Corticodependent or Corticoresistant Brain Radionecrosis After Radiotherapy for Brain Metastases

Inclusion Criteria:

• Patient with a diagnosis of radionecrosis based on a clinical onset of symptoms andradiological findings of RN following radiotherapy, with or without pathologicalconfirmation:

MRI evidence to support the diagnosis of RN (transient increase in irradiated lesion volume -FLAIR hypersignal and/or enhanced portion- without rCBV increase) COMBINED with nuclear medicine imaging:

biphasic 18FDG-PET-TDM/MRI according to Horky or 18F-FDOPA with stage 0-1 according to Lizarraga;

• Symptoms are persistent or worsening despite administration of corticosteroids: atleast 1 mg/kg/d of prednisolone or equivalent:

Corticoresistant: neurological symptoms despite administration of at least 2 weeks of 1 mg/kg/d prednisolone or equivalent; Corticodependant: worsening of neurological signs or symptoms after an initial improvement when weaning off steroids at a dose < 0.5 mg/kg/d prednisolone or equivalent;

• Patients must have received the last cranial irradiation with photons or protontherapy for brain metastases ≥ 3 months with one or more sequences;

• Age≥18-year-old;

• ECOG performance status score ≤ 3

• Life expectancy of at least 3 months assessed by graded prognostic score (DS-GPA)score 0.5 or greater;

• Patient who has never received Bevacizumab for the indication of radionecrosis.

• Adequate organ function:

Bone marrow function

• Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 Platelet Count ≥ 100,000/mm3,Haemoglobin ≥ 10 g/dL (allowing transfusion or other intervention to achieve thisminimum haemoglobin) Coagulation

• International normalized ratio (INR) or prothrombin time < 1.5 × ULN Renal function

• No proteinuria with urine dipstick for proteinuria > 2+

• Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min (measured orcalculated using the CDK-EPI formula) Hepatic Function

• Total bilirubin ≤1.5 x the upper limit of normal (ULN)

• Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN

• Women of childbearing potential must use effective contraceptive measuresduring the treatment and for 6 months following its cessation;

• Signed informed consent;

• Patient affiliated to a social security scheme.

Exclusion Criteria:

• Evidence of active bleeding or a pathological condition at high risk of bleeding:CNS hemorrhage, bleeding diathesis or coagulopathy, hemoptysis (>2.5ml of bright redblood per episode), evidence of history of bowel obstruction, abdominal fistula, orgastrointestinal tract perforation or gastro intestinal abscess occurring less than 28 days prior study entry;

• Grade 4 venous thromboelism and peripheral arterial thrombus

• Evidence of very high intracranial pressure that suggests brain hernia and needsemergency surgery;

• Major surgical procedure or significant traumatic injury less than 28 days priorstudy entry; minor surgery within 3 days prior to initiation of study treatment;

• Clinically significant cardiovascular disease such as uncontrolled arterialhypertension (BP ≥160 mm Hg or diastolic BP ≥100 mm Hg despite maximal medicaltherapy), cerebrovascular event, myocardial infarction, cardiac arrhythmias,unstable angina, or congestive heart failure within the last 6 months;

• History of hypertensive crisis or hypertensive encephalopathy

• Patients scheduled to undergo head and neck, thoracic, or abdominal radiotherapyduring the study treatment

• Prior bevacizumab ≤ 3 months before randomization;

• Progressive brain metastases;

• History of severe allergic anaphylactic reactions to bevacizumab

• Patients with a known hypersensitivity to the active substance or to any of theexcipients of bevacizumab are not eligible for participation;

• Patients with a contraindication to the treatment with bevacizumab according to theEuropean SmPC

• Patient pregnant and/or nursing;

• Mental impairment (psychiatric illness/social situations) that may compromise theability of the patient to give informed consent and comply with the requirements ofthe study;

• Patient who has forfeited his/her freedom by administrative or legal award or who isunder guardianship;

• New cerebral metastasis detected during the inclusion imaging evaluation;

• Prior diagnosis of Posterior Reversible Encephalopathy Syndrome (PRES) withbevacizumab;

• Hypersensitivity known to Chinese Hamster Ovary (CHO) cell products or otherrecombinant human or humanised antibodies.