Corticodependent or Corticoresistant Brain Radionecrosis After Radiotherapy for Brain Metastases

Overview

Brain metastases (BM) afflict a significant portion of cancer patients, ranging from 10% to 50%, leading to debilitating symptoms and diminished quality of life, thereby impacting overall survival. Treatment options typically include surgery, stereotactic radiosurgery (SRS), and whole brain radiotherapy (WBRT). SRS has emerged as the preferred focal treatment due to its efficacy, delivering ablative doses with notable overall survival benefits, especially for single BM or postoperative cases, while being less invasive than neurosurgery and capable of addressing inoperable sites and multiple lesions. Contrastingly, WBRT is now reserved for select cases with multiple BMs ineligible for SRS, owing to its lower rate of neurocognitive toxicities and high local control rates at one year. Despite its advantages, SRS can engender late side effects, with cerebral radio necrosis (RN) being the most common, occurring in approximately 10% of patients treated. The exact pathophysiology of RN remains unclear but is thought to involve vascular injury, immune-mediated mechanisms, and direct neuronal effects, culminating in radiological changes or symptomatic manifestations necessitating treatment. Corticosteroids are the mainstay therapy, albeit with associated side effects and instances of cortico-resistance or cortico-dependence. Bevacizumab, an anti-VEGF agent, has shown promise in small studies but awaits validation in larger trials. Consequently, a randomized phase III trial seeks to evaluate the efficacy of adding bevacizumab to standard corticosteroid therapy in patients with symptomatic RN. The trial aims to determine if this combination therapy yields superior symptomatic improvement compared to corticosteroids alone. RN will be diagnosed using multimodal imaging, and the primary objective is to assess the efficacy of bevacizumab in reducing corticosteroid usage and neurological symptoms associated with RN at three months. Secondary endpoints include toxicities, quality of life, imaging changes, and response duration. Additionally, an ancillary study will explore correlations between initial imaging parameters and treatment response, as well as changes in biological parameters with bevacizumab therapy.

Brain metastases (BM) are increasingly common in cancer patients; between 10% and 50% (1) will develop BM resulting in potentially disabling symptoms, degrading quality of life and impacting overall survival. The main local treatment options include surgery, hypo-fractionated radiotherapy in stereotactic condition (SRS) and whole brain radiotherapy (WBRT). Over the past decade, SRS has become the most frequently administered focal treatment(2). SRS delivers a single or multi-fraction "ablative" dose as the sole treatment for BM with an overall survival (OS) benefit in patients with single BM (HR = 0.76; CI95%: 0.66 - 0.88)(3) or postoperatively decreasing the risk of recurrence (HR = 0.46; CI95%: 0.24 - 0.88)(4). SRS compared to neurosurgery, has the ability to treat inoperable sites, multiple lesions, and has the advantage of being less invasive. WBRT is now limited to certain patients with multiple BMs and not eligible for SRS. SRS is often preferred to WBRT because of a lower rate of neurocognitive toxicities at 12 months (difference, -34.4%; CI95%: -74.4% to 5.5%; P = .04) for patients with 5 to 10 BMs. Local control at 1 year is high in the order of 90%, and SRS is generally considered a cost-effective treatment. However, after SRS there can be late side effects, that can start 3 months to several years after irradiation, the most common is cerebral radio necrosis (RN) in 10% of treated patients. The pathophysiology is poorly understood and includes vascular injury, immune-mediated mechanisms and direct neuronal effects. Vascular injury leads to increased permeability after radiotherapy resulting in vasogenic oedema and ischemia, induce hypoxia and an increase in hypoxia inducible factor (HIF-1α) then upregulating vascular endothelial growth factor (VEGF) which exacerbates the oedema by increasing vascular permeability which creates a vicious cycle and RN, hence the importance of inhibiting VEGF(5). RN may remain as radiological changes (CTCAE v5 grade I toxicity approximately 50%)(6) to be monitored or be symptomatic (grade II-IV) and requiring treatment. Symptoms are usually manifested by focal neurological signs and symptoms related to cerebral oedema. Corticosteroids are the only standard of care before surgery, which is performed when possible. The problem is that high-dose, long-term corticosteroids have multiple side effects and some patients with RN may remain symptomatic despite corticosteroid administration (cortico-resistance) or relapse while decreasing the corticosteroid dose (cortico-dependence) and no standard treatment is available. Only one small (14 patients) randomized double-blind study compared bevacizumab 7.5 mg/kg every 3 weeks versus placebo in RN after irradiation. All 7 patients in the bevacizumab arm had a decrease in FLAIR oedema volume with clinical improvement in contrast to the placebo arm where everything worsened(7). Thus, the anti-VEGF, bevacizumab, is an option but needs to be validated in a phase 3 randomized trial. This randomized phase III trial aims to determine whether the impact of adding bevacizumab to standard corticosteroid therapy results in greater symptomatic improvement than corticosteroid therapy alone in patients with symptomatic RN. RN will be defined by a multimodal imaging approach combining brain MRI and nuclear medicine imaging (18F-FDOPA PET or dual phase 18F-FDG PET on CT or MRI). The primary objective of this study is to investigate whether the addition of bevacizumab to standard corticosteroid therapy, compared to corticosteroid therapy plus placebo, results in greater efficacy at 3 months on decrease in corticosteroids and in neurological symptoms associated with radionecrosis (RN). Secondary endpoints were toxicities, quality of life, PROs (Patient Reported Outcomes) and Clinician Reported Outcomes (CRO), imaging changes at 3 months, total weaning of corticosteroids and response duration. An ancillary study will evaluate the correlation between the initial nuclear medicine imaging parameters and the response to treatment as well as the evolution of biological parameters under bevacizumab.