Abstract
Most brain tumors oversecrete vascular endothelial growth factor (VEGF), which leads to an abnormally permeable tumor vasculature. This hyperpermeability allows fluid to leak from the intravascular space into the brain parenchyma, which causes vasogenic cerebral edema and increased interstitial fluid pressure. Increased interstitial fluid pressure has an important role in treatment resistance by contributing to tumor hypoxia and preventing adequate tumor penetration of chemotherapy agents. In addition, edema and the corticosteroids needed to control cerebral edema cause significant morbidity and mortality. Agents that block the VEGF pathway are able to decrease vascular permeability and, thus, cerebral edema, by restoring the abnormal tumor vasculature to a more normal state. Decreasing cerebral edema minimizes the adverse effects of corticosteroids and could improve clinical outcomes. Anti-VEGF agents might also be useful in other cancer-related conditions that increase vascular permeability, such as malignant pleural effusions or ascites.
Key Points
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Peritumoral vasogenic cerebral edema is a significant cause of morbidity and mortality in patients with brain tumors
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VEGF is secreted by brain tumors and has an important role in increasing vascular permeability and, thus, contributing to peritumoral edema
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Peritumoral edema increases interstitial fluid pressure, which leads to poor penetration of chemotherapeutics and treatment resistance
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Antiangiogenic agents, particularly those that target the VEGF pathway, have been shown to reduce peritumoral edema in phase II studies of patients with brain tumors, and have been shown to improve progression-free survival and overall survival
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Anti-VEGF therapy exerts its effects by restoring vascular permeability and normalizing tumor blood vessels
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Anti-VEGF agents could also be useful in other cancer-related conditions that increase vascular permeability, such as malignant pleural effusions or ascites
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References
Del Maestro, R. F., Megyesi, J. F. & Farrell, C. L. Mechanisms of tumour-associated edema: a review. Can. J. Neurol. Sci. 17, 177–183 (1990).
Klatzo, I. Presidential address. Neuropathological aspects of brain edema. J. Neuropathol. Exp. Neurol. 26, 1–14 (1967).
Eichler, A. F. & Loeffler, J. S. Multidisciplinary management of brain metastases. Oncologist 12, 884–898 (2007). .
Carlson, M. et al. Relationship between survival and edema in malignant gliomas: role of vascular endothelial growth factor and neuronal pentraxin 2. Clin. Cancer Res. 13, 2592–2598 (2007).
Kofman, S., Garvin, J. S., Nagamani, D. & Taylor, S. G. 3rd. Treatment of cerebral metastases from breast carcinoma with prednisolone. J. Am. Med. Assoc. 163, 1473–1476 (1957).
Hendryk, S., Jedrzejowska-Szypulka, H., Josko, J., Jarzab, B. & Döhler, K. D. Influence of the corticotropin releasing hormone (CRH) on the brain–blood barrier permeability in cerebral ischemia in rats. J. Physiol. Pharmacol. 53, 85–94 (2002).
Villalona-Calero, M. A. et al. A phase I trial of human corticotropin-releasing factor (hCRF) in patients with peritumoral brain edema. Ann. Oncol. 9, 71–77 (1998).
Tjuvajev, J. et al. Corticotropin-releasing factor decreases vasogenic brain edema. Cancer Res. 56, 1352–1360 (1996).
Jain, R. K. Normalizing tumour vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7, 987–989 (2001).
Kroll, R. A. & Neuwelt, E. A. Outwitting the blood–brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 42, 1083–1099 (1998).
Boucher, Y., Salehi, H., Witwer, B., Harsh, G. R. 4th & Jain, R. K. Interstitial fluid pressure in intracranial tumours in patients and in rodents. Br. J. Cancer 75, 829–836 (1997).
Bertossi, M., Virgintino, D., Maiorano, E., Occhiogrosso, M. & Roncali, L. Ultrastructural and morphometric investigation of human brain capillaries in normal and peritumoral tissues. Ultrastruct. Pathol. 21, 41–49 (1997).
Hasegawa, H., Ushio, Y., Hayakawa, T., Yamada, K. & Mogami, H. Changes of the blood–brain barrier in experimental metastatic brain tumours. J. Neurosurg. 59, 304–310 (1983).
