Fractionated Stereotactic Radiotherapy in People with Drug-Resistant Focal Epilepsy: First-in-Human Experience with a Healthy Tissue-Preserving Dose-Fractionation Concept

Cas Stefaan Dejonckheere^1*Attila Racz¹Gustavo R. Sarria¹Julian Philipp Layer¹Younèss Nour¹Lara Caglyan¹Molina Grimmer¹Victoria Volkenborn¹Fabian Kugel¹Thomas Müdder¹Tobias Baumgartner¹Valeri Borger¹Alexander Radbruch¹Hartmut Vatter¹Frank Anton Giordano²Eleni Gkika¹Rainer Surges¹Davide Scafa¹

• ¹University Hospital Bonn, Bonn, Germany
• ²University Medical Center Mannheim, Mannheim, Germany

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 two weeks. Each epileptogenic zone was defined by a multidisciplinary team, including a radiation oncologist, epileptologist, neurosurgeon, and neuroradiologist.The irradiated volumes were 10.3, 11.3, and 16.5 cm 3 . After a follow-up of 12, 29, and 36 months, all three patients experienced an improvement in both seizure frequency and severity (two already during or shortly after fSRT). One patient achieved complete seizure freedom. All patients reported improvements in quality of life and regained independence or displayed functional recovery. Tolerability was excellent, with radiation-induced side effects being mild (grade 1 only) and transient. RN was not observed. One patient died 29 months after radiotherapy most likely from a ruptured aneurysm of a vertebral artery, unrelated to the treatment.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.