Effect of anti-epileptic drugs on the survival of patients with glioblastoma multiforme: A retrospective, single-center study

Abstract

Glioblastoma multiforme (GBM) is a lethal and aggressive malignant tumor of the central nervous system. The World Health Organization classifies it as a grade IV astrocytoma. Controlling seizures is essential during GBM treatment because they are often present and closely associated with the quality of life of GBM patients. Some antiepileptic drugs (AEDs) exhibit antitumor effects and could decrease the mortality of patients with GBM. In this retrospective cohort study, we examined 418 patients treated with surgery, radiotherapy, and chemotherapy with temozolomide (TMZ) at Severance Hospital in South Korea, per the current protocol. Median overall survival (OS) was 21 months [95% confidence interval (CI): 18.1–23.9] in the levetiracetam (LEV) treatment group, whereas it was 16 months [95% CI: 14.1–17.9] in the group without LEV, exhibiting a statistically significant difference between the two groups (P < 0.001). Of nine AED groups, only LEV treatment [P = 0.001; hazard ratio (HR), 0.65; 95% CI: 0.51–0.83] exhibited a statistically significant difference in the OS, in the univariate analysis. In the risk analysis of the baseline characteristics, age, administration of LEV, and O6-methylguanine-DNA methyltransferase (MGMT) promoter status correlated with OS. The use of LEV in the group with a methylated MGMT promoter resulted in a positive impact on the OS [P = 0.006; HR, 0.174; 95% CI: 0.050–0.608], but the effect of LEV on the OS was not statistically significant in the unmethylated MGMT promoter group (P = 0.623). This study suggests that, compared with other AEDs, the administration of LEV may prolong the survival period in GBM patients with methylated MGMT promoters, who are undergoing chemotherapy with TMZ.

Ion Channels as Therapeutic Targets in High Grade Gliomas

“… Channel Tumour Drug References Cav3.2 GSC Mibefradil [ 92 ] Cav1.1, Cav1.2, Cav1.3, Cav1.4 Rat Derived GBM GBM mouse models GBM cell lines Pimozide Fluspirilene [ 107 , 108 , 109 ] Nav1.1 and Nav1.2. Human GBM Valporate Levetiracetam [ 110 , 111 , 112 ] Nav1.4 and Nav1.5 GBM cell line Riluzole [ 113 , 114 ] Kv1.4 GBM cell line Tamoxifen [ 115 ] Kv1.3 Human and mouse GBM biopsies Clofazimine [ 116 , 117 ] EAG1 Glioma Imipramine [ 118 , 119 ] …”

“…Furthermore, in MGMT methylated group, LEV treatment had a positive impact on overall survival. These data suggest that LEV treatment may have a capacity to prolong survival of patients undergoing normal GBM treatment [ 112 ]. Studying anti-epileptic drugs in glioma models may have a double pronged benefit, whilst some of these drug exhibit antitumour effects they also provide relief from seizures, a common side effect of brain tumours, thus increasing quality of life.…”

Use of Anti-Epileptic Drugs During Adjuvant Chemo-Radiotherapy is Associated with Increased Mortality in Patients with Glioblastoma: A Nationwide Population-Based Cohort Study

“…To go a step further, the positive impact of LEV on OS was seen in the group with a methylated MGMT promoter (HR 0.174, p = 0.006), but not in the unmethylated group (p = 0.623). In addition, the median OS in patients with VPA was shorter than those without VPA (18 vs 20 months, p = 0.38) [16].…”

The Potential Effect of the IDH1 Mutation and MGMT Gene Promotor Methylation on the Control of Glioblastoma-Associated Epilepsy in Patients Receiving Anti-Epileptic Agents and Chemotherapies

“…Scattered studies found that levetiracetam and valproic acid are the main anti-epileptic drugs that exhibit antitumor effects and have shown an actual decrease in the mortality rate among glioblastoma patients with epilepsy (13) ( 14) (15). Valproic acid exhibits antitumor effects via inhibition of mSin3A/histone deacetylase 1 and modulation of the mitogen-activated protein kinase pathway.…”

“…Levetiracetam is the most potent MGMT inhibitor among several anti-epileptic medications with diverse MGMT regulatory actions and is considered the rst-line drug to control seizures in glioma patients (12). Multiple studies concluded that levetiracetam and valproic acid are the main anti-epileptic drugs that exhibit antitumor effects and decrease the mortality rate among glioblastoma patients with epilepsy (13) ( 14) (15). In this study, we also have investigated which antiepileptic drug exerts the best effective control of glioblastoma-associated epilepsy in Saudi Arabia and have also identi ed the relationship of seizure control with different anti-epileptic drugs and the recurrence interval.…”