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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Docetaxel

Last Update: October 13, 2020.

OVERVIEW

Introduction

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 tumors including breast and lung cancer. Docetaxel therapy is frequently associated with serum enzyme elevations which are usually transient and mild, but more importantly has been linked to rapid onset, severe hypersensitivity reactions that can be associated with acute hepatic necrosis, liver failure and death.

Background

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 mitotic 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 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 or at least ameliorate severe hypersensitivity reactions. The product label for docetaxel includes a black box warning of toxic deaths, hepatotoxicity, neutropenia, hypersensitivity reactions and fluid retention, with rates of death ranging from 0.6% to 2.8% of patients, the highest risk in those with preexisting liver test abnormalities.

Hepatotoxicity

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) occur 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. Nevertheless, individual case reports of severe acute hepatic necrosis attributed to docetaxel have been published, usually arising within a few days or weeks after a severe hypersensitivity reaction to the first or second infusion of docetaxel (Case 1). The typical case arises within days of the infusion of docetaxel and is associated with rapid, marked rises in serum aminotransferase levels with subsequent appearance of jaundice. With severe injury there is early hepatic and multiorgan failure with jaundice and progressive hepatic encephalopathy, coagulopathy, and ascites. Immunoallergic features (fever, rash, flushing) are common initially, but may be obscured by corticosteroid therapy. Liver biopsy generally reveals zone 3 (centrolobular) necrosis and variable degrees of inflammation and cholestasis. 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.

Likelihood score: C (probable cause of acute hepatic necrosis associated with a hypersensitivity reaction to an 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. Cases of clinically apparent liver injury have usually occurred in the setting of a severe hypersensitivity reaction, implying an immunoallergic component of injury. Docetaxel is metabolized in the liver by the cytochrome P450 system, predominantly CYP 3A4 and 3A5 and metabolites excreted in bile and feces.

Outcome and Management

Clinically significant liver injury from docetaxel is uncommon. Nevertheless, routine monitoring of liver tests is recommended before each docetaxel infusion, and administration held if serum bilirubin is elevated, ALT or AST are above 1.5 times ULN or alkaline phosphatase is above 2.5 times ULN. The serum enzyme elevations that occur on docetaxel therapy are usually self-limited and resolve with temporary discontinuation or modification of dosage. Liver injury associated with hypersensitivity reactions can be severe and docetaxel should be discontinued immediately. Re-exposure should be avoided. Because docetaxel is a structural analogue of paclitaxel, some degree of cross sensitivity to hypersensitivity reactions and hepatic injury should be expected. High doses of corticosteroids are often used to treat the hypersensitivity reaction, but it is not clear whether corticosteroids ameliorate the liver damage.

Drug Class: Antineoplastic Agents, Taxanes

Other Drugs in the Subclass, Taxanes: Cabazitaxel, Paclitaxel

CASE REPORT

Case 1. Acute hepatocellular injury after an infusion of docetaxel.(1)

A 31 year old woman with endometrial cancer developed abdominal pain and serum aminotransferase elevations the week following an initial infusion of docetaxel and carboplatin. She had no history of liver disease, drug allergies, alcohol abuse or risk factors for viral hepatitis. Her other medical conditions included seasonal allergies, reactive airway disease and dyspepsia. Her endometrial carcinoma was initially treated surgically with hysterectomy and bilateral oophorectomy, followed by pelvic irradiation and intravenous cisplatin which was poorly tolerated. She then started paclitaxel and carboplatin but had an immediate hypersensitivity reaction during the infusion manifested by chest tightness with arm and facial flushing despite premedication with antihistamines and dexamethasone. The following week her chemotherapy regimen was switched to docetaxel and carboplatin with intravenous dexamethasone followed by oral dexamethasone. She had mild symptoms of hypersensitivity during the infusions, but during the ensuing week she developed fatigue and abdominal pain. At the time of the next planned infusion, serum ALT was found to be 649 U/L, AST 211 U/L and alkaline phosphatase 161 U/L (R=11.7: hepatocellular). Serum bilirubin and albumin were normal and INR 0.9. (Table). Therapy was held. The following day, serum ALT levels had decreased. Serologic markers for acute hepatitis A, B and C were negative. Serum ANA was weakly positive (1:80) but SMA and AMA were negative. Imaging of the liver was normal without evidence of biliary or portal venous obstruction. Her symptoms resolved and over the next few weeks her serum aminotransferase levels fell to near normal levels. She was restarted on carboplatin without docetaxel and serum enzymes remained normal or minimally elevated.

Key Points

Medication:Docetaxel (124 mg iv once)
Pattern:Hepatocellular (R=11.7)
Severity:1+ symptomatic (no jaundice)
Latency:1 week
Recovery:5 weeks
Other medications:Carboplatin, dexamethasone

Laboratory Values

Time After
Starting		Time After
Stopping		ALT
(U/L)		Alk P
(U/L)		Bilirubin
(mg/dL)		Other
Pre (-2 mo)Pre25730.2
Pre (-1 mo)PrePaclitaxel and carboplatin: hypersensitivity reaction during infusion
Pre (-1 wk)Pre35660.3Docetaxel and carboplatin
7 days06491610.2Therapy held
8 days1 day5451480.3INR 0.9
14 days7 days295920.3
19 days12 days126780.2Carboplatin restarted
26 days19 days64870.3
35 days28 days94950.3
44 days37 days30840.2
Normal Values <40 <125 <1.2

Comment

This young woman with endometrial cancer and history of season allergies, had a mild hypersensitivity reaction during an infusion of paclitaxel and significant hepatic injury with a subsequent single infusion of docetaxel. The injury was symptomatic but without jaundice or evidence of hepatic synthetic dysfunction. The rapid rise and equally rapid fall in serum aminotransferase levels suggests direct hepatic injury and acute hepatic necrosis. In this case the injury was mild and self-limited injury, but docetaxel hypersensitivity reactions can be severe and associated with jaundice and hepatic failure. This patient appeared to have cross sensitivity with paclitaxel.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Docetaxel – Generic, Taxotere®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Docetaxel 148408-66-6 C43-H53-N-O14.3H2-O image 135106328 in the ncbi pubchem database

CITED REFERENCE

1.
Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

ANNOTATED BIBLIOGRAPHY

References updated: 13 October 2020

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