Effectiveness of Antiseizure Medication Triple Therapy in Patients With Glioma With Refractory Epilepsy: An Observational Cohort Study

Abstract

Background and objectives: Approximately 10% of patients with glioma with epilepsy need antiseizure medication (ASM) triple therapy due to refractory epilepsy. The aim of this study was to evaluate whether levetiracetam combined with valproic acid and clobazam (LEV + VPA + CLB), a frequently prescribed triple therapy, has favorable effectiveness compared with other triple therapy combinations in patients with glioma.

Methods: This was a multicenter retrospective observational cohort study. The primary outcome was the cumulative incidence of time to treatment failure for any reason, from the start of ASM triple therapy treatment. The secondary outcomes included cumulative incidences of the following: (1) time to treatment failure due to uncontrolled seizures; (2) time to treatment failure due to adverse effects; and (3) time to recurrent seizures. Patients were followed up for a maximum duration of 36 months.

Results: Of 1,435 patients in the original cohort, 90 patients received ASM triple therapy after second-line ASM treatment failure due to uncontrolled seizures. LEV + VPA + CLB was prescribed to 48% (43/90) and other ASM triple therapy to 52% (47/90) of patients. The cumulative incidence of treatment failure for any reason of LEV + VPA + CLB did not statistically significantly differ from that of other ASM triple therapy combinations (12 months: 47% [95% CI 31%-62%] vs 42% [95% CI 27%-56%], p = 0.892). No statistically significant differences for treatment failure due to uncontrolled seizures (12 months: 12% [95% CI 4%-25%] vs 18% [95% CI 8%-30%], p = 0.445), adverse effects (12 months: 22% [95% CI 11%-36%] vs 15% [95% CI 7%-27%], p = 0.446), or recurrent seizures (1 month: 65% [95% CI 48%-78%] vs 63% [95% CI 47%-75%], p = 0.911) were found.

Discussion: LEV + VPA + CLB might show equivalent effectiveness compared with other ASM triple therapy combinations in patients with glioma.

Classification of evidence: This study provides Class III evidence that for patients with glioma with refractory epilepsy on triple therapy ASMs, LEV + VPA + CLB demonstrated similar effectiveness and tolerability compared with other ASM triple therapy combinations.

Figure 1. Time to Treatment Failure for Any Reason: LEV + VPA + CLB vs Other Triple Therapy

¹Number of patients at risk refers to the number of patients who have not experienced an event (i.e., the event treatment failure of the event death) at that particular time point (e.g., 3 months) and who are still at risk of experiencing an event (i.e., not censored). CIF = cumulative incidence function; CLB = clobazam; LEV = levetiracetam; n = number of patients; VPA = valproic acid.

Figure 2. Time to Recurrent Seizure: LEV + VPA + CLB vs Other Triple Therapy

¹Number of patients at risk refers to the number of patients who have not experienced an event (i.e., the event treatment failure of the event death) at that particular time point (e.g., 3 months) and who are still at risk of experiencing an event (i.e., not censored). ²Patients who experienced treatment failure (due to adverse effects, withdrawal due to remission, or other reasons) before experiencing their recurrent seizure can no longer experience a recurrent seizure on their first-line monotherapy LEV or VPA, and therefore, treatment failure was handled as competing risk. CIF = cumulative incidence function; CLB = clobazam; LEV = levetiracetam; n = number of patients; VPA = valproic acid.