Valproic Acid May Prolong Survival in Glioblastoma

Michael Weller, MD

New data suggest that patients with glioblastoma who are treated with valproic acid, an antiepileptic drug (AED), are likely to outlive patients who receive another type of AED or no AED at all. The study found that patients assigned to valproic acid added to conventional temozolomide radiochemotherapy survived 3 months longer than patients receiving other AEDs or no treatment.

Michael Weller, MD, with the University Hospital Zurich in Switzerland, and colleagues analyzed the use of AEDs in 573 newly diagnosed patients with glioblastoma who were enrolled in a study comparing the use of radiation therapy with and without temozolomide. Upon enrollment, 398 patients were receiving an AED while 173 patients were not. Of patients on AED treatment, 97 of them were taking valproic acid as their only AED therapy. The study was conducted by investigators from the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group.

Weller and associates observed that the lifetime risk of epileptic seizures in glioblastoma patients ranges from 30% to 50%. The choice of AED in these patients needs to take into account such factors as the resistance of the seizure disorder, drug-drug interaction, and adverse side effects. After surgery, conventional treatment in newly diagnosed patients involves radiation therapy combined with temozolomide.

The investigators noted that the older AEDs, which include phenytoin, phenobarbital, and carbamazepine, induce several coenzymes of the cytochrome P450 system and may therefore increase the metabolism of corticosteroids and several commonly used chemotherapy agents. By contrast, valproic acid has an enzyme-inhibiting effect, which seems to have less clinical significance; however, increased myelosuppression may be a concern in patients receiving concurrent nitrosoureas or cisplatin-based chemotherapy. A possible risk of perioperative bleeding with valproic acid has also been cited, although the risk seems to be unsubstantiated.

Results showed that the overall survival was similar in patients who were receiving an AED at baseline and patients who were not receiving any AED.

The subgroup of patients receiving solo valproic acid seemed to have a larger survival benefit from temozolomide radiotherapy (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.24-0.63) than patients receiving an enzyme-inducing antiepileptic drug (EIAED) only (HR, 0.69; 95% CI, 0.53-0.90) or patients not receiving any AED (HR, 0.67; 95% CI, 0.49-0.93).

The lifetime risk of epileptic seizures in glioblastoma patients ranges from 30% to 50%. The choice of antiepileptic drug in these patients needs to take into account such factors as the resistance of the seizure disorder, drug-drug interaction, and adverse side effects.

Patients who received valproic acid only had more grade 3/4 thrombopenia and leukopenia than patients not taking an AED or patients taking an EIAED only. In addition, patients treated with valproic acid had only 30% of their adjuvant cycles postponed versus 16% in patients treated with EIAED only and 17% in patients who received no AED (P = .0001).

Weller and associates said that their findings may bolster the notion that valproic acid’s histone deacetylase (HDAC)-inhibiting properties may contribute to the improved benefit occurring with radiochemotherapy.

They pointed out that their analysis is distinct from earlier reports in that it is “contemporary and evaluates patients treated with the current standard of care with concomitant chemoradiotherapy,” in contrast to an earlier analysis that looked at a pooled database of clinical studies with negative results. Their study is also notable in that it analyzed the hazard ratios for treatment benefit within a randomized trial rather than prognostic values, which offsets possible “inhomogeneities of hidden prognostic factors.”

At the same time, they emphasize that their results need to be interpreted with caution given that they are derived from “an unplanned and insufficiently powered retrospective analysis.” Also, because the investigators decided on the prescription and the type of AED with randomization stratified by participating center, the differences in outcomes may have resulted from patient selection.

Finally, Weller and colleagues said that, despite potential shortcomings, the results of this retrospective analysis “suggest that the choice of AED in patients with brain tumors should be carefully considered because it may affect survival.”

Weller M, Gorlia T, Cairncross JG, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma [published online ahead of print August 31, 2011]. Neurol. 2011;77:1156-1164.