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

• For Phase II - Time to Tumoral Event (TTE) [ Time Frame: Every 4 months ] [ Designated as safety issue: No ]
  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.
  
  
• For Phase III - Overall Survival [ Time Frame: Every 4 months ] [ Designated as safety issue: No ]
  Time form the date of randomization and the date of death, with censoring at the date of last contact for event-free patients
  
  

• Transplant vs. non transplant strategy cost-benefit analysis [ Time Frame: Approx. 1 year after the last patient randomized ] [ Designated as safety issue: No ]
  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 modified RECIST criteria of radiological response to downstaging treatments [ Time Frame: Approx. 8 months after the last patient randomized ] [ Designated as safety issue: No ]
  Radiology/pathology correlation on efficacy of downstaging treatments in achieving tumor response, as a basis for possible validation of modified RECIST criteria.
  
  
• Validation of the Metroticket model for the prognosis of survival after liver transplantation in patients exceeding Milan Criteria [ Time Frame: Approx. 1 year after the last patient randomized ] [ Designated as safety issue: No ]
  http://www.hcc-olt-metroticket.org/calculator/
  
  

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.