Fractionated stereotactic radiotherapy in people with drug-resistant focal epilepsy: first-in-human experience with a healthy tissue-preserving dose-fractionation concept.

Objective: Stereotactic radiosurgery (SRS) emerges as a non-surgical treatment option for drug-resistant non-neoplastic focal epilepsy. Previous studies have reported that in about 20% of patients treated with radiotherapy, however, subsequent salvage surgery is required, among other because of symptomatic radiation necrosis (RN). We propose a novel and radiobiologically substantiated dose-fractionation regimen which minimizes the RN risk while aiming to preserve efficacy and report our first-in-human experience. Methods: From February 2021 to April 2024, three patients (aged 42, 45, and 47 years) with different underlying etiologies were treated, including a post-hemorrhagic lesion, Rasmussen encephalitis, and focal cortical dysplasia. We applied linac-based frameless fractionated stereotactic radiotherapy (fSRT) to a total dose of 50 Gy in 10 fractions over 2 weeks. Each epileptogenic zone was defined by a multidisciplinary team, including a radiation oncologist, epileptologist, neurosurgeon, and neuroradiologist. Results: The irradiated volumes were 10.3, 11.3, and 16.5 cm Significance: Frameless fSRT of 50 Gy in 10 fractions was feasible and might be safe and effective in selected patients with drug-resistant non-neoplastic focal epilepsy and large suspected epileptogenic zones. A prospective single-arm evaluation with structured long-term follow-up including assessment of patient-reported outcome measures is currently being conducted.