Antiangiogenic Therapy For Glioblastomas

March 28, 2008

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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
Author Disclosure

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.

  • These tumors secrete a variety of angiogenic factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor/scatter factor which contribute to neovascularization.
  • In addition, VEGF is an important cause of the increased vascular permeability and peritumoral edema that contributes significantly to the morbidity associated with these tumors.

Glioblastomas (WHO grade IV) are the most common type of primary brain tumor in adults, with an annual incidence in the United States of approximately 12,000. Despite optimal therapy with surgery, radiotherapy, and temozolomide chemotherapy, the median survival of patients with glioblastomas is only 12–15 months. When these tumors recur, conventional salvage therapies produce minimal benefit, with only 8–15% of patients alive and free from progression at 6 months (6M-PFS). There is a desperate need for more effective therapies.

Bevacizumab is Active in GBM

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.

  • In one phase II study, the combination of bevacizumab and irinotecan produced a response rate of 67% and 6M-PFS of 56% in recurrent anaplastic gliomas, and a response rate of 57% and a 6M-PFS of 46% in recurrent glioblastomas.1,2
  • For purposes of comparison, ineffective therapies provide response rates of less than 10% and 6M-PFS of 31% in anaplastic gliomas and 15% in glioblastomas. Although the high "response rates" may be partly the result of reduced vascular permeability and contrast enhancement as a result of VEGF inhibition, the improvement in 6M-PFS suggests that there is also a real anti-tumor effect. The regimen was generally well tolerated and intracerebral hemorrhage occurred in only 1 out of the 35 patients with glioblastomas.2

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.

Newer VEGF Strategies

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.

Targeting Other Angiogenic Pathways

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.

Conclusions

  • After over two decades of minimal progress in the treatment of recurrent glioblastomas, antiangiogenic therapies, such as bevacizumab, represent an important breakthrough.
  • In addition, by reducing peritumoral edema, these agents frequently allow patients to decrease or eliminate their need for corticosteroids, significantly improving their quality of life.
  • The risk of hemorrhage with these agents is modest, but they are associated with other complications such as an increased risk of venous thromboembolism, impaired wound healing, proteinuria and hypertension.
  • These agents are also very expensive and important issues regarding their economics remain to be resolved.

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

References

  1. Vredenburgh JJ, Desjardins A, Herndon JE, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13(4):1253-9.
  2. Vredenburgh JJ, Desjardins A, Herndon JE, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25(30):4722-9.
  3. Cloughesy T, Prados M, Wen P, et al. A Phase II, Randomized, Non-Comparative Clinical Trial of Bevacizumab Alone or in Combination with CPT-11 Prolongs 6-month PFS in Recurrent, Treatment-Refractory Glioblastoma. Society for Neuro-Oncology 12th Annual Meeting, 2007.
  4. Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11(1):83-95.
  5. Norden AD, Young GS, Setayesh K, et al. Bevacizumab for Recurrent Malignant Gliomas: Efficacy, Toxicity, and Patterns of Recurrence. Neurology 2008;70:779-787.

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.

A. B.
C. D.

Author Disclosure

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:

NCI
Genentech
AstraZeneca
Schering
Celgene
Amgen
GlaxoSmithKline