Current role of anti-angiogenic strategies for glioblastoma

Glioblastoma, an incurable, malignant, and highly vascular tumor, is a seemingly ideal target for anti-angiogenic therapies such as bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody. Phase II trials in recurrent glioblastoma demonstrated bevacizumab was associated with clinical benefits, including decreases in brain edema and corticosteroids use resulting from reduced vascular permeability, as well as radiographic responses in 25 %-40 % of patients. In newly diagnosed disease, a phase III trial (AVAglio) showed adding bevacizumab to standard chemoradiotherapy improved progression free survival (PFS), with preservation of quality of life, and reduced corticosteroids use, but did not improve overall survival (OS). Another similar phase III trial (RTOG 0825) found similar PFS and OS trends, but suggested that the addition of bevacizumab resulted in more frequent cognitive decline compared with standard chemoradiotherapy. However, interpretation of those findings is limited by the fact that progressing patients were not evaluated, and patients remained longer on study in the bevacizumab arm. It is possible that the observed cognitive decline represented unrecognized tumor progression, rather than deleterious bevacizumab effects. Regardless, even if real, it is difficult to ascertain how improvements in PFS and quality of life compare with the associated economic costs and increased toxicities of bevacizumab, in the setting of no survival benefit. Further studies in recurrent disease are being conducted; preliminary results of a randomized trial showed favorable results with the combination with CCNU, and final results are awaited. Meanwhile, outside the realm of clinical trials, the current trend appears to be to reserve bevacizumab for use in recurrent disease, or for patients with moderate or severe neurologic symptoms, either in the newly diagnosed or recurrent setting. Further research efforts are needed to determine optimal candidates for this treatment from a molecular standpoint, as well as to develop imaging tools capable of accurately identifying response and progression, and to establish new drug combinations that could result in unquestionable clinical benefit and improved survival in these patients.