Valproic acid, compared to other antiepileptic drugs, is associated with improved overall and progression-free survival in glioblastoma but worse outcome in grade II/III gliomas treated with temozolomide

J Neurooncol. 2016 May;127(3):505-14. doi: 10.1007/s11060-016-2054-8. Epub 2016 Feb 1.


Valproic acid (VPA) is an anti-epileptic drug with properties of a histone deacetylase inhibitor (HDACi). HDACi play a key role in epigenetic regulation of gene expression and have been increasingly used as anticancer agents. Recent studies suggest that VPA is associated with improved survival in high-grade gliomas. However, effects on lower grade gliomas have not been examined. This study investigates whether use of VPA correlates with tumor grade, histological progression, progression-free and overall survival (OS) in grade II, III, and IV glioma patients. Data from 359 glioma patients (WHO II-IV) treated with temozolomide plus an antiepileptic drug (VPA or another antiepileptic drug) between January 1997 and June 2013 at the Massachusetts General Hospital was analyzed retrospectively. After confounder adjustment, VPA was associated with a 28 % decrease in hazard of death (p = 0.031) and a 28 % decrease in the hazard of progression or death (p = 0.015) in glioblastoma. Additionally, VPA dose correlated with reduced hazard of death by 7 % (p = 0.002) and reduced hazard of progression or death by 5 % (p < 0.001) with each 100 g increase in total dose. Conversely, in grade II and III gliomas VPA was associated with a 118 % increased risk of tumor progression or death (p = 0.014), and every additional 100 g of VPA raised the hazard of progression or death by 4 %, although not statistically significant (p = 0.064). Moreover, grade II and III glioma patients taking VPA had 2.17 times the risk of histological progression (p = 0.020), although this effect was no longer significant after confounder adjustment. In conclusion, VPA was associated with improved survival in glioblastoma in a dose-dependent manner. However, in grade II and III gliomas, VPA was linked to histological progression and decrease in progression-free survival. Prospective evaluation of VPA treatment for glioma patients is warranted to confirm these findings.

Keywords: Glioblastoma; Glioma; HDAC; Histone deacetylase inhibitor; Low-grade; Progression; Survival; Valproic acid.

Publication types

  • Comparative Study

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anticonvulsants / therapeutic use
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / mortality*
  • Brain Neoplasms / pathology
  • Child
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / therapeutic use
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Glioblastoma / drug therapy
  • Glioblastoma / mortality*
  • Glioblastoma / pathology
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / mortality*
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Retrospective Studies
  • Survival Rate
  • Temozolomide
  • Valproic Acid / therapeutic use*
  • Young Adult


  • Anticonvulsants
  • Antineoplastic Agents, Alkylating
  • Valproic Acid
  • Dacarbazine
  • Temozolomide