Bevacizumab Versus Corticosteroids As First-line Treatment in Patients with Symptomatic Cerebral Radiation Necrosis After Radiation for High-grade Glioma or Brain Metastases

Inclusion Criteria:

Inclusion all patients (both HGG and BM):

1. Age ≥ 18 years old

2. First episode of sCRN ≥ 3 months after completion of focal (re-)irradiation, asdetermined by the local Multidisciplinary Neuro-Oncology Board. A clear workingdiagnosis of CRN without evidence of a combination with tumour progression isrequired

3. KPS score ≤ 90 and a minimum loss of two points in at least one domain of the NANOscale as compared to the maximum score of at that domain due to sCRN

4. Maximum daily dexamethasone use of 1 mg/day for the 8 weeks preceding randomization

5. Dexamethasone may have been prescribed for various indications, except formanaging (ongoing) cerebral edema

6. Higher doses of dexamethasone are permitted during the week immediatelypreceding randomization if used specifically for the treatment of sCRN

7. Able to understand the patient information, online tests and questionnaires

8. Written informed consent

Inclusion BM:

1. BM of solid tumour, including all primary tumour types

Inclusion HGG:

1. A confirmed histological diagnosis of high-grade diffuse glioma according to WHO 2021 criteria, including: astrocytoma, IDH-mutant, grade 3-4; astrocytoma,IDH-wildtype (sybtype molecular glioblastoma); oligodendroglioma, 1p/19q codeleted,grade 3; diffuse glioma, NEC, grade 3-4; or glioblastoma, IDH-wildtype, grade 4

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study, both for the BM and HGG group:

1. Prior treatment with bevacizumab <6 months before diagnosis of sCRN

2. Life expectancy <3 months

3. Impending radiological or clinical signs of brain herniation necessitating immediatedecompressive surgery

4. Any comorbidity or condition that prevents safe administration of the studiedmedication, determined by the treating physician, including but not limited to:

5. Intolerance for murine proteins

6. Hypersensitivity or allergy to the active substance or to any of the excipientsof bevacizumab or dexamethasone

7. Nephrotic syndrome or abnormal renal functiono Calculated (Cockcroft-Gault) or measured creatinine clearance <30 mL/min;urine dipstick for proteinuria ≥ 2+. Patients with ≥ 2+ proteinuria on dipstickurinalysis at baseline should undergo 24 hours urine collection and mustdemonstrate ≤ 1 g of protein/24 hr.

8. Clinical significant cardiovascular disease

• Uncontrolled hypertension (systolic BP >150mmHg and/or diastolic >100mmHg)despite the use of ≥ 3 antihypertensive drugs
• Previous hypertensive crisis, hypertensive encephalopathy or previousreversible posterior leukoencephalopathy syndrome (RPLS)
• Non tumour related vascular event (e.g. cerebral or cardiacischemia/bleeding (including transient ischemic attack, cerebral ischemia,unstable angina or angina requiring intervention, myocardial infarction),peripheral arterial thrombus, peripheral artery disease, deep venousthrombosis, lung embolism) < 6 months
• History of aortic aneurysm or dissection
• Congestive heart failure NYHA II-IV

5. History of gastro-intestinal fistula, perforation or abscess < 6 months

6. History of bleeding

• Relevant pulmonary hemorrhage/ hemoptysis < 1 month or the presence of apulmonary lesion with a high risk of bleeding (= central lung tumourand/or untreated squamous cell carcinoma) according to the treatingphysician
• Active gastrointestinal bleeding < 6 months
• Evidence of recent intracranial hemorrhage on MRI brain <3 months.Asymptomatic presence of hemosiderin depositions or punctate hemorrhage inthe tumour do not serve as a ground for exclusion

7. Excess risk of bleeding

• History or evidence of inherited bleeding diathesis or significantcoagulopathy with the risk of bleeding
• Decreased platelet count < 75x109/L

8. Risk of wound healing complications

• Significant non-healing wound, (peptic) ulcer or bone fracture
• Major surgical procedure (including open biopsy) or significant traumaticinjury within 28 days prior to first study treatment or planned surgicalprocedure within the following next 28 days after planned study inclusion
• Minor surgical procedure, stereotactic/core biopsy, fine needle aspirationwithin 7 days prior to first study treatment

9. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline shouldundergo 24 hours urine collection and must demonstrate ≤ 1 g of protein/24 hr.

10. Previous, current or planned high dose radiotherapy in the abdomen

11. Pregnancy or lactation. Women of child bearing potential (WOCBP) must have anegative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent unitsof HCG) within 7 days prior to randomization. WOCBP and female partners of malepatients must comply with adequate contraception methods as requested by thestudy protocol

12. Evidence of any other medical conditions (such as psychiatric illness, physicalexamination or laboratory findings) that may interfere with the studytreatment, affect patient compliance or place the patient at high risk fortreatment-related complications according to the treating physician

13. Current or recent (within 30 days of first study treatment) treatment withanother investigational drug or participation in another interventional studyIn case of uncertainty, consult the principal investigator of the study site.