By Patrick Y. Wen, MD, FAAN
Division of Cancer Neurology, Department of Neurology, Brigham and Women's Hospital and Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center
Over three decades ago, Judah Folkman proposed the hypothesis that inhibition of angiogenesis may potentially be an effective treatment for cancers. Glioblastomas (GBMs) are among the most vascular tumors in the body and as such represent a particularly attractive target for this therapeutic strategy.
VEGF induces a potent angiogenic response through diverse effects, including endothelial cell proliferation, survival, migration, and tube formation, recruitment of circulating tumor-associated cells, and promotion of hematopoietic stem cell survival. Bevacizumab (Avastin®) is a humanized monoclonal antibody that binds VEGF, preventing it from activating its receptors, especially VEGFR2, abrogating subsequent biologic effects. This drug has shown benefit in colorectal, non-small cell lung, and breast cancers, and is approved by the Food and Drug Administration for these indications. Several studies have now evaluated the combination of bevacizumab and the chemotherapeutic agent irinotecan in recurrent malignant gliomas and the results have been encouraging.
These preliminary findings have been recently confirmed by a large multi-center randomized phase II study of 167 patients with recurrent GBM who were treated with bevacizumab alone or in combination with irinotecan.3 Patients receiving bevacizumab alone had a response rate of 20% and a 6M-PFS of 35.1%, while patients receiving the combination of bevacizumab in combination with irinotecan had a response rate of 34% and 6M-PFS of 51%.3 The median survival was 9.7 months for bevacizumab (Avastin) alone, and 8.7 months for the combination. In addition, treatment with bevacizumab was also associated with a significant reduction in peritumoral edema and the need for corticosteroids. This study again confirmed that the regimens were generally well-tolerated, with only 1 intracranial hemorrhage in each group. As a result of these studies, the combination of bevacizumab with irinotecan is increasingly used for the treatment of patients with recurrent malignant gliomas.
Aflibercept (VEGF-Trap) is a soluble hybrid receptor, composed of portions of VEGFR-1 and VEGFR-2 fused to an immunoglobulin G1 Fc domain. Like bevacizumab, it is designed to deplete circulating VEGF, but has significantly greater affinity for VEGF than bevacizumab itself. A phase II study conducted by the North American Brain Tumor Consortium was recently completed and the results of this potentially promising agent are eagerly awaited.
There are also encouraging results with inhibitors of VEGF receptors. In a phase II trial study of a potent pan-VEGFR inhibitor, cediranib (AZD2171; Recentin) in patients with recurrent glioblastomas, response rates in excess of 50% were observed and the 6M-PFS was increased to approximately 25%. At the time of tumor recurrence, serum levels of bFGF, stromal derived growth factor 1α, and circulating endothleial cells were increased, suggesting that these may be contributing to resistance to VEGFR inhibition.4 Studies with other inhibitors of VEGFR such as sorafenib (Nexavar), sunitinib (Sutent), vandetanib (ZD6474; Zactima), pazopanib (GW786034), and vatalanib (PTK787) in glioblastomas are in progress.
In comparison with drugs targeting VEGF or VEGFR, agents inhibiting other angiogenic pathways have produced less success. Drugs that inhibit PDGF receptors such as imatinib mesylate (Gleevec) were ineffective, due partly to its poor penetration across the blood-brain barrier. Cilengitide, a drug that inhibits αvβ3 and αvβ5 integrins has shown modest activity in glioblastomas and studies combining it with other agents are in progress.
As experience with antiangiogenic agents accumulates, it is clear that the benefit is only transient, and most tumors eventually progress after a number of months. In a subset of patients, these tumors recur not as enhancing masses, but with a more infiltrative phenotype resembling gliomatosis. This raises the possibility that by inhibiting angiogenesis, anti-VEGF and anti-VEGFR agents force tumors cells to coopt and grow along existing blood vessels, changing their natural history.5
Figures A–D: 48 year old man with recurrent glioblastomas. Axial T1-contrast enhanced MRI before (A) and 4 weeks after treatment with bevacizumab and irinotecan (B) showing significant reduction in the amount of contrast enhancing tumor. Axial FLAIR MRI before (C) and after treatment (D) showed significant reduction in peritumoral edema. Over these 4 weeks, the patient’s symptoms of headache and word finding difficulties improved.
Within the past 24 months, the author discloses that he served as editor of the Neuro-Oncology Section of UpToDate Oncology. He further discloses that he has received research support from the following corporations or entities: