Effect of bevacizumab on radiation necrosis of the brain

Purpose: Because blocking vascular endothelial growth factor (VEGF) from reaching leaky capillaries is a logical strategy for the treatment of radiation necrosis, we reasoned that bevacizumab might be an effective treatment of radiation necrosis.

Patients and Methods: Fifteen patients with malignant brain tumors were treated with bevacizumab or bevacizumab combination for their tumor on either a 5 mg/kg/2-week or 7.5 mg/kg/3-week schedule. Radiation necrosis was diagnosed in 8 of these patients on the basis of magnetic resonance imaging (MRI) and biopsy. MRI studies were obtained before treatment and at 6-week to 8-week intervals.

Results: Of the 8 patients with radiation necrosis, posttreatment MRI performed an average of 8.1 weeks after the start of bevacizumab therapy showed a reduction in all 8 patients in both the MRI fluid-attenuated inversion-recovery (FLAIR) abnormalities and T1-weighted post-Gd-contrast abnormalities. The average area change in the T1-weighted post-Gd-contrast abnormalities was 48% (±22 SD), and the average change in the FLAIR images was 60% (±18 SD). The average reduction in daily dexamethasone requirements was 8.6 mg (±3.6).

Conclusion: Bevacizumab, alone and in combination with other agents, can reduce radiation necrosis by decreasing capillary leakage and the associated brain edema. Our findings will need to be confirmed in a randomized trial to determine the optimal duration of treatment.

Introduction

The treatment of radiation necrosis has traditionally consisted of corticosteroids to control edema. However, the long-term usage of corticosteroids is problematic because of the myriad debilitating chronic side effects. Antiplatelet agents, anticoagulants, hyperbaric oxygen, and surgery have also been tried as treatments for this condition, but there are no large trials to support their routine use in clinical practice (1).

The mechanisms of radiation-induced injury are not completely understood, but several hypotheses have been advanced based on findings in animal models and experimental data in humans. Radiation necrosis constitutes a continuous process in which endothelial cell dysfunction leads to tissue hypoxia and necrosis, with the concomitant liberation of a vasoactive compound such as the vascular endothelial growth factor (VEGF). Indeed, elevated levels of VEGF have been found in several models of radiation necrosis, and these may perpetuate the condition, leading to further blood–brain barrier dysfunction and brain edema (2, 3). Thus, blocking VEGF from reaching its capillary targets is a logical treatment strategy for radiation necrosis. What makes this approach particularly appealing is that it promises to be effective in managing the associated leaky (nontight) endothelium occurring in otherwise normal brain tissue that leads to increased vascular permeability to plasma constituents and the associated flux of plasma into extracellular milieu in the brain (i.e., edema). In fact, in the first isolation and descriptions of VEGF by Dvorak and Senger (4, 5, 6, 7), they used the term vascular permeability factor to recognize the dramatic properties of the agent in promoting vascular permeability.

Bevacizumab (Avastin), a humanized murine monoclonal antibody against the VEGF molecule, is under investigation to determine its role in the treatment of several different solid tumors (8). This agent, alone and in combination with Camptosar (Irinotecan), has also been evaluated in patients with recurrent malignant gliomas and, with a response rate of 63%, shown to be at least on par with other forms of chemotherapy (9). Because radiotherapy forms part of the treatment of patients with gliomas, we reasoned that this would also be a good population in which to assess the efficacy of bevacizumab in the treatment of radiation necrosis. Indeed, the relatively high response rate observed in the CPT-11 and bevacizumab trial might be in part explained by the profound effect this molecule has on blood vessel permeability.

We therefore retrospectively reviewed our experience with bevacizumab therapies in patients with malignant gliomas who also developed radiation necrosis.