Chemotherapy

Chemotherapy involves the use of drugs to kill cancer cells. They may be given by mouth, injected into an IV, or injected directly into the central nervous system. Chemotherapy is not an effective initial treatment for low-grade brain tumors, mostly because standard drugs cannot pass through the blood-brain barrier. In general, chemotherapy for brain tumors is usually administered following surgery or radiation therapy. It is often given as salvage therapy for recurrent or slowly progressing cancers in patients who have previously been treated.

The role of chemotherapy with brain cancers is constantly under investigation, and there are some promising studies. For instance, researchers have identified certain genetic arrangements in specific brain tumors that make them sensitive to the effects of chemotherapy.

Drugs Used in Chemotherapy

Carmustine (also called BCNU). Carmustine is known as a nitrosourea. The response of gliomas to these drugs appears to depend upon certain genetic factors. About 70% of gliomas have an enzyme (MGMT) that protects against their actions. The other 30% are sensitive to it. At this time, it is commonly used for glioblastoma multiforme and, to date, no drug has proved to be superior for these tumors. Unfortunately, most patients quickly develop resistance to the drug, so there have been few improvements in survival rates with its use.

PCV and its Drugs. The drug regimen called PCV (procarbazine, CCNU, and vincristine) is an effective treatment for many common brain tumors. (CCNU is also referred to as lomustine and, like carmustine above, is a nitrosourea.) PCV has significant benefits for about two-thirds of patients with oligodendrogliomas. It has produced improvements in patients with anaplastic astrocytoma and glioblastoma multiforme, but does not appear to be any more effective than carmustine for these tumors. This regimen has significant toxicity, including suppression of red blood cell production and causing nausea, vomiting, and weight loss. Patients must adhere to certain dietary restrictions. Each of these drugs is also used separately and in other combinations.

Temozolomide (Temodar). Temozolomide, the first new drug approved for brain tumors in several decades, may improve quality of life and increase the time to progression for many patients with malignant gliomas. Temozolomide is taken by mouth and has relatively few side effects. In 1999, it was approved for adult patients with anaplastic astrocytoma that did not respond to other treatments. In 2005, it was approved for use during and after radiation therapy for patients newly diagnosed with glioblastoma multiforme. It is showing promise for recurrent high-grade gliomas, anaplastic oligodendrogliomas, and low-grade astrocytomas. It has only modest and short-lived effects on recurrent gliomas. Clinical trial results presented at the 2004 American Society of Clinical Oncology (ASCO) meeting confirm that temozolomide administered during and after radiation is a first-line treatment for glioblastoma multiforme. A 2005 study, published in the New England Journal of Medicine, reported that adults with newly diagnosed glioblastoma who received temozolomide during and after radiation therapy had a higher rate of 2-year survival than patients who received radiation alone.

Other Chemotherapy Drugs Used or Investigated for Recurring or High-Grade Cancers

Several drugs and treatments are being tested or used for primary and recurring tumors.

  • Tamoxifen, a breast-cancer drug, may benefit some patients with glioma when administered continuously at high doses. More research is needed to determine which patients may benefit.
  • High-dose thiotepa along with bone marrow or stem cell transplantation is being tested for newly diagnosed aggressive oligodendroglioma as an alternative to radiotherapy. Although some patients have prolonged disease-free survival time, thiotepa has very toxic side effects, including encephalopathy (brain damage), liver damage, severe weight loss, and a drop in blood platelet count. High-dose thiotepa along with bone marrow or stem cell transplantation is being investigated for recurrent aggressive oligodendroglioma.
  • Paclitaxel (Taxol), a drug used for breast cancer, is also being investigated for gliomas. It is showing promise for patients with recurrent gliomas. In one study, paclitaxel with stereotactic radiosurgery improved results for patients with glioblastoma multiforme.
  • Topo I inhibitors block topoisomerase I, an enzyme involved in cell replication. Clinical studies have shown that the Topo I inhibitors topotecan and irinotecan injure brain tumor cells. Combinations of Topo I inhibitors with standard chemotherapy drugs, such as BCNU, is proving to be effective for some patients. Some studies suggest it may help some children with gliomas. They may also be important drugs in radiochemotherapy. Less positive studies on irinotecan report that combinations with anti-seizure medications reduce its effectiveness.
  • 5-fluorouracil (5-FU) is a standard chemotherapy drug for numerous malignancies. It has not, to date, been useful for brain tumors because, like most of these drugs, it cannot pass the blood brain barrier. A new form (Ethypharm), however, employs a microsphere containing the drug that is implanted in the tissue. Early studies are promising. Investigators are also looking at genetic therapies to deliver the drug directly to the tumor.
  • Carboplatin with or without vincristine is being studied for low-grade progressive gliomas, which are difficult to treat with surgery or radiation.

Side Effects of Chemotherapy

Because chemotherapeutic drugs may also affect normal cells, side effects are common. To help offset these effects, chemotherapy is given intermittently over a scheduled period to allow normal cells to recover between treatments. Side effects include nausea, vomiting, fatigue, infection, bleeding, and hair loss. In addition, the drugs used to treat symptoms (anti-seizure drugs, antidepressants, and corticosteroids) may interfere with standard chemotherapeutic drugs. Specific drugs may have different complications. For example, vincristine can cause nerve injury, and cisplatin may result in hearing loss. Procarbazine requires dietary restrictions. Side effects are almost always temporary and may be managed with other medications.

Approaches to Enhance Drug Access to the Tumor

To make chemotherapy more effective, scientists are working on several approaches to overcome an obstacle unique to brain cancer: the blood-brain barrier, a functional barrier that protects the brain and prevents certain molecules from passing through.

  • Certain drugs, such as mannitol or receptor-mediated permeabilizers, may open the barrier without worsening neurological deficits.
  • Interstitial chemotherapy uses disc-shaped wafers (known as Gliadel wafers) soaked with carmustine, the standard chemotherapeutic drug for brain cancer. The doctor places the wafer directly into the surgical cavity after a tumor is removed. Studies suggest that this approach can improve survival in some patients. The procedure does not appear to increase the risks of side effects over those of the surgery itself.
  • Intrathecal infusion delivers chemotherapeutic drugs directly into the spinal fluid.
  • Intraarterial delivery administers high-dose chemotherapy into arteries in the brain using tiny catheters. In a 2000 study, this approach was used within 2 weeks of radiotherapy in patients with high-grade astrocytomas, and the survival rates for glioblastoma multiforme tripled (20 months) compared to those who had chemotherapy and radiation at the same time.
  • Enclosing highly potent anti-cancer drugs, such as anthracyclines, in protective microspheres (called liposomes) may allow the drugs time to enter tumors without unduly increasing the risk for severe toxicity. Such drugs are not ordinarily used for brain cancers because of high toxicity and poor penetration of brain tumors.
  • An investigational technique called electrochemotherapy (ECT) applies high-voltage pulses to deliver drugs across cancerous tissues, including those of the brain.
Review Date: 10/19/2006
Reviewed By: Harvey Simon, M.D., Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.