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

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.

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.

Eligibility Criteria:
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