Seizure Treatment IN Glioma (STING): comparing a treatment strategy with levetiracetam versus treatment with valproic acid in glioma patients with a first seizure

Gliomas are the most common malignant primary brain tumors, with an annual
incidence of 6 cases per 100.000 persons. Despite the fact that gliomas are a
relatively rare malignancy, they result in a disproportionate share of cancer
morbidity and mortality. To date, multimodal treatment with surgery,
chemotherapy and radiotherapy does not result in cure, although prolongation of
(progression-free) survival can be achieved. Median survival rates range from
15 months to more than 15 years, depending on tumor histology and molecular
parameters.

Epileptic seizures are a common symptom in patients with gliomas. The chance of
developing a seizure depends on the tumor type, tumor location and its
proximity to the cortical gray matter. In general, the epileptogenicity of the
tumor is inversely related with its growth rate. In other words, low-grade
gliomas (LGG) are more epileptogenic than faster growing tumors such as
glioblastomas (GBM). Approximately 70-90% of all LGG patients present with
epilepsy compared to 30-60% of high-grade glioma (HGG) patients.

Previous studies have shown that a reduction in seizure frequency is associated
with less morbidity and improved health-related quality of life (HRQoL).
Therefore, achieving sustained seizure control is one of the main goals of
treatment in patients with brain tumor-related epilepsy. Both antiepileptic
drugs (AEDs) and antitumor treatment may lead to seizure control. Nevertheless,
treatment with AEDs may also cause side effects, which may have a negative
impact on the patients* neurocognitive functioning and HRQoL. Moreover,
enzyme-inducing AEDs may interfere with chemotherapeutic drugs and
corticosteroids, leading to additional side effects. In due course, more than
one third of patients will be refractory to AED treatment.

Guidelines recommend that patients with brain tumor-related epilepsy who
experienced at least one seizure should receive anticonvulsant drug treatment
until the tumor is controlled. If seizure freedom is achieved, tapering of AEDs
could be attempted. In case of seizure recurrence, anticonvulsant treatment
should be (restarted and) continued during the whole disease trajectory. The
choice of drug is guided by various considerations, such as tolerability,
adverse effects, and interactions with other agents, and no specific AED is
recommended. Although there are no studies who support the use of a specific
AED in brain tumor patients, the Dutch Society of Neurology recommends to use
of non-enzyme inducing AEDs such as levetiracetam, valproic acid or
lamotrigine. A second choice would be gabapentin or pregabalin. Due to their
enzyme-inducing effect, interfering with chemotherapeutic drugs, treatment with
carbamazepine, phenobarbital, phenytoine, oxcarbazepine and toparimate are not
advised.

Currently, treatment of glioma patients with a specific AED mainly depends on
the physicians* preference, as there is no robust evidence from randomized
controlled trials supporting the use of one specific anticonvulsant above the
other in glioma patients. The effect of the most commonly used AEDs,
levetiracetam and valproic acid, on outcomes such as seizure freedom, toxicity,
and HRQoL, and also on survival has been investigated, but results have been
conflicting. This may be explained by small sample sizes and the retrospective
study design of most studies. Nevertheless, better information is necessary for
physicians to make evidence-based treatment decisions.

The overall aim of this strategy study is to directly compare the effectiveness
of treatment with levetiracetam or valproic acid in glioma patients with de
novo seizures. In addition, we aim to examine the level of toxicity, the impact
of seizures on HRQoL, performance status and survival.

In this strategy study, patients treated with levetiracetam or valproic acid
will be compared. Glioma patients with a first seizure will be allocated by
block randomization (stratified by follow-up frequency; 3-monthly follow-up or
6-monthly follow-up, as decided by the treating physician) to treatment with
levetiracetam (arm A) or valproic acid (arm B).
In case of insufficient response on initial treatment, patients go the next
treatment step as described in the protocol. In treatment step 2-4, drug dosage
will be increased and in step 5 another anticonvulsant will be added. The
choice of this add-on drug is based on the preference of the treating
physician. In case of failure on step 5, further treatment will be initiated
according to the physician*s preference. An insufficient response comprises
toxicity or ineffectiveness. Toxicity is defined as grade 2 or higher according
to the Common Toxicity Criteria for Adverse Events (CTCAE version 4.0) and
ineffectiveness as having a seizure despite treatment with AEDs.

Patients will receive either levetiracetam (brand name: *Keppra*) or valproic
acid (brand name: *Depakine*) for treatment of epileptic seizures.

There are no direct benefits for the patients participating in this study.
Nevertheless, their participation will contribute to a better understanding of
the effectiveness of treatment with levetiracetam or valproic acid in glioma
patients. Results of this study may provide the physician with better
information, which may facilitate the choice of a specific AED and subsequently
improve seizure treatment in this specific patient population.
In current daily clinical practice, patients receive either levetiracetam or
valproic acid, suggesting that there will be no additional risk for patients
(besides known adverse effects that are related to the drugs) participating in
this study. However, it will cost the participants time to complete the
questionnaires. Nevertheless, since follow-up is not that frequent and visits
will be integrated with their regular visits to the neuro-oncology outpatient
clinic, the participant burden is believed not to be substantial.