Abstract
Angiogenesis refers to the growth of newly formed blood vessels from pre-existing vasculature (Wang et al., Oncotarget. 8:53854–72, 2017). Blocking the formation of blood vessels, theoretically, would stop a tumor from growing and metastasizing. For decades researchers have studied tumor growth and metastasis, ultimately discovering tumor-angiogenesis factor vascular endothelial growth factor (VEGF). This discovery led to a different way of treating cancer, blocking certain targets to stop tumor growth (targeted therapy). The discoveries of VEGF, immunotherapy, and driver mutations have changed the treatment paradigm of lung cancer.
There are two anti-angiogenic agents, bevacizumab and ramucirumab, used in combination with chemotherapy agents as first-line and second-line therapy for patients with non-small cell lung cancer (NSCLC). These agents provide an option for VEGF targeted therapy treatment for NSCLC with relatively manageable toxicities.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Camp-Sorrell D. Anti-angiogenesis: the fifth cancer treatment modality? Oncol Nurs Forum. 2003;30(6):934–44. https://doi.org/10.1188/03.ONF.934-944.
Viele CS. Keys to unlock cancer; targeted therapy. Oncol Nurs Forum. 2005;32(5):935–40. https://doi.org/10.1188/05.ONF.
Al-Abd AM, Alamoudi AJ, Abdel-Naim AB, Neamatallah TA, Ashour OM. Anti-angiogenic agents for the treatment of solid tumors: potential pathways, therapy and current strategies-a review. J Adv Res. 2017;8(6):591–605. https://doi.org/10.1016/j.jare.2017.06.006.
Hashimoto T, Shibasaki F. Hypoxia-inducible factor as an angiogenic master switch. Front Pediatr. 2015;3(33):1–15. https://doi.org/10.3389/fped.2015.00033.
Ellis LM. The biology of VEGF and tumor angiogenesis. Horizons in Cancer Therapeutics: From Bench to Bedside. 2004;5:4–10.
Aggarwal C, Somaiah N, Simon G. Antiangiogenic agents in the management of non-small cell lung cancer: where do we stand now and where are we headed? Cancer Biol Ther. 2012;13(5):247–63. https://doi.org/10.4161/cbt.13.5.19594.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(2):646–74. https://doi.org/10.1016/j.cell.2011.02.03.
Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23(5):1011–27. https://doi.org/10.1200/JCO.2005.06.081.
Blagosklonny MV. Hypoxia-inducible factor: Achilles’ heel of antiangiogenic cancer therapy. Int J Oncol. 2001;19:257–62. https://doi.org/10.3892/ijo.19.2.257.
Brooks NA, Kilgour E, Smith PD. Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res. 2012;18(7):1855–62. https://doi.org/10.1158/1078-0432.CCR-11-1590.
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307.
Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009;21(2):154–65. https://doi.org/10.1016/J.CEB.2008.12.012.
Fontanini G, Lucchi M, Viganti S, Mussi A, Ciardiello F, De Laurentiis M, De Placido S, Basolos F, Angeletti CA, Bevilaqua G. Angiogenesis as a prognostic indicator of survival in non-small cell lung cancer: a prospective study. J Natl Cancer Inst. 1997;89(12):881–6. https://doi.org/10.1093/JNCI/89.12.881.
Lucchi M, Fontanini G, Mussi A, Vignati S, Ribechini A, Menconi GF, Bevilaqua G, Angeletti CA. Tumor angiogenesis and biologic markers in resected stage I non-small cell lung cancer. Eur J Cardiothorac Surg. 1997;12(4):535–41. https://doi.org/10.1016/S1010-7940(97)00218-2.
Tammela T, Alitalo K. Lymphangiogenesis: molecular mechanisms and future promise. Cell. 2010;140(4):460–76. https://doi.org/10.1016/j.cell.2010.01.045.
Tozer GM, Kanthou C, Baguley BC. Disrupting tumour blood vessels. Nat Rev Cancer. 2005;5(6):423–35. https://doi.org/10.1038/nrc1628.
Skliarenko JV, Lunt SJ, Gordon ML, Vitkin A, Milosevic M, Hill RP. Effects of the vascular disrupting agent ZD6126 on interstitial fluid pressure and cell survival in tumors. Cancer Res. 2006;66(4):2074–80. https://doi.org/10.1158/0008-5472.CAN-05-2046.
Robinson SP, McIntyre DJ, Checkley D, Tessier JJ, Howe FA, Griffiths JR, Ashton SE, Ryan AJ, Blakey DC, Waterton JC. Tumour dose response to the antivascular agent ZD6126 assessed by magnetic resonance imaging. Br J Cancer. 2003;88(10):1592–7. https://doi.org/10.1038/sj.bjc.6600926.
