Skip to main content
SpringerLink
Log in

Safety and Tolerability of Anti-Angiogenic Protein Kinase Inhibitors and Vascular-Disrupting Agents in Cancer: Focus on Gastrointestinal Malignancies

  • Review Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Angiogenesis is an essential process for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown significant results in a plethora of tumors. Anti-angiogenic agents are currently part of many standard-of-care options for several metastatic gastrointestinal cancers. Bevacizumab, aflibercept, ramucirumab, and regorafenib have significantly improved both progression-free and overall survival in different lines of treatment in metastatic colorectal cancer. Second-line ramucirumab and third-line apatinib are effective anti-angiogenic treatments for patients with metastatic gastric cancer. Unfortunately, the anti-angiogenic strategy has major practical limitations: resistance inevitably develops through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions. Anti-angiogenic agents may be more effective in combination therapies, with not only cytotoxics but also other emerging compounds in the anti-angiogenic class or in the separate class of the so-called vascular-disrupting agents. This review aims to provide an overview of the approved and “under development” anti-angiogenic compounds as well as the vascular-disrupting agents in the treatment of gastrointestinal cancers, focusing on the actual body of knowledge available on therapy challenges, pharmacodynamic and pharmacokinetic mechanisms, safety profiles, promising predictive biomarkers, and future perspectives.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.

    Article  CAS  Google Scholar 

  2. Wildiers H, Guetens G, De Boeck G, Verbeken E, Landuyt B, Landuyt W, et al. Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11. Br J Cancer. 2003;88(12):1979–86.

    Article  CAS  Google Scholar 

  3. Bagri A, Berry L, Gunter B, Singh M, Kasman I, Damico LA, et al. Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy. Clin Cancer Res. 2010;16(15):3887–900. https://doi.org/10.1158/1078-0432.CCR-09-3100.

    Article  CAS  PubMed  Google Scholar 

  4. Heijmen L, Punt CJA, Ter Voert EGW, de Geus-Oei LF, Heerschap A, Bussink J, et al. Monitoring the effects of bevacizumab beyond progression in a murine colorectal cancer model: a functional imaging approach. Invest New Drugs. 2013;31(4):881–90. https://doi.org/10.1007/s10637-012-9920-9.

    Article  CAS  PubMed  Google Scholar 

  5. Escudier B, Szczylik C, Porta C, Gore M. Treatment selection in metastatic renal cell carcinoma: expert consensus. Nat Rev Clin Oncol. 2012;9(6):327–37. https://doi.org/10.1038/nrclinonc.2012.59.

    Article  CAS  PubMed  Google Scholar 

  6. Butler JM, Kobayashi H, Rafii S. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nature Reviews Cancer. 2010;10(2):138–46. https://doi.org/10.1038/nrc2791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kerbel RS. Tumor angiogenesis. NEJM. 2008;358(19):2039–49. https://doi.org/10.1056/NEJMra0706596.

    Article  CAS  PubMed  Google Scholar 

  8. Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet (London, England). 2016;388(10043):518–29. https://doi.org/10.1016/S0140-6736(15)01088-0.

    Article  CAS  Google Scholar 

  9. Wadhwa R, Song S, Lee J-S, Yao Y, Wei Q, Ajani JA. Gastric cancer—molecular and clinical dimensions. Nat Rev Clin Oncol. 2013;10(11):643–55. https://doi.org/10.1038/nrclinonc.2013.170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Segelov E, Chan D, Shapiro J, Price TJ, Karapetis CS, Tebbutt NC, et al. The role of biological therapy in metastatic colorectal cancer after first-line treatment: a meta-analysis of randomised trials. Br J Cancer. 2014;111(6):1122–31. https://doi.org/10.1038/bjc.2014.404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hofheinz R-D, Ronellenfitsch U, Kubicka S, Falcone A, Burkholder I, Hacker UT. Treatment with antiangiogenic drugs in multiple lines in patients with metastatic colorectal cancer: meta-analysis of randomized trials. Gastroenterol Res Pract. 2016;2016:9189483. https://doi.org/10.1155/2016/9189483.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29(30):3968–76. https://doi.org/10.1200/JCO.2011.36.2236.

    Article  CAS  PubMed  Google Scholar 

  13. Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blin. Lancet Oncol. 2015;16(5):499–508. https://doi.org/10.1016/S1470-2045(15)70127-0.

    Article  CAS  PubMed  Google Scholar 

  14. Doughervermazen M, Hulmes JD, Bohlen P, Terman BI. Biological activity and phosphorylation sites of the bacterially expressed cytosolic domain of the KDR VEGF-receptor. Biochem Biophys Res Commun. 1994;205(1):728–38. https://doi.org/10.1006/bbrc.1994.2726.

