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.
Age ≥ 18 years old
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
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
Maximum daily dexamethasone use of 1 mg/day for the 8 weeks preceding randomization
Prior treatment with bevacizumab <6 months before diagnosis of sCRN
Life expectancy <3 months
Impending radiological or clinical signs of brain herniation necessitating immediate decompressive surgery
Intolerance for murine proteins
Parallel
Bevacizumab
DrugIntravenous bevacizumab at a 600 mg flat dose every three weeks for four courses over 12 weeks
Dexamethasone
DrugDaily oral dexamethasone followed by a protocol-based tapering dose over 12 weeks
Clinical efficacy: dexamethasone ≤ 1.5 mg/day plus KPS increased ≥10 with stable NANO (1)
The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care. The Neurologic Assessment in Neuro-Oncology (NANO) scale evaluates nine neurologic domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, consciousness, and behavio) each scored from normal (0) to most impaired (2-3), with a maximum total score of 23.
Clinical efficacy: dexamethasone ≤ 1.5 mg/day plus NANO increased ≥ 2 with stable KPS (2)
The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care. The Neurologic Assessment in Neuro-Oncology (NANO) scale evaluates nine neurologic domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, consciousness, and behavio) each scored from normal (0) to most impaired (2-3), with a maximum total score of 23.
Clinical efficacy: dexamethasone ≤ 1.5 mg/day plus KPS and NANO both improved (3)
The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care. The Neurologic Assessment in Neuro-Oncology (NANO) scale evaluates nine neurologic domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, consciousness, and behavio) each scored from normal (0) to most impaired (2-3), with a maximum total score of 23.
Clinical efficacy: dexamethasone ≤ 1.5 mg/day plus stable KPS/NANO with headache improved (NRS ≥2, remaining <5) (4)
The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care. The Neurologic Assessment in Neuro-Oncology (NANO) scale evaluates nine neurologic domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, consciousness, and behavio) each scored from normal (0) to most impaired (2-3), with a maximum total score of 23. The headache intensity is measured using the 0-10 Numeric Rating Scale (NRS), where 0 indicates no pain and 10 the worst imaginable pain.
Health-related quality of life using the EORTC-QLQ-C30
The EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30) is a validated tool designed to assess the overall health-related quality of life in cancer patients. It consists of 30 items measuring five functional scales (physical, role, emotional, cognitive, and social functioning), three symptom scales (fatigue, pain, and nausea/vomiting), a global health status/quality of life scale, and five single items evaluating additional symptoms (dyspnea, insomnia, appetite loss, constipation, and diarrhea) as well as perceived financial impact. Each item is scored on a 4-point Likert scale (1 = "Not at all" to 4 = "Very much"), except for the global quality of life domain, which is rated on a 7-point Likert scale. For functional and global quality of life scales, higher scores indicate better functioning and quality of life. For symptom scales and single items, higher scores reflect greater symptom burden and worse quality of life.
Health-related quality of life using EORTC-QLQ-BN20
The EORTC QLQ-BN20 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Brain Neoplasm 20) is a brain cancer-specific module designed to assess the quality of life in brain cancer patients. It consists of 20 items, including seven symptom items (headaches, seizures, drowsiness, hair loss, itchy skin, leg weakness, and bladder control) and four multi-item scales (future uncertainty, visual disorder, motor dysfunction, and communication deficit). Each item is scored on a 4-point Likert scale (ranging from 1 = "Not at all" to 4 = "Very much"). The total score is converted to a 0-100 scale, with higher scores indicating a worse quality of life due to greater symptom burden.
Health-related quality of life using the QLQ-IADL-BN32
The EORTC QLQ-IADL-BN32 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Instrumental Activities of Daily Living in Brain Neoplasms 32) is a validated questionnaire designed to assess the quality of life of brain tumor patients in relation to their ability to perform instrumental activities of daily living (IADL). It consists of five multi-item scales and two single-item scales, with each item scored on a 4-point Likert scale (ranging from 1 = "Not at all" to 4 = "Very much"). The total score is converted to a 0-100 scale, where higher scores indicate a greater impairment in IADL and worse quality of life.
Clinical efficacy using the KPS
The Karnofsky Performance Score (KPS) is a standard tool used to assess a patients' overall functional status and ability to carry out daily activities. The KPS is scored on a scale of 0 to 100, with higher scores indicating better physical function and lower scores indicating greater disability or dependence on others for care.
Immuno-oncology protein biomarkers using Olink Target 96 Immuno-oncology panel
Immuno-oncology proteins as blood-based biomarkers for (early) treatment response in both treatment arms using Olink Target 96 Immuno-oncology panel
Tumour educated platelets
Platelet RNA profiles as blood-based biomarkers for (early) treatment response in both treatment arms
Pharmacokinetics bevacizumab and dexamethasone
Bevacizumab and dexamethasone serum and plasma concentrations pre- and post-dose
Click on the lead sponsor to view all of their trials.
The Netherlands Cancer Institute
Lead sponsor
UMC Utrecht
Collaborator
Amsterdam UMC
Collaborator
Medical Center Haaglanden
Collaborator
Leiden University Medical Center
Collaborator
Maastricht University Medical Center
Collaborator