Manzo A, Montanino A, Carillio G, Costanzo R, Sandomenico C, Normanno N, Piccirillo MC, Morabito A. Angiogenesis inhibitors in NSCLC: review. Int J Mol Sci. 2017;18(2021):1–17. https://doi.org/10.3390/ijms18102021.
Homsi J, Daud AI. Spectrum of activity and metabolism of action of VEGF/PDGR inhibitors. Cancer Control. 2007;14(3):285–94.
Wang J, Chen J, Guo Y, Wang B, Chu H. Strategies targeting angiogenesis in advanced non-small cell lung cancer. Oncotarget. 2017;8(32):53854–72. https://doi.org/10.18632/oncotarget.17957.
Sandler AB, Gray R, Perry MC, Brahmer J, Schiller J, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med. 2006;355(24):2542–50. https://doi.org/10.1056/NEJMoa061884.
Sandler AB, Yi J, Dahlberg S, Kolb MM, Wang L, Hambleton J, Schiller J, Johnson DH. Treatment outcomes by tumor histology in Eastern Cooperative Group (ECOG) Study E4599 of bevacizumab with paclitaxel/carboplatin for Advanced Non-Small Cell Lung Cancer (NSCLC). J Thorac Oncol. 2010;5(9):1416–23. https://doi.org/10.1097/JTO.0b013e3181da36f4.
Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsch V, Leighl N, Mezger J, Archer V, Moore C, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for non-squamous non-small cell lung cancer: AVAiL. J Clin Oncol. 2009;27(8):1227–34. https://doi.org/10.1200/JCO.2007.14.5466.
Soria JC, Mauguen A, Reck M, Sandler AB, Saijo N, Johnson DH, Burcoveanu D, Fukuoka M, Bess P, Pignon JP, on Behalf of the Meta-Analysis of Bevacizumab in Advanced NSCLC Collaborative Group. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol. 2013;24(1):20–30. https://doi.org/10.1093/annonc/mds590.
Behera M, Pillai RM, Owonikoko TK, Kim S, Steuer C, Chen Z, Saba NF, Belani CP, Khuri FR, Ramalingam SS. Bevacizumab in combination with taxane versus non-taxane containing regimens for advanced/nonsquamous non-small cell lung cancer: a systematic review. J Thorac Oncol. 2015;10(8):1142–7. https://doi.org/10.1097/JTO.0000000000000572.
Patel JD, Bonomi P, Socinski MA, Govindan R, Hong S, Obasaju C, Pennella EJ, Girvan AC, Guba SC. Treatment rationale and study design for the PointBreak study: a randomized, open-label phase III study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small cell lung cancer. Clin Lung Cancer. 2009;10(4):252–6. https://doi.org/10.3816/CLC.2009.n.035.
Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vistrom A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJM. Randomized phase III trial of maintenance bevacizumab, with or without pemetrexed after first-line induction with and pemetrexed in advanced non-squamous non-small cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013;31(24):3004–11. https://doi.org/10.1200/JCO.2012.42.3749.
Herbst RS, Ansari R, Bustin F, Flynn P, Hart L, Otterson GA, Vlahovic G, Soh C-H, O’Connor P, Hainsworth J. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377(9780):1846–54. https://doi.org/10.1016/S0140-6736(11)60545-X.
Li M, Kroetz DL. Bevacizumab-induced hypertension: clinical and molecular understanding. Pharmacol Ther. 2018;182:152–60. https://doi.org/10.1016/j.pharmthera.2017.08.012.
Genentech Inc. Avastin prescribing information. 2016. https://www.gene.com/download/pdf/avastin_prescribing.pdf.
Marrs J, Zubal BA. Oncology nursing in a new era: optimizing treatment with bevacizumab. Clin J Oncol Nurs. 2009;13(5):564–72. https://doi.org/10.1188/09.CJON.564-572.
Maitland ML, Bakris GL, Black HR, Chen HX, Durand JB, Elliott WJ, Ivy SP, Cardiovascular Toxicities Panel Convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst. 2010;102(9):596–604. https://doi.org/10.1093/jnci/djq091.
Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49(2):186–93. https://doi.org/10.1053/j.ajkd.2006.11.039.
Yang ZY, Simari RD, Perkins ND, San H, Gordon D, Nabel GJ, Nabel EG. Role of p21 cyclin-dependent kinase inhibitor in limiting intimal cell proliferation in response to arterial injury. Proc Natl Acad Sci. 1996;93(15):7905–10.
Izzedine H, Ederhy S, Goldwasser F, Soria JC, Milano G, Cohen A, Khayat D, Spano JP. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol. 2009;20(5):807–15. https://doi.org/10.1093/annonc/mdn713.
