Int J Radiat Oncol Biol Phys 2008;71:1372C1380 [PubMed] [Google Scholar] 20

Int J Radiat Oncol Biol Phys 2008;71:1372C1380 [PubMed] [Google Scholar] 20. of endothelial cells and formation of new blood vessels.1 VEGF has a role in endothelial cell survival, proliferation, invasion, and migration, which all affect tumor progression and angiogenesis.2 Treatment with bevacizumab was quickly implemented for salvage therapy in progressive malignant gliomas after its efficacy was demonstrated in metastatic colon cancer3 and in non-small-cell lung cancer.4 Multiple groups using bevacizumab plus chemotherapy2,5,C12 and 2 phase II trials using bevacizumab alone13,14 have demonstrated impressive imaging responses with increased overall survival (OS) and progression-free survival (PFS) in recurrent glioma patients relative to historical data in patients who received chemotherapy alone.15,16 The results of the phase II trials were so compelling that in May 2009, the US Food and Drug Administration granted approval for the use of bevacizumab for the second-line treatment of glioblastoma multiforme (GBM).17 Additionally, 2 recent phase II trials explored the use of bevacizumab plus chemotherapy as initial therapy for newly diagnosed GBM18,19 and several other centers are enrolling patients in 2 large phase III trials of temozolomide and radiation with and without bevacizumab for the treatment of newly diagnosed GBM.20,21 VESSEL NORMALIZATION The general rationale behind using bevacizumab in combination with chemotherapy for malignant gliomas is twofold. First, bevacizumab normalizes vessels in the CNS by a mechanism similar to that of solid tumors outside the CNS. Bevacizumab decreases the abnormal morphology and organization of tumor-related vasculature that causes inefficient transport of oxygen and therapeutic drugs to the tumor.22 As malignant glioma cells are known to express VEGF,23 bevacizumab may have direct antitumor activity24 and may increase tumor cell responsiveness to the cytotoxic effects of chemotherapy that penetrates into the tumor. Secondly, bevacizumab decreases tumor interstitial pressure, which is thought to improve delivery of chemotherapy to the tumor cells.25 In preclinical studies, bevacizumab has been shown to Aclacinomycin A improve the delivery and efficacy of systemic chemotherapeutic agents in EYA1 a neuroblastoma xenograft model.26 However, extrapolating Aclacinomycin A the mechanism of bevacizumab in non-CNS solid tumors to the mechanism of bevacizumab in malignant gliomas neglects the complexities of the bloodCbrain barrier (BBB) compared to the vasculature of solid tumors. Using another anti-VEGF agent, vandetanib, in a malignant glioma model, Claes et al.27 demonstrated that the amount of apoptosis conferred by temozolomide (Temodar?, Schering-Plough, Kenilworth, NJ) was significantly decreased in animals that received vandetanib (Zactima?, AstraZeneca, London, UK). This led the authors to conclude that Vessel normalization has an antagonizing rather than a synergistic or additive effect. 27 Vandetanib is a tyrosine kinase inhibitor with specificity toward epidermal growth factor receptor and VEGF receptor 2,28 while bevacizumab blocks signaling through VEGF receptor 1 as well as VEGF receptor 2.1 Given the similarities in the mechanisms of vandetanib and bevacizumab, the Claes et al. results potentially contradict the hypothesis that therapy targeting the VEGF pathway improves chemotherapy delivery to CNS tumors. In addition, the tumor phenotype changes in response to vessel normalization following treatment with bevacizumab, which may cause increased invasiveness and further resistance to antiangiogenic agents.29 Using microdialysis techniques, Portnow et al.30 demonstrated that the average maximum concentration of temozolomide in the brain compared to plasma was 13.6% lower than predicted by animal models. Future studies using similar microdialysis techniques with and without bevacizumab would more definitively elucidate the potential for bevacizumab to lower tumor temozolomide concentrations. PATTERNS OF TUMOR INVASION There is histologic evidence that tumors may adapt to antiangiogenic agents with increased tumor invasiveness Aclacinomycin A and vessel cooption. In patients, de Groot et al.31 recently identified normalized vessels adjacent to necrotic areas in GBM histologic specimens with tumor progression and necrosis occurring simultaneously with normalization and vessel pruning after treatment with bevacizumab. These findings were Aclacinomycin A also seen in a malignant glioma model in which rats treated with bevacizumab had increased tumor with more invasive borders than controls.31 Patterns of tumor progression on MRI of patients receiving bevacizumab plus chemotherapy have also raised questions regarding tumor invasiveness. Zuniga et al.32 found that 19 of 38 patients had both local and distant recurrence while another 4 had only distant progression, suggesting that inhibiting angiogenesis may result in normal vessel cooption and infiltration. This same study also showed progression on fluid-attenuated inversion recovery (FLAIR) MRI in 21 patients. Other groups have also observed significant distal progression and progression of nonenhancing tumor on FLAIR MRI.33.