Expansion of Conventional Criteria for Liver Transplantation in Hepatocellular Carcinoma Through Downstaging

Not Applicable

Completed

• Conditions: Carcinoma, Hepatocellular; Cirrhosis
• Interventions: Procedure: Liver transplantation

• Registration Number: NCT01387503
• Lead Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Brief Summary

This clinical trial is aimed at extending the chance of liver transplantation, through downstaging procedures, to patients with hepatocellular carcinoma (HCC) exceeding conventional Milan Criteria.

Those patients that will achieve a sustained tumor response after downstaging will be randomized either to undergo liver transplantation or to proceed with conventional non-transplant treatments.

The aim of the study is to demonstrate unequivocally that liver transplantation may provide a survival benefit, with an acceptable survival rate of at least 60% at 5 years, to patients that demonstrate a radiological and sustained tumor response after downstaging. Noteworthy is that response is chosen rather than stage migration as endpoint of downstaging.

Detailed Description

1. Downstaging phase

Patients that will be considered eligible for the study will undergo downstaging procedures according their stage of disease and to Center's policies. Length and intensity of downstaging will be center specific and not centrally pre-determined, but should be inferior to 18 months. Downstaging procedures will be stopped when, according to the Investigators' judgement, the best possible tumor response has been achieved: at this timepoint a radiological evaluation of tumor response according to modified RECIST (mRECIST) criteria will be performed. Patients that have achieved a Complete or Partial Response (PR or CR) will proceed to Bridging Phase, while those with a Stable or Progressive disease (SD or PD) will drop-out from the study.

2. Bridging phase

Patients that achieved PR or CR after downstaging will receive systemic therapy with sorafenib for three months. After three months radiological response will be assessed according to mRECIST criteria. If a sustained response will be demonstrated patients will proceed to randomization. PD during bridging phase will cause drop-out from the study.

3. Randomization and study period

Patients will be randomized in a 1:1 ratio, using computer generated list stratified by Center and by compliance to sorafenib treatment (based on whether ≤50% or \> 50% of the standard dosage (800 mg/day) has been administered).

1. The experimental group (Group 1 - transplant strategy) will be enlisted for transplantation and will undergo liver transplantation within 8 months unless major medical or oncological contraindications should occur.

2. The control group (Group 2 - non-transplant strategy) will continue with sorafenib until progression. Then they may be treated with either medical or locoregional/surgical therapies according to best practice and Centers' policy, excluding transplantation.

Study Timeline

• Study Start: 2011-01
• Study First Submitted: 2011-06-30
• Study First Submitted QC: 2011-07-01
• Study First Posted: 2011-07-04
• Primary Completion: 2015-03-31
• Study Completion: 2019-07-31
• Status Verified: 2021-10
• Last Update Submitted: 2021-10-04
• Last Update Posted: 2021-10-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 74

Inclusion Criteria

• Patient's age ≥ 18 yrs and ≤ 65 yrs
• Presence of cirrhosis of any etiology
• Child-Pugh class ≤ B7
• ECOG Performance Status ≤ 1
• Diagnosis of HCC either by biopsy or according to AASLD criteria
• HCC exceeding Milan Criteria with a 5-yr estimated survival after transplantation >50% according to the Metroticket calculator (http://www.hcc-olt-metroticket.org/calculator)
• Women of child bearing potential with a negative serum pregnancy test performed before enrolment
• Absence of general contraindications to sorafenib/molecular targeted therapies

Exclusion Criteria

• Presence of extra-hepatic tumor spread
• Presence of macrovascular invasion
• Sorafenib therapy started > 2 months before enrolment
• Concurrent cancer, distinct from HCC (except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors)
• Previous history of any cancer, even if curatively treated, < 5 years prior to entry
• Active intra-venous or alcohol abusers
• HIV infection
• History of serious cardiac disease
• Severe pulmonary hypertension not treatable by medical therapy
• Patients with a life expectancy of less than 3 months due to HCC or less than 6 months due to any other disease

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1 - Transplant strategy	Liver transplantation	Patients randomized to Group 1 will be enlisted for liver transplantation and will undergo liver transplantation within 8 months unless oncological (i.e. extrahepatic disease) or medical (i.e. cardiac insufficiency) will occur

Primary Outcome Measures

Name	Time	Method
For Phase III - Overall Survival	Every 4 months	Time form the date of randomization and the date of death, with censoring at the date of last contact for event-free patients
For Phase II - Time to Tumoral Event (TTE)	Every 4 months	TTE after randomization will be calculated as the interval between the randomization date and the date of tumour recurrence for tumor-free patients (either because of liver transplantation or complete response after downstaging procedures) or the date of tumour progression otherwise, with censoring at the date of last contact for event-free patients.

Secondary Outcome Measures

Name	Time	Method
Transplant vs. non transplant strategy cost-benefit analysis	Approx. 1 year after the last patient randomized	Comparison between the cost/benefit of a downstaging strategy followed by liver transplantation (treatment group) Vs the cost/benefit of convenional therapies (control group), analyzed according to the Quality Adjusted Life Years (QALY) gained in the treatment group
Validation of the Metroticket model for the prognosis of survival after liver transplantation in patients exceeding Milan Criteria	Approx. 1 year after the last patient randomized	http://www.hcc-olt-metroticket.org/
Validation of modified RECIST criteria of radiological response to downstaging treatments	Approx. 8 months after the last patient randomized	Radiology/pathology correlation on efficacy of downstaging treatments in achieving tumor response, as a basis for possible validation of modified RECIST criteria.

Trial Locations

Locations (10)

Ospedale Maggiore di Milano Policlinico; 🇮🇹 Milano, Italy

Istituto Nazionale Tumori; 🇮🇹 Milano, Italy

Ospedali Riuniti di Bergamo; 🇮🇹 Bergamo, Italy

Azienda Ospedaliera Ospedale Niguarda Ca' Granda; 🇮🇹 Milano, Italy

Azienda Ospedaliera Universitaria di Padova; 🇮🇹 Padova, Italy

Ospedale Umberto Iº Policlinico di Roma; 🇮🇹 Roma, Italy

Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT); 🇮🇹 Palermo, Italy

Ospedale Universitario Molinette S. Giovanni Battista di Torino; 🇮🇹 Torino, Italy

Policlinico Tor Vergata; 🇮🇹 Roma, Italy

Ospedale "Lazzaro Spallanzani"; 🇮🇹 Roma, Italy