Stewart, P. A., Hayakawa, K., Farrell, C. L. & Del Maestro, R. F. Quantitative study of microvessel ultrastructure in human peritumoral brain tissue. Evidence for a blood–brain barrier defect. J. Neurosurg. 67, 697–705 (1987).
Hobbs, S. K. et al. Regulation of transport pathways in tumour vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95, 4607–4612 (1998).
Fidler, I. J., Yano, S., Zhang, R. D., Fujimaki, T. & Bucano, C. D. The seed and soil hypothesis: vascularization and brain metastases. Lancet Oncol. 3, 53–57 (2002).
Jain, R. K. et al. Angiogenesis in brain tumours. Nat. Rev. Neurosci. 8, 610–622 (2007).
Provias, J. et al. Meningiomas: role of vascular endothelial growth factor/vascular permeability factor in angiogenesis and peritumoral edema. Neurosurgery 40, 1016–1026 (1997).
Strugar, J. G., Criscuolo, G. R., Rothbart, D. & Harrington, W. N. Vascular endothelial growth/permeability factor expression in human glioma specimens: correlation with vasogenic brain edema and tumor-associated cysts. J. Neurosurg. 83, 682–689 (1995).
Yano, S. et al. Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis. Cancer Res. 60, 4959–4967 (2000).
Plate, K. H., Breier, G., Weich, H. A. & Risau, W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359, 845–848 (1992).
Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).
Dobrogowska, D. H., Lossinky, A. S., Tarnawski, M. & Vorbrodt, A. W. Increased blood–brain barrier permeability and endothelial abnormalities induced by vascular endothelial growth factor. J. Neurocytol. 27, 163–173 (1998).
Machein, M. R., Kullmer, J., Fiebich, B. L., Plate, K. H. & Warnke, P. C. Vascular endothelial growth factor expression, vascular volume, and, capillary permeability in human brain tumors. Neurosurgery 44, 732–740 (1999).
Chan, A. S. et al. Expression of vascular endothelial growth factor and its receptors in the anaplastic progression of astrocytoma, oligodendroglioma, and ependymoma. Am. J. Surg. Pathol. 22, 816–826 (1998).
Tervonen, O., Forbes, G., Scheithauer, B. W. & Dietz, M. J. Diffuse “fibrillary” astrocytomas: correlation of MRI features with histopathologic parameters and tumor grade. Neuroradiology 34, 173–178 (1992).
Heiss, J. D. et al. Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor. J. Clin. Invest. 98, 1400–1408 (1996).
Machein, M. et al. Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells. Neuropathol. Appl. Neurobiol. 25, 104–112 (1999).
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
Tong, R. T. et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64, 3731–3736 (2004).
Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).
Lee, C. G. et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 60, 5565–5570 (2000).
Jain, R. K. Antiangiogenic therapy for cancer: current and emerging concepts. Oncology (Williston Park) 19, 7–16 (2005).
Jain, R. K. Taming vessels to treat cancer. Sci. Am. 298, 56–63 (2008).
Drevs, J. et al. PTK787/ZK 222584, a specific vascular endothelial growth factor-receptor tyrosine kinase inhibitor, affects the anatomy of the tumor vascular bed and the functional vascular properties as detected by dynamic enhanced magnetic resonance imaging. Cancer Res. 62, 4015–4022 (2002).
Conrad, C. et al. A phase I/II trial of single-agent PTK 787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in patients with recurrent glioblastoma multiforme (GBM) [abstract 1512]. ASCO Meeting Abstracts 22, 1512 (2004).
Vredenburgh, J. J. et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin. Cancer Res. 13, 1253–1259 (2007).
Pope, W. B., Lai, A., Nghiemphu, P., Mischel, P. & Cloughesy, T. F. MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 66, 1258–1260 (2006).
Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).
Sorensen, A. G., Batchelor, T. T., Wen, P. Y., Zhang, W. T. & Jain, R. K. Response criteria for glioma. Nat. Clin. Pract. Oncol. 5, 634–644 (2008).
Kimura, T., Ohkubo, M., Igarashi, H., Kwee, I. L. & Nakada, T. Increase in glutamate as a sensitive indicator of extracellular matrix integrity in peritumoral edema: a 3.0-tesla proton magnetic resonance spectroscopy study. J. Neurosurg. 106, 609–613 (2007).
Rubenstein, J. L. et al. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 4, 306–314 (2000).
