Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: analysis of single-agent and combined modality approaches

Abstract

Surgical resection followed by radiotherapy and temozolomide in newly diagnosed glioblastoma can prolong survival, but it is not curative. For patients with disease progression after frontline therapy, there is no standard of care, although further surgery, chemotherapy, and radiotherapy may be used. Antiangiogenic therapies may be appropriate for treating glioblastomas because angiogenesis is critical to tumor growth. In a large, noncomparative phase II trial, bevacizumab was evaluated alone and with irinotecan in patients with recurrent glioblastoma; combination treatment was associated with an estimated 6-month progression-free survival (PFS) rate of 50.3%, a median overall survival of 8.9 months, and a response rate of 37.8%. Single-agent bevacizumab also exceeded the predetermined threshold of activity for salvage chemotherapy (6-month PFS rate, 15%), achieving a 6-month PFS rate of 42.6% (p < 0.0001). On the basis of these results and those from another phase II trial, the US Food and Drug Administration granted accelerated approval of single-agent bevacizumab for the treatment of glioblastoma that has progressed following prior therapy. Potential antiangiogenic agents-such as cilengitide and XL184-also show evidence of single-agent activity in recurrent glioblastoma. Moreover, the use of antiangiogenic agents with radiation at disease progression may improve the therapeutic ratio of single-modality approaches. Overall, these agents appear to be well tolerated, with adverse event profiles similar to those reported in studies of other solid tumors. Further research is needed to determine the role of antiangiogenic therapy in frontline treatment and to identify the optimal schedule and partnering agents for use in combination therapy.

Figure 1

Molecular targets of antiangiogenic agents in glioblastoma. Cilengitide is a cyclic peptide that binds to and inhibits the activities of the alpha(v)beta(3) and alpha(v)beta(5) integrins. Bevacizumab is a humanized monoclonal immunoglobulin G1 antibody that binds to and inhibits VEGF-A. Aflibercept is a fusion protein that binds all isoforms of VEGF-A, as well as PlGF. Cediranib, sunitinib, vandetanib, XL184, and CT-322 are multireceptor tyrosine kinase inhibitors. ABT-510 is a nonapeptide that targets the thrombospondin-1 receptor CD36. Abbreviations: EGFR = epidermal growth factor receptor; PDGFR = platelet-derived growth factor receptor; PlGF = placental growth factor; VEGF-A = vascular endothelial growth factor A; VEGFR = vascular endothelial growth factor receptor.

Figure 2

Intravital microscopy images showing the effect of a single dose of bevacizumab on the intratumoral vascular phenotype of an orthotopic neuroblastoma (NB-1691 xenograft) model. Images were obtained on days 0, 1, 3, and 7. Original magnification was ×40. Vasculature of normal skin is also shown [19]. Reprinted with permission from Dickson PV, Hamner JB, Sims TL, et al. Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res 2007;13:3942-3950; Figure 2.

Figure 3

Dose-dependent effect of radiation on VEGF protein expression. VEGF protein levels in LLC-conditioned medium are shown after radiation exposure. LLCs were plated in six-well plates at 25% confluence, allowed to attach overnight, and then irradiated with 0, 5, 10, or 20 Gy. Conditioned medium was collected every 24 hours and VEGF levels were normalized to cell number. Data are presented as mean plus standard error [70]. Abbreviations: LLC = Lewis lung carcinoma; VEGF = vascular endothelial growth factor. Reprinted with permission from Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 1999;59:3374-3378; Figure 1B.