Langenberg MHG, van Herpen CML, De Bono J, Schellens JHM, Unger C, Hoekman K, Blum HE, Voest EE. Effective strategies for management of hypertension after vascular endothelial growth factor signaling inhibition therapy: results from a phase II randomized, factorial, double-blind study of cediranib in patients with advanced solid tumors. J Clin Oncol. 2009;27(36):6152–9. https://doi.org/10.1200/JCO.2009.22.2273.
Neill, T.A. Reversible posterior leukoencephalopathy syndrome. 2018. http://www.uptodate.com. Accessed 25 Jan 2018.
Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, Pessin MS, Lamy C, Mas J-L, Caplan LR. A reversible leukoencephalopathy syndrome. N Engl J Med. 1996;334(8):494–500. https://doi.org/10.1056/NEJM199602223340803.
Choueiri TK, Sonpavde G. Toxicity of molecularly targeted antiangiogenic agents: non-cardiovascular effects. 2017. http://www.uptodate.com. Accessed 15 Sept 2017.
Sclafani F, Giuseppe G, Mezynski J, Collins C, Crown J. Reversible posterior leukoencephalopathy syndrome in breast cancer. J Clin Oncol. 2012;30(26):e257–9. https://doi.org/10.1200/JCO.2011.38.8942.
Strandgaard S, Paulson OB. Cerebral autoregulation. Stroke. 1984;15(3):413–6. https://doi.org/10.1161/01.STR.15.3.413.
Bastos B, Ibrahim M, Hoffman J, Kernan W, Pinto D. Reversible posterior leukoencephalopathy syndrome secondary to bevacizumab. J Hematol Oncol Pharm. 2011;1(2):1–8.
Marinella MA, Markert RJ. Reversible posterior leucoencephalopathy syndrome associated with anticancer drugs. Intern Med J. 2009;39(12):826–34. https://doi.org/10.1111/j.1445-5994.2008.01829x.
Vaughn C, Zhang L, Schiff D. Reversible posterior leukoencephalopathy syndrome in cancer. Curr Oncol Rep. 2008;10(1):86–91.
Shord SS, Bresler LR, Tierney LA, Cuellar S, Geroge A. Understanding and managing the possible adverse effects associated with bevacizumab. Am J Health Syst Pharm. 2009;66(11):999–1013. https://doi.org/10.2146/ajhp080455.
Wu S, Kim C, Baer L, Zhu X. Bevacizumab increased risk for severe proteinuria in cancer patients. J Am Soc Nephrol. 2010;21(8):1381–9. https://doi.org/10.1681/ASN.2010020167.
Izzedine H, Massard C, Spano JP, Goldwasser F, Khayat D, Soria JC. VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management. Eur J Cancer. 2010;46(2):439–48. https://doi.org/10.1016/J.EJCA.2009.11.001.
Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Quaggin SE. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358(11):1129–36. https://doi.org/10.1056/NEJMoa0707330.
Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Kabbinavar F. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer. J Clin Oncol. 2004;22(11):2184–91. https://doi.org/10.1200/JCO.2004.11.022.
Maynard SE, Min JY, Merchan J, Lim K-H, Li J, Mondal S, Libermann TA, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111(5):649–58. https://doi.org/10.1172/JCI17189.
Bollee G, Patey N, Cazajous G, Robert C, Goujon J-M, Fakhouri F, Bruneval P, Noel L-H, Knebelmann B. Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib. Nephrol Dial Transplant. 2009;24(2):682–5. https://doi.org/10.1093/ndt/gfn657.
George BA, Zhou XJ, Toto R. Nephrotic syndrome after bevacizumab: case report and literature review. Am J Kidney Dis. 2007;49(2):e23–9. https://doi.org/10.1053/j.ajkd.2006.11.024.
Dincer M, Altundag K. Angiotensin-converting enzyme inhibitors fbevacuzmab-induced hypertension. Ann Pharmacother. 2006;40(12):2278–9. https://doi.org/10.1345/aph.1H244.
Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, Ruff P, Allegra C. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506. https://doi.org/10.1200/JCO.2012.42.8201.
Zangari M, Fink LM, Elice F, Zhan F, Adcock DM, Tricot GJ. Thrombotic events in patients with cancer receiving antiangiogene agents. J Clin Oncol. 2009;27(29):4865–73. https://doi.org/10.1200/JCO.2009.22.3875.
Mir O, Mouthon L, Alexandre J, Mallion J-M, Deray G, Guillevin L, Goldwasser F. Bevacizumab-induced cardiovascular events: a consequence of cholesterol emboli syndrome? J Natl Cancer Inst. 2007;99(1):85–6. https://doi.org/10.1093/jnci/djk011.
Choueiri TK, Sonpavde G. Toxicity of molecularly targeted antiangiogenic agents: cardiovascular effects. 2017. http://www.uptodate.com. Accessed 15 Sept 2017.
