Precision Radiation treatment for Epilepsy

Rationale: The PRECISION-study offers a non-invasive, curative intervention for
patients with drug-resistant focal epilepsy who are not eligible for open
brainsurgery. The intervention will consist of a single LINAC-based
stereotactic radiotherapy (SRT) treatment and is given by the
radiation-oncologist after detailed localisation of the epileptogenic zone (EZ)
by the neurologist, radiologist and neurosurgeon. This intervention is not yet
available and reimbursed in The Netherlands and will offer the selected
patient, who otherwise would be treated with palliative therapy, a non-invasive
curative treatment option as a non-competitive alternative to epilepsy surgery.
It is expected that the health costs for this curative treatment will not
exceed standard treatment, such as lifelong medication and neuromodulation. We
hypothesize that: SRT is a superior treatment option compared to palliative
standard of care (i.e. anti-epileptic drugs (AED's) and neuromodulation), for
patients with drug-resistant focal epilepsy, not eligible for open surgery,
which will result in a higher reduction of seizures (with 50% of the patients
reaching a 75% reduction at 2 years).

Objectives: Primary: to determine whether SRT reduces the seizure frequency
resulting in a reduction of at least 75% (RAEC I-III) in patients with
drug-resistant focal epilepsy when compared to standard of care. Secondary:
Assess quality of life (QoL) after SRT, define safety, (serious) adverse
effects, AED use and tolerability of SRT, investigate the cost-effectiveness
(CEA) of SRT compared to standard of care.

Study design: Randomised controlled trial in which SRT is the intervention and
AED continuation and neuromodulation are the standard treatment with a 1:1
randomization to firmly establish QoL and CEA. Randomisation will be based on
block randomisation with variable block size of 2, 4 and 6.

Intervention: LINAC-based Stereotactic Radiotherapy (SRT): Target definition:
the target volume is defined as the epileptogenic zone (EZ) on all (non)
invasive examinations of the presurgical trajectory. A single fraction SRT with
a prescribed isotoxic dose of 24 Gy to the 100% surrounding isodose.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: There is currently in the Netherlands no
non-invasive, curative intent treatment for adult/pediatric patients with
drug-resistant, focal epilepsy, who are not eligible for surgery, therefore
there is an unmet need for the innovative treatment that the PRECISION-trial
will provide. SRT for epilepsy is already applied in neighboring European
countries (e.g. France, Belgium and Germany), the USA, China and Japan with
reported effectiveness is 58% post-treatment satisfactory seizure outcome (RAEC
scale I + II = no to rare seizures) at 2 years follow-up.

The risks of the SRT treatment are based on the location of the EZ zone.
Information is available in the literature on the risks of treating patients
with epilepsy, brain metastases or benign brain lesions.

The most common acute adverse reaction of SRT is headache, nausea and/or
vomiting caused by reversible intracranial edema and can be treated with
corticosteroids. Long-term side effects include transient neurologic deficits
and seizure exacerbation, changes in mMagnetic resonance imaging (MRI),
expected and usually asymptomatic superior quadrantanopia (for lesions treated
in the temporal lobe), ischemic events, cognitive changes, and radiation
necrosis rarely leading to symptomatic edema or cysts requiring surgical
intervention.

If the EZ zone is close to the pituitary, potential risks can be estimated
based on the literature on the management of patients with pituitary tumors.
Cerebral infarction has been described as a long-term complication of
stereotactic radiotherapy of benign skull base tumors, mainly pituitary tumors
(SIR 1.48 - 4.2). When treating the amygdala, patients may face a similar risk
due to its close relationship with the internal carotid artery].

In patients with a pituitary adenoma, it is known that hypopituitarism can
occur after conventional and stereotactic radiotherapy in 50% of patients, 10
years after treatment. However, in patients with a non-functional pituitary
adenoma population in 37-85% of patients already have hypopituitarism at the
time of diagnosis. Hormone production deficiency after conventional
radiotherapy of the pituitary gland with 45Gy is 45-100% for GH, 18-30% for
LH/FSH, 15-22% for ACTH and 25% for TSH.


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