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. 2016 Mar 1;34(7):731-9.
doi: 10.1200/JCO.2015.63.6563. Epub 2016 Jan 19.

Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma

Caroline Happold  1 , Thierry Gorlia  1 , Olivier Chinot  1 , Mark R Gilbert  1 , L Burt Nabors  1 , Wolfgang Wick  1 , Stephanie L Pugh  1 , Monika Hegi  1 , Timothy Cloughesy  1 , Patrick Roth  1 , David A Reardon  1 , James R Perry  1 , Minesh P Mehta  1 , Roger Stupp  1 , Michael Weller  2
Affiliations

Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma

Caroline Happold et al. J Clin Oncol. .

Abstract

Purpose: 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.

Patients and 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.

Conclusion: 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.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Prognostic factors for PFS (left) and OS (right) in the pooled cohort. (A) Age, (B) WHO performance status, (C) extent of resection, and (D) MGMT promoter methylation status. MGMT, O6-methylguanine–DNA methyltransferase; N, number; O, observed; OS, overall survival; PFS, progression-free survival.
Fig 1.
Fig 1.
Prognostic factors for PFS (left) and OS (right) in the pooled cohort. (A) Age, (B) WHO performance status, (C) extent of resection, and (D) MGMT promoter methylation status. MGMT, O6-methylguanine–DNA methyltransferase; N, number; O, observed; OS, overall survival; PFS, progression-free survival.
Fig 2.
Fig 2.
Prognostic significance of baseline VPA use in the validation cohort (A and B) and EORTC NCIC cohort (C and D) or of continued VPA use in the validation cohort (E and F) and EORTC NCIC cohort (G and H) for PFS (left) and OS (right). EORTC, European Organisation for Research and Treatment of Cancer; NCIC, NCIC Clinical Trials Group; N, number; O, observed; OS, overall survival; PFS, progression-free survival; VPA, valproic acid.
Fig 2.
Fig 2.
Prognostic significance of baseline VPA use in the validation cohort (A and B) and EORTC NCIC cohort (C and D) or of continued VPA use in the validation cohort (E and F) and EORTC NCIC cohort (G and H) for PFS (left) and OS (right). EORTC, European Organisation for Research and Treatment of Cancer; NCIC, NCIC Clinical Trials Group; N, number; O, observed; OS, overall survival; PFS, progression-free survival; VPA, valproic acid.
Fig 3.
Fig 3.
Prognostic significance of baseline LEV use (A and B) or continued LEV use (C and D) in the validation cohort for PFS (left) and OS (right). LEV, levetiracetam; N, number; O, observed; OS, overall survival, PFS, progression-free survival.
Fig A1.
Fig A1.
Prognostic factors for PFS (left) and OS (right) in the pooled cohort. (A) Sex, (B) Mini-Mental State Examination, and (C) use of steroids at study entry. N, number; O, observed; OS, overall survival; PFS, progression-free survival.
Fig A2.
Fig A2.
Prognostic significance of VPA use in the pooled cohort for PFS (left; A, C, and E) and OS (right; B, D, and F). (A and B) VPA versus no AED, (C and D) VPA versus EI-AED, and (E and F) VPA versus other non–EI-AED. AED, antiepileptic drug; EI, enzyme-inducing; N, number; O, observed; OS, overall survival; PFS, progression-free survival; VPA, valproic acid.
Fig A3.
Fig A3.
Prognostic significance of LEV use for PFS (left) and OS (right). (A and B) LEV versus no AED, (C and D) LEV versus EI-AED, and (E and F) LEV versus other non–EI-AED. AED, antiepileptic drug; EI, enzyme-inducing; LEV, levetiracetam; N, number; O, observed; OS, overall survival; PFS, progression-free survival.
See this image and copyright information in PMC

Comment in

  • Valproate in Adjuvant Glioblastoma Treatment.
    Fay MF, Head R, Sminia P, Dowson N, Cosgrove L, Rose SE, Martin JH. Fay MF, et al. J Clin Oncol. 2016 Sep 1;34(25):3105-7. doi: 10.1200/JCO.2016.67.2162. Epub 2016 Jun 13. J Clin Oncol. 2016. PMID: 27298401 No abstract available.
  • Reply to F. Felix et al and M.F. Fay et al.
    Happold C, Gorlia T, Chinot O, Gilbert MR, Nabors LB, Wick W, Pugh SL, Hegi M, Cloughesy T, Roth P, Reardon DA, Perry JR, Mehta MP, Stupp R, Weller M. Happold C, et al. J Clin Oncol. 2016 Sep 1;34(25):3107-8. doi: 10.1200/JCO.2016.68.0926. Epub 2016 Jun 13. J Clin Oncol. 2016. PMID: 27298403 No abstract available.
  • Valproic Acid May Be Tested in Patients With H3F3A-Mutated High-Grade Gliomas.
    Felix F, Fontenele J. Felix F, et al. J Clin Oncol. 2016 Sep 1;34(25):3104-5. doi: 10.1200/JCO.2016.67.1073. Epub 2016 Jun 13. J Clin Oncol. 2016. PMID: 27298407 No abstract available.

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