The Intention-to-treat Effect of Bridge Therapies in the Setting of Milan-in Patients

The Intention-to-treat Effect of Bridging Therapies in the Setting of Milan-in Patients Waiting for Liver Transplantation

In patients with hepatocellular cancer (HCC) meeting the Milan Criteria (MC), the usefulness of loco-regional therapies (LRT) in the context of liver transplantation (LT) is still debated. The inconsistent literature data are the result of initial selection biases among treated and untreated patients. In order to overcome these shortcomings, an inverse probability of treatment weighting (IPTW) analysis was done in a large patient cohort. After using a competing-risk analysis, the primary end-point of the study aims at identifying the risk factors of HCC-specific LT failure, defined as pre-LT tumour-related drop-out or post-LT recurrence.

Study Overview

• Status: Completed
• Conditions: Liver Cancer; Transplant; Failure, Liver
• Intervention / Treatment: Procedure: Direct liver transplant; Procedure: Bridging followed by transplant

Detailed Description

Liver transplantation (LT) is the best curative treatment of hepatocellular cancer (HCC) developed in an underlying liver disease. LT is considered as an oncologic successful procedure when a long-term post-transplant tumour-free survival is obtained. Conversely, a failure is equal to pre-transplant drop-out, post-transplant tumour recurrence or death. Due to the allograft scarcity, a HCC patient waiting for a LT is most often treated using neo-adjuvant loco-regional therapies (LRT) in order to minimise the risk of drop-out. When the tumour burden meets the Milan Criteria (MC) at moment of diagnosis, such an approach is called "bridging towards LT".

Two recent international guidelines underlined the importance of the bridging strategy, due to its potential to reduce the risk of pre-LT drop-out and post-LT recurrence. This is especially valid in the case in which a partial/complete tumour response is achieved before LT. Unfortunately, the quality of the evidence obtained from the currently available literature is low due to the lack of randomized controlled trials (RCT). Actually, it is inconceivable to realize RCT in this setting because of logistical and, even more, ethical reasons. Consequently, the majority of reported studies just compare post-LT outcome of treated and untreated patients, failing thereby to analyse the clinical course from an intention-to-treat (ITT) point of view.

Even when looking at studies including the waiting list period, one should keep in mind that substantial differences may exist among initially bridged vs untreated HCC patients regarding tumour burden. In order to overcome these limits, a retrospective analysis of a large European population of MC-IN HCC patients listed for LT was done. After "balancing" this cohort with an inverse probability of treatment weighting (IPTW), we investigated the risk factors for tumour-specific LT failure, especially focusing at the role of LRT.

• Study Type: Observational
• Enrollment (Actual): 1083

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • UCL

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with radiological/post-bioptic diagnosis of hepatocellular cancer listed for liver transplantation receiving or not receiving any neo-adjuvant treatment before transplant/drop-out

Description

Inclusion Criteria:

• adults (≥18-year old) listed for liver transplant with a morphologic and/or histologic confirmed hepatocellular cancer

Exclusion Criteria:

• Milan Criteria-out status at first referral
• transplantation or de-listing before January 1, 2001
• other means of loco-regional treatments such as partial hepatectomy, trans-arterial radio-embolization or external radiotherapy
• misdiagnosed mixed hepatocellular-cholangiocellular cancer or cholangiocellular cancer

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Direct liver transplant; All the cases listed for liver transplantation and then transplanted/dropped-out without undergoing any neo-adjuvant loco-regional treatment	Procedure: Direct liver transplant; Direct liver transplant (no neoadjuvant approaches during the waiting time period)
Bridging followed by transplant; All the cases listed for liver transplantation and then transplanted/dropped-out after undergoing at least one neo-adjuvant loco-regional treatment	Procedure: Bridging followed by transplant; Trans-arterial chemoembolization or percutaneous alcohol injection or radio-frequency ablation during the waiting time followed by liver transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumour-specific liver transplant failure rate	Any case of tumor-related drop-out during the waiting list period or post-transplant recurrence	up to 5 years from first referral

Collaborators and Investigators

• Sponsor: European Hepatocellular Cancer Liver Transplant Group
• Investigators: Principal Investigator: Quirino Lai, MD PhD, UCL Brussels

Publications and helpful links

General Publications

• Lai Q, Vitale A, Iesari S, Finkenstedt A, Mennini G, Onali S, Hoppe-Lotichius M, Manzia TM, Nicolini D, Avolio AW, Mrzljak A, Kocman B, Agnes S, Vivarelli M, Tisone G, Otto G, Tsochatzis E, Rossi M, Viveiros A, Ciccarelli O, Cillo U, Lerut J; European Hepatocellular Cancer Liver Transplant Study Group. The Intention-to-Treat Effect of Bridging Treatments in the Setting of Milan Criteria-In Patients Waiting for Liver Transplantation. Liver Transpl. 2019 Jul;25(7):1023-1033. doi: 10.1002/lt.25492.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Actual): October 15, 2018
• Study Completion (Actual): October 15, 2018

Study Registration Dates

• First Submitted: October 25, 2018
• First Submitted That Met QC Criteria: October 26, 2018
• First Posted (Actual): October 29, 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

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms
• Other Study ID Numbers: #0002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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