
    slow accrual.
  
['bclc stage c hcc', 'cp-b liver cirrhosis']
['sorafenib']

        Inclusion Criteria:

          -  Male or female, 18 years of age or older

          -  Diagnosis of HCC: diagnosis based on the following criteria:

               1. 1 radiologic technique: Focal lesion >1 cm with arterial hypervascularization in
                  4-phase CT or dynamic contrast enhanced MRI OR

               2. 2 coincidental dynamic radiologic techniques (CT or MRI) in case one imaging
                  technique is non-conclusive and lesion > 1 cm OR

               3. biopsy proven HCC

          -  Patients with advanced HCC - BCLC stage C

          -  Cancer related symptoms (symptomatic tumors, ECOG Performance status 1-2),
             macrovascular invasion (either segmental or portal invasion) or extrahepatic spread
             (lymph node involvement or distant metastases)

          -  Not eligible for TACE (; i.e. diffuse tumors, tumors larger than 5 cm)

          -  Not eligible for curative resection or RFA

          -  Patients with CP-B liver cirrhosis (CP-B score 7 or 8)

          -  Capable of giving written informed consent

          -  History of organ transplant (including prior liver transplantation) is allowed

          -  HIV, congenital immune defect, any immunosuppressive therapy for autoimmune disease
             (rheumatoid arthritis) is allowed

        Exclusion Criteria:

        Subjects will not be enrolled in the study if any of the following criteria apply:

          -  CP-B9 liver cirrhosis

          -  CP-C liver cirrhosis

          -  Mental conditions rendering the subject incapable to understand the nature, scope, and
             consequences of the trial

          -  Concurrent antitumoral treatment for HCC or other malignancies

          -  Not eligible for sorafenib treatment

          -  Bilirubin > 51 micromol/L

          -  If female, pregnant or breast feeding (females of child-bearing potential must use
             adequate contraception and must have a negative pregnancy test performed within 7 days
             prior to inclusion into this study)

          -  If male, not using adequate birth control measures

          -  One or more of the following: - WBC <2,500 cells/mm3, - ANC <1,500 cells/mm3, -
             platelets <50,000/mm3,

          -  ECOG performance status >2

          -  Patients with known GFR <30 mL/min/1.73m2

          -  Significant cardiovascular disease; e.g., myocardial infarction within 6 months of
             inclusion, chronic heart failure (New York Heart Association class III or IV),
             unstable coronary artery disease

          -  Uncontrolled hypertension i.e. systolic blood pressure > 150 mm Hg and/or diastolic
             blood pressure > 90 mm Hg despite optimal medical management (2 classes of
             antihypertensive drugs)

          -  History of hemorrhage / bleeding events of grade 3 or worse within 30 days before
             inclusion into this study

          -  Previous variceal bleeding within the past 3 months

        Additional exclusion criteria for cocktail test

          -  Consumption of grapefruit or grapefruit juice and/or kumquats, pummelos, exotic citrus
             fruit (i.e., star fruit, bitter melon) or grapefruit hybrids from seven days prior to
             the first dose of cocktail.

          -  Use of herbal medicine or medication that induce or inhibit CYP3A4/5, CYP2C9, CYP2D6,
             CYP1A2 and CYP2C19

          -  Use of omeprazole, warfarin, metoprolol, caffeine or midazolam (=medication of the
             probe cocktail)

          -  Concurrent anticoagulant therapy
      