Effect of Levetiracetam Use Duration on Overall Survival of Isocitrate Dehydrogenase Wildtype Glioblastoma in Adults: An Observational Study

OBJECTIVES The association between Levetiracetam and survival of Isocitrate Dehydrogenase (IDH) wildtype glioblastomas is controversial. We investigated whether the duration of Levetiracetam use during the standard chemoradiation protocol impacts overall survival of IDH-wildtype glioblastoma patients. METHODS Observational single-institution cohort study (2010-2018). Inclusion criteria were: 1) patients ≥18 years old; 2) newly diagnosed supratentorial tumor; 3) histomolecular diagnosis of IDH-wildtype glioblastoma; 4) standard chemoradiation protocol. To assess the survival benefit of Levetiracetam use during the standard chemoradiation protocol (whole duration, part time, and never subgroups), a Cox proportional hazard model was constructed. We performed a case-matched analysis (1:1) between patients with Levetiracetam use during the whole duration of the standard chemoradiation protocol and patients with Levetiracetam use part time or never according to the following criteria: sex, age, epileptic seizures at diagnosis, RTOG-RPA class, tumor location, preoperative volume, extent of resection, and O6-Methylguanine-DNA methyltransferase promoter methylation status. Patients with unavailable O6-Methylguanine-DNA methyltransferase promoter methylation status (48.5%) were excluded. RESULTS 460 patients were included. The median overall survival was longer in the 116 patients with Levetiracetam use during the whole duration of the standard chemoradiation protocol (21.0 months; 95%CI, 17.2-24.0) than in the 126 patients with part time Levetiracetam use (16.8 months; 95%CI, 12.4-19.0], and in the 218 patients who never received Levetiracetam (16.0 months; 95%CI, 15.5-19.4; p=0.027). Levetiracetam use during the whole duration of the standard chemoradiation protocol (adjusted Hazard Ratio (aHR) 0.69; 95%CI, 0.52-0.93; p=0.014), O6-Methylguanine-DNA methyltransferase promoter methylation (aHR 0.53; 95%CI, 0.39-0.71; p<0.001), and gross total tumor resection (aHR 0.57; 95%CI, 0.44-0.74; p<0.001) were independent predictors of a longer overall survival. After case matching (n=54 per group), a longer overall survival was found for Levetiracetam use during the whole duration of the standard chemoradiation protocol (HR=0.63; 95%CI, 0.42-0.94, p=0.023). DISCUSSION Levetiracetam use during the whole standard chemoradiation protocol possibly improves overall survival of IDH-wildtype glioblastoma patients. It should be considered in the anti-tumor strategy of future multicentric trials. CLASSIFICATION OF EVIDENCE This study provides Class III evidence that in individuals with IDH-wildtype glioblastoma, levetiracetam use throughout the duration of standard chemotherapy is associated with longer median overall survival.