title: A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma.
abstract: OBJECTIVE
  Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM.
  
  
  METHODS
  Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment).
  
  
  RESULTS
  A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels.
  
  
  CONCLUSIONS
  Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.
authors.affiliation: Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland.
authors.forename: Andra V
authors.initials: AV
authors.lastname: Krauze
authors.affiliation: Department of Radiation Oncology, Lakeridge Health Durham Regional Cancer Centre, Oshawa, Ontario, Canada.
authors.forename: Sten D
authors.initials: SD
authors.lastname: Myrehaug
authors.affiliation: Massey Cancer Center Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Chang
authors.affiliation: Massey Cancer Center Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Holdford
authors.affiliation: Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland.
authors.forename: Sharon
authors.initials: S
authors.lastname: Smith
authors.affiliation: Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Shih
authors.affiliation: Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Tofilon
authors.affiliation: New York University Langone Medical Center, New York, New York.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Fine
authors.affiliation: Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland. Electronic address: camphauk@mail.nih.gov.
authors.forename: Kevin
authors.initials: K
authors.lastname: Camphausen
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy*; D059248:Chemoradiotherapy / Q000379:methods; D017024:Chemotherapy, Adjuvant; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy*; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D000077204:Temozolomide; D013997:Time Factors; D014635:Valproic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood
chemical_list: D018906:Antineoplastic Agents, Alkylating; D056572:Histone Deacetylase Inhibitors; D011838:Radiation-Sensitizing Agents; D014635:Valproic Acid; D003606:Dacarbazine; D000077204:Temozolomide