A Worldwide Score for Hepatocellular Cancer and Liver Transplantation (TRAIN-SCORE)

A Worldwide Usable Scoring System for Patients With Hepatocellular Cancer Waiting for Liver Transplantation

The present study has been developed with multiple aims: 1) to refine available models for liver transplantation which would be able to cover the fate of HCC candidates from an ITT point of view; 2) to develop such an approach on cohorts coming from both Eastern and Western countries; 3) to maintain simplicity of use; 4) to provide individual prognostication taking into account different causes of death, through a competing-risk model; 5) to provide an external validation on cohorts coming from both Eastern and Western countries. All these aims converge at providing a comprehensive and useful assessment suitable for both candidates selection and allocation priority.

Study Overview

• Status: Completed
• Conditions: Recurrence; Liver Cancer; Dropout, Patient
• Intervention / Treatment: Procedure: Liver transplantation

Detailed Description

For two decades, the Milan Criteria (MC) have represented the cornerstone in the selection of patients with hepatocellular cancer (HCC) as candidates for liver transplantation (LT). Since then, several Western and Eastern centres have tried to overcome MC stringency with the aim to expand the number of potentially transplantable patients without increasing the risk of post-LT tumour recurrence. Recently, variables correlated with HCC biology have been introduced to capture its aggressiveness and suitability for LT. Among the most commonly proposed, we can cite the alpha-fetoprotein (AFP) and the radiological response after neo-adjuvant loco-regional treatments (LRT). The effort to combine HCC morphology and biology is now emerging as the more promising approach for further refining the selection process of HCC candidates. The recently proposed prognostic indexes Metroticket 2.0, Time-Radiological-response-Alpha-fetoprotein-INflammation (TRAIN), Model Of Recurrence After Liver transplant (MORAL) and French AFP-model represent the most promising results of such planned endeavours.

With the intent to be clinically useful, a prognostic system must achieve not only the most common performance metrics, such as discrimination and calibration, but also an adequate coverage of the population in which it would be applied. It can be argued that a prognostic system based only on criteria available at the moment of LT could not satisfy such a pre-requisite when the entire population of HCC patients waiting in the list for LT is taken into account, considering an intention-to-treat (ITT) point of view. In this sense, only the TRAIN system developed an ITT analysis, whereas the remaining were all based on pre-transplant information. The second quality that a clinically useful prognostic system should have is its immediacy. Thus, it should be based on commonly available information, not requiring additional analyses or exams if not justified by a substantial improvement in accuracy. Last but not least, a prognostic system should also provide for an individual prediction in addition to risk-stratification, with the intent to offer personalized prognostication for each different patient. To date, only the Metroticket 2.0 fulfils these two last requisites. A final important quality of the Metroticket 2.0 is that it applied a competing-risk analysis able to clean up the HCC-related cause of death from other non-tumour-related causes.

On this background, we developed the present study with multiple aims: 1) to refine available models which would be able to cover the fate of HCC candidates from an ITT point of view; 2) to develop such an approach on cohorts coming from both Eastern and Western countries; 3) to maintain simplicity of use; 4) to provide individual prognostication taking into account different causes of death, through a competing-risk model; 5) to provide an external validation on cohorts coming from both Eastern and Western countries. All these aims converge at providing a comprehensive and useful assessment suitable for both candidates selection and allocation priority.

• Study Type: Observational
• Enrollment (Actual): 3100

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • UCL

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The participating centers for the creation of the training set cohort were: Brussels (Belgium; n=355), New York Columbia University/Weill Cornell Medical Center (USA; n=353), Innsbruck (Austria; n=330), New Delhi (India; n=270), Rome Sapienza University (Italy; n=265), Kyoto (Japan; n=230), Taiwan (Republic of China; n=200), Mainz (Germany; n=176), Kyushu (Japan; n=161), and Hangzhou Shulan Health Hospital/First Affiliated Hospital (Popular Republic of China; n=94).

For the testing/external cohort, two additional centres participated to the study, namely the Western center from Padua (Italy; n=630) and the Easter center from Hong Kong (n=330) applying the same inclusion/exclusion criteria as for the training cohort.

Description

Inclusion Criteria:

• All the adult ((≥18 years) patients enlisted for liver transplant with the radiological/histological diagnosis of hepatocellular cancer during the period 01/01/2000-31/03/2017

Exclusion Criteria:

• Mixed hepatocellular-cholangiocellular
• Cholangiocellular cancer misdiagnosed as HCC
• Post-LT incidental HCC.
• Patients enlisted before 01/01/2000

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Training set; 2200 HCC cases from East and West centres enlisted for LT and then delisted or transplanted	Procedure: Liver transplantation; Liver transplantation
West validation set; 630 HCC cases from a Western centre enlisted for LT and then delisted or transplanted	Procedure: Liver transplantation; Liver transplantation
East validation set; 300 HCC cases from a Eastern centre enlisted for LT and then delisted or transplanted	Procedure: Liver transplantation; Liver transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumour-specific death	Death for recurrence or other HCC-related causes	5 years after transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Drop-out	Drop-out for death or HCC progression	1 year after waiting list inscription

Collaborators and Investigators

• Sponsor: European Hepatocellular Cancer Liver Transplant Group

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 15, 2016
• Primary Completion (ACTUAL): October 15, 2018
• Study Completion (ACTUAL): October 15, 2018

Study Registration Dates

• First Submitted: July 11, 2018
• First Submitted That Met QC Criteria: July 11, 2018
• First Posted (ACTUAL): July 23, 2018

Study Record Updates

• Last Update Posted (ACTUAL): October 29, 2018
• Last Update Submitted That Met QC Criteria: October 26, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: delisting; tumor-specific death; Milan Criteria
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Disease Attributes; Digestive System Neoplasms; Liver Diseases; Carcinoma, Hepatocellular; Recurrence; Liver Neoplasms
• Other Study ID Numbers: #0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No