Patients undergoing chemotherapy and radiotherapy for malignant glioblastoma appeared to have better overall survival if they also received the anti-seizure medication valproic acid, a retrospective analysis found.
The adjusted hazard ratio for overall survival benefit with temozolomide (Temodar) plus radiation therapy was 0.39 (95% CI 0.24 to 0.63) in patients taking valproic acid, according to Michael Weller, MD, of University Hospital Zurich in Switzerland, and colleagues.
In comparison, similarly treated patients who received an enzyme-inducing anti-epileptic drug, such as carbamazepine, had an adjusted HR for overall survival of 0.69 (95% CI 0.53 to 0.90).
Those receiving valproic acid also fared better than patients not on any anti-epileptic agent, who had an HR of 0.67 (95% CI 0.49 to 0.93), the investigators reported in the Sept. 20 issue of Neurology.
Up to half of patients with glioblastoma have seizures, and they are typically given one or more anti-epileptic medications, despite the potential for side effects or drug interactions.
Some studies have suggested that anti-epileptic drugs can act synergistically with chemotherapy and radiotherapy, so Weller and colleagues analyzed data from a pivotal trial of temozolomide and radiation for glioblastoma to see if overall survival or progression-free survival (PFS) were influenced by anti-epileptic drug use.
The study included 573 patients with glioblastoma who were treated with radiotherapy alone or with temozolomide between 2000 and 2002.
A total of 68% received an anti-epileptic drug and of those, 28% were prescribed a non-enzyme inducing agent, which most often was valproic acid. The remaining patients received carbamazepine, oxcarbazepine, phenytoin, or phenobarbital.
Proportional hazards models were used to compare treatment efficacy after adjustment for patient age, degree of tumor resection, use of corticosteroids, and scores on Mini-Mental State Examination.
OS increased by about three months among patients receiving valproic acid, but no benefit was seen for PFS.
Tests for interaction found that the comparison of valproic acid versus an enzyme-inducing agent was significant (P=0.042), while the comparison of valproic acid versus no anti-epileptic drug was borderline (P=0.09). An enzyme-inducing agent versus no antiepileptic drug was nonsignificant (P=0.76).
Although survival improved among patients taking valproic acid, these patients experienced more hematologic toxicities:
- Thrombocytopenia, P=0.002
- Neutropenia, P=0.004
- Leukopenia, P=.03
Patients given valproic acid also had to delay 30% of their chemotherapy cycles, compared with 16% of cycles in patients on other anti-epileptic drugs.
The researchers suggested that the improved response to radiotherapy and chemotherapy in patients treated with valproic acid may result from the drug's ability to inhibit histone deacetylase, leading to radiochemotherapy sensitization.
They noted that trials are under way evaluating more potent inhibitors of this enzyme such as vorinostat (Zolinza) in combination with temozolomide to see if efficacy could improve further and tolerability improve.
They pointed out various limitations to the study, cautioning that their results "were generated from an unplanned and insufficiently powered retrospective analysis."
In addition, there may have been differences in medical practice, such as imaging, across the study centers.
But the study also had strengths, such as the use of current standard of care chemotherapy and radiotherapy.
"Despite the limitations of this retrospective analysis, these results suggest that the choice of [anti-epileptic drug] in patients with brain tumors should be carefully considered because it may affect survival," concluded Weller and colleagues.
The investigators reported numerous disclosures, including serving on advisory boards and receiving research support from Roche, Merck Serono, Bristol-Myers Squibb, Schering-Plough, OncoMethylome Sciences, and Boehringer Ingelheim.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner