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The Waiting Room: Antiepileptic Drugs for Brain Tumors?

Collier, Andrea King

doi: 10.1097/01.NNN.0000414209.14213.31


A study in the September 20, 2011, edition of Neurology, the official medical journal of the American Academy of Neurology (AAN), suggests that valproic acid—a commonly prescribed antiepileptic drug (AED)—may help people living with the brain tumor known as glioblastoma live longer.

The study was conducted by Michael Weller, M.D., a professor in the department of neurology at University Hospital in Zurich, Switzerland, and colleagues. They found that valproic acid had a greater impact on survival than other AEDs used in tandem with chemotherapy.

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Glioblastoma (or glioblastoma multiforme) is one of several kinds of glioma, which are tumors that arise from glial cells in the brain or spinal cord. Glial cells form the “gluey” brain tissue that provides structure and function for neurons, which carry nerve signals.

Nearly 17,000 primary brain tumors (tumors that start in the brain) are diagnosed in the United States each year, and more than half are gliomas.

Glioblastomas are faster growing and have a shorter overall survival rate than other gliomas, such as oligodendrogliomas.

The average survival rate for someone with glioblastoma is approximately 15 months. Another 10 percent of patients have a five-year survival rate. Half of the patients who are diagnosed but not treated only survive three months.

According to the American Cancer Society, there has been little improvement in survival rates for glioblastomas over the past two decades. Glioblastoma is the cancer that claimed the life of the late Senator Edward Kennedy.

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Seizures have long been a hallmark symptom of people with glioblastoma.

“About 25 percent of glioblastoma patients will have had seizures at the time of their first office visit. Another 20 percent or so will develop seizures later on during the course of their illness,” says David Schiff, M.D., the Harrison Distinguished Professor of Neurology, Neurological Surgery and Medicine a the University of Virginia in Charlottesville, VA, and co-director of the UVA Neuro-Oncology Center.

The use of AEDs to manage the epileptic symptoms of glioblastoma led to research on their impact on survival rates. In 2009, a retrospective analysis of three trials performed by the North Central Cancer Treatment Group suggested a possible association between certain kinds of AEDs and longer survival in people with glioblastoma.

In a retrospective analysis, researchers look back at data from an earlier trial. Many important studies, such as several that identified risk factors for breast cancer, have been retrospective. However, numerous opportunities for bias exist in a retrospective study. For example, researchers may subconsciously select only certain patients from the earlier study to include in the analysis.

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In the study published in Neurology, the investigators found that valproic acid had a greater impact on survival than other AEDs used in tandem with chemotherapy. Patients who received valproic acid also fared better than patients who were not on any AED.

The investigators conducted a retrospective analysis of temozolomide (chemotherapy) and radiation therapy for glioblastoma to see if overall survival or progression-free survival (PFS)—which is the time during and after treatment that the patient's cancer does not worsen—were influenced by AED use.

The study included 573 patients with glioblastoma who were treated with radiation therapy alone, or radiation therapy with temozolomide, between 2000 and 2002. A total of 68 percent received an AED. (The study authors inferred that patients were receiving an AED to treat or prevent seizures associated with their glioblastoma.) According to the study, patients who were given valproic acid survived three months longer than those who were given other AEDs or no treatment.

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The study suggests that valproic acid increased survival not by controlling seizures—which by themselves are usually not life threatening, says Dr. Schiff—but by improving the body's response to radiation therapy and chemotherapy.

“Despite the limitations of this retrospective analysis, these results suggest that the choice of [AED] in patients with brain tumors should be carefully considered because it may affect survival,” concluded Dr. Weller and colleagues. They are now looking to conduct further studies on other AEDs to see if any offer longer survival with fewer side effects.

However, “Patients and physicians need to be cautious in interpreting the importance of this study,” says Gary Gronseth, MD., professor and vice chairman of the neurology department at the University of Kansas in Kansas City and a Fellow of the AAN. “There is a reasonable chance that a rigorous trial will show that valproic acid has no effect on survival. Furthermore, people who have glioblastoma without seizures should not be given AEDs, including valproic acid. Rigorous studies show that prescribing AEDs does not prevent the development of seizures and that the AEDs cause side effects.”

The side effects of AEDs can include dizziness, weight gain, and negative interactions with other medications, such as those for HIV. Valproic acid can also produce low blood counts in people with glioblastoma; some patients have had to delay 30 percent of their chemotherapy cycles as a result, the study reports.

The short-term improvement in survival due to AEDs may come at too high a cost in terms of quality of life, some experts say.

“I was disappointed because the study did not address the impact these drugs have on quality of life,” says Lynne P. Taylor, M.D., Fellow of the AAN and neuro-oncologist and Director of Palliative Care at Tufts Medical Center in Boston, MA.

“If you are talking about a better quality of life for the time you have versus using a therapy that may prolong life for a month but decrease the quality of life, most patients choose quality of life,” Dr. Taylor says.

©2012 American Academy of Neurology