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:

Hemorrhagic and ischemic risks of anti-VEGF therapies in glioblastoma

Cancer Gene Therapy volume 32, pages 762–777 (2025)Cite this article

Subjects

Abstract

Glioblastoma (GBM) is one of the most aggressive primary brain tumors, characterized by extensive neovascularization and a highly infiltrative phenotype. Anti-vascular endothelial growth factor (VEGF) therapies, such as bevacizumab, have emerged as significant adjunct treatments for recurrent and high-grade GBM by targeting abnormal tumor vasculature. Despite demonstrated benefits in slowing tumor progression and alleviating peritumoral edema, these agents are associated with notable vascular complications, including hemorrhagic and ischemic events. Hemorrhagic complications range from minor intracranial microbleeds to life-threatening intracranial hemorrhages (ICH). Mechanistically, VEGF inhibition disrupts endothelial function and decreases vascular integrity, making already fragile tumor vessels prone to rupture. Glioma-associated vascular abnormalities, including disorganized vessel networks and compromised blood-brain barrier, further exacerbate bleeding risks. Concurrent use of anticoagulants, hypertension, and genetic predispositions also significantly elevate hemorrhagic risk. In addition to bleeding complications, ischemic events are increasingly recognized in patients receiving anti-VEGF therapy. Reduced vascular endothelial cells (ECs) survival and diminished microvascular density can lead to regional hypoperfusion and potentially precipitate cerebrovascular ischemia. Impaired vasoreactivity and increased vascular resistance, often accompanied by endothelial dysfunction and microvascular rarefaction, contribute to elevated stroke and arterial thrombotic risk. This review synthesizes current evidence on hemorrhagic and ischemic complications arising from anti-VEGF therapy in GBM. We discuss underlying pathophysiological mechanisms, risk factors, and clinically relevant biomarkers, as well as prevention strategies—such as rigorous blood pressure (BP) control and close monitoring of coagulation parameters. We further highlight emerging avenues in precision medicine, including pharmacogenomic profiling and targeted adjunct agents that protect vascular integrity, aimed at mitigating adverse vascular events while preserving therapeutic efficacy. The goal is to optimize outcomes for GBM patients by balancing the benefits of anti-VEGF therapy with vigilant management of its inherent vascular risks. In addition, this study analyzes existing clinical trials of the use of anti-VEGF drugs in the treatment of gliomas using data from the clinicaltirals.gov website.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Main anti-vascular endothelial growth factor (VEGF) agents in glioblastoma (GBM) treatment.
Fig. 2: Mechanism of adverse effects of bevacizumab in patients with glioblastoma.
Fig. 3: Schematic illustration of the mechanism of development of arterial hypertension after the use of anti-vascular endothelial growth factor (VEGF) therapy in glioma patients.
Fig. 4: Schematic illustration of the mechanism of atherosclerosis progression after the use of anti-vascular endothelial growth factor (VEGF) therapy in glioma patients.
Fig. 5
Fig. 6: Analysis of clinical trials using anti-vascular endothelial growth factor (VEGF) agents in brain tumors based on clinicaltrials.gov.

Similar content being viewed by others

Data availability

No datasets were generated or analyzed during the current study.

References

  1. Price M, Ballard C, Benedetti J, Neff C, Cioffi G, Waite KA, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2017–2021. Neuro Oncol. 2024;26:vi1–vi85. https://doi.org/10.1093/neuonc/noae145.

    Article  PubMed  Google Scholar 

  2. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96. https://doi.org/10.1056/NEJMoa043330.

    Article  CAS  PubMed  Google Scholar 

  3. Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013;31:2205–18. https://doi.org/10.1200/JCO.2012.46.3653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Marmé D. Tumor angiogenesis: a key target for cancer therapy. Oncol Res Treat. 2018;41:164. https://doi.org/10.1159/000488340.

    Article  PubMed  Google Scholar 

  5. Vredenburgh JJ, Desjardins A, Herndon JE, Marcello J, Reardon DA, Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722–9. https://doi.org/10.1200/JCO.2007.12.2440.

    Article  CAS  PubMed  Google Scholar 

  6. Gilbert MR. Antiangiogenic Therapy for Glioblastoma: Complex Biology and Complicated Results. J Clin Oncol. 2016;34:1567–9. https://doi.org/10.1200/JCO.2016.66.5364.

