Sorafenib is an oral multi-kinase inhibitor that is used in the therapy of advanced renal cell, liver and thyroid cancer. Sorafenib has been associated with a low rate of transient elevations in serum aminotransferase levels during therapy that are generally mild and asymptomatic. Sorafenib has also been linked to rare instances of clinically apparent liver injury which can be severe and even fatal.
Sorafenib (soe raf’ e nib) is an orally available, small molecule, multi-specific tyrosine kinase inhibitor with activity against vascular endothelial growth factors (VEGF) receptors -1, -2 and -3 as well as against the receptor for platelet derived growth factor (PDGF) and several Raf kinases. Inhibition of these kinases decreases angiogenesis, which plays an important role in the growth and spread of several forms of solid tumors. Sorafenib received approval for use in the United States in 2005 for therapy of advanced renal cell carcinoma, and indications were subsequently expanded to hepatocellular carcinoma in 2007 and refractory thyroid cancer in 2014. Sorafenib is available in tablets of 200 mg under the brand name Nexavar. The typical dose is 400 mg twice daily, continued until there is tumor progression or unacceptable toxicity. Side effects are common and can include fatigue, diarrhea, anorexia, weight loss, nausea, abdominal pain, hand-foot syndrome, rash, hair loss, pruritus, bleeding and sensory neuropathy. Uncommon, but potentially severe side effects include bone marrow suppression, bleeding, venous thrombosis, gastrointestinal perforation, QTc prolongation and Stevens Johnson syndrome.
In large clinical trials of sorafenib, elevations in serum aminotransferase levels were common, occurring in up to half of patients, but values greater than 5 times the upper limit of normal (ULN) occurred in only 1% to 3% of treated subjects. In addition, there have been several single case reports of clinically apparent liver injury arising during sorafenib therapy which was often severe and occasionally fatal. The onset of acute liver injury ranged from a few days to 8 weeks of starting sorafenib, and the pattern of injury was typically hepatocellular with marked elevations in serum aminotransferase levels. Immunoallergic and autoimmune features were absent. Recovery was usually rapid once sorafenib was stopped, but some cases were associated with progressive liver injury and hepatic failure. Most of the reports of severe liver injury occurred in patients being treated for hepatocellular carcinoma who also had cirrhosis or in patients receiving other potentially hepatotoxic drugs31.
Likelihood score: B (likely cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of injury accounting for serum enzyme elevations during sorafenib therapy is not known. Sorafenib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic intermediate. Sorafenib is susceptible to drug-drug interactions with agents that inhibit or induce hepatic CYP 3A4 activity. Sorafenib, like many tyrosine kinase inhibitors can inhibit UDP glucuronosyltransferase activity which can result in mild indirect hyperbilirubinemia and may predispose to acetaminophen toxicity.
Outcome and Management
Monitoring of routine liver tests is recommended during sorafenib therapy. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to dose reduction or temporary cessation. Sorafenib has been implicated in cases of acute liver failure, but not in instances of chronic hepatitis or vanishing bile duct syndrome. There does not appear to be cross reactivity in risk for hepatic injury between sorafenib and other kinase inhibitors including the angiogenesis inhibitors such axitinib and sunitinib.
REPRESENTATIVE TRADE NAMES
Sorafenib – Nexavar®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 22 June 2018
Abbreviations: HCC, hepatocellular carcinoma; NSCLC, non-small cell lung cancer;
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Lancet Gastroenterol Hepatol 2018; 3: 424-432. PubMed Citation. (Among 206 patients with advanced HCC treated with sorafenib alone vs sorafenib with hepatic arterial infusions with cisplatin and fluorouracil, mean overall survival was similar in the two groups [11.8 vs 11.5 months] and adverse event rates were similar, ALT elevations arising in 67% vs 68% and to above 5 times ULN in 30% vs 29%).
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