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, as determined by the local Multidisciplinary Neuro-Oncology Board. A clear working diagnosis of CRN without evidence of a combination with tumour progression is required
3. KPS score ≤ 90 and either (a) a minimum loss of two points in at least one domain of the Neurologic Assessment in Neuro-Oncology (NANO) scale as compared to the maximum score of that domain due to sCRN, or (b) a headache attributable to sCRN with an average intensity ≥5/10 on the NRS, persisting for ≥10 consecutive days, with inadequate relief despite an adequate trial of paracetamol and/or an NSAID unless these medications are contra-indicated or not tolerated
4. Maximum daily dexamethasone use of 1 mg/day for the 8 weeks preceding randomization

   1. Dexamethasone may have been prescribed for various indications, except for managing (ongoing) cerebral edema
   2. Higher doses of dexamethasone are permitted 3 weeks immediately preceding randomization if used specifically for the treatment of sCRN
5. Able to understand the patient information, online tests and questionnaires
6. 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 immediate decompressive surgery
4. Any comorbidity or condition that prevents safe administration of the studied medication, determined by the treating physician, including but not limited to:

   1. Intolerance for murine proteins
   2. Hypersensitivity or allergy to the active substance or to any of the excipients of bevacizumab or dexamethasone
   3. Nephrotic syndrome or abnormal renal function

      o Calculated (Cockcroft-Gault) or measured creatinine clearance \<30 mL/min; urine dipstick for proteinuria ≥ 2+. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate ≤ 1 g of protein/24 hr.
   4. 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 previous reversible posterior leukoencephalopathy syndrome (RPLS)
      * Non tumour related vascular event (e.g. cerebral or cardiac ischemia/bleeding (including transient ischemic attack, cerebral ischemia, unstable angina or angina requiring intervention, myocardial infarction), peripheral arterial thrombus, peripheral artery disease, deep venous thrombosis, 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 a pulmonary lesion with a high risk of bleeding (= central lung tumour and/or untreated squamous cell carcinoma) according to the treating physician
      * Active gastrointestinal bleeding \< 6 months
      * Evidence of recent intracranial hemorrhage on MRI brain \<3 months. Asymptomatic presence of hemosiderin depositions or punctate hemorrhage in the tumour do not serve as a ground for exclusion
   7. Excess risk of bleeding

      * History or evidence of inherited bleeding diathesis or significant coagulopathy 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 traumatic injury within 28 days prior to first study treatment or planned surgical procedure within the following next 28 days after planned study inclusion
      * Minor surgical procedure, stereotactic/core biopsy, fine needle aspiration within 7 days prior to first study treatment
   9. High-dose radiotherapy to the mediastinum, abdomen, or lower pelvis; administration of bevacizumab should only be considered after prior consultation with a pulmonologist or oncologist
   10. Pregnancy or lactation. Women of child bearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to randomization. WOCBP and female partners of male patients must comply with adequate contraception methods as requested by the study protocol
   11. Evidence of any other medical conditions (such as psychiatric illness, physical examination or laboratory findings) that may interfere with the study treatment, affect patient compliance or place the patient at high risk for treatment-related complications according to the treating physician
   12. Current or recent (within 30 days of first study treatment) treatment with another investigational drug or participation in another interventional study In case of uncertainty, consult the principal investigator of the study site.