Antiepileptic drug therapy in brain tumor patients: a complex relationship

Management of seizures is an important and challenging topic in neuro-oncology. Seizures are a common symptom in brain tumor patients with an incidence ranging from 20% to 80% depending on the underlying tumor type and location within the brain. While most patients can be effectively managed and achieve sufficient seizure control with monotherapy, others require combinations of antiepileptic drugs (AEDs). Both poorly controlled seizures and AED-associated side effects can have a negative impact on a patient’s well-being and quality of life. With a wide range of AEDs available to manage seizure disorders, the choice of a specific agent may be influenced by the side effect profile of the drug, the patient’s comorbidities, the type of seizures that are being treated, and the type of antineoplastic treatment regimen to avoid possible drug–drug interactions. However, large prospective and randomized controlled clinical trials that compare the efficacy of specific AEDs to control seizures in brain tumor patients are generally lacking.¹

Newer agents such as Levetiracetam and Lacosamide are often favored by healthcare providers managing brain tumor-related seizure disorders. This preference can be attributed to the compatibility of both drugs with conventional chemotherapy agents and perhaps their favorable side effect profile compared to older agents such as Phenobarbital, Phenytoin, Valproic acid, and Carbamazepine, even though these agents have historically proven effective in controlling brain tumor-related seizures.

The use of non-enzyme-inducing agents (non-EIAED) (eg, Levetiracetam and Lamotrigen) has been generally recommended and again highlighted in a recent EANO/ESMO clinical practice guideline.² An issue of some controversy has been the prophylactic use of AEDs in patients with primary or secondary brain tumors without known seizures. A recently updated SNO/EANO practice guideline paper renewed the prior recommendation to generally avoid prophylactic use of antiepileptics in brain tumor patients without prior seizures.³ Walbert et al. point out, however, that insufficient evidence exists in other scenarios, such as recommending AEDs to reduce seizure risk in the peri- or postoperative period.

In this issue of Neuro-Oncology Practice, van der Meer et al.⁴ provide some insights into the prescription preferences of antiepileptic drugs in brain tumor patients among members of the European Association of Neuro-Oncology (EANO) who manage patients with brain tumor-related epilepsy syndromes (BTRE). The findings were based on the responses to an electronic survey consisting of 31 questions. One hundred and seventy-nine out of 217 respondents completed the survey and 90% identified Levetiracetam as their preferred choice. The main reasons for this preference were related to the perceived efficacy in reducing seizure frequency, a preferential side effect profile compared to other AEDs, the lack of enzyme-inducing activities and consequently compatibility with most anticancer drugs. Lacosamide was also considered an acceptable first-line drug therapy to control seizures in brain tumor patients by a third of respondents, followed by lamotrigine and valproic acid as other good choices, though some regional preferences within European countries were identified.

The aim of the study was further to obtain insights into considerations that play a role when initiating or when discontinuing AED treatment. Prophylactic use of antiepileptics in patients without seizures was considered by a minority of 29% of respondents, and approximately 80% were in favor of drug discontinuation after completion of all cancer-directed therapies and in patients who have remained seizure-free. Notably, differences in prescription patterns were found among countries and between medical professions, such as between neurosurgeons and medical oncologists in terms of the preference for prophylactic use of AEDs in patients without known seizures and the timing of drug discontinuation.

With less than 200 responses analyzed and the virtue of a survey as the research tool and potential bias in respondents, the study has some limitations, and it is unclear to what extent this study is truly representative of prescription patterns in EANO providers and in various countries.

The best choice of AEDs in brain tumor patients is probably more complicated than previously anticipated and may go beyond the goal of seizure control given previous reports suggesting that the use of valproic acid may confer improved survival in brain tumor patients.⁵ Although this topic has been discussed controversially,⁶ recent discoveries regarding the role of neuronal activity, neurotransmitters, ion channels and glutamatergic synaptic activity in tumor biology and the tumor microenvironment^7–9 implicate a much more complex relationship between brain tumors, seizures, and AEDs, highlighting the need for further research in this field of neuro-oncology.