Abstract
Glioblastoma (GBM) represents the most frequent primary brain tumor in adults and carries a dismal prognosis despite aggressive, multimodal treatment regimens involving maximal resection, radiochemotherapy, and maintenance chemotherapy. Histologically, GBMs are characterized by a high degree of VEGF-mediated vascular proliferation. In consequence, new targeted anti-angiogenic therapies, such as the monoclonal anti-VEGF-A antibody bevacizumab, have proven effective in attenuating tumor (neo)angiogenesis and were shown to possess therapeutic activity in several phase II trials. However, the role of bevacizumab in the context of multimodal therapy approaches appears to be rather complex. This review will give insights into current concepts, limitations, and controversies regarding the molecular mechanisms and the clinical benefits of bevacizumab treatment in combination with radio(chemo)therapy - particularly in face of the results of recent phase III trials, which failed to demonstrate convincing improvements in overall survival (OS).
Highlights
GBMs are highly vascularized tumors that critically depend on the generation of tumor-associated blood vessels [1, 2]
Among multiple factors controlling the complex process of angiogenesis, vascular endothelial growth factor (VEGF) and its associated signaling cascade are considered to be of central importance [5, 7]
Glioma cells are a major source of VEGF, and high levels of VEGF have been reported to correlate with high-grade malignancy and poor prognosis [8, 9]
Summary
GBMs are highly vascularized tumors that critically depend on the generation of tumor-associated blood vessels [1, 2]. Several preclinical and clinical studies raised the concern that BEV treatment might induce a more invasive tumor phenotype, thereby potentially limiting the efficacy of radiation therapy due to the stimulation of tumor cell emigration out of the RT field [35,36,37,38]. A significant reduction in the cerebral blood flow and the amount of large and median-sized blood vessels upon anti-angiogenic treatment was associated with a dramatic increase in glioma cell invasion into the tumor-surrounding CNS.
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