Pauleit, D. et al. Can the apparent diffusion coefficient be used as a noninvasive parameter to distinguish tumor tissue from peritumoral tissue in cerebral gliomas? J. Magn. Reson. Imaging 20, 758–764 (2004).
van Westen, D., Lätt, J., Englund, E., Brockstedt, S. & Larsson, E. M. Tumor extension in high-grade gliomas assessed with diffusion magnetic resonance imaging: values and lesion-to-brain ratios of apparent diffusion coefficient and fractional anisotropy. Acta Radiol. 47, 311–319 (2006).
Sorensen, A. G. Magnetic resonance as a cancer imaging biomarker. J. Clin. Oncol. 24, 3274–3281 (2006).
Verheul, H. M. & Pinedo, H. M. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat. Rev. Cancer 7, 475–485 (2007).
Vredenburgh, J. J. et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol. 25, 4722–4729 (2007).
Jain, R. K., Finn, A. V., Kolodie, F. D., Gold, H. K. & Virmani, R. Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nat. Clin. Pract. Cardiovasc. Med. 4, 491–502 (2007).
Yoshiji, H., Harris, S. R. & Thorgeirsson, U. P. Vascular endothelial growth factor is essential for initial but not continued in vivo growth of human breast carcinoma cells. Cancer Res. 57, 3924–3928 (1997).
Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279–280 (2002).
Kunkel, P. et al. Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res. 61, 6624–6628 (2001).
Du, R. et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).
Claes, A. et al. Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol. Cancer Ther. 7, 71–78 (2008).
Gonzalez, J., Kumar, A. J., Conrad, C. A. & Levin, V. A. Effect of bevacizumab on radiation necrosis of the brain. Int. J. Radiat. Oncol. Biol. Phys. 67, 323–326 (2007).
Senger, D. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983).
Sack, U. et al. Vascular endothelial growth factor in pleural effusions of different origin. Eur. Respir. J. 25, 600–604 (2005).
Verheul, H. M., Hoekman, K., Jorna, A. S., Smit, E. F. & Pinedo, H. M. Targeting vascular endothelial growth factor blockade: ascites and pleural effusion formation. Oncologist 5, 45–50 (2000).
Yano, S. et al. Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation. Clin. Cancer Res. 6, 957–965 (2000).
Xu, L. et al. Inhibition of malignant ascites and growth of human ovarian carcinoma by oral administration of a potent inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Int. J. Oncol. 16, 445–454 (2000).
Aoki, Y. & Tosato, G. Role of vascular endothelial growth factor/vascular permeability factor in the pathogenesis of Kaposi sarcoma associated herpesvirus-infected primary effusion lymphoma. Blood 94, 4247–4254 (1999).
Numnum, T. M., Rocconi, R. P., Whitworth, J. & Barnes, M. N. The use of bevacizumab to palliate symptomatic ascites in patients with refractory ovarian carcinoma. Gynecol. Oncol. 102, 425–428 (2006).
Pichelmayer, O., Gruenberger, B., Zielinski, C. & Raderer, M. Bevacizumab is active in malignant effusion. Ann. Oncol. 17, 1853 (2006)
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ER Gerstner is a consultant for AstraZeneca, Genentech, Imclone, and Millennium Pharmaceuticals, and receives honoraria from Schering Plough. TT Batchelor has is a consultant for Acceleron Pharma, Enzon Inc., Exelixis Inc. and Vertex Pharmaceuticals, and receives honoraria from Enzon Inc. RK Jain is a consultant for AstraZeneca, Dyax, Millennium Pharmaceuticals and Takeda and receives research support from AstraZeneca and Dyax. He is also an Advisory Board member for SynDevRx. AG Sorensen is a consultant and receives funding from the following companies ACRIN Image Matrix, AstraZeneca, Genentech, Epix Pharmaceuticals, Millennium Pharmaceuticals, and Mitsubishi Pharma. AG Sorensen receives research support from the following companies: AstraZeneca, Amgen, Exelixis Inc., GlaxoSmithKline, General Electric Healthcare, National Institutes of Health, Novartis Pharmaceuticals, Schering–Plough and Siemens Medical Solutions. The other authors declared no competing interests.
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Gerstner, E., Duda, D., di Tomaso, E. et al. VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer. Nat Rev Clin Oncol 6, 229–236 (2009). https://doi.org/10.1038/nrclinonc.2009.14
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DOI: https://doi.org/10.1038/nrclinonc.2009.14
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