    Article  CAS  PubMed  Google Scholar 

  7. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28:1963–72. https://doi.org/10.1200/JCO.2009.26.3541.

    Article  PubMed  Google Scholar 

  8. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709–22. https://doi.org/10.1056/NEJMoa1308345.

    Article  CAS  PubMed  Google Scholar 

  9. Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021;18:170–86. https://doi.org/10.1038/s41571-020-00447-z.

    Article  PubMed  Google Scholar 

  10. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15:232–9. https://doi.org/10.1016/j.ccr.2009.01.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307. https://doi.org/10.1038/nature10144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Coso S, Zeng Y, Sooraj D, Williams ED. Conserved signaling through vascular endothelial growth (VEGF) receptor family members in murine lymphatic endothelial cells. Exp Cell Res. 2011;317:2397–407. https://doi.org/10.1016/j.yexcr.2011.07.023.

    Article  CAS  PubMed  Google Scholar 

  13. Arrillaga-Romany I, Norden AD. Antiangiogenic therapies for glioblastoma. CNS Oncol. 2014;3:349–58. https://doi.org/10.2217/cns.14.31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee CH, Motzer RJ. Kidney cancer in 2016: The evolution of anti-angiogenic therapy for kidney cancer. Nat Rev Nephrol. 2017;13:69–70. https://doi.org/10.1038/nrneph.2016.194.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22. https://doi.org/10.1016/j.ccr.2012.02.022.

    Article  CAS  PubMed  Google Scholar 

  16. Auer TA, Renovanz M, Marini F, Brockmann MA, Tanyildizi Y. Ischemic stroke and intracranial hemorrhage in patients with recurrent glioblastoma multiforme, treated with bevacizumab. J Neurooncol. 2017;133:571–9. https://doi.org/10.1007/s11060-017-2467-z.

    Article  CAS  PubMed  Google Scholar 

  17. Mantia C, Uhlmann EJ, Puligandla M, Weber GM, Neuberg D, Zwicker JI. Predicting the higher rate of intracranial hemorrhage in glioma patients receiving therapeutic enoxaparin. Blood. 2017;129:3379–85. https://doi.org/10.1182/blood-2017-02-767285.

    Article  CAS  PubMed  Google Scholar 

  18. Perry JR. Anticoagulation of malignant glioma patients in the era of novel antiangiogenic agents. Curr Opin Neurol. 2010;23:592–6. https://doi.org/10.1097/WCO.0b013e32833feb73.

    Article  CAS  PubMed  Google Scholar 

  19. Armstrong TS, Wen PY, Gilbert MR, Schiff D. Management of treatment-associated toxicites of anti-angiogenic therapy in patients with brain tumors. Neuro Oncol. 2012;14:1203–14. https://doi.org/10.1093/neuonc/nor223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Batchelor TT, Reardon DA, de Groot JF, Wick W, Weller M. Antiangiogenic therapy for glioblastoma: current status and future prospects. Clin Cancer Res. 2014;20:5612–9. https://doi.org/10.1158/1078-0432.CCR-14-0834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Taylor J, Gerstner ER. Anti-angiogenic therapy in high-grade glioma (treatment and toxicity). Curr Treat Options Neurol. 2013;15:328–37. https://doi.org/10.1007/s11940-013-0224-y.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Angom RS, Nakka NMR, Bhattacharya S. Advances in glioblastoma therapy: an update on current approaches. Brain Sci. 2023;13:1536. https://doi.org/10.3390/brainsci13111536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang N, Jain RK, Batchelor TT. New directions in anti-angiogenic therapy for glioblastoma. Neurotherapeutics. 2017;14:321–32. https://doi.org/10.1007/s13311-016-0510-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fraum TJ, Kreisl TN, Sul J, Fine HA, Iwamoto FM. Ischemic stroke and intracranial hemorrhage in glioma patients on antiangiogenic therapy. J Neurooncol. 2011;105:281–9. https://doi.org/10.1007/s11060-011-0579-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ostrowski RP, He Z, Pucko EB, Matyja E. Hemorrhage in brain tumor – an unresolved issue. Brain Hemorrhages. 2022;3:98–102. https://doi.org/10.1016/j.hest.2022.01.005.

