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  • Targeted intra-arterial anti-VEGF therapy for medically refractory radiation-induced necrosis in the brain

    Final Number:

    Shervin R. Dashti MD PhD; Aaron Spalding MD, PhD; Robert J Kadner MD; Tom L. Yao MD; David A. Sun MD, PhD; Arooshi Kumar BS; Renato V LaRocca

    Study Design:

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2014 Annual Meeting

    Introduction: Radiation necrosis (RN) is a serious complication that can occur in up to 10% of brain radiotherapy cases, with the incidence dependent on both dose and brain location. Available medical treatment for RN includes steroids, vitamin E, pentoxiphylline, and hyperbaric oxygen. A significant number of patients however, are medically refractory and experience progressive neurological decline, disabling headaches, and decreased quality of life. Vascular endothelial growth factor (VEGF) is a known mediator of cerebral edema in radiation necrosis. Recent reports have shown successful treatment of RN with intravenous bevacizumab, a monoclonal antibody for VEGF. Bevacizumab however, is associated with significant systemic complications including venous thrombosis, pulmonary embolus, GI perforation, wound dehiscence, and severe hypertension. We hypothesize that using lower drug doses would lower systemic exposure and decrease complication rates. By using intra-arterial route of drug administration following blood-brain-barrier disruption (BBBD), we aim to lower the bevacizumab dose while increasing target delivery.

    Methods: Herein, we present two pediatric patients with cerebral arteriovenous malformations, who presented with medically intractable RN following stereotactic radiosurgery. They received a single intra-arterial infusion of 2.5 mg/kg bevacizumab after hyperosmotic BBBD.

    Results: At mean follow-up period of 6-months, the patients experienced significant and durable clinical and radiographic response: Both patients experienced resolution of their previously intractable headaches as well as reversal of cushingoid features as they were successfully weaned off steroids. One patient regained significant motor strength. There was an associated greater than 70% reduction in cerebral edema.

    Conclusions: Intra-arterial administration of a single low dose of bevacizumab after blood brain barrier disruption was safe, and resulted in durable clinical and radiographic improvement at concentrations well below the typical systemic intravenous route. Advantages over intravenous route may include higher concentration of drug delivery to the affected brain, decreased systemic toxicity, as well as significantly lower cost.

    Patient Care: We have shown that intra-arterial bevacizumab after hyperosmotic blood brain barrier breakdown appears to be safe and effective treatment for medically refractory radiation necrosis in the brain. Advantages over intravenous route may include higher concentration of drug delivery to the target brain tissue, decreased systemic toxicity because of the much smaller dose of bevacizumab used, as well as significantly lower cost.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) Understand the role of anti-VEGF (bevacizumab) therapy for medically refractory radiation necrosis. 2) Discuss known serious systemic complications of intravenous bevacizumab treatment. 3) Discuss the use of intra-arterial bevacizumab delivery following blood-brain-barrier breakdown to maintain drug efficacy while markedly reducing systemic exposure and potential toxicity. 4) Understand technical considerations for intra-arterial bevacizumab administration following blood-brain barrier breakdown.

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