Effect of valproic acid on survival in glioblastoma: A prospective single-arm study

Abstract

Background:Retrospective evidence suggests that valproic acid (VPA), an antiepileptic drug, is associated with improved outcomes in glioblastoma. The exact mechanism of interaction of VPA with radiation and temozolomide (TMZ) is still unclear. Laboratory studies show that VPA can enhance tumor cell kill while at the same time protect the normal neural tissue. The aim of this study was to prospectively evaluate the benefit of VPA on outcomes in glioblastoma.Materials and Methods:In this single-arm prospective study, patients of glioblastoma were started on seizure prophylaxis with VPA (15–20 mg/kg/day) following maximal safe resection. All patients were treated with chemoradiation to a dose of 60 Gy in 30 fractions with concurrent TMZ followed by adjuvant TMZ for 6 cycles. VPA was continued during adjuvant treatment and follow-up. Survival analysis was done using Kaplan–Meier analysis.Results:Twenty patients were enrolled in the study. Median age was 47 years. M:F ratio was 3:1. Treatment was well tolerated with no grade 3/4 adverse events. 8/20 patients experience seizure episodes during treatment and/or follow-up which needed additional antiepileptic drugs for control. Median progression-free survival (PFS) and overall survival (OS) were 10 months and 16 months, respectively. Younger patients (age ≤45 years) showed a significantly better OS (25 months) versus older patients (8 months) (P = 0.002).Conclusions:Incidence of seizures on VPA prophylaxis was 40%. Median PFS and OS were comparable to historical controls. There was no significant treatment-related toxicity. The results need validation in larger prospective randomized studies.

Ion Channels as Therapeutic Targets in High Grade Gliomas

“…Evidence from clinical studies suggest that VPA is significantly linked to improved outcome in GBM patients; although the mechanism of VPA interaction with mainstay treatments is unclear, synergy is clear between VPA, TMZ and radiation. Invitro lab studies confirm clinical findings and demonstrate that VPA can induce tumour cell death, whilst preserving healthy brain tissue [ 111 ].…”

“… Channel Tumour Drug References Cav3.2 GSC Mibefradil [ 92 ] Cav1.1, Cav1.2, Cav1.3, Cav1.4 Rat Derived GBM GBM mouse models GBM cell lines Pimozide Fluspirilene [ 107 , 108 , 109 ] Nav1.1 and Nav1.2. Human GBM Valporate Levetiracetam [ 110 , 111 , 112 ] Nav1.4 and Nav1.5 GBM cell line Riluzole [ 113 , 114 ] Kv1.4 GBM cell line Tamoxifen [ 115 ] Kv1.3 Human and mouse GBM biopsies Clofazimine [ 116 , 117 ] EAG1 Glioma Imipramine [ 118 , 119 ] …”

Recent Advances in Oncolytic Virotherapy and Immunotherapy for Glioblastoma: A Glimmer of Hope in the Search for an Effective Therapy?

“…Levetiracetam is now the most frequently prescribed drug for brain tumor-related epilepsy, followed by valproic acid [70,71]. Although multiple retrospective clinical studies stated improved outcome of patients with newly diagnosed glioblastoma after the addition of valproic acid [73,74,75,76,77,78,79,80,81] or levetiracetam [82] to standard therapy, while others did not reveal a significant effect on overall survival [70,75,83,84,85,86,87], the analysis of the prospective phase III clinical trials with a pooled cohort of 1869 patients demonstrated that levetiracetam or valproic acid did not influence median overall survival on multivariate analysis [88]. No significant impact on overall survival of patients with glioblastoma was also documented for other anti-epileptic drug [70].…”

Synthetic mRNA-based gene therapy for glioblastoma: TRAIL-mRNA synergistically enhances PTEN-mRNA-based therapy

“…16,17 Previous studies showed that the separate use of TRAIL or PTEN has only limited antitumor effect on gliomas, [18][19][20][21] and the clinical trials have revealed only little therapeutic benefit. 5 During the past twenty years, various targeted therapies have been explored to treat GBM based on the study of genomic tools, such as inhibitors of multiple tyrosine kinase pathways, 22 poly (ADP-ribose) polymerase 1/2 (PARP1/2) inhibitors, 23 mTOR inhibitors, 24 histone deacetylase inhibitors, 25,26 and proteasome inhibitors. 27,28 But these treatments are unable to target the GBM patients' genomic and molecular characteristics sufficiently.…”