    Article  Google Scholar 

  26. Brandes AA, Bartolotti M, Tosoni A, Poggi R, Franceschi E. Practical management of bevacizumab-related toxicities in glioblastoma. Oncologist. 2015;20:166–75. https://doi.org/10.1634/theoncologist.2014-0330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee SY, Devos P, Bink A, Regli L, Weller M, Le RE. Intracranial hemorrhage in glioblastoma: Incidence, risk factors, and outcome. J Clin Oncol. 2024;42:2074–2074. https://doi.org/10.1200/JCO.2024.42.16_suppl.2074.

    Article  Google Scholar 

  28. de Jesus-Gonzalez N, Robinson E, Moslehi J, Humphreys BD. Management of antiangiogenic therapy-induced hypertension. Hypertension. 2012;60:607–15. https://doi.org/10.1161/HYPERTENSIONAHA.112.196774.

    Article  CAS  PubMed  Google Scholar 

  29. Perry JR. Thromboembolic disease in patients with high-grade glioma. Neuro Oncol. 2012;14:iv73–80. https://doi.org/10.1093/neuonc/nos197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lee SH, Choi JW, Kong DS, Seol HJ, Nam DH, Lee JI. Effect of bevacizumab treatment in cerebral radiation necrosis: investigation of response predictors in a single-center experience. J Korean Neurosurg Soc. 2023;66:562–72. https://doi.org/10.3340/jkns.2022.0229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lin X, Daras M, Pentsova E, Nolan CP, Gavrilovic IT, DeAngelis LM, et al. Bevacizumab in high-grade glioma patients following intraparenchymal hemorrhage. Neurooncol Pr. 2017;4:24–28. https://doi.org/10.1093/nop/npw008.

    Article  Google Scholar 

  32. de Groot JF, Lamborn KR, Chang SM, Gilbert MR, Cloughesy TF, Aldape K, et al. Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study. J Clin Oncol. 2011;29:2689–95. https://doi.org/10.1200/JCO.2010.34.1636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lei J, Zhou Z. Efficacy and safety of bevacizumab combined with temozolomide in the treatment of recurrent malignant gliomas and its influence on serum tumor markers. Am J Transl Res. 2021;13:13886–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Scheer KG, Ebert LM, Samuel MS, Bonder CS, Gomez GA. Bevacizumab-induced hypertension in glioblastoma patients and its potential as a modulator of treatment response. Hypertension. 2023;80:1590–7. https://doi.org/10.1161/HYPERTENSIONAHA.123.21119.

    Article  CAS  PubMed  Google Scholar 

  35. Zhang AB, Mozaffari K, Aguirre B, Li V, Kubba R, Desai NC, et al. Exploring the past, present, and future of anti-angiogenic therapy in glioblastoma. Cancers. 2023;15:830. https://doi.org/10.3390/cancers15030830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Touyz RM, Herrmann SMS, Herrmann J. Vascular toxicities with VEGF inhibitor therapies-focus on hypertension and arterial thrombotic events. J Am Soc Hypertens. 2018;12:409–25. https://doi.org/10.1016/j.jash.2018.03.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–23. https://doi.org/10.1016/S0140-6736(05)17741-1.

    Article  PubMed  Google Scholar 

  38. O’Donnell A, Padhani A, Hayes C, Kakkar AJ, Leach M, Trigo JM, et al. A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points. Br J Cancer. 2005;93:876–83. https://doi.org/10.1038/sj.bjc.6602797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hamnvik OP, Choueiri TK, Turchin A, McKay RR, Goyal L, Davis M, et al. Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway. Cancer. 2015;121:311–9. https://doi.org/10.1002/cncr.28972.

    Article  CAS  PubMed  Google Scholar 

  40. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42. https://doi.org/10.1056/NEJMoa035291.

    Article  CAS  PubMed  Google Scholar 

  41. Atkins KM, Raghavan D, Chen C, Guha G, Blinder V, Steingart RM, et al. Discrepancies between office and home blood pressure monitoring in patients receiving bevacizumab. Hypertension. 2011;58:1205–12. https://doi.org/10.1161/HYPERTENSIONAHA.111.168469.

    Article  Google Scholar 

  42. European Society of Hypertension. Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39:3021–104. https://doi.org/10.1093/eurheartj/ehy339.

