Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer

Nature Reviews Clinical Oncology volume 6, pages 229–236 (2009)Cite this article

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

  • Peritumoral vasogenic cerebral edema is a significant cause of morbidity and mortality in patients with brain tumors

  • VEGF is secreted by brain tumors and has an important role in increasing vascular permeability and, thus, contributing to peritumoral edema

  • Peritumoral edema increases interstitial fluid pressure, which leads to poor penetration of chemotherapeutics and treatment resistance

  • 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

  • Anti-VEGF therapy exerts its effects by restoring vascular permeability and normalizing tumor blood vessels

  • Anti-VEGF agents could also be useful in other cancer-related conditions that increase vascular permeability, such as malignant pleural effusions or ascites

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The permeability of junctions in normal and disrupted blood–brain barrier.
Figure 2: Schematic diagram to illustrate the process of vascular normalization
Figure 3: Effects of cediranib on cerebral edema in patients with recurrent glioblastoma.
Figure 4: Serial MRI images from the same patient (as shown in Figure 3) with a left frontal glioblastoma treated with cediranib.

Similar content being viewed by others

References

  1. 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).

    Article  CAS  PubMed  Google Scholar 

  2. Klatzo, I. Presidential address. Neuropathological aspects of brain edema. J. Neuropathol. Exp. Neurol. 26, 1–14 (1967).

    Article  CAS  PubMed  Google Scholar 

  3. Eichler, A. F. & Loeffler, J. S. Multidisciplinary management of brain metastases. Oncologist 12, 884–898 (2007). .

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    Article  CAS  PubMed  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. 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).

    CAS  PubMed  Google Scholar 

  7. 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).

    Article  CAS  PubMed  Google Scholar 

  8. Tjuvajev, J. et al. Corticotropin-releasing factor decreases vasogenic brain edema. Cancer Res. 56, 1352–1360 (1996).

    CAS  PubMed  Google Scholar 

  9. Jain, R. K. Normalizing tumour vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7, 987–989 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Kroll, R. A. & Neuwelt, E. A. Outwitting the blood–brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 42, 1083–1099 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  Google Scholar 

  15. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. Jain, R. K. et al. Angiogenesis in brain tumours. Nat. Rev. Neurosci. 8, 610–622 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Provias, J. et al. Meningiomas: role of vascular endothelial growth factor/vascular permeability factor in angiogenesis and peritumoral edema. Neurosurgery 40, 1016–1026 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    CAS  PubMed  Google Scholar 

  21. 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).

    Article  CAS  PubMed  Google Scholar 

  22. 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).

    Article  CAS  PubMed  Google Scholar 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    CAS  PubMed  Google Scholar 

  32. 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).

    CAS  PubMed  Google Scholar 

  33. Jain, R. K. Antiangiogenic therapy for cancer: current and emerging concepts. Oncology (Williston Park) 19, 7–16 (2005).

    Google Scholar 

  34. Jain, R. K. Taming vessels to treat cancer. Sci. Am. 298, 56–63 (2008).

    Article  PubMed  Google Scholar 

  35. 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).

    CAS  PubMed  Google Scholar 

  36. 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).

    Google Scholar 

  37. Vredenburgh, J. J. et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin. Cancer Res. 13, 1253–1259 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. Rubenstein, J. L. et al. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 4, 306–314 (2000).

    Article  Google Scholar 

  43. 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).

    Article  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. Sorensen, A. G. Magnetic resonance as a cancer imaging biomarker. J. Clin. Oncol. 24, 3274–3281 (2006).

    Article  PubMed  Google Scholar 

  46. Verheul, H. M. & Pinedo, H. M. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat. Rev. Cancer 7, 475–485 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Vredenburgh, J. J. et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol. 25, 4722–4729 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    CAS  PubMed  Google Scholar 

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. 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).

    CAS  PubMed  Google Scholar 

  52. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Claes, A. et al. Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol. Cancer Ther. 7, 71–78 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. 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).

    Article  CAS  PubMed  Google Scholar 

  55. Senger, D. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983).

    Article  CAS  PubMed  Google Scholar 

  56. Sack, U. et al. Vascular endothelial growth factor in pleural effusions of different origin. Eur. Respir. J. 25, 600–604 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    CAS  PubMed  Google Scholar 

  59. 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).

    CAS  PubMed  Google Scholar 

  60. 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).

    CAS  PubMed  Google Scholar 

  61. 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).

    Article  CAS  PubMed  Google Scholar 

  62. Pichelmayer, O., Gruenberger, B., Zielinski, C. & Raderer, M. Bevacizumab is active in malignant effusion. Ann. Oncol. 17, 1853 (2006)

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Elizabeth R. Gerstner & Peter A. Ryg

  2. Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Dan G. Duda, Emmanuelle di Tomaso, Jay S. Loeffler & Rakesh K. Jain

  3. Stephen E and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Tracy T. Batchelor

  4. Center for Biomarkers and Imaging, Massachusetts General Hospital Cancer Center, Boston, MA, USA

    A. Gregory Sorensen

  5. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Percy Ivy

Authors
  1. Elizabeth R. Gerstner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dan G. Duda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emmanuelle di Tomaso
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter A. Ryg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jay S. Loeffler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Gregory Sorensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Percy Ivy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rakesh K. Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tracy T. Batchelor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tracy T. Batchelor.

Ethics declarations

Competing interests

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2009.14

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing