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

Deepthi Valiyaveetti; Monica Malik; Deepa M. Joseph; Syed Fayaz Ahmed; Syed Akram Kothwal; M. Vijayasaradhi

doi:10.4103/sajc.sajc_188_17

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ORIGINAL ARTICLE: Brain Tumors

07 (

); 159-162

doi:

10.4103/sajc.sajc_188_17

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

Deepthi Valiyaveetti¹, Monica Malik^1,, Deepa M. Joseph¹, Syed Fayaz Ahmed¹, Syed Akram Kothwal¹, M. Vijayasaradhi²

1 Department of Radiation Oncology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana

2 Department of Neurosurgery, Nizam's Institute of Medical Sciences, Hyderabad, Telangana

*Corresponding author: Dr. Monica Malik. dr_monica11@yahoo.com

Published: 2020-12-22

MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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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.

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References

Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol 2013;15 Suppl 2:ii1-56.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66.
Guthrie GD, Eljamel S. Impact of particular antiepileptic drugs on the survival of patients with glioblastoma multiforme. J Neurosurg 2013;118:859-65.
Binello E, Green S, Germano IM. Radiosurgery for high-grade glioma. Surg Neurol Int 2012;3:S118-26.
Nieder C, Andratschke N, Wiedenmann N, Busch R, Grosu AL, Molls M, et al. Radiotherapy for high-grade gliomas. Does altered fractionation improve the outcome? Strahlenther Onkol 2004;180:401-7.
Waters JD, Rose B, Gonda DD, Scanderbeg DJ, Russell M, Alksne JF, et al. Immediate post-operative brachytherapy prior to irradiation and temozolomide for newly diagnosed glioblastoma. J Neurooncol 2013;113:467-77.
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455:1061-8.
Knüpfer MM, Pulzer F, Schindler I, Hernaíz Driever P, Knüpfer H, Keller E, et al. Different effects of valproic acid on proliferation and migration of malignant glioma cells in vitro. Anticancer Res 2001;21:347-51.
Shao Y, Gao Z, Marks PA, Jiang X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A 2004;101:18030-5.
Munshi A, Kurland JF, Nishikawa T, Tanaka T, Hobbs ML, Tucker SL, et al. Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res 2005;11:4912-22.
Michaelis M, Doerr HW, Cinatl J Jr. Valproic acid as anti-cancer drug. Curr Pharm Des 2007;13:3378-93.
Kuendgen A, Gattermann N. Valproic acid for the treatment of myeloid malignancies. Cancer 2007;110:943-54.
Duenas-Gonzalez A, Candelaria M, Perez-Plascencia C, Perez-Cardenas E, de la Cruz-Hernandez E, Herrera LA, et al. Valproic acid as epigenetic cancer drug: Preclinical, clinical and transcriptional effects on solid tumors. Cancer Treat Rev 2008;34:206-22.
Huang Z, Cheng L, Guryanova OA, Wu Q, Bao S. Cancer stem cells in glioblastoma – Molecular signaling and therapeutic targeting. Protein Cell 2010;1:638-55.
van Breemen MS, Wilms EB, Vecht CJ. Epilepsy in patients with brain tumours: Epidemiology, mechanisms, and management. Lancet Neurol 2007;6:421-30.
Wick W, Menn O, Meisner C, Steinbach J, Hermisson M, Tatagiba M, et al. Pharmacotherapy of epileptic seizures in glioma patients: Who, when, why and how long? Onkologie 2005;28:391-6.
Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC, et al. Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:1886-93.
Weller M, Gorlia T, Cairncross JG, van den Bent MJ, Mason W, Belanger K, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 2011;77:1156-64.
Barker CA, Bishop AJ, Chang M, Beal K, Chan TA. Valproic acid use during radiation therapy for glioblastoma associated with improved survival. Int J Radiat Oncol Biol Phys 2013;86:504-9.
Wen PY, Schiff D. Valproic acid as the AED of choice for patients with glioblastoma? The jury is out. Neurology 2011;77:1114-5.
Krauze AV, Myrehaug SD, Chang MG, Holdford DJ, Smith S, Shih J, et al. Aphase 2 study of concurrent radiation therapy, temozolomide, and the histone deacetylase inhibitor valproic acid for patients with glioblastoma. Int J Radiat Oncol Biol Phys 2015;92:986-92.
Happold C, Gorlia T, Chinot O, Gilbert MR, Nabors LB, Wick W, et al. Does valproic acid or levetiracetam improve survival in glioblastoma? A Pooled analysis of prospective clinical trials in newly diagnosed glioblastoma. J Clin Oncol 2016;34:731-9.
Fay MF, Head R, Sminia P, Dowson N, Cosgrove L, Rose SE, et al. Valproate in adjuvant glioblastoma treatment. J Clin Oncol 2016;34:3105-7.

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[1] Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol 2013;15 Suppl 2:ii1-56.

[2] Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66.

[3] Guthrie GD, Eljamel S. Impact of particular antiepileptic drugs on the survival of patients with glioblastoma multiforme. J Neurosurg 2013;118:859-65.

[4] Binello E, Green S, Germano IM. Radiosurgery for high-grade glioma. Surg Neurol Int 2012;3:S118-26.

[5] Nieder C, Andratschke N, Wiedenmann N, Busch R, Grosu AL, Molls M, et al. Radiotherapy for high-grade gliomas. Does altered fractionation improve the outcome? Strahlenther Onkol 2004;180:401-7.

[6] Waters JD, Rose B, Gonda DD, Scanderbeg DJ, Russell M, Alksne JF, et al. Immediate post-operative brachytherapy prior to irradiation and temozolomide for newly diagnosed glioblastoma. J Neurooncol 2013;113:467-77.

[7] Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455:1061-8.

[8] Knüpfer MM, Pulzer F, Schindler I, Hernaíz Driever P, Knüpfer H, Keller E, et al. Different effects of valproic acid on proliferation and migration of malignant glioma cells in vitro. Anticancer Res 2001;21:347-51.

[9] Shao Y, Gao Z, Marks PA, Jiang X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A 2004;101:18030-5.

[10] Munshi A, Kurland JF, Nishikawa T, Tanaka T, Hobbs ML, Tucker SL, et al. Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res 2005;11:4912-22.

[11] Michaelis M, Doerr HW, Cinatl J Jr. Valproic acid as anti-cancer drug. Curr Pharm Des 2007;13:3378-93.

[12] Kuendgen A, Gattermann N. Valproic acid for the treatment of myeloid malignancies. Cancer 2007;110:943-54.

[13] Duenas-Gonzalez A, Candelaria M, Perez-Plascencia C, Perez-Cardenas E, de la Cruz-Hernandez E, Herrera LA, et al. Valproic acid as epigenetic cancer drug: Preclinical, clinical and transcriptional effects on solid tumors. Cancer Treat Rev 2008;34:206-22.

[14] Huang Z, Cheng L, Guryanova OA, Wu Q, Bao S. Cancer stem cells in glioblastoma – Molecular signaling and therapeutic targeting. Protein Cell 2010;1:638-55.

[15] van Breemen MS, Wilms EB, Vecht CJ. Epilepsy in patients with brain tumours: Epidemiology, mechanisms, and management. Lancet Neurol 2007;6:421-30.

[16] Wick W, Menn O, Meisner C, Steinbach J, Hermisson M, Tatagiba M, et al. Pharmacotherapy of epileptic seizures in glioma patients: Who, when, why and how long? Onkologie 2005;28:391-6.

[17] Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC, et al. Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:1886-93.

[18] Weller M, Gorlia T, Cairncross JG, van den Bent MJ, Mason W, Belanger K, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 2011;77:1156-64.

[19] Barker CA, Bishop AJ, Chang M, Beal K, Chan TA. Valproic acid use during radiation therapy for glioblastoma associated with improved survival. Int J Radiat Oncol Biol Phys 2013;86:504-9.

[20] Wen PY, Schiff D. Valproic acid as the AED of choice for patients with glioblastoma? The jury is out. Neurology 2011;77:1114-5.

[21] Krauze AV, Myrehaug SD, Chang MG, Holdford DJ, Smith S, Shih J, et al. Aphase 2 study of concurrent radiation therapy, temozolomide, and the histone deacetylase inhibitor valproic acid for patients with glioblastoma. Int J Radiat Oncol Biol Phys 2015;92:986-92.

[22] Happold C, Gorlia T, Chinot O, Gilbert MR, Nabors LB, Wick W, et al. Does valproic acid or levetiracetam improve survival in glioblastoma? A Pooled analysis of prospective clinical trials in newly diagnosed glioblastoma. J Clin Oncol 2016;34:731-9.

[23] Fay MF, Head R, Sminia P, Dowson N, Cosgrove L, Rose SE, et al. Valproate in adjuvant glioblastoma treatment. J Clin Oncol 2016;34:3105-7.

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

Abstract

Abstract

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