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. 2013 Apr 15:6:371-89.
doi: 10.2147/OTT.S38628. Print 2013.

Bevacizumab in high-grade gliomas: a review of its uses, toxicity assessment, and future treatment challenges

Gazanfar Rahmathulla  1 , Elizabeth J Hovey, Neda Hashemi-Sadraei, Manmeet S Ahluwalia
Affiliations

Bevacizumab in high-grade gliomas: a review of its uses, toxicity assessment, and future treatment challenges

Gazanfar Rahmathulla et al. Onco Targets Ther. .

Abstract

High-grade gliomas continue to have dismal prognosis despite advances made in understanding the molecular genetics, signaling pathways, cytoskeletal dynamics, and the role of stem cells in gliomagenesis. Conventional treatment approaches, including surgery, radiotherapy, and cytotoxic chemotherapy, have been used with limited success. Therapeutic advances using molecular targeted therapy, immunotherapy, and others such as dietary treatments have not been able to halt tumor progression and disease-related death. High-grade gliomas (World Health Organization grades III/IV) are histologically characterized by cellular and nuclear atypia, neoangiogenesis, and necrosis. The expression of vascular endothelial growth factor, a molecular mediator, plays a key role in vascular proliferation and tumor survival. Targeting vascular endothelial growth factor has demonstrated promising results, with improved quality of life and progression-free survival. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, is approved by the Food and Drug Administration as a single agent in recurrent glioblastoma and is associated with manageable toxicity. This review discusses the efficacy, practical aspects, and response assessment challenges with the use of bevacizumab in the treatment of high-grade gliomas.

Keywords: antiangiogenesis; bevacizumab; glioblastoma; glioma; vascular endothelial growth factor.

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Figures

Figure 1
Figure 1
(A) Axial T1-weighted postgadolinium contrast-enhanced magnetic resonance image of a 53-year-old patient with a progressive multifocal glioblastoma revealing two lesions: one in the left cerebellar hemisphere and the other extending into the cerebellar peduncle and infiltrating the brainstem. Both the lesions have uniform contrast enhancement, along with ill-defined irregular margins. (B) Axial fluid attenuated inversion recovery images reveal a more diffuse hyperintense lesion infiltrating into the adjacent cerebellum and brainstem. The hyperintense signal crosses the midline vermis and involves the contralateral cerebellar hemisphere as well.
Figure 2
Figure 2
(A) An axial T1-weighted postgadolinium contrast-enhanced magnetic resonance image of the same patient after bevacizumab treatment reveals a significant reduction in the size and shape of the cerebellar/brainstem contrast enhancing tumor. There is also a decrease in the adjacent mass effect with opening up of the adjacent fourth ventricle. (B) An axial fluid attenuated inversion recovery image of the patient after bevacizumab treatment reveals a significant reduction in the hyperintensity of the cerebellar and brainstem involvement. This is associated with a decrease in the adjacent mass effect and opening up of the sulci and adjacent fourth ventricle.
Figure 3
Figure 3
Mechanisms of resistance to BEV appear to be of two major types. Notes: The first being mechanisms that develop in ECs. ECs can possess primary resistance to VEGF therapies (BEV) and not have any initial response to treatment; this may be a reason for unresponsiveness in certain patients. An alternative mechanism of EC resistance is acquired secondary to fusion with malignant cells followed by altered genetic characteristics such as chromosomal aberrations and aneuploidy, making them resistant to antiangiogenic agents. They may thus become activated via alternative pathways via ligand-independent mechanisms and by recruiting factors other than VEGF (eg, FGF and SDF-α). An alternative pathway of resistance lies with the malignant glioma cells themselves and could involve increased invasiveness, upregulation of altered p53 variants, and recruitment of pericytes, which are proangiogenic and release factors such as Ang-1. Additionally, it could involve the release of factors such as PlGF, which recruit myeloid cells. Myeloid cells produce various cytokines such as IL6 and IL8, which are proangiogenic and resistant to various antiangiogenic therapies. Abbreviations: Ang-1, angiopoietin-1; BEV, bevacizumab; CED, cediranib; EC, endothelial cell; FGF, fibroblast growth factor; IL, interleukin; p53, protein-53; PlGF, placental-derived growth factor; SDF-α, stromal-derived factor-α; VEGF, vascular endothelial growth factor.
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