*3.2. Identification of a Patient Cohort with Cerebral Radiation NECROSIS and Treatment with Bevacizumab*

Forty patients with bevacizumab treatment and cerebral radiation necrosis were identified. Routine cortisol testing is not included in institutional guidelines and at least one cortisol analysis was available in 17 of these patients. Fifteen patients (88%) suffered from primary brain tumours (six GBs, five anaplastic astrocytomas, two diffuse astrocytomas, one ependymoma, one anaplastic meningioma). One patient had a radiation necrosis of the frontal lobe after radiation therapy of a paranasal extracranial tumour, and one patient had a tumour of the cervical myelon without histological confirmation of the tumour entity. Patients' mean age at the time of tumour diagnosis was 43 years (range 20–65), whereas at the time of cortisol analysis patients were 48 years (range 29–67). Six patients were treated with radiation therapy as first-line treatment; 11 patients had repeated radiation treatment of a recurrent tumour prior to bevacizumab. All but two patients were treated with conventional radiation therapy. Radiation doses varied from 54 to 60 Gy for first-line therapy and 20 to 36 Gy for recurrent tumours. One patient treated for meningioma had undergone C12 ion irradiation; another patient suffering from ependymoma had been treated with stereotactic radiosurgery. In three patients, bevacizumab was part of a tumour therapy regimen; the other 14 patients received 1–7 infusions of bevacizumab, specifically as a treatment of radiation necrosis (Table S1).

Bevacizumab was highly effective in reducing local disruption of the BBB and reducing brain edema, as all patients showed a partial response—defined as a reduction of contrast enhancement by at least 50% in the first follow-up MRI. Fifteen of the 17 patients had a reduction of the edema by at least 25%. However, one GB patient 58 years of age receiving treatment for radiation necrosis after re-irradiation with a cumulative dose of 20 Gy suffered a major stroke after seven infusions as a potential bevacizumab side effect. Two patients developed hypertension, which required antihypertensive medication; otherwise, bevacizumab was well tolerated.