    Article  Google Scholar 

  43. Davenport A, Howell SB, Zhang H, Hudes GR, Dutcher JP, Tarazi JC, et al. Blood pressure changes in patients with metastatic renal cell carcinoma treated with sunitinib. J Clin Oncol. 2008;26:3558–64. https://doi.org/10.1200/JCO.2007.15.7440.

    Article  Google Scholar 

  44. Johnson DB, Griffin RJ, Ryan CJ, Patel J, Thomas AA, Lewis BD, et al. Antihypertensive therapy can mitigate sunitinib-induced blood pressure increases. J Hypertens. 2009;27:2245–51. https://doi.org/10.1097/HJH.0b013e32832d28b6.

    Article  Google Scholar 

  45. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34. https://doi.org/10.1056/NEJMoa066061.

    Article  CAS  PubMed  Google Scholar 

  46. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. Cediranib in combination with chemotherapy for recurrent ovarian cancer: a phase III trial. J Clin Oncol. 2012;30:3917–23. https://doi.org/10.1200/JCO.2011.38.7923.

    Article  Google Scholar 

  47. Staessen JA, Fagard RH, Thijs L, Celis H, O’Brien E, Dolan E, et al. Age, BMI, and prehypertension as predictors of hypertension in patients treated with VEGF inhibitors. Hypertension. 2015;65:702–8. https://doi.org/10.1161/HYPERTENSIONAHA.114.04317.

    Article  Google Scholar 

  48. Zhou X, Qiu J, Zhang L, Wang Y, Chen H, Li M, et al. Predictors of hypertensive response in cancer patients treated with VEGF inhibitors: a meta-analysis. Cancer Med. 2021;10:6512–23. https://doi.org/10.1002/cam4.4065.

    Article  CAS  Google Scholar 

  49. Neyt M, Carmeliet P. Hypertension and VEGF signaling inhibitors: mechanisms and management. Nat Rev Nephrol. 2013;9:210–7. https://doi.org/10.1038/nrneph.2013.12.

    Article  CAS  Google Scholar 

  50. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592–603. https://doi.org/10.1038/nrc2458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang G, Huang S, Wang Z. A meta-analysis of bevacizumab alone and in combination with irinotecan in the treatment of patients with recurrent glioblastoma multiforme. J Clin Neurosci. 2012;19:1636–40. https://doi.org/10.1016/j.jocn.2011.12.028.

    Article  CAS  PubMed  Google Scholar 

  52. van Linde ME, Brahm CG, de Witt Hamer PC, Wagemakers M, Reijneveld JC, Vandertop WP, et al. Survival prediction model of new or progressive intracranial hemorrhage in glioblastoma patients receiving antiangiogenic therapy: a prospective single-center study. J Neurooncol. 2022;159:257–66. https://doi.org/10.1007/s11060-022-04033-0.

    Article  Google Scholar 

  53. Piao Y, Liu N, Xu Y, Li Y, Jiang T, Zhang W, et al. Incidence and risk factors of bleeding in patients with glioblastoma receiving bevacizumab: a retrospective cohort study. J Neurooncol. 2021;155:145–53. https://doi.org/10.1007/s11060-021-03876-z.

    Article  Google Scholar 

  54. Tonder M, Liht M, Stupp R, Taal W. Bevacizumab in glioblastoma: an update on clinical evidence of safety, efficacy and current perspectives. Expert Opin Biol Ther. 2022;22:611–23. https://doi.org/10.1080/14712598.2022.2049182.

    Article  Google Scholar 

  55. Zhou S, Wang L, Li G, Liu R. Factors affecting the incidence of bevacizumab-related thrombocytopenia in Chinese metastatic colorectal cancer patients. Support Care Cancer. 2021;29:4645–53. https://doi.org/10.1007/s00520-021-06007-y.

    Article  Google Scholar 

  56. Plate KH, Scholz A, Dumont DJ. Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited. Acta Neuropathol. 2012;124:763–75. https://doi.org/10.1007/s00401-012-1066-5.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Tsien CI, Pugh SL, Dicker AP, Raizer JJ, Matuszak MM, Lallana EC, et al. NRG oncology/RTOG1205: a randomized phase II trial of concurrent bevacizumab and reirradiation versus bevacizumab alone as treatment for recurrent glioblastoma. J Clin Oncol. 2023;41:1285–95. https://doi.org/10.1200/JCO.22.00164.

