Brain Tumors: Primary

Description

Alternative Names

Chemotherapy

Chemotherapy involves the use of toxic drugs to kill cancer cells. They may be given orally, intravenously, or administered 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. Of some promise, researchers have identified certain genetic arrangements in specific brain tumors that make them sensitive to the effects of chemotherapy. In general, however, chemotherapy is usually administered in brain cancer 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.

Drugs Used in Chemotherapy

Carmustine (also called BCNU). Carmustine is known as a nitrosourea. The response of gliomas to these agents 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 agent 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 Agents. The drug regimen called PCV (procarbazine, CCNU, and vincristine) is 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 to date 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 cause 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. Temozolomide (Temodal, Temodar), the first drug to be approved for brain tumors in 20 years, is an oral agent that improves quality of life and increases the time to progression for many patients with recurrent malignant gliomas. It has been specifically indicated for adult patients with anaplastic astrocytoma that does not respond to other treatments. It is showing promise for recurrent high-grade gliomas, glioblastoma multiforme, anaplastic oligodendrogliomas, and low-grade astrocytomas. It has only modest and short-lived effects on recurrent gliomas. It has few serious adverse effects and may even be beneficial for elderly patients with glioblastoma who have good performance status. It is being studied in combination with other agents and with radiation therapy.

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

A number of drugs and treatments are being tested or used for primary and recurring tumors.

• Tamoxifen, a breast-cancer drug, may also be beneficial in a minority of 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 agents 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 agent for a number of malignancies. It has not, to date, been useful for brain tumors, because like most of these agents, 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 that allows normal cells to recover between treatments. Side effects include nausea, vomiting, fatigue, infection, bleeding, and hair loss. In addition, the agents used to treat symptoms (anti-seizure drugs, antidepressants, and corticosteroids) may interfere with standard chemotherapeutic agents. 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 a number of 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 agents called 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 physician 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 two 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 agents are not ordinarily used for brain cancers because of high toxicity and poor penetration of brain tumors.
• An investigative technique called electrochemotherapy (ECT) applies high-voltage pulses to deliver drugs across cancerous tissues, including those of the brain.