Han ES, Monk BJ. What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecol Oncol. 2007;105(1):3–6. https://doi.org/10.1016/j.ygyno.2007.01.038.
Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer. 2007;7(6):475–85. https://doi.org/10.1038/nrc2152.
Ganapathi AM, Westmoreland T, Tyler D, Mantyh CR. Bevacizumab-associated fistula formation in postoperative colorectal cancer patients. J Am Coll Surg. 2012;214(4):582–8. https://doi.org/10.1016/j.jamcollsurg.2011.12.030.
Cortes J, Caralt M, Delaloge S, Cortes-Funes H, Pierga JY, Pritchard KI, Bollag DT, Miles DW. Safety of bevacizumab in metastatic breast cancer patients undergoing surgery. Eur J Cancer. 2012;48(4):475–81. https://doi.org/10.1016/j.ejca.2011.11.021.
Hapani S, Sher A, Chu D, Wu S. Increased risk of serious hemorrhage with bevacizumab in cancer patients: a meta-analysis. Oncology. 2010;79:27–38. https://doi.org/10.1159/000314980.
Lai X-X, Xu R-A, Li Y-P, Yang H. Risk of adverse events with bevacizumab addition to therapy in advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials. Onco Targets Ther. 2016;9:2421–8.
Gridelli C, Maione P, Rossi A, De Marinis F. The role of bevacizumab in the treatment of non-small cell lung cancer: current indications and future developments. Oncologist. 2007;12:1183–93.
Spratlin J, Cohen R, Eadens M, Gore L, Camidge D, Diab S, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1Monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010;28(5):780–7.
Fuchs C, Tomasek J, Yong C, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-esophageal junction adenocarcinoma (REGARD): an international, randomized multicenter, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–9.
Cyramza (ramucirumab) [prescribing information]. Indianopolis, IN: Eli Lilly and Company. http://pi.lilly.com/us/cyramza-pi.pdf.
Garon E, Ciuleanu T, Arrieta O, Prabhash K, Syrigos K, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomized phase 3 trial. Lancet. 2014;384(9944):665–73. https://doi.org/10.1016/S0140-6736(14)60845-X.
Reck M, Paz-Ares L, Bidoli P, Cappuzzo F, Dakhil S, Moro-Sibilot D, Borghaei H, Johnson M, Jotte R, Pennell NA, Shepherd FA, Tsao A, Thomas M, Carter GC, Chan-Diehl F, Alexandris E, et al. Outcomes in patients with aggressive or refractory disease from REVEL: a randomized phase III study of docetaxel with ramucirumab or placebo for second-line treatment of stage IV non-small-cell lung cancer. Lung Cancer. 2017;112:181–7. https://doi.org/10.1016/j.lungcan.2017.07.038.
Avastin (bevacizumab) [prescribing information]. Genentech. https://www.avastin-hcp.com.
Wang ZP, Zhang HF, Zhang F, Hu BL, Wei HT, Guo YY. Bevacizumab did not reduce the risk of anemia associated with chemotherapy: an up-to-date meta-anlaysis. Eur J Clin Pharmacol. 2015;71(5):517–24. https://doi.org/10.1007/s00228-015-1818-y.
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. June 2010. National Institutes of Health, National Cancer Institute. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.
Maitland M, Bakris G, Black H, Chen H, Durand J, Elliott W, Ivy S, Leier C, Lindenfeld J, Liu G, Remick S, Steingart R, Tang W. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. JNCI: J Natl Cancer Inst. 2010;102(9):596–604.
Grenon N. Managing toxicities associated with antiangiogenic biologic agents in combination with chemotherapy for metastatic colorectal cancer. Clin J Oncol Nurs. 2013;17(4):425–33.
Thompson K. Hemoptysis. Cancer Therapy Advisor. 2017. http://www.cancertherapyadvisor.com/hospital-medicine/hemoptysis/article/602521/. Accessed 10 Mar 2018.
Damron B, Brant J, Belansky H, Friend P, Samsonow S, Schaal A. Putting evidence into practice. Clin J Oncol Nurs. 2009;13(5):573–83.
Rushing J. Managing epistaxis. Nurs Crit Care. 2011;6(2):48.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Oliver, M., Waxman, E.S. (2019). The Role of Anti-Angiogenic Agents (VEGF). In: Davies, M., Eaby-Sandy, B. (eds) Targeted Therapies in Lung Cancer: Management Strategies for Nurses and Practitioners. Springer, Cham. https://doi.org/10.1007/978-3-030-16550-5_8
Download citation
DOI: https://doi.org/10.1007/978-3-030-16550-5_8
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-16549-9
Online ISBN: 978-3-030-16550-5
eBook Packages: MedicineMedicine (R0)