Temozolomide

Temozolomide is a prescription drug used for the treatment of adults with newly diagnosed glioblastoma multiforme. It is also indicated for the treatment of adults with refractory anaplastic astrocytoma. Both diseases are forms of a malignant brain cancer. The Food and Drug Administration approved temozolomide on August 11, 1999. This was only the third drug to be approved in the United States since the 1960s for the treatment of brain tumors.

Other Names

Schering–Plough markets temozolomide in the U.S. under the brand names Temodal and Temodar. Temozolomide is also called Methazolastone.

Uses

Glioblastoma multiforme in a brain. Source: Wikimedia Commons

For the treatment of newly diagnosed glioblastoma multiforme, temozolomide is used concurrently with radiation therapy and then by itself as maintenance treatment. Temozolomide is used in people with anaplastic astrocytoma for whom treatment with the standard chemotherapy of nitrosurea (Temodar) and procarbazine (Matulane) was ineffective (i.e., refractory disease).

How Temozolomide is Taken

Temozolomide is available in 5 mg, 20 mg, 100 mg, and 250 mg oral capsules. It is taken once daily with a full glass of water according to one of two dosing regimens:

• 42 days (up to 49 days) of temozolomide taken daily with radiotherapy;
• 5 consecutive days of temozolomide taken daily, then NO temozolomide for the next 23 days. This "5 days on" and "23 days off" cycle is repeated several times.

More temozolomide is absorbed into the body if the drug is taken at least one hour before or after a meal.

How Temozolomide Works

Temozolomide itself is not active. Rather, it is converted into two active forms in the body. These forms are alkylating agents. Alkylating agents are drugs that add a chemical group (alkyl) to DNA. This alkylation damages the integrity of a cell's DNA, which leads to cell death. Alkylating agents are particularly lethal to rapidly dividing cells, such as those that have turned cancerous.

How the Body Affects Temozolomide

Temozolomide is rapidly and completely absorbed by the body. Peak circulating levels of the drug occur in one hour. Food reduces the rate and degree of absorption. Temozolomide is spontaneously converted into MTIC, which is one active form of the drug. The half-life of MTIC, the time needed for the concentration in the blood to be reduced by half, is approximately two hours. Almost 40% of a dose is excreted in the urine within a week. About 8% is excreted in feces.

Side Effects

The most common side effects of temozolomide are the following:

• low blood platelet count
• nausea
• vomiting
• anorexia
• constipation
• hair loss
• headache
• fatigue
• convulsions

Risks and Precautions

A decrease in the production of blood cells (myelosuppression) has been reported in some patients. Women and the elderly have an increased risk of developing this disorder. For treatment of anaplastic astrocytoma, temozolomide is more likely to cause abnormally low white blood cell counts in patients over the age of 70 years in the first cycle of therapy than in patients younger than 70 years of age.

• Patients with glioblastoma multiforme need to be treated to prevent infection by Pneumocystis carinii pneumonia (PCP) when undergoing therapy with radiation and temozolomide.

• Temozolomide may complicate pregnancy and harm the fetus.

• Caution is used in patients with severe liver or kidney impairment.

• Temozolomide is not prescribed to patients who have a history of hypersensitivity or allergy to dacarbazine because the drugs are metabolized into the same active compound.

Drug Interactions

Valproic acid (Depakene) reduces the elimination of temozolomide from the body to a minor extent. This is not expected to have any influence on the safety or effectiveness of temozolomide. No significant drug interactions with temozolomide have been reported.

Research

A review of the results of numerous clinical trials involving temozolomide is available at the Musella Foundation web site.^[1] The effectiveness of temozolomide depends on the activity of a specific gene. Data suggest that if the MGMT gene is silenced (by methylating DNA) outcome of treatment with temozolomide improves.^[2] This gene encodes a protein that helps repair DNA. When this gene is silenced, DNA damage caused by temozolomide accumulates and is more likely to kill the cancer cells.

Newly diagnosed glioblastoma multiforme

In one study, over 500 patients received either temozolomide + radiation or radiation alone.^[1] The addition of temozolomide to radiation in the treatment of newly diagnosed glioblastoma multiforme showed a significant improvement in overall survival compared to radiation alone. The average survival was increased by 2.5 months in the temozolomide + radiation over just radiation alone.

Refractory anaplastic astrocytoma

A study was conducted in 162 patients who had anaplastic astrocytoma.^[1] Fifty-four patients had prior chemotherapy with a nitrosourea/procarbazine combination with poor result. Their cancer was considered refractory to chemotherapy (refractory anaplastic astrocytoma population). In this population, the overall tumor response rate was 22% and the complete response rate was 9%. Overall survival at 6 months was 74% and 12-month overall survival was 65%. Average overall survival was 15.9 months.

References

1. ↑ ^{1.0 1.1 1.2} Parker AJ. Musella Foundation Web site. Temozolomide Review
2. ↑ Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. Abstract | Full Text | PDF

External Links

FDA: Patient Information Sheet

Rx List