    Article  CAS  Google Scholar 

  15. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76. https://doi.org/10.1038/nm0603-669.

    Article  CAS  PubMed  Google Scholar 

  16. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling—In control of vascular function. Nat Rev Mol Cell Biol. 2006;7(5):359–71. https://doi.org/10.1038/nrm1911.

    Article  CAS  PubMed  Google Scholar 

  17. Tozer GM, Kanthou C, Baguley BC. Disrupting tumour blood vessels. Nat Rev Cancer. 2005;5(6):423–35. https://doi.org/10.1038/nrc1628.

    Article  CAS  PubMed  Google Scholar 

  18. Siemann DW, Bibby MC, Dark GG, Dicker AP, Eskens FALM, Horsman MR, et al. Differentiation and definition of vascular-targeted therapies. Clin Cancer Res. 2005;11(2 Pt 1):416–20.

    CAS  PubMed  Google Scholar 

  19. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8:579. https://doi.org/10.1038/nrc2403.

    Article  CAS  PubMed  Google Scholar 

  20. Fan F, Wey JS, McCarty MF, Belcheva A, Liu W, Bauer TW, et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene. 2005;24(16):2647–53. https://doi.org/10.1038/sj.onc.1208246.

    Article  CAS  PubMed  Google Scholar 

  21. Mésange P, Poindessous V, Sabbah M, Escargueil AE, de Gramont A, Larsen AK. Intrinsic bevacizumab resistance is associated with prolonged activation of autocrine VEGF signaling and hypoxia tolerance in colorectal cancer cells and can be overcome by nintedanib, a small molecule angiokinase inhibitor. Oncotarget. 2014;5(13):4709–21. https://doi.org/10.18632/oncotarget.1671.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–24. https://doi.org/10.1056/NEJMoa065044.

    Article  CAS  PubMed  Google Scholar 

  23. 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(2):125–34. https://doi.org/10.1056/NEJMoa060655.

    Article  CAS  PubMed  Google Scholar 

  24. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–8. https://doi.org/10.1200/JCO.2009.23.9764.

    Article  CAS  PubMed  Google Scholar 

  25. Tian S, Quan H, Xie C, Guo H, Lü F, Xu Y, et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci. 2011;102(7):1374–80. https://doi.org/10.1111/j.1349-7006.2011.01939.x.

    Article  CAS  PubMed  Google Scholar 

  26. Aoyama T, Yoshikawa T. Targeted therapy: Apatinib-new third-line option for refractory gastric or GEJ cancer. Nat Rev Clin Oncol. 2016;13(5):268–70. https://doi.org/10.1038/nrclinonc.2016.53.

    Article  CAS  PubMed  Google Scholar 

  27. LSK BioPharma. LSK BioPharma. LSK BipPharma’s apatinib receives orphan drug designation in the European Union. 2017. http://www.lskbipharma.com. Accessed 23 Jan 2018.

  28. LSK BioPharma. LSK BioPharma. The US FDA grants Apatinib orphan drug designation for treatment of gastric cancer. 2017. http://www.lskbipharma.com. Accessed 23 Jan 2018.

  29. Li B, Xiu R. Angiogenesis: From molecular mechanisms to translational implications. Clin Hemorheol Microcirc. 2013;54(4):345–55. https://doi.org/10.3233/CH-121647.

    Article  CAS  PubMed  Google Scholar 

  30. Cooney MM, van Heeckeren W, Bhakta S, Ortiz J, Remick SC. Drug Insight: vascular disrupting agents and angiogenesis—novel approaches for drug delivery. Nat Clin Pract Oncol. 2006;3:682. https://doi.org/10.1038/ncponc0663.

    Article  CAS  PubMed  Google Scholar 

  31. Thorpe PE. Vascular targeting agents as cancer therapeutics. Clin Cancer Res. 2004;10(2):415–27. https://doi.org/10.1158/1078-0432.CCR-0642-03.

    Article  PubMed  Google Scholar 

  32. Quatrale AE, Porcelli L, Gnoni A, Numico G, Azzariti AP. New vascular disrupting agents in upper gastrointestinal malignancies. Curr Med Chem. 2014;21(8):1039–49. https://doi.org/10.2174/09298673113209990233.

    Article  CAS  PubMed  Google Scholar 

  33. Hurwitz HI, Yi J, Ince W, Novotny WF, Rosen O. The Clinical Benefit of Bevacizumab in Metastatic Colorectal Cancer Is Independent of K-ras Mutation Status: Analysis of a Phase III Study of Bevacizumab with Chemotherapy in Previously Untreated Metastatic Colorectal Cancer. Oncol. 2009;14(1):22–8. https://doi.org/10.1634/theoncologist.2008-0213.

