Temozolomide is an orally administered alkylating agent used largely in the therapy of malignant brain tumors including glioblastoma and astrocytoma. Temozolomide has been associated with a low rate of serum enzyme elevations during treatment and with rare instances of clinically apparent acute liver injury.
Temozolomide (tem" oh zol' oh mide) is an imidazotetrazine derivative similar to dacarbazine (DTIC), which acts as an alkylating agent disrupting DNA replication, causing modification and cross linking of DNA, thus inhibiting DNA, RNA and protein synthesis and causing programmed cell death (apoptosis) in rapidly dividing cells. Temozolomide rapidly crosses the blood-brain barrier and has been evaluated largely in the therapy of malignant brain tumors. Temozolomide has been shown to induce tumor regression and remissions in patients with malignant astrocytoma and glioblastoma multiforme. It may also have activity in melanoma. Temozolomide was approved for use in the United States in 1999 and is now commonly used in treating patients with malignant brain tumors. Temozolomide is available in capsules of 5, 20, 100, 140, 180 and 250 mg and as a solution for injection under the brand name of Temodar. The recommended dose regimen is calculated based on phase (initial cycles, maintenance), body weight, bone marrow toxicity and tolerance. Temozolomide is considered somewhat less toxic and better tolerated than many other alkylating agents, but does have the common side effects of fatigue, nausea and vomiting, gastrointestinal upset and bone marrow suppression.
Serum aminotransferase elevations occur during temozolomide therapy in up to 12% of patients, but these elevations are usually mild and self limited, not requiring dose adjustment or drug discontinuation. An instance of serum aminotransferase elevation with jaundice was reported in the registration trials of temozolomide and subsequent to its approval, there have been several single case reports and case series of temozolomide hepatotoxicity in the literature. The onset of injury was within 1 to 7 months of starting temozolomide and several patients had received multiple courses before the onset of liver injury. The pattern of serum enzyme elevations was usually mixed hepatocellular-cholestatic initially, but the disease tended to be cholestatic. In several instances, jaundice was deep and prolonged. Features of hypersensitivity (rash, fever, eosinophilia) and autoantibody formation were not present. Liver histology demonstrated bile duct injury and loss in several instances. Rechallenge was not done, but several patients subsequently received other antineoplastic agents, some of which were alkylating agents without recurrence of liver injury. In addition, temozolomide has been associated with cases of reactivation of chronic hepatitis B in patients who are hepatitis B surface antigen (HBsAg) positive at the start of chemotherapy. Clinical symptoms and signs of a flare of hepatitis B have arisen 6 to 12 weeks after starting temozolomide frequently in a cyclic pattern. Most patients have not received corticosteroids or other immunosuppressive agents that are more traditionally associated with reactivation. The episodes are marked by rises in HBV DNA levels and mild jaundice and have responded to antiviral therapy for hepatitis B which allows for restarting of temozolomide. Fatal cases of reactivation have not been reported, but in general hepatitis B reactivation with jaundice has a mortality rate in excess of 10%.
Mechanism of Injury
Temozolomide is hydrolyzed to the active intermediate at physiological pH and does not require hepatic metabolism or affect the cytochrome P450 (CYP) system to a major degree, perhaps accounting for its relative lack of hepatotoxicity.
Outcome and Management
The severity of liver injury caused by temozolomide ranges from minor transient elevations in serum enzymes to severe cholestatic hepatitis that can be prolonged. Temozolomide has not been reported to cause acute liver failure, chronic liver injury or vanishing bile duct syndrome. However, several instances of prolonged jaundice with paucity of bile ducts on liver biopsy have been reported. There is no evidence for cross sensitivity to hepatic injury between temozolomide and other alkylating agents. In instances of reactivation of hepatitis B due to temozolomide, therapy with an antiviral with potent activity against HBV is appropriate (such as entecavir or tenofovir). The antiviral therapy should continued as long as the chemotherapy is planned and for 3 to 6 months thereafter.
Case 1. Severe mixed hepatocellular-cholestatic hepatitis due to temozolomide.