    Article  CAS  PubMed  Google Scholar 

  58. Facemire CS, Nixon AB, Griffiths R, Hurwitz H, Coffman TM. Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression. Hypertension. 2009;54:652–8. https://doi.org/10.1161/HYPERTENSIONAHA.109.133546.

    Article  CAS  PubMed  Google Scholar 

  59. Kappers MH, van Esch JH, Sluiter W, Sleijfer S, Danser AH, van den Meiracker AH. Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 and reduced microvascular density. J Hypertens. 2010;28:2427–37. https://doi.org/10.1097/HJH.0b013e328340d111.

    Article  Google Scholar 

  60. Izzedine H, Ederhy S, Goldwasser F, Soria JC, Milano G, Cohen A, et al. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol. 2009;20:293–300. https://doi.org/10.1093/annonc/mdn573.

    Article  Google Scholar 

  61. van der Veldt AA, Boven E, Helgason HH, van Wouwe M, Berkhof J, de Gast G, et al. Predictive factors for severe toxicity of sunitinib in patients with advanced renal cell cancer. Br J Cancer. 2008;99:259–65. https://doi.org/10.1038/sj.bjc.6604450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol. 2009;6:465–77. https://doi.org/10.1038/nrclinonc.2009.94.

    Article  CAS  PubMed  Google Scholar 

  63. Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U, et al. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2007;25:3045–54. https://doi.org/10.1200/JCO.2006.07.2066.

    Article  CAS  PubMed  Google Scholar 

  64. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab therapy for cancer patients: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2008;3:386–93. https://doi.org/10.2215/CJN.03610807.

    Article  Google Scholar 

  65. Kappers MH, Smedts FM, Horn T, van Esch JH, Sleijfer S, Leijten F, et al. The vascular endothelial growth factor receptor tyrosine kinase inhibitor sunitinib causes a preeclampsia-like syndrome with activation of the endothelin system. Hypertension. 2011;58:295–302. https://doi.org/10.1161/HYPERTENSIONAHA.111.172783.

    Article  CAS  PubMed  Google Scholar 

  66. Arima Y, Oshima S, Noda K, Fukushima H, Taniguchi I, Nakamura S, et al. Sorafenib-induced acute myocardial infarction due to coronary artery spasm. J Cardiol. 2009;54:512–5. https://doi.org/10.1016/j.jjcc.2009.03.009.

    Article  PubMed  Google Scholar 

  67. Touyz RM, Herrmann J. Cardiotoxicity with vascular endothelial growth factor signaling inhibitors: evidence and mechanisms. Toxicol Pathol. 2018;46:459–71. https://doi.org/10.1177/0192623318781029.

    Article  Google Scholar 

  68. Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Investig. 2006;116:2610–21. https://doi.org/10.1172/JCI28330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003;101:3597–605. https://doi.org/10.1182/blood-2002-07-2307.

    Article  CAS  PubMed  Google Scholar 

  70. Tsai HT, Marshall JL, Weiss SR, Huang CY, Warren JL, Freedman AN, et al. Bevacizumab use and risk of cardiovascular adverse events among elderly patients with colorectal cancer receiving chemotherapy: a population-based study. Ann Oncol. 2013;24:1574–9. https://doi.org/10.1093/annonc/mdt019.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer. 2007;7:475–85. https://doi.org/10.1038/nrc2152.

    Article  CAS  PubMed  Google Scholar 

  72. Iñarrairaegui M, Martinez-Cuesta A, Rodríguez M, Bilbao JI, Arbizu J, Benito A, et al. Analysis of prognostic factors after yttrium-90 radioembolization of advanced hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2010;77:1441–8. https://doi.org/10.1016/j.ijrobp.2009.07.006.

    Article  PubMed  Google Scholar 

  73. Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol. 2009;27:4839–47. https://doi.org/10.1200/JCO.2009.22.3271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Falanga A, Brenner B, Khorana AA, Francis CW. Thrombotic complications in patients with cancer: advances in pathogenesis, prevention, and treatment-A report from ICTHIC 2021. Res Pr Thromb Haemost. 2022;6:e12744. https://doi.org/10.1002/rth2.12744.

