Sorafenib and Transarterial Chemoembolization for Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) as the third most common cause of cancer-related death has a very poor prognosis. Aim of this open label single arm non randomized pilot trial is the evaluation of the efficacy and safety of sorafenib in combination with TACE in patients with unresectable HCC. Efficacy ad safety will be compared with a historical TACE-only group of a placebo controlled TACE-trial.
Procedure: Transarterial chemoembolisation (TACE)
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Sorafenib as Inhibitor of Collateral Tumor Vessel Growth During Transarterial Chemoembolisation (TACE) for Hepatocellular Carcinoma (HCC)- a Pilot Trial to Evaluate Safety and Biological Response|
- Time to Progression (Efficacy) [ Time Frame: Until disease progression ] [ Designated as safety issue: No ]
- Safety of Sorafenib in combination with TACE [ Time Frame: Continuously until 12 weeks after the last TACE ] [ Designated as safety issue: Yes ]
|Study Start Date:||September 2008|
|Study Completion Date:||November 2010|
|Primary Completion Date:||October 2010 (Final data collection date for primary outcome measure)|
Experimental: Treatment arm
all patients will be treated with sorafenib
All patients will receive Sorafenib (800 mg/day) p.o. beginning two weeks before the first TACE and every day thereafter until patient death or premature withdrawal from study.
Other Name: Nexavar (brand name)Procedure: Transarterial chemoembolisation (TACE)
TACE will be carried out with doxorubicin (75 - 50 - 25 mg/m2, depending on serum bilirubin levels ≤ 1.5, 1.5 - 3, 3 - 5 mg/dL) : lipiodol (1:1) in a total volume of 20 mL; after administration of doxorubicin:lipiodol, additional embolisation will be carried out with bead block-endospheres. TACE will be repeated every 4 weeks for 3 cycles; additional cycles will be offered if clinically indicated (but no PEI or RF-ablation should be carried out after inclusion into the study)
Hepatocellular carcinoma (HCC) as the third most common cause of cancer-related death has a very poor prognosis.
Aim 1: Efficacy of Sorafenib in combination with TACE TACE is an established therapy for patients with unresectable HCC and has been shown to significantly improve survival in these patients compared to no treatment. Quite often after cutting off the blood supply through the hepatic artery, the tumor induces active angiogenesis to promote collateral blood vessel growth from liver capsule arteries or collaterals from the gastroduodenal artery leading to tumor recovery and proliferation. Inhibition of this neoangiogenetic and proliferation activity after TACE by the multikinase inhibitor Sorafenib, already approved for HCC, could lead to significantly improvement in tumor control and survival in patients with advanced stage HCC.Safety will be compared with a historical TACE-only group of a placebo controlled TACE-trial.
Aim 2: Safety of Sorafenib in combination with TACE:
So far there are no reports about the safety of Sorafenib in combination with TACE. Here we evaluate the safety and tolerability of this combination until 12 weeks after the last TACE.
Aim 3: PPG-Measurement:
Development of portal hypertension in cirrhosis occurs due to two main pathophysiologic mechanisms: the increase in resistance to portal blood flow resulting from increased intrahepatic resistance and the decreased arteriolar vascular tone in the splanchnic vascular bed leading to increased splanchnic inflow of blood. Very recently, it has been shown that increased splanchnic inflow does not only result from arteriolar vasodilation due to excess NO-production in the splanchnic vascular bed but also from an increase in neoangiogenesis in the splanchnic circulation. Increased neovessel formation occurred within a few days of onset of portal hypertension both in a cirrhotic and an extrahepatic murine model of portal hypertension. Neoangiogenesis was effectively inhibited by either an antibody against VEGF-R2 or an inhibitor of VEGF-R2 autophosphorylation, resulting in a reduction of splanchnic blood flow.
Most recently, a combination of a VEGF and a PDGF blocker further decreased portal pressure in an experimental preclinical model.
As Sorafenib is a VEGF and PDGF blocker, we aim to analyze the influence of Sorafenib on portal hypertension and systemic and hepatic hemodynamics.
Aim 4: Biomarkers for treatment response:
Furthermore, we aim to analyze methylated tumor DNA in serum of patients with HCC undergoing Sorafenib treatment and TACE as possible marker of treatment response.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00768937
|Abteilung Gastroenterologie und Hepatologie, Medizinische Universität und AKH Wien|
|Vienna, Austria, 1090|
|Principal Investigator:||Markus Peck-Radosavljevic, Prof. Dr.||Abteilung Gastroenterologie und Hepatologie, Medizinische Universität und AKH Wien|