International Journal of Radiation Oncology*Biology*Physics
Rapid communicationEffect of bevacizumab on radiation necrosis of the brain
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.
Section snippets
Patients and methods
We conducted a retrospective search of the Neuro-Oncology Department database to identify patients with brain tumors treated with bevacizumab. Information about demographics, prior chemotherapy, and radiation treatment was obtained from the clinical charts. All patients had previously received radiation treatment. All also had a pretreatment contrast-enhanced magnetic resonance imaging (MRI) of the brain within 4 weeks of bevacizumab treatment. All patients were treated under institutional
Demographic data
Between September 2005 and May 2006, we found that 8 of 15 patients treated with bevacizumab had radiation necrosis diagnosed on the basis of MRI and confirmed by biopsy in 2 patients (Table 1). Bevacizumab was given in different combinations at 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks. Four had glioblastoma, 3 anaplastic glioma, and 1 hemangiopericytoma. The average time from conventional radiation treatment to bevacizumab was 38.8 months. Four patients received stereotactic radiation
Discussion
Radiation injury to the brain can be a serious consequence of brain tumor irradiation. It can be classified as acute (during radiation), early delayed (up to 12 weeks postirradiation), and late (months to years postirradiation) (11). Brain irradiation can be associated with cognitive side effects (12) and even tumor-like behavior with more significant morbidity and even mortality (1).
Because radiation-induced changes can closely resemble those of tumors on MRI studies, this poses a diagnostic
Acknowledgment
We thank Betty Notzon for editorial assistance.
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This study was supported in part by the Alan Gold Memorial Fund.
Conflict of interest: none.