Temozolomide, or TMZ, is an oral chemotherapy medication used in the treatment of specific brain cancers. Its ability to cross the blood-brain barrier—a protective lining that stops many drugs from reaching the brain—makes it particularly effective for managing certain aggressive tumors. This medication is often a component of a comprehensive treatment plan that may also include surgery and radiation.
Mechanism of Action
Temozolomide is an alkylating agent, a class of chemotherapy that damages the DNA of cancer cells to stop their growth. After being taken orally, TMZ is absorbed into the bloodstream and converts into its active compound, MTIC. This molecule travels to the tumor site and attaches methyl groups to the DNA of cancer cells, a process called methylation that most often targets guanine.
The addition of these methyl groups causes structural damage to the DNA, creating mismatches in the genetic code. When the cancer cell attempts to replicate its damaged DNA, it is unable to do so correctly. This disruption triggers internal processes that lead to programmed cell death, also known as apoptosis. The effectiveness of this process is linked to the cancer cells’ repair capabilities.
A DNA repair enzyme, O-6-methylguanine-DNA methyltransferase (MGMT), can counteract TMZ’s effects. The MGMT enzyme removes the methyl groups that TMZ adds to DNA, repairing the damage before it can cause cell death. In some tumors, the gene producing the MGMT enzyme is silenced through promoter methylation. When this gene is silenced, tumor cells cannot produce the repair enzyme, making them more vulnerable to temozolomide.
Cancers Treated with TMZ
Temozolomide is used for high-grade brain tumors in adults, most prominently for newly diagnosed glioblastoma multiforme. This is the most common and aggressive type of primary brain tumor. For glioblastoma, TMZ is administered in two phases: first with radiation therapy, and then as a maintenance monotherapy treatment.
The medication is also an approved treatment for anaplastic astrocytoma, another malignant glioma. It is used for patients whose tumor has progressed or returned after a prior chemotherapy regimen. In some cases, it may be used for newly diagnosed anaplastic astrocytoma following radiation.
Administration and Dosing Schedule
Temozolomide is an oral medication in capsule form. The capsules must be swallowed whole with a glass of water and should not be opened, crushed, or chewed. Because the drug can be present in bodily fluids for several days, careful handling is important to prevent exposure to caregivers.
TMZ dosing is calculated based on a person’s body surface area and the treatment protocol. A common maintenance regimen is the 5/28 cycle, where the drug is taken once daily for five consecutive days, followed by a 23-day rest period. For newly diagnosed glioblastoma, an initial phase involves taking a lower daily dose of TMZ for 42 to 49 days alongside radiation therapy.
Patients should take the capsule at the same time each day, often on an empty stomach. If a patient vomits after taking a dose, a second dose should not be taken that day. Patients should communicate with their medical team about any missed doses for proper guidance.
Common Side Effects and Management
The most frequent side effects of temozolomide include:
- Nausea
- Vomiting
- Fatigue
- Loss of appetite
Nausea and vomiting can be managed with antiemetic medications, and taking TMZ in the evening may also help. Fatigue is also common, and patients are advised to schedule periods of rest.
A more significant side effect is myelosuppression, a decrease in bone marrow’s production of blood cells. This can lead to low white blood cells (neutropenia), increasing infection risk; low platelets (thrombocytopenia), causing bruising or bleeding; and low red blood cells (anemia), resulting in fatigue and shortness of breath. Regular blood tests are required to monitor these counts, especially on day 22 of each 28-day cycle, and dose adjustments may be necessary if they fall to unsafe levels.
When temozolomide is given with radiation therapy, there is an increased risk of a lung infection called Pneumocystis pneumonia (PCP). This is due to a drop in a type of white blood cell called a lymphocyte. To prevent this, patients are prescribed a prophylactic antibiotic for the duration of the combined treatment phase.
Monitoring Treatment Response
Periodic magnetic resonance imaging (MRI) scans of the brain are the primary method for monitoring a tumor’s response to temozolomide. These scans allow the medical team to see if the tumor has shrunk, remained stable, or grown. Follow-up imaging is scheduled at regular intervals to track changes, and these results are combined with clinical and neurological exams to assess treatment efficacy.
Pseudoprogression is a phenomenon that can complicate MRI interpretation. It is a treatment-related effect where the tumor appears to have grown on an MRI scan taken shortly after chemoradiation. This apparent growth is caused by inflammation from the treatment, not an increase in cancer cells. This effect occurs within the first few months after treatment and can resolve on its own.
Distinguishing between true tumor progression and pseudoprogression is a challenge. Advanced imaging techniques, such as perfusion MRI or amino acid PET scans, can provide additional information to help clarify the situation. Often, the most reliable approach is a follow-up MRI several weeks later to see if the lesion has stabilized or continued to grow.