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

Cerebral radiation necrosis (CRN) is a severe complication of high-dose radiation for brain metastases (BM) or glioma, which can potentially cause significant neurologic symptoms leading to serious morbidity and impaired quality of life (QoL). The first-line therapy for symptomatic CRN (sCRN) is corticosteroids, primarily dexamethasone, which often leads to complications, refractory symptoms, and interference with anti-cancer treatment. Since 2017, bevacizumab, an antibody against Vascular Endothelial Growth Factor (VEGF), has been used in a second-line treatment setting for refractory sCRN. A small randomized clinical trial (RCT) has shown that bevacizumab significantly diminishes cerebral edema on MRI and decreases clinical symptoms of sCRN in irradiated glioma patients. Several non-randomized clinical studies demonstrated a beneficial radiological and clinical effect of bevacizumab in patients with sCRN after irradiation for BM. The optimal first-line treatment for sCRN is currently unknown. Effective and safe first-line treatment of sCRN will optimize the patient's well-being and health-related QoL. Furthermore, minimizing corticosteroid use will benefit the clinical treatment options and outcomes of concomitant or future anti-cancer treatment. This phase III multicenter, open-label, randomized clinical trial compares the clinical efficacy of first-line bevacizumab versus standard-of-care dexamethasone for sCRN in patients with high-grade glioma (HGG) or BM.

The primary objective of this trial is to compare the clinical efficacy of first-line bevacizumab versus dexamethasone for sCRN in HGG and BM patients at 12 weeks.

Both patients with HGG and patients with BM will be randomly assigned in a 1:1 ratio to one of two following treatment arms.

ARM 1 Intervention arm: intravenous bevacizumab at a 600 mg flat dose every three weeks for four courses over 12 weeks at hospital daycare.

ARM 2 Control arm: daily oral dexamethasone followed by a protocol-based tapering dose over 12 weeks.

Patients in the intervention (bevacizumab) arm may use dexamethasone concurrently with bevacizumab if clinically indicated.

The study treatment will be administered over 12 weeks, with a follow-up period of 2 years. Patients in both arms will have regular inpatient hospital visits and MRI brain scans, complete the Amsterdam Cognition scan twice during treatment, complete QoL, epilepsy, productivity, and medical costs questionnaires during treatment and follow up, and undergo optional blood withdrawal for translational research purposes. Standard of care laboratory blood tests during treatment depend on the treatment arm.

Eligibility Criteria:
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 a minimum loss of two points in at least one domain of the NANO scale 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

   1. Dexamethasone may have been prescribed for various indications, except for managing (ongoing) cerebral edema
   2. Higher doses of dexamethasone are permitted during the week 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. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo 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 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
   12. 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
   13. 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.