title: 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.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White Building Room, Gray 502, Boston, MA, 02114, USA. nredjal@gmail.com.
authors.forename: Navid
authors.initials: N
authors.lastname: Redjal
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, 02114, Boston, MA, USA.
authors.forename: Clemens
authors.initials: C
authors.lastname: Reinshagen
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White Building Room, Gray 502, Boston, MA, 02114, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Le
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White Building Room, Gray 502, Boston, MA, 02114, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Walcott
authors.affiliation: MGH Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, 50 Staniford Street, Boston, MA, 02114, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: McDonnell
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, 02114, MA, USA.
authors.forename: Jorg
authors.initials: J
authors.lastname: Dietrich
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White Building Room, Gray 502, Boston, MA, 02114, USA.
authors.forename: Brian V
authors.initials: BV
authors.lastname: Nahed
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D002648:Child; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D000077204:Temozolomide; D014635:Valproic Acid / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D018906:Antineoplastic Agents, Alkylating; D014635:Valproic Acid; D003606:Dacarbazine; D000077204:Temozolomide
keywords: Glioblastoma; Glioma; HDAC; Histone deacetylase inhibitor; Low-grade; Progression; Survival; Valproic acid
references.citation: J Neurooncol. 2008 Nov;90(2):133-40
references.pmid: 18618226
references.citation: EMBO J. 2001 Dec 17;20(24):6969-78
references.pmid: 11742974
references.citation: Lancet Oncol. 2009 May;10 (5):459-66
references.pmid: 19269895
references.citation: Lancet Neurol. 2007 May;6(5):421-30
references.pmid: 17434097
references.citation: J Clin Oncol. 2013 Jan 20;31(3):337-43
references.pmid: 23071247
references.citation: Neurology. 2011 Sep 20;77(12 ):1156-64
references.pmid: 21880994
references.citation: Curr Neurol Neurosci Rep. 2010 May;10(3):224-31
references.pmid: 20425038
references.citation: Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):223-9
references.pmid: 15850925
references.citation: Curr Oncol. 2008 Oct;15(5):237-43
references.pmid: 19008999
references.citation: Int J Cancer. 2005 Apr 10;114(3):380-6
references.pmid: 15578701
references.citation: Int J Radiat Oncol Biol Phys. 2013 Jul 1;86(3):504-9
references.pmid: 23523186
references.citation: J Neurooncol. 2012 Mar;107(1):61-7
references.pmid: 22037799
references.citation: Lancet Oncol. 2012 Sep;13(9):916-26
references.pmid: 22877848
references.citation: Eur J Cell Biol. 2005 Mar;84(2-3):109-21
references.pmid: 15819394
references.citation: Cancer Treat Res. 2015;163:75-87
references.pmid: 25468226
references.citation: Curr Treat Options Oncol. 2014 Dec;15(4):529-38
references.pmid: 25139406
references.citation: Front Neurol. 2012 Oct 18;3:140
references.pmid: 23087667
references.citation: Cancer Res. 2004 Feb 1;64(3):1079-86
references.pmid: 14871841
references.citation: J Natl Cancer Inst. 1998 Oct 7;90(19):1473-9
references.pmid: 9776413
references.citation: Mol Pharmacol. 2005 Oct;68(4):917-32
references.pmid: 15955865
references.citation: J Clin Oncol. 1999 Sep;17 (9):2762-71
references.pmid: 10561351
references.citation: Int J Radiat Oncol Biol Phys. 2010 Sep 1;78(1):237-45
references.pmid: 20646843
references.citation: BMC Cancer. 2008 Aug 19;8:243
references.pmid: 18713462
references.citation: J Biol Chem. 2005 Dec 23;280(51):42433-41
references.pmid: 16251190
references.citation: Oncologist. 2009 Feb;14(2):155-63
references.pmid: 19182242
references.citation: J Biol Chem. 2001 Sep 28;276(39):36734-41
references.pmid: 11473107
references.citation: Neurosurgery. 2014 Aug;61 Suppl 1:74-83
references.pmid: 25032534
references.citation: Clin Cancer Res. 2008 Sep 1;14(17):5410-5
references.pmid: 18765532
references.citation: J Neurosurg. 2013 Apr;118(4):859-65
references.pmid: 23176328
references.citation: Cancer Treat Rev. 2008 May;34(3):206-22
references.pmid: 18226465
references.citation: Neuro Oncol. 2014 Oct;16 Suppl 4:iv1-63
references.pmid: 25304271
references.citation: Lancet. 2005 Sep 17-23;366(9490):985-90
references.pmid: 16168780
references.citation: Lancet. 2012 May 26;379(9830):1984-96
references.pmid: 22510398
references.citation: Lancet Oncol. 2012 Jul;13(7):707-15
references.pmid: 22578793
references.citation: Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6066-71
references.pmid: 15447991
references.citation: J Clin Oncol. 2013 Jan 20;31(3):344-50
references.pmid: 23071237
references.citation: N Engl J Med. 2005 Mar 10;352(10 ):997-1003
references.pmid: 15758010
references.citation: Adv Tech Stand Neurosurg. 2010;35:213-35
references.pmid: 20102116
references.citation: Neuro Oncol. 2013 Jul;15(7):961-7
references.pmid: 23680820
references.citation: Brain Pathol. 2007 Jan;17(1):5-10
references.pmid: 17493032
references.citation: Blood. 2013 Apr 25;121(17):3459-68
references.pmid: 23440245
references.citation: Neuro Oncol. 2007 Apr;9(2):82-8
references.pmid: 17347490
references.citation: N Engl J Med. 2005 Mar 10;352(10 ):987-96
references.pmid: 15758009
references.citation: Brain Pathol. 2011 Nov;21(6):633-44
references.pmid: 21554472
references.citation: J Biol Chem. 2003 Jul 25;278(30):27586-92
references.pmid: 12748177
references.citation: EMBO J. 2003 Jul 1;22(13):3411-20
references.pmid: 12840003
references.citation: Pediatr Hematol Oncol. 2011 Oct;28(7):556-70
references.pmid: 21699466
references.citation: J Neurosurg. 2001 Aug;95(2):190-8
references.pmid: 11780887