[Clinical Center, National Institutes of Health]
A 67 year old woman developed jaundice 40 days after starting temozolomide therapy of a malignant glioblastoma. She had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. She had undergone resection of a left temporal lobe brain tumor 3 months earlier at which time she received local radiation and dexamethasone. Shortly thereafter she was started on temozolodine and levetiracetam along with dexamethasone (6 mg daily). She was also prescribed pantoprazole (40 mg daily) and ondansetron (4 mg orally as needed). Her past medical history was otherwise unremarkable, and she denied previous drug allergies. For many years, she had used a daily transdermal estradiol (0.0375 mg) patch and taken calcium, vitamin D and a multivitamin. When the jaundice was detected, she admitted to mild fatigue, but specifically denied fever, rash, itching, abdominal pain, anorexia or nausea. On examination, she was jaundiced but had no fever, rash, hepatic enlargement or tenderness. Laboratory tests showed a total bilirubin of 7.7 (6.6 mg/dL direct), ALT 896 U/L, AST 262 U/L, alkaline phosphatase 427 U/L and serum albumin 3.3 g/dL. Her serum ALT levels had been slightly abnormal at the time of her craniotomy, before temozolomide therapy (Table). Levetiracetam was stopped but temozolomide was continued. She developed deepening jaundice and serum enzyme elevations continued to rise, whereupon temozolomide was also stopped. Tests for hepatitis A, B and C (including HCV RNA and HBV DNA) were negative as were autoantibodies. Abdominal ultrasound showed no evidence of biliary obstruction. A liver biopsy showed marked cholestatic hepatitis with bile duct damage suggestive of drug induced liver injury. There was no reduction in the number of bile ducts. Serum bilirubin levels peaked at 46.8 mg/dL, ALT at 2783 U/L and alkaline phosphatase at 1219 U/L approximately 14 days after temozolomide was discontinued. Thereafter, serum bilirubin and enzymes slowly improved. Despite the height of the serum bilirubin and ALT, the prothrombin time remained normal and she had no signs of hepatic encephalopathy and continued to deny symptoms of abdominal pain, nausea or itching. Jaundice resolved after 3 months and liver tests were minimally abnormal 12 months later. Because of reappearance of seizures, levetiracetam was restarted without recurrence of jaundice or worsening of liver tests. Temozolomide was not restarted.
|Pattern:|| Hepatocellular-mixed (R=5.8, falling to 2.1 at time of peak bilirubin)|
||3+ (jaundice, hospitalization)
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Protime 12.9 seconds
| Normal Values
Cholestatic hepatitis arose after 6 weeks of therapy with temozolomide and levetiracetam. Both drugs were stopped, but recovery was delayed. A liver biopsy showed cholestasis and bile duct injury, but importantly did not show massive or submassive necrosis. The patient had few symptoms but biochemical recovery was delayed. Levetiracetam (which rarely causes liver injury) was restarted without worsening of the liver condition, making the diagnosis of temozolomide induced liver injury more likely. While the liver injury ultimately resolved, it did cause an interruption of therapy and significantly disturbed the quality of life in an already compromised patient.
Clinical cases of drug-induced liver injury that have been submitted to LiverTox ("Submit a Case Report") are available for review. Most of these reference cases are from
the Drug-Induced Liver Injury Network, but others are from users of LiverTox who have submitted data from an actual clinical case. All cases have been reviewed and cleared
of personal identifiers and a brief comment added by the LiverTox editors. Click on the following link to view the submitted case reports that have been made publically available.
REPRESENTATIVE TRADE NAMES
Temozolomide – Temodar®
Antineoplastic Agents, Alkylating
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 10 March 2015
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and other uncommon toxicities: a systematic review. Anticancer Drugs 2012; 23: 1099-106. PubMed Citation (Systematic review of rare complications of temozolomide therapy mentions 5 published cases of idiosyncratic liver injury, usually cholestatic, 3 with prolonged jaundice and one dying of liver failure).
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