title: Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma.
abstract: OBJECTIVE
  Symptomatic epilepsy is a common complication of glioblastoma and requires pharmacotherapy. Several uncontrolled retrospective case series and a post hoc analysis of the registration trial for temozolomide indicated an association between valproic acid (VPA) use and improved survival outcomes in patients with newly diagnosed glioblastoma.
  
  
  METHODS
  To confirm the hypothesis suggested above, a combined analysis of survival association of antiepileptic drug use at the start of chemoradiotherapy with temozolomide was performed in the pooled patient cohort (n = 1,869) of four contemporary randomized clinical trials in newly diagnosed glioblastoma: AVAGlio (Avastin in Glioblastoma; NCT00943826), CENTRIC (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Methylated Gene Promoter Status; NCT00689221), CORE (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status; NCT00813943), and Radiation Therapy Oncology Group 0825 (NCT00884741). Progression-free survival (PFS) and overall survival (OS) were compared between: (1) any VPA use and no VPA use at baseline or (2) VPA use both at start of and still after chemoradiotherapy. Results of Cox regression models stratified by trial and adjusted for baseline prognostic factors were analyzed. The same analyses were performed with levetiracetam (LEV).
  
  
  RESULTS
  VPA use at start of chemoradiotherapy was not associated with improved PFS or OS compared with all other patients pooled (PFS: hazard ratio [HR], 0.91; 95% CI, 0.77 to 1.07; P = .241; OS: HR, 0.96; 95% CI, 0.80 to 1.15; P = .633). Furthermore, PFS and OS of patients taking VPA both at start of and still after chemoradiotherapy were not different from those without antiepileptic drug use at both time points (PFS: HR, 0.92; 95% CI, 0.74 to 1.15; P = .467; OS: HR, 1.10; 95% CI, 0.86 to 1.40; P = .440). Similarly, no association with improved outcomes was observed for LEV use.
  
  
  CONCLUSIONS
  The results of this analysis do not justify the use of VPA or LEV for reasons other than seizure control in patients with newly diagnosed glioblastoma outside clinical trials.
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: Caroline
authors.initials: C
authors.lastname: Happold
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: Olivier
authors.initials: O
authors.lastname: Chinot
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: L Burt
authors.initials: LB
authors.lastname: Nabors
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Pugh
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: Monika
authors.initials: M
authors.lastname: Hegi
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cloughesy
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roth
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: James R
authors.initials: JR
authors.lastname: Perry
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: Minesh P
authors.initials: MP
authors.lastname: Mehta
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD.
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.affiliation: Caroline Happold, Patrick Roth, Roger Stupp, and Michael Weller, University Hospital Zurich; Monika Hegi, University Hospital Lausanne, Switzerland; Thierry Gorlia, EORTC Data Centre, Brussels, Belgium; Olivier Chinot, Aix-Marseille University, Marseille, France; Mark R. Gilbert, The University of Texas MD Anderson Cancer Center, Houston, TX; L. Burt Nabors, University of Alabama at Birmingham, Birmingham, AL; Wolfgang Wick, University of Heidelberg & German Cancer Research Center, Heidelberg, Germany; Stephanie L. Pugh, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Timothy Cloughesy, UCLA Neuro-Oncology Program, Los Angeles, CA; David A. Reardon, Dana-Farber Cancer Institute, Boston, MA; James R. Perry, University of Toronto, Toronto, Ontario, Canada; and Minesh P. Mehta, University of Maryland, Baltimore, MD. michael.weller@usz.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000150:complications / Q000188:drug therapy*; D059248:Chemoradiotherapy; D002986:Clinical Trials as Topic; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004827:Epilepsy / Q000188:drug therapy* / Q000209:etiology*; D005260:Female; D005909:Glioblastoma / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011379:Prognosis; D016019:Survival Analysis; D000077204:Temozolomide; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D018906:Antineoplastic Agents, Alkylating; D000077287:Levetiracetam; D014635:Valproic Acid; D003606:Dacarbazine; D000077204:Temozolomide; D010889:Piracetam