Expansion of Conventional Criteria for Liver Transplantation in Hepatocellular Carcinoma Through Downstaging
Condition: Carcinoma, Hepatocellular; Cirrhosis
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Study type: Interventional

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.
    

Intervention name(s): Liver transplantation
Intervention type(s): Procedure
Intervention description(s): Once randomized to Group 1, patients will be enlisted for liver transplantation at the recruiting Center. Prioritization is encouraged as a waiting time of more than 8 months could cause patients' drop-out from the study
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hepatocellular Carcinoma; Liver Transplantation; Downstaging; Trans-arterial chemoembolization (TACE); Radiofrequency ablation (RFA); Liver resection; Sorafenib