Randomized Double-Blind Placebo-Controlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System

Abstract

Purpose-To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain.Methods and Materials-Fourteen patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system (CNS) radiation necrosis. All patients were required to have radiographic or biopsy proof of CNS radiation necrosis and progressive neurological symptoms or signs. Eligible patients received irradiation for head and neck carcinomas, meningioma, or low-to mid-grade gliomas. Patients were randomized to receive IV saline or bevacizumab at 3-week intervals. MRI 3-weeks after the second treatment and clinical signs and symptoms defined response or progression. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. and T 1 -weighted gadolinium-enhanced volumes and decrease K trans . All bevacizumab-treated patients -and none of the placebo-treated patients -showed improvement in neurological symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all 4 study doses, only 2 patients had experienced a recurrence of MRI changes consistent with progressive radiation necrosis, and this was the only patient to receive only 2 treatments with bevacizumab. Results-The Conflict of InterestConclusions-This class I evidence of bevacizumab efficacy in the treatment of CNS radiation necrosis justifies consideration of this treatment option for people who suffer radiation necrosis secondary to the treatment of head and neck and brain cancers.

Pathobiology of radiation myelopathy and strategies to mitigate injury

“…35 Targeting VEGF has a strong biological rationale, and promising clinical data are emerging for the use of bevacizumab, a monoclonal antibody against VEGF in the treatment of radiation-induced cerebral necrosis. 36 Bevacizumab has also been reported to result in neurologic improvement in a patient with radiation myelopathy. 37 Erythropoietin (EPO) has been used extensively over the past 10 to 15 years for the treatment of anemia in cancer patients.…”

Dynamic perfusion CT in brain tumors

“…True progressive brain tumors are malignancies with increased vascularity, immature leaky vessels, and upregulated VEGF expression resulting in higher BF, BV and PS. On the other hand, the moderate PS observed in TIN is likely mediated by the release of VEGF in the pathogenesis of radiation necrosis [41]. In addition, susceptibility artefacts from blood products (hemorrhage, thrombus) and calcification can potentially complicate the analysis of DSC-MR studies while PCT is not affected by these artefacts [39,42].…”

Exploration of the Recurrence of Radiation Brain Necrosis After Bevacizumab Discontinuation

“…However, bevacizumab is an anti-angiogenic drug recognized for its role in pruning vessels and promoting blood supply, which is inconsistent with the above inference [25]. We believe that several mechanisms are [26].Among many previous studies, only a few have reported several recurrence cases [4][5][6][7][8][9][10]. Our literature review shows that previous researchers may have missed progression in many cases reported as "without progression" due to individual differences in bevacizumab sensitivity, short follow-up times after bevacizumab is discontinued, or death shortly after bevacizumab is discontinued.…”

“…Compared to previous reports, most studies [4][5][6][7][8][9][10] only reported the efficacy of bevacizumab in the treatment of radiation-induced cerebral necrosis, while there were fewer studies on the recurrence and progression of radiation-induced cerebral necrosis after treatment. No studies have yet explored the reasons for recurrence and progression.…”

“…Many clinical studies have shown that bevacizumab produces good shortterm effects on radiation brain necrosis [4][5][6][7][8][9][10][11].However, few studies have reported on radiation brain necrosis progression following bevacizumab discontinuation, and the causes of such progression have not been studied. To provide a reference for clinical treatment, we statistically analyzed bevacizumab treatment efficacy in patients with radiation brain necrosis treated at the Tianjin Cancer Hospital and their progression after bevacizumab discontinuation.…”