoma

    J Natl Cancer Inst

    (2008)
  • FE Harrell et al.

    Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors

    Stat Med

    (1996)
  • S Durrleman et al.

    Flexible regression models with cubic splines

    Stat Med

    (1989)
  • Cited by (0)

    Investigators are listed at the end of the Article

    View full text