Numerous chemotherapeutic regimens have been tested for use against hepatocellular carcinoma (HCC). HCC is, however, highly resistant to chemotherapy; doxorubicin and 5- fluorouracil containing regimens, alone or in combinations, results in less than a 20% response, with a median survival of less than 4 months. Furthermore even the objective responses are short-lasting. In a metaanalysis of the published randomized studies on HCC, neither doxorubicin nor any chemotherapeutic agent has been shown to have any survival benefit for HCC patients.~Sorafenib (Bay 43-9006) is a novel signal transduction inhibitor that prevent tumor cell proliferation and angiogenesis through blockade of the Raf/Mek/Erk pathway at the level of Raf Kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-beta.~Recent preclinical studies have shown the activation of Mek-1/2 and its downstream target MAPK in HCC tumors. In a phase II study 137 patients advanced primary liver cancer with have been treated with Sorafenib administered as a single agent. Investigators reported seven patients with partial responses, five minor responses and 59 with stable disease for at least 4 months. Median overall survival was 9.2 months and median time to progression 4.2 months. This study showed that Sorafenib was well tolerated and side-effects were manageable and reversible.~Rationale~5-Fluorouracil (5-FU) is a widely used agent for patients with unresectable advanced HCC, with objective responses rates around 10%. Compared to bolus administration, infusional 5-FU in metastatic colorectal cancers has demonstrated increased activity with less toxicity.~Sorafenib as single agent in HCC has demonstrated activity in terms of objective responses and promising duration of stable disease.~The combination of Sorafenib and 5-FU was evaluated in a phase I study where the drug is associated with different 5FU based schedules with good toxicity profile and objectives responses in particular in colorectal carcinoma.~Based on these data our purpose is to study infusional 5-FU with Sorafenib to evaluate the activity, efficacy, safety, pharmacokinetics and pharmacodynamics of this combination.~Study design and duration of treatment~5-FU 3000 mg/sqm 48 hours continuous infusion every 14 days Sorafenib 400 mg bid orally continuously 5-FU will be administered for a maximum of 12 cycles. Sorafenib will be administered from the start of treatment in combination with 5-FU until progression of disease.
The purpose of this study is to use Sorafenib + 5-FU to evaluate activity, efficacy, safety, pharmacodynamics (PD) and pharmacokinetics (PK) in patients with advanced hepatocellular carcinoma (HCC).