Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma

Abstract

The results of this analysis do not justify the use of VPA or LEV for reasons other than seizure control in patients with newly diagnosed glioblastoma outside clinical trials.

Reply to F. Felix et al and M.F. Fay et al

“…A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma," 1 we reported that drug repurposing has attracted a lot of interest, specifically in glioblastoma, given the disappointing results obtained with initially promising, but ultimately inactive novel treatments and the availability of large databases suitable for exploratory analyses. In that regard, the potential impact on survival of the anticonvulsant drug, valproic acid, has been in focus for more than a decade.…”

“…Yet, the pooled analysis of several contemporary clinical trials that enrolled almost 2,000 patients, which set out to strengthen the rationale for testing valproic acid in a randomized definitive phase III trial in newly diagnosed glioblastoma, failed to provide an adequate signal to support such a hypothesis in an otherwise molecularly unselected group of adult glioblastoma. 1 Felix and Fontenele 2 rightly raise the issue that patients in these trials were not enriched for any biomarker that predicted potential benefit from valproic acid and propose that valproic acid be tested specifically in pediatric patients with H3F3A mutation, mostly pontine gliomas. There is a possible biologic and molecular rationale to explore valproic acid in this subgroup of patients on the basis of the predicted epigenetic effects of valproic acid; however, three issues arise.…”

Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

“…A meta study analyzing the largest cohort (1,800 patients), in sharp contrast, could not confirm that VPA treatment of newly diagnosed glioblastoma patients associates with longer progression-free and overall survival [32]. A further multivariate analysis of 647 patients with de novo glioblastoma identified epilepsy as a prognostic factor for longer survival.…”

Valproate in Adjuvant Glioblastoma Treatment

“…The study recently published in Journal of Clinical Oncology by Happold et al 1 pooled a number of trial data sets to study a variety of interventions for glioblastoma in which patients had taken anticonvulsants, including VPA. The study concluded that VPA showed no benefit on survival.…”

“…Some are cited by Happold et al 1 The studies are not without issue. The analysis is retrospective, and definitions for positive VPA use vary (data source was an included factor).…”