Levetiracetam as a sensitizer of concurrent chemoradiotherapy in newly diagnosed glioblastoma: An open-label phase 2 study

Abstract

Background: An open-label single-arm phase 2 study was conducted to evaluate the role of levetiracetam as a sensitizer of concurrent chemoradiotherapy (CCRT) for patients with newly diagnosed glioblastoma. This study aimed to determine the survival benefit of levetiracetam in conjunction with the standard treatment for glioblastoma.

Methods: Major eligibility requirements included histologically proven glioblastoma in the supratentorial region, patients 18 years or older, and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Levetiracetam was given at 1,000-2,000 mg daily in two divided doses during CCRT and adjuvant chemotherapy thereafter. The primary and the secondary endpoints were 6-month progression-free survival (6mo-PFS) and 24-month overall survival (24mo-OS), respectively. Outcomes of the study group were compared to those of an external control group.

Results: Between July 2016 and January 2019, 76 patients were enrolled, and 73 patients were included in the final analysis. The primary and secondary outcomes were improved in the study population compared to the external control (6mo-PFS, 84.9% vs. 72.3%, p = 0.038; 24mo-OS, 58.0% vs. 39.9%, p = 0.018), but the differences were less prominent in a propensity score-matched analysis (6mo-PFS, 88.0% vs. 76.9%, p = 0.071; 24mo-OS, 57.1% vs. 38.8%, p = 0.054). In exploratory subgroup analyses, some results suggested that patients with ages under 65 years or unmethylated MGMT promoter might have a greater survival benefit from the use of levetiracetam.

Conclusions: The use of levetiracetam during CCRT in patients with newly diagnosed glioblastoma may result in improved outcomes, but further investigations are warranted.

Trial registration: ClinicalTrials.gov NCT02815410.

Keywords: anti-epileptic drug; concurrent chemoradiotherapy; drug repurposing; glioblastoma; levetiracetam.

Conflict of interest statement

The authors have no conflicts of interest to declare.

© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Flow diagram for Consolidated Standards of Reporting Trials (CONSORT) statement

FIGURE 2

Kaplan–Meier curves for progression‐free and overall survival. The study group exhibited a slightly improved survival compared to the control group at primary (6mo‐PFS) and secondary (24mo‐OS) endpoints (A, B). Differences between the study and the control groups were still prominent in the younger population aged less than 65 years (C, D). Survival curves also displayed differential survival outcomes according to MGMTp status (E). Interestingly, individuals with unmethylated MGMTp who received levetiracetam (MGMT−LEV⁺) showed slightly improved PFS compared to those counterparts from the control group (MGMT−LEV−). GE65⁺, aged ≥65 years; GE65−, aged <65 years; MGMT⁺, methylated; MGMT−, unmethylated; LEV⁺, study group (with levetiracetam), LEV−, control group (without levetiracetam)