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 breast and lung cancer. Therapy with docetaxel has been associated with a low rate of serum enzyme elevations, but has not been clearly linked to cases of 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 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 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 has not been convincingly linked to docetaxel therapy. Because docetaxel is often given with other antineoplastic agents, liver injury arising during therapy cannot always be attributed reliably to docetaxel or 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.
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 clinically apparent or severe acute liver injury linked to docetaxel therapy in the published literature.
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