Precision Radiation treatment for Epilepsy

The PRECISION trial offers a non-invasive, curative intervention for patients
with resistant focal epilepsy who are not eligible for open brain surgery. The
intervention will consist of a single LINAC (Linear Accelateror) based
stereotactic radiotherapy (SRT) treatment and is given by the
radiotherapist-oncologist after detailed localization of the epileptogenic zone
(EZ) together with the neurologist, radiologist and neurosurgeon. This
intervention is not yet available in the Netherlands and is not reimbursed and
in selected patients, who would otherwise be treated palliatively, will offer 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. A cost-effectiveness analysis is performed for this study.
This analysis also includes indirect costs of the informal caregivers of the
included epilepsy patients in the PRECISION trial. We assume that: SRT is
curative and is a non-inferior treatment option compared with the palliative
standard treatment (ie, antiepileptic drugs (AEDs) and neuromodulation), for
patients with drug-resistant focal epilepsy, who are not eligible for
neurosurgery, which will result in a higher reduction in seizures (with 50% of
patients achieving a 75% reduction after 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.

Randomised waitlist controlled trial in which SRT is the intervention and AED
continuation and neuromodulation are the standard treatment with a 1:1
randomization. After 2-year follow up (waitlist) of the controlgroup, patients
are offered the intervention (optional). 

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.

Benefit-risk balance: It is not known if SRT is superior to the standard
treatment for patients not eligible for curative resective epilepsy surgery
(which is the control group: AED and neuromodulation). For the patients in the
waitlist-control group there is no additional risk, since they receive the
current standard of care treatment during the 2 year waiting/follow-up time.
Also the risk for sudden unexpected death in epilepsy (SUDEP) is equal. Given
the chronic nature of the epilepsy there is no additional risk.

For the patients treated with SRT the risks are based on the location of the EZ
zone. Information is available from treatment of patients with epilepsy, brain
metastases or benign brain lesions. Treatment related side effect in patients
with epilepsy are based on an update of the review of Eekers et al. 2018.

The most common acute side-effect of SRT is a headache, nausea and/or vomiting
caused by reversible intracranial oedema and can be treated with
corticosteroids. Long-term side-effects include transient neurological deficits
and exacerbation of seizures, magnetic resonance imaging (MRI) changes,
expected and mostly asymptomatic superior quadrantanopia (for lesions treated
in the temporal lobe), ischemic events, cognitive changes [L. Douw et al.,
2009] and radiation necrosis rarely leading to symptomatic oedema or cysts
requiring surgical intervention [N.M. Barbaro et al. 2018], [D.B.P. Eekers et
al 2018].

If the EZ zone is close to the pituitary, potential risks can be estimated from
the literature of treatment of patients with a pituitary tumor. 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 have a similar risk due to the
close relationship with the internal carotid artery [M.G.A. Sattler et al.
2013], [P.D. Brown et al. 2014].

For patients with a pituitary adenoma it is known that hypopituitarism can
occur after conventional and stereotactic radiotherapy in 50% of the patients,
10 years after treatment [G. Minniti et al. 2011], [G. Barrande et al. 2000],
[N.R. Biermasz et al. 2000]. However, in patients with a non-functional
pituitary adenoma population in 37-85% of the patients has already
hypopituitarism at the start of diagnosis [C.E. Higham et al. 2016]. Deficit of
hormone production after conventional radiotherapy of the pituitary with 45Gy
is 45-100% for GH, 18-30% for LH/FSH, 15-22% for ACTH and 25% for TSH [K. H.
Darzy et al. 2009], [P.J. Jenkins et al. 2006].

Location in the eloquent cortex is associated with neurological complications
in patients with brain metastasis, therefore when the location of the EZ is
within the eloquent areas we can limit the dose prescription to 18Gy in order
to reduce this risk.

The possible side effects of SRT will be registered carefully and will be
weighed against the anticipated gain in quality of life. Side-effects from
AED's include nausea and vomiting, ataxia, somnolence and rare, idiosyncratic
reactions. DBS involves the surgical placement of neurostimulators in the
brain, reducing seizure frequency while in the epileptogenic zone, and has
headache, infection, seizure, cerebral haemorrhage, stroke, confusion and
difficulty concentrating as potential side-effects. NVS is performed by
implantation an electrode coil around the left cervical vagus nerve connected
with a subcutaneous lead to the pulsgenerator in a subcutaneous thoracic pocket
reducing the seizure frequency up to 50% in two thirds of the patients with
hoarseness, bradycardia, infection, paraesthesia and dysphonia as known
side-effects [A.D. Farmer et al. 2016].