International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationRandomized Double-Blind Placebo-Controlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System
Introduction
Radiotherapy, although helpful in the management of central nervous system (CNS) and head-and-neck tumors, can cause devastating radiation necrosis of normal CNS tissues. At present, we believe this damage results from local cytokine release, an increase in capillary permeability and extracellular edema, and the loss of the myelin covering of neurons. If allowed to progress, radiation necrosis can lead to small vessel occlusive disease and bleeding from friable small vessels 4, 5. These changes combine to cause a definable worsening in patients' neurologic signs and symptoms 1, 2, 3, 4.
Traditionally, physicians have tried to combat CNS radiation necrosis with corticosteroids, antiplatelet agents, anticoagulants, hyperbaric oxygen, high-dose vitamins, and surgery 2, 6. However, none of these approaches has proved effective in controlled clinical trials.
The development of effective therapy for CNS radiation necrosis is complicated because the mechanisms of radiation-induced injury are not completely understood. The current dogma views radiation necrosis as a continuous process from endothelial cell dysfunction to tissue hypoxia and necrosis, with the concomitant liberation of a vasoactive compound such as the vascular endothelial growth factor (VEGF) that can lead to progressive blood–brain barrier dysfunction and brain edema 7, 8, 9, 10, 11. We hypothesized that blocking VEGF from reaching its capillary targets was a logical treatment strategy for radiation necrosis to reduce the movement of plasma and plasma water through leaky brain capillary endothelium to the extracellular space. Early descriptions of VEGF by Dvorak et al. (12) and Senger et al. 13, 14, 15 used the term “vascular permeability factor” to recognize VEGF's ability to dramatically increase vascular permeability.
Recently, we observed that in 8 patients with CNS radiation necrosis, bevacizumab (16), alone or with anticancer agents, markedly reduced the apparent lesion extent on T2-weighted fluid attenuated inversion recovery (FLAIR) and T1-weighted gadolinium-enhanced magnetic resonance imaging (MRI), and reduced the patients' dexamethasone dependence (17). Others have reported similar observations (18). Thus, to better determine whether bevacizumab can effectively treat symptomatic and progressive CNS radiation necrosis, we conducted a placebo-controlled double-blind study to determine the extent that intravenous bevacizumab, administered every 3 weeks, could reduce active radiation necrosis in the CNS.
Section snippets
Study design
Eligible patients were randomized to Group A to receive intravenous bevacizumab at a dose of 7.5 mg/kg at 3-week intervals for two treatments or to Group B to receive intravenous placebo at 3-week intervals for two treatments. It was planned that all patients would undergo MRI before beginning treatment and 3 weeks after the second dose of placebo/bevacizumab (i.e., 6 weeks after study entry). At that point, the patients responding to the treatment or placebo and showing no adverse effects that
Patient demographics
Table 1 summarizes the demographic data for the patients included in the present study. Most patients had not had primary CNS tumors. The symptoms varied from headaches to hemiparesis and decreasing macular vision. In the process of screening the patients for eligibility for the present study, we found that not all patients with obvious MRI evidence of radiation necrosis had neurologic symptoms or signs. Thus, 2 patients were followed by serial clinical visits with MRI until they developed
Discussion
The results of the present study have demonstrated Class I evidence (27) of the efficacy of bevacizumab therapy for CNS radiation necrosis. Only bevacizumab-treated patients showed improvement in clinical symptoms and signs and a reduction in the volume of necrosis on T2-weighted FLAIR and T1-weighted gadolinium-contrast MRI and a 90–100% reduction in the Ktransnormalized. Formal neurocognitive testing revealed a mixed pattern of findings from the objective tests of neurocognitive function and
Acknowledgments
The magnetic resonance imaging data acquisition contributions by David T. Evans, R.T., are gratefully acknowledged; the authors also acknowledge the support of Sandeep N. Gupta, Ph.D. (GE Global Research) for his support of the CineTool software package used for the dynamic contrast-enhanced magnetic resonance imaging analyses.
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Supported in part by National Institutes of Health N01 Phase II contract N01-CM-62202 and from the University of Texas M. D. Anderson Cancer Center institutional funds and Core Grant CA 16672 to support clinical trials.
Conflict of interest: J. Wefel is a neuropsychology consultant and M. Gilbert is a consultant to Genentech, Hoboken, NJ.