Withdrawal of antiepileptic drugs in low grade and anaplastic glioma patients after long-term seizure freedom

Epilepsy is common in patients with brain tumours with incidence rates from
20-85%, depending on tumour type. Slowly growing tumours, mainly consisting of
low grade gliomas (LGGs) and anaplastic gliomas, are most epileptogenic. A
decrease in seizure frequency is known to contribute to less morbidity and
improved quality of life. LGGs and anaplastic gliomas are associated with
substantially longer survival compared to glioblastoma multiforme. Therefore,
sustained seizure control in these patients is an important part of the brain
tumour treatment.

Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Apart from
the AEDs, the anti-tumour treatment which currently consists of surgery,
radiotherapy and/or chemotherapy, largely contributes to a reduction in seizure
frequency. In patients with seizure freedom after anti-tumour therapy the
question raises whether AEDs should be continued endlessly, particularly
because AEDs may cause side effects and negatively impact neurocognitive
functioning and quality of life. Small observational studies on AED use in
meningioma and LGG patients show ongoing seizure freedom after AED withdrawal
in a majority of patients. However, knowledge about the feasibility of AED
withdrawal after anti-tumour therapy and the effect on seizure frequency in
glioma patients is currently lacking. In patients with non-tumour-related
epilepsy AED use is generally discontinued after a prolonged period of seizure
freedom. We think a similar decision is justified in glioma patients,
particularly those with both long-term stable disease activity and prolonged
seizure freedom.

We propose to explore the possibility of AED withdrawal in LGG and WHO grade
III glioma patients with seizure freedom after anti-tumour therapy and without
signs of tumour activity for at least one year. The decision to withdraw AEDs
will be effectuated provided that the treating physician and the patient both
agree on this decision. Otherwise, the existing AED regime will be continued.
The decision to continue or withdraw AEDs and the subsequent effect on seizure
frequency will be closely monitored in all patients. As the possibility of AED
withdrawal is explored in a carefully selected group of glioma patients, this
study may contribute to a more tailored AED treatment and prevent unnecessary
and possibly harmful AED use in glioma patients.

Primary Objectives: To identify the rate of successful AED withdrawal in LGG
and anaplastic glioma patients with epilepsy and long-term seizure freedom
after anti-tumour therapy.

Secondary Objectives:
- Exploring the physician*s and patient*s decision to either continue or
withdraw AEDs after prolonged period of seizure freedom.
- Prospective monitoring of ongoing seizure freedom and AED treatment from the
point of decision of AED withdrawal or continuation.
- Evaluating the association between seizure recurrence and tumour recurrence
- Evaluating treatment-related adverse events

Patients with a histologically confirmed LGG or anaplastic glioma treated in
the VUmc, Medical Centre Haaglanden (MCH) or Erasmus MC will be included.
Patients with epilepsy, stable disease and seizure freedom one year after
anti-tumour therapy will be included, as well as patients with non-acute
symptomatic post-operative or post radiation seizures when seizure freedom
exists for at least two years.

The investigator explores which patients experience seizure freedom as
described above and are eligible for inclusion. Before the possibility of AED
withdrawal will be discussed with the patient, the treating physician (mostly
the neuro-oncologist) must consider the patient appropriate for withdrawal.
AEDs will be continued when the physician finds any clinica disadvantages in
AED withdrawal (e.g. due to status epilepticus in medical history, high
morbidity risk with recurrent seizures). Physician*s objection*s against AED
withdrawal will be recorded. When the patient fulfills all in- and exclusion
criteria (see 4.2) and the physician has no objections to withdraw, the
decision will be discussed at the next regular appointment at the out-patient
clinic. The patient and the treating physician subsequently make a shared
decision on the preferred AED treatment (continuation or withdrawal). In case
of reluctance to discontinue AEDs, patient*s and/or physician*s arguments
against withdrawal are explicitly recorded. AEDs are withdrawn according to a
fixed schedule.

Patients will be divided in 2 groups: one in which AEDs are continued and the
other in which AEDs are withdrawn. Follow-up in patients that withdraw AEDs
takes place 6 weeks and 3 months after start of withdrawal. Patients that
continu AEDs will have standard follow-up depending on tumour type and
symptoms, usually every 6 months. During follow-up data about AED treatment,
including start of AED withdrawal and completion of withdrawal where
applicable, as well as data about seizure frequency and type, adverse effects
and brain tumour symptoms and its treatment will be collected. The follow-up is
part of the regular treatment of LGG and anaplastic glioma patients at the
outpatient clinic. In case of seizure recurrence, AEDs will be adapted or
restarted according to the expertise of the treating physician.

The proposed withdrawal of AEDs is a widely used practice in patients with
seizures without a brain tumour. We think that the benefits of withdrawing AEDs
in LGG patients may outweigh the disadvantages of endless AED continuation,
particularly in patients that experience seizure freedom for a prolonged period
of time. AED reduction may contribute to a decrease in adverse drug reactions
and improve cognition and quality of life. Given the antiepileptic effect of
the anti-tumour therapy and relatively good prognosis in these patients, we
consider the risk of seizure recurrence acceptably low to withdraw AEDs.
Seizure recurrence might result in a status epilepticus or cause additional
traumatic injuries. However, similar risks are present in case of renewed
tumour growth, when seizure recurrence appears to be inevitable in most
patients despite their AED treatment.