Palliative Treatment of Hepatocellular Carcinoma in Patient With CHILD B Cirrhosis

The incidence of Hepatocellular Carcinoma (HCC) is currently increasing in Europe and in France and about 2 / 3 of patients, are not eligible for curative treatment at the time of diagnosis. The palliative management of patients with advanced and symptomatic disease is complex and requires treatment combining anti-tumor activity and safety in patients with impaired liver functions. Sorafenib is the standard of care in a palliative setting, but the benefit of sorafenib in patient with altered liver function is uncertain. The aim of this trial is to study the interest of sorafenib in patients with HCC and impaired liver function compared to pravastatin (a drug with anti-tumoral activity in HCC) or to the combination sorafenib/pravastatin or to best supportive care (usually used in these patients).

Sex

All

Minimum age

18 Years

Inclusion Criteria:

\- Male and female subjects \> 18 years age

\- Hepatocellular carcinoma histologically diagnosed or in case of inability to perform a histology by non invasive radiological criteria in presence of known cirrhosis: (i) Hepatic lesion measuring between 1 and 2 cm in diameter : CT-scan + MRI (eventually an Ultrasound contrast) : HCC diagnosed with contrast uptake in the arterial phase and rapid wash out in the venous /late phase on two imaging techniques.

(ii)Hepatic lesion with a diameter \> 2 cm : CT-scan or MRI +alpha fetoprotein : HCC diagnosed with contrast uptake in the arterial phase and a rapid wash out in the venous /late phase or a alpha fetoprotein \> 200µg/L

* Patient not eligible for curative treatment (transplantation, resection, destruction or percutaneous chemo-embolization) or HCC still evolving after failure of a specific treatment
* Score CHILD B
* ECOG performance status 0/1/2
* Score BCLC B or C
* Adequate haematologic function with haemoglobin \> 8 g/dl, platelet count \> 50000x 109/L, absolute neutrophil count \> 1000 / mm3
* Creatinine \< 2 times the upper limit of normal
* Written informed consent

Exclusion Criteria:

* Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study
* Pregnancy
* Myocardial infarction less than 6 months, uncontrolled hypertension, congestive heart failure(NYHA class \> 2) , anti- arrhythmic treatment other than beta-blockers or digoxin
* Digestive bleeding within 30 days before inclusion
* Hepatic transplantation
* Patients receiving or having received a statine for less than 6 months before HCC diagnostic
* Prior use of sorafenib
* Psychiatric illness/social situations that would limit compliance with study requirements.
* Previous or concurrent cancer, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumor. Any cancer curatively treated \> 5 years prior to entry is permitted
* Known or suspected history of allergy to sorafenib or pravastatin.

• BACKGROUNDLlovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/NEJMoa0708857. PMID 18650514
• BACKGROUNDTaras D, Blanc JF, Rullier A, Dugot-Senant N, Laurendeau I, Vidaud M, Rosenbaum J. Pravastatin reduces lung metastasis of rat hepatocellular carcinoma via a coordinated decrease of MMP expression and activity. J Hepatol. 2007 Jan;46(1):69-76. doi: 10.1016/j.jhep.2006.06.015. Epub 2006 Jul 28. PMID 16935385
• BACKGROUNDKawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y, Inada M, Tamura S, Noda S, Imai Y, Matsuzawa Y. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer. 2001 Apr 6;84(7):886-91. doi: 10.1054/bjoc.2000.1716. PMID 11286466
• BACKGROUNDLersch C, Schmelz R, Erdmann J, Hollweck R, Schulte-Frohlinde E, Eckel F, Nader M, Schusdziarra V. Treatment of HCC with pravastatin, octreotide, or gemcitabine--a critical evaluation. Hepatogastroenterology. 2004 Jul-Aug;51(58):1099-103. PMID 15239254
• BACKGROUNDCohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol. 2006 Apr 17;97(8A):77C-81C. doi: 10.1016/j.amjcard.2005.12.014. Epub 2006 Feb 3. PMID 16581333
• BACKGROUNDLlovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ; Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008 May 21;100(10):698-711. doi: 10.1093/jnci/djn134. Epub 2008 May 13.