    Article  CAS  Google Scholar 

  75. Scott BJ, Quant EC, McNamara MB, Ryg PA, Batchelor TT, Wen PY. Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors. Neuro Oncol. 2010;12:603–7. https://doi.org/10.1093/neuonc/nop073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Shi Y, Kang X, Ge Y, Cao Y, Li Y, Guo X, et al. The molecular signature and prognosis of glioma with preoperative intratumoral hemorrhage: a retrospective cohort analysis. BMC Neurol. 2024;24:202. https://doi.org/10.1186/s12883-024-03703-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bianconi A, Prior A, Zona G, Fiaschi P. Anticoagulant therapy in high grade gliomas: a systematic review on state of the art and future perspectives. J Neurosurg Sci. 2023;67:236–40. https://doi.org/10.23736/S0390-5616.21.05536-3.

    Article  PubMed  Google Scholar 

  78. Beal K, Abrey LE, Gutin PH. Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: analysis of single-agent and combined modality approaches. Radiat Oncol. 2011;6:2. https://doi.org/10.1186/1748-717X-6-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Field KM, Phal PM, Fitt G, Goh C, Nowak AK, Rosenthal MA, et al. The role of early magnetic resonance imaging in predicting survival on bevacizumab for recurrent glioblastoma: Results from a prospective clinical trial (CABARET). Cancer. 2017;123:3576–82. https://doi.org/10.1002/cncr.30838.

    Article  CAS  PubMed  Google Scholar 

  80. Hayes J, French P, Van Den Bent M, Gregory W, Westhead D, Lawler S, et al. Geno-17: an 8-microRNA signature predicts response to bevacizumab in glioblastoma. Neuro Oncol. 2015;17:v95 https://doi.org/10.1093/neuonc/nov215.17.

    Article  PubMed Central  Google Scholar 

  81. Kawai N, Watanabe K, Tani N, Sato M, Yamamoto Y, Nishiyama Y, et al. Surgical management and bevacizumab re-challenge in intracranial hemorrhage during glioblastoma therapy: a case report. World Neurosurg. 2023;174:82–88. https://doi.org/10.1016/j.wneu.2023.04.162.

    Article  Google Scholar 

  82. Daneshimehr F, Barabadi Z, Abdolahi S, Soleimani M, Verdi J, Ebrahimi-Barough S, et al. Angiogenesis and its targeting in glioblastoma with focus on clinical approaches. Cell J. 2022;24:555–68. https://doi.org/10.22074/cellj.2022.8154.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Goldman M, Lucke-Wold B, Martinez-Sosa M, Katz J, Mehkri Y, Valisno J, et al. Steroid utility, immunotherapy, and brain tumor management: an update on conflicting therapies. Explor Target Antitumor Ther. 2022;3:659–75. https://doi.org/10.37349/etat.2022.00106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Giammalva GR, Iacopino DG, Azzarello G, Gaggiotti C, Graziano F, Gulì C, et al. End-of-life care in high-grade glioma patients. The palliative and supportive perspective. Brain Sci. 2018;8:125 https://doi.org/10.3390/brainsci8070125.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Reardon DA, Turner S, Peters KB, Desjardins A, Gururangan S, Sampson JH, et al. A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma. J Natl Compr Cancer Netw. 2011;9:414–27. https://doi.org/10.6004/jnccn.2011.0038.

    Article  CAS  Google Scholar 

  86. Castro BA, Aghi MK. Bevacizumab for glioblastoma: current indications, surgical implications, and future directions. Neurosurg Focus. 2014;37:E9 https://doi.org/10.3171/2014.9.focus14516.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Hummel TR, Salloum R, Drissi R, Kumar S, Sobo M, Goldman S, et al. A pilot study of bevacizumab-based therapy in patients with newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas. J Neurooncol. 2016;127:53–61. https://doi.org/10.1007/s11060-015-2008-6.