    Article  CAS  Google Scholar 

  34. 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(23):2335–42. https://doi.org/10.1056/NEJMoa032691.

    Article  CAS  PubMed  Google Scholar 

  35. Lenz H-J, Lee F-C, Yau L, Koh HA, Knost JA, Mitchell EP, et al. MAVERICC, a phase 2 study of mFOLFOX6-bevacizumab (BV) vs. FOLFIRI-BV with biomarker stratification as first-line (1L) chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 2016;34(15_suppl):3515. https://doi.org/10.1200/JCO.2016.34.15_suppl.3515.

    Article  Google Scholar 

  36. Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37. https://doi.org/10.1016/S1470-2045(12)70477-1.

    Article  CAS  PubMed  Google Scholar 

  37. Masi G, Investigators on behalf of the BS, Salvatore L, Investigators on behalf of the BS, Boni L, Investigators on behalf of the BS, et al. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015;26(4):724–30. http://dx.doi.org/10.1093/annonc/mdv012.

  38. Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171–85. https://doi.org/10.1007/s10456-011-9249-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, et al. VEGF-Trap: A VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99(17):11393–8. https://doi.org/10.1073/pnas.172398299.

    Article  CAS  PubMed  Google Scholar 

  40. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausov J, Macarulla T, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  41. Sanofi-aventis. Sanofi-aventis. Zaltrap (aflibercept): US prescribing information 2012. http://www.fda.gov. Accessed 12 May 2015.

  42. Saif MW. Anti-VEGF agents in metastatic colorectal cancer (mCRC): are they all alike? Cancer Manag Res. 2013;5:103–15. https://doi.org/10.2147/CMAR.S45193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Enzinger PC, McCleary NJ, Zheng H, Abrams TA, Yurgelun MB, Azzoli CG, et al. Multicenter double-blind randomized phase II: FOLFOX + ziv-aflibercept/placebo for patients (pts) with chemo-naive metastatic esophagogastric adenocarcinoma (MEGA). J Clin Oncol. 2016;34(4_suppl):4. https://doi.org/10.1200/jco.2016.34.4_suppl.4.

    Article  Google Scholar 

  44. Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G 1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010;28(5):780–7. https://doi.org/10.1200/JCO.2009.23.7537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chiorean EG, Hurwitz HI, Cohen RB, Schwartz JD, Dalal RP, Fox FE, et al. Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors. Ann Oncol. 2015;26(6):1230–7. https://doi.org/10.1093/annonc/mdv144.

    Article  CAS  PubMed  Google Scholar 

  46. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–9. https://doi.org/10.1016/S0140-6736(13)61719-5.

    Article  CAS  PubMed  Google Scholar 

  47. Wilke H, Muro K, Van Cutsem E, Oh S-C, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224–35. https://doi.org/10.1016/S1470-2045(14)70420-6.

    Article  CAS  PubMed  Google Scholar 

  48. Chen L-T, Oh D-Y, Ryu M-H, Yeh K-H, Yeo W, Carlesi R, et al. Anti-angiogenic therapy in patients with advanced gastric and gastroesophageal junction cancer: a systematic review. Cancer Res Treat. 2017;49(4):851–68. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654167/.

  49. Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol. 2013;172(3):500–6. https://doi.org/10.1111/cei.12069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. A study of ramucirumab (LY3009806) in combination with capecitabine and cisplatin in participants with stomach cancer (RAINFALL). Clinicaltrials. https://clinicaltrials.gov/NCT02314117.

  51. Cohn AL, Yoshino T, Heinemann V, Obermannova R, Bodoky G, Prausová J, et al. Exposure–response relationship of ramucirumab in patients with advanced second-line colorectal cancer: exploratory analysis of the RAISE trial. Cancer Chemother Pharmacol. 2017;80(3):599–608. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573752/.

  52. Giampieri R, Caporale M, Pietrantonio F, De Braud F, Negri FV, Giuliani F, et al. Second-line angiogenesis inhibition in metastatic colorectal cancer patients: Straightforward or overcrowded? Crit Rev Oncol/Hematol. 2016;100:99–106. https://doi.org/10.1016/j.critrevonc.2016.02.005.

    Article  Google Scholar 

  53. Aprile G, Ferrari L, Cremolini C, Bergamo F, Fontanella C, Battaglin F, et al. Ramucirumab for the treatment of gastric cancers, colorectal adenocarcinomas, and other gastrointestinal malignancies. Expert Rev Clin Pharmacol. 2016;9(7):877–85. https://doi.org/10.1080/17512433.2016.1182861.

