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Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update.

ABSTRACT: Sorafenib is the first and only p.o. administrated drug currently approved to treat advanced hepatocellular carcinoma (HCC). However, concerns have been raised about sorafenib therapy, including acquired drug resistance. This review provides an overview of sorafenib in the treatment of HCC on the basis of data obtained in the laboratory and in clinical studies. Three underlying mechanisms have been found to support sorafenib therapy. First, sorafenib blocks HCC cell proliferation by inhibiting BRaf and Raf1/c-Raf serine/threonine kinase phosphorylation in the mitogen-activated protein kinase pathway. Second, sorafenib induces apoptosis by reducing elF4E phosphorylation and downregulating Mcl-1 levels in tumor cells. Third, sorafenib prevents tumor-associated angiogenesis by inactivating vascular endothelial growth factor receptors (VEGFR-2 and -3) and the platelet-derived growth factor receptor-?. Clinical trials have demonstrated the effectiveness and relative safety of sorafenib, and thus the drug is used in unresectable HCC. However, many patients may develop acquired resistance to sorafenib, so their response to sorafenib is eventually lost. Sorafenib may induce autophagy, which leads to apoptosis. However, autophagy can also cause drug resistance. Many studies have combined sorafenib with other treatments in an effort to increase its effects, reduce the necessary dose or overcome resistance. It is urgent to study the mechanisms underlying how sorafenib interacts with cellular molecules and other drugs to increase its efficacy and reduce resistance in HCC patients.

SUBMITTER: Gauthier A

PROVIDER: S-EPMC3574194 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update.

Gauthier Angela A Ho Mitchell M

Hepatology research : the official journal of the Japan Society of Hepatology 20121112 2

Sorafenib is the first and only p.o. administrated drug currently approved to treat advanced hepatocellular carcinoma (HCC). However, concerns have been raised about sorafenib therapy, including acquired drug resistance. This review provides an overview of sorafenib in the treatment of HCC on the basis of data obtained in the laboratory and in clinical studies. Three underlying mechanisms have been found to support sorafenib therapy. First, sorafenib blocks HCC cell proliferation by inhibiting B ...[more]

PMID: 23145926

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Project description:BackgroundPhase III trials show sorafenib improves survival in advanced hepatocellular carcinoma (HCC). Because of narrow trial eligibility, results may not be generalizable to a broader HCC population. We sought to evaluate the effectiveness of initial sorafenib versus no treatment among Medicare beneficiaries with advanced HCC.Materials and methodsPatients with advanced HCC diagnosed from 2008 to 2011 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Eligible patients received initial sorafenib or no therapy and were covered by Medicare parts A, B, and D. Sorafenib use and outcomes were described in this population. Using a propensity score (PS)-matched sample, we compared the effectiveness of sorafenib versus no treatment by Cox proportional hazards and binomial regression, using a landmark requiring all patients to survive ?60 days after diagnosis.ResultsOf 1,532 patients, 27% received initial sorafenib. Median duration of sorafenib use was 60 days (interquartile range [IQR], 30-107 days), and median survival from first prescription was 3 months (IQR, 1-8 months). In the PS-matched cohort, median survival was 3 months from the 60-day landmark in sorafenib-treated (n = 223) and 2 months in untreated (n = 223) patients (adjusted hazard ratio, 0.95 [95% confidence interval (CI), 0.78-1.16]). Sorafenib was associated with a nonsignificant reduction in mortality at 3 months (44% versus 51%; adjusted risk ratio, 0.88 [95% CI, 0.72-1.07]), but no reduction thereafter.ConclusionSurvival after sorafenib initiation in newly diagnosed Medicare beneficiaries with HCC is exceptionally short, suggesting trial results are not generalizable to all HCC patients. The downsides of sorafenib use-high drug-related symptom burden and high drug cost-must be considered in light of this minimal benefit.Implications for practiceThe findings of a median survival of only 3 months in Medicare beneficiaries with HCC prescribed sorafenib as first-line therapy highlight the questionable value of sorafenib in this population. Patients should be cautioned that outside of the narrow confines of randomized trials, their life expectancy may be very short, and any benefit of sorafenib is likely to be quite small. Given that sorafenib causes considerable adverse effects and offers no symptom palliation, supportive care should be discussed as a reasonable alternative to sorafenib, particularly for patients who have a poor performance status or advanced cirrhosis.

Dataset Information

Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update.

Publications

Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update.

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