Symptomatic Bevacizumab-Induced Cerebral Infarction Following Treatment for Radiation Necrosis

Dear Editor, Bevacizumab (BEV) is an anti-angiogenic monoclonal antibody targeting vascular endothelial growth factor (VEGF). BEV is used to treat brain metastases, glioblastoma, other primary central nervous system (CNS) tumors, and radiation brain necrosis (RBN). However, it is associated with rare serious adverse CNS reactions. We describe a case of BEV-induced cerebral infarction following four cycles of treatment for radiation necrosis. A 56-year-old woman was diagnosed with a left parieto-occipital meningioma after undergoing magnetic resonance imaging (MRI) of the brain for an intractable headache. She underwent a left parieto-occipital craniotomy in 2020. Postoperative MRI of the brain showed no residual lesion and a significant reduction in mass effect. Histopathology suggested a World Health Organization (WHO) grade II atypical meningioma of 10 × 10 × 3 cm size with multiple foci of necrosis and mitosis 6–7/10 high-power fields. Brain parenchymal invasion was noted. Immunohistochemistry was positive for epithelial membrane antigen and progesterone receptor. A high Ki-67 index of 25%–33% led to reclassification as a WHO Grade 3 anaplastic/malignant meningioma (>20% Ki-67 index). She received External beam radiation therapy (EBRT) 60 Gy in 30 fractions to the postoperative tumor bed. A follow-up MRI done 1 year later reported no new lesions. Clinically, she had a left homonymous hemianopia. In March 2023, she presented with severe headaches and a new seizure. She was started on lacosamide 100 mg/day and levetiracetam 1 g/day. MRI showed recurrent nodular lesions along the left parafalcine and left parietal convexity measuring 2 × 2 cm, and she underwent a second total excision of the meningioma. A whole-body positron emission tomography–computed tomography showed low-grade 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA),1-Na13-octreotide (DOTANOC) tracer uptake in the dural-based soft tissue lesion medial to the postoperative site. She underwent image-guided, intensity-modulated proton therapy (radiation dose of 54 GyE in 30 fractions in two phases) (June 2023) over the next 41 days. MRI of the brain in September 2023 showed a stable residual lesion. In April 2024, a repeat MRI showed a left parieto-occipital contrast-enhancing lesion with moderate edema and mild midline shift showing hypoperfusion and necrotic changes, which were likely radiation induced. She was planned for intravenous BEV 7.5 mg/kg, three weekly cycles × six cycles. Three days after her fourth cycle (July 2024), she developed speaking difficulty and a left-sided headache. On examination, she had a new global aphasia with impaired comprehension, reduced fluency, impaired repetition, and difficulty with reading and writing. The differential diagnoses at this point were symptomatic seizures, stroke and migraine like attacks after radiation therapy (SMART) syndrome, and a new cerebral infarction associated with radiation vasculopathy or BEV infusion. An electroencephalogram was normal, except for a “breach rhythm.” MRI showed multiple small and confluent cerebral infarcts in the area of edema, with significant resolution of cerebral edema (suggestive of partial response of RBN). The lack of cortical thickening on fluid-attenuated inversion recovery sequences, absence of cortical contrast enhancement, and predominant diffusion weighted imaging (DWI)/apparent diffusion coefficient diffusion restriction were more consistent with infarction than SMART syndrome [Figure 1]. The temporal relationship with BEV infusion and a moderate Naranjo Adverse Drug Reaction Probability Scale score of 5 suggested probable new small vessel ischemia secondary to BEV. BEV was discontinued, and she was started on a short course of steroids.Figure 1: (a) Axial T1 post-contrast image showing the homogenously enhancing left parieto-occipital lesion in 2020 (arrow). (b and c) Diffusion-weighted and FLAIR images of MRI of the brain taken in July 2023 showing white matter edema suggestive of radiation injury (arrow). (d and e) (axial) Diffusion-weighted and ADC maps showing periventricular subcortical white matter diffusion-restricted lesions with corresponding decreased ADC suggestive of new cerebral infarcts (arrow). ADC: apparent diffusion coefficient, FLAIR: fluid-attenuated inversion recovery, MRI: magnetic resonance imagingBEV inhibits angiogenesis in cancer cells and stops tumor growth. It induces endothelial dysfunction, impairs vascular repair, and promotes arterial thrombotic activity, leading to thromboembolic events. BEV also forms a complex with VEGF and activates the platelet FcγRIIa (IgG) receptor, thereby inducing platelet aggregation, degranulation, and thrombosis.[1] In cerebral radiation necrosis, vascular damage is followed by VEGF expression at high levels. BEV alleviates brain edema and neoangiogenesis. Blood–brain barrier disruption leads to a proinflammatory state and an increased production of VEGF. BEV’s action against VEGF leads to reduced vascular permeability and inflammation in the brain and acting on vascular tissue around the necrotic area. Systemic adverse events of BEV include hypertension, nephrotic syndrome, bleeding, and thrombosis. CNS adverse events due to inhibition of angiogenesis include an increased risk of cerebrovascular events. CNS adverse events occur early after BEV therapy. The median and quartiles of time to CNS ischemia were 53 (20–132) days, although it could occur up to 6 months after the initiation of BEV in 64% of patients.[2] Cerebral infarction (relative risk [RR] of 3.22) is slightly more frequent than intracerebral hemorrhage (RR of around 3.09).[3] Nevertheless, of the >89% of patients on BEV therapy for RBN who develop MRI-detectable CNS ischemia or hemorrhage, only 10%–11% are symptomatic, although this subgroup shows a reduced median survival of around 9.8 (for ischemic lesions) and 3.7 months (hemorrhagic lesions). Most patients (~78%) have asymptomatic lesions that are diagnosed only on serial imaging. RR of BEV-induced cerebrovascular adverse events (BEV-CVA) is positively correlated with the dose of BEV; at a dose of 5 mg/kg/week, RR is 3.97 and at a lower dose of 2.5 mg/kg/week, RR reduces to 1.96.[4] A dose of 10 mg/kg of BEV every 2 weeks for a total of 12 cycles is well tolerated by patients with RBN in CNS metastasis or primary brain tumors. However, the risk of BEV-CVA is higher in patients with comorbidities such as older age (>65%), hypertension, diabetes, and previous cerebrovascular events. Even intravitreal BEV for age-related macular degeneration is associated with a higher rate of all-cause mortality in patients who have had a previous history of cerebral infarction in the preceding 3 months.[5] Therefore, patients require continuous blood pressure monitoring and other cardiovascular risk factors during BEV therapy. BEV should be discontinued early in patients who develop CNS events (ischemic or hemorrhagic events), and symptomatic treatment should be considered. The onset of cerebrovascular events in these patients is usually a poor prognostic event, with 60% of elderly patients succumbing within 3 months.[6] BEV therapy induces significant radiographic improvement of RBN on MRI (reduction of edema volume). Clinically, BEV also improves neurocognitive parameters within 2 months of treatment, compared to corticosteroids.[7] Vertebral artery dissection and cerebral amyloid angiopathy-related inflammation are other rare complications of BEV therapy.[8,9] While BEV is effective in treating radiation necrosis, it is associated with an increased risk of cerebral infarcts (within or outside the area of necrosis). Patients should be carefully monitored for these adverse events during and for a few months after BEV infusions. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her names and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.