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
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
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.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Time to Progression (Efficacy)
Until disease progression
Markus Peck-Radosavljevic, Prof. Dr.
Abteilung Gastroenterologie und Hepatologie, Medizinische Universität und AKH Wien
Austria: Agency for Health and Food Safety