Docetaxel is an antineoplastic agent that has a unique mechanism of action as an inhibitor of cellular mitosis and that currently plays a central role in the therapy of many solid tumor including breast and lung cancer. Therapy with docetaxel has been associated with a low rate of serum enzyme elevations and rarely to instances of acute hepatic necrosis generally due to severe hypersensitivity reactions or sepsis. Docetaxel has not been clearly linked to cases of idiopathic, clinically apparent acute liver injury.
Docetaxel (doe" se tax' el) is a complex diterpenoid molecule that contains a central 8-member taxane ring. Docetaxel is a semisynthetic analogue of paclitaxel and was initially isolated from the needles of the European Yew tree (Taxus baccata). It is a potent antineoplastic agent and its mechanism of action appears to be mediated by its binding to microtubulin, which is important in the mitototic phase of cell division. The binding of docetaxel prevents the disassembly of the cytoskeletal microtubules, preventing cell division and leading to cell death. Docetaxel was approved for use in the United States in 1996 and it remains an important agent in the therapy of several neoplasms including breast, gastric, prostate, head and neck, and non-small cell lung cancer. Docetaxel is available in solution for injection generically and under the brand names such as Taxotere and Docefrez. Docetaxel is administered intravenously, typically as one hour infusions every three weeks in cycles in combination with other antineoplastic agents. The dose varies by indication and body weight. Preexisting liver disease is considered a relative contraindication of its use. Side effects are common and include diarrhea, nausea, vomiting, mucositis, fatigue, myalgias, skin rash, alopecia, phlebitis, bone marrow suppression, fluid retention, cardiomyopathy, peripheral neuropathy and hypersensitivity reactions. Premedication with oral corticosteroids is recommended to prevent severe hypersensitivity reactions.
Docetaxel has been associated with serum aminotransferase elevations in up to half of patients, but values greater than 5 times the upper limit of normal (ULN) occurr in less than 2%. Similar rates of alkaline phosphatase elevations and occasional mild bilirubin elevations also occur. The abnormalities are usually asymptomatic, mild and self-limited, rarely requiring dose modification or discontinuation. Despite the frequency of serum enzyme elevations during therapy, clinically apparent liver injury from docetaxel is rare. Individual case reports of severe acute hepatic necrosis attributed to docetaxel have been published, but most likely represent ischemic liver injury due to a severe hypersensitivity reaction to the initial infusion of docetaxel, the typical case arising within 1 to 2 days of initiating therapy and associated with rapid, marked rises in serum aminotransferase levels and early hepatic and multiorgan failure with only mild jaundice. Because docetaxel is often given with other antineoplastic agents, liver injury arising during therapy cannot always be attributed reliably to docetaxel as opposed to another specific agent. Furthermore, docetaxel in combination with other antineoplastic agents may be associated with reactivation of hepatitis B, increased risk of opportunistic viral infections, sinusoidal obstruction syndrome and sepsis, any of which can cause liver test abnormalities or clinically apparent liver injury. Convincing cases of idiosyncratic acute liver injury have not been reported with docetaxel use.
Likelihood score: C (probable cause of acute hepatic necrosis associated with hypersensitivity reaction to initial infusion).
Mechanism of Injury
Docetaxel likely has a direct toxic effect on hepatocytes, accounting for the frequency of serum enzyme elevations during therapy, particularly with higher doses. Docetaxel is metabolized in the liver by the cytochrome P450 system, predominantly CYP 3A4 and 3A5.
Outcome and Management
The serum aminotransferase elevations that occur on docetaxel therapy are usually self-limited and do not require dose modification or discontinuation of therapy. There have been no cases of idiosyncratic, clinically apparent or severe acute liver injury linked to docetaxel therapy in the published literature.
REPRESENTATIVE TRADE NAMES
– Generic, Taxotere®
Product labeling at DailyMed, National Library of Medicine, NIH
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