    Article  CAS  PubMed  Google Scholar 

  88. Ammari S, Sallé de Chou R, Assi T, Touat M, Chouzenoux E, Quillent A, et al. Machine-learning-based radiomics MRI model for survival prediction of recurrent glioblastomas treated with bevacizumab. Diagnostics. 2021;11:1263 https://doi.org/10.3390/diagnostics11071263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Horowitz JR, Rivard A, van der Zee R, Hariawala M, Sheriff DD, Esakof DD, et al. Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium. Arterioscler Thromb Vasc Biol. 1997;17:2793–800. https://doi.org/10.1161/01.atv.17.11.2793.

    Article  CAS  PubMed  Google Scholar 

  90. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Investig. 2003;111:707–16. https://doi.org/10.1172/JCI17423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. DeLeve LD, Wang X, Hu L, McCuskey MK, McCuskey RS. Rat liver endothelial cells are targets of LPS-induced oxidative stress. Am J Physiol Gastrointest Liver Physiol. 2004;287:G676–G684. https://doi.org/10.1152/ajpgi.00096.2004.

    Article  Google Scholar 

  92. Kamba T, Tam BY, Hashizume H, Haskell A, Sennino B, Mancuso MR, et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol. 2006;290:H560–76. https://doi.org/10.1152/ajpheart.00133.2005.

    Article  CAS  PubMed  Google Scholar 

  93. Lambrechts D, Carmeliet P. VEGF at the neurovascular interface: therapeutic implications for motor neuron disease?. Biochim Biophys Acta. 2006;1762:1109–21. https://doi.org/10.1016/j.bbadis.2006.09.003.

    Article  CAS  PubMed  Google Scholar 

  94. Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004;165:35–52. https://doi.org/10.1016/S0002-9440(10)63273-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Baffert F, Le T, Sennino B, Thurston G, Kuo CJ, Hu-Lowe D, et al. Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol. 2006;290:H547–59. https://doi.org/10.1152/ajpheart.00616.2005.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Bashkir State Medical University Strategic Academic Leadership Program (PRIORITY-2030).

Author information

Author notes

  1. These authors contributed equally: Ozal Beylerli, Ilgiz Gareev.

Authors and Affiliations

  1. Central Research Laboratory, Bashkir State Medical University, Ufa, Russia

    Ozal Beylerli & Ilgiz Gareev

  2. National Medical Research Radiological Centre (NMRRC) of the Ministry of Health of the Russian Federation, Moscow, Russia

    Andrey Kaprin

  3. Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar

    Aamir Ahmad

  4. Pirogov Russian National Research Medical University of the Ministry of Healthcare of Russian Federation, Moscow, Russia

    Vladimir Chekhonin

  5. Serbsky Federal Medical Research Centre of Psychiatry and Narcology of the Ministry of Healthcare of Russian Federation, Moscow, Russia

    Vladimir Chekhonin

  6. Endocrinology Research Center, Moscow, Russia

    Vladimir Chekhonin

  7. Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China

    Shanshan Yang

  8. Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China

    Guang Yang

  9. Heilongjiang Province Neuroscience Institute, Harbin, China

    Guang Yang

Authors
  1. Ozal Beylerli
    View author publications

    Search author on:PubMed Google Scholar

  2. Ilgiz Gareev
    View author publications

    Search author on:PubMed Google Scholar

  3. Andrey Kaprin
    View author publications

    Search author on:PubMed Google Scholar

  4. Aamir Ahmad
    View author publications

    Search author on:PubMed Google Scholar

  5. Vladimir Chekhonin
    View author publications

    Search author on:PubMed Google Scholar

  6. Shanshan Yang
    View author publications

    Search author on:PubMed Google Scholar

  7. Guang Yang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Conceptualization, project administration, and writing–original draft, conceptualization, resources, and writing–review and editing, OB and IG; data curation, formal analysis, investigation, and methodology, AK, AA, and VC; software, validation, and visualization, SY and GY; supervision and funding acquisition, OB and IG. All authors agreed on the journal to which the article would be submitted, gave final approval for the version to be published, and agreed to be accountable for all aspects of the work.

Corresponding authors

Correspondence to Shanshan Yang or Guang Yang.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Beylerli, O., Gareev, I., Kaprin, A. et al. Hemorrhagic and ischemic risks of anti-VEGF therapies in glioblastoma. Cancer Gene Ther 32, 762–777 (2025). https://doi.org/10.1038/s41417-025-00914-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41417-025-00914-8

Search

Advanced search

Quick links