    Article  CAS  PubMed  Google Scholar 

  54. Bernaards C, Hegde P, Chen D, Holmgren E, Zheng M, Jubb AM, et al. Circulating vascular endothelial growth factor (VEGF) as a biomarker for bevacizumab-based therapy in metastatic colorectal, non-small cell lung, and renal cell cancers: Analysis of phase III studies. J Clin Oncol. 2010;28(15_suppl):10519. https://doi.org/10.1200/jco.2010.28.15_suppl.10519.

  55. Hegde PS, Jubb AM, Chen D, Li NF, Meng YG, Bernaards C, et al. Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab. Clin Cancer Res. 2013;19(4):929–37. https://doi.org/10.1158/1078-0432.CCR-12-2535.

    Article  CAS  PubMed  Google Scholar 

  56. Zuurbier L, Rahman A, Cordes M, Scheick J, Wong TJ, Rustenburg F, et al. Apelin: A putative novel predictive biomarker for bevacizumab response in colorectal cancer. Oncotarget. 2017;8(26):42949–61. https://doi.org/10.18632/oncotarget.17306.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Paiva TF, de Jesus VHF, Marques RA, da Costa AABA, de Macedo MP, Peresi PM, et al. Angiogenesis-related protein expression in bevacizumab-treated metastatic colorectal cancer: NOTCH1 detrimental to overall survival. BMC Cancer. 2015;15(1):643. https://doi.org/10.1186/s12885-015-1648-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Tabernero J, Hozak RR, Yoshino T, Cohn AL, Obermannova R, Bodoky G, et al. Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study. Ann Oncol. 2018;29(3):602–9. https://doi.org/10.1093/annonc/mdx767.

    Article  CAS  PubMed  Google Scholar 

  59. Loupakis F, Cremolini C, Yang D, Salvatore L, Zhang W, Wakatsuki T, et al. Prospective Validation of Candidate SNPs of VEGF/VEGFR Pathway in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Plus Bevacizumab. PLoS One. 2013;8(7):e66774. https://doi.org/10.1371/journal.pone.0066774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Battaglin F, Puccini A, Intini R, Schirripa M, Ferro A, Bergamo F, et al. The role of tumor angiogenesis as a therapeutic target in colorectal cancer. Expert Rev Anticancer Ther. 2018;18(3):251–66. https://doi.org/10.1080/14737140.2018.1428092.

    Article  CAS  PubMed  Google Scholar 

  61. Kircher SM, Nimeiri HS, Benson AB III. Targeting angiogenesis in colorectal cancer: tyrosine kinase inhibitors. Cancer J. 2016;22(3):182–9. https://doi.org/10.1097/PPO.0000000000000192.

    Article  CAS  PubMed  Google Scholar 

  62. Rini BI, Melichar B, Ueda T, GrÜnwald V, Fishman MN, Arranz JA, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol. 2013;14(12):1233–42. https://doi.org/10.1016/S1470-2045(13)70464-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90. https://doi.org/10.1056/NEJMoa0708857.

    Article  CAS  PubMed  Google Scholar 

  64. Demetri GD, Reichardt P, Kang Y-K, Blay J-Y, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib: an international, multicentre, prospective, randomised, placebo-controlled phase 3 trial (GRID). Lancet. 2013;381(9863):295–302. https://doi.org/10.1016/s0140-6736(12)61857-1.

    Article  CAS  PubMed  Google Scholar 

  65. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329–38. https://doi.org/10.1016/S0140-6736(06)69446-4.

    Article  CAS  PubMed  Google Scholar 

  66. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621–30. https://doi.org/10.1056/NEJMoa1406470.

    Article  CAS  PubMed  Google Scholar 

  67. Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in locally advanced or metastatic, radioactive iodine-refractory, differentiated thyroid cancer: a randomized, double-blind, phase 3 trial. Lancet. 2014;384(9940):319–28. https://doi.org/10.1016/S0140-6736(14)60421-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bible KC, Suman VJ, Molina JR, Smallridge RC, Maples WJ, Menefee ME, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010;11(10):962–72. https://doi.org/10.1016/S1470-2045(10)70203-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Leboulleux S, Bastholt L, Krause T, de la Fouchardiere C, Tennvall J, Awada A, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13(9):897–905. https://doi.org/10.1016/S1470-2045(12)70335-2.

    Article  CAS  PubMed  Google Scholar 

  70. Kulke MH, Lenz H-J, Meropol NJ, Posey J, Ryan DP, Picus J, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26(20):3403–10. https://doi.org/10.1200/JCO.2007.15.9020.

    Article  CAS  PubMed  Google Scholar 

  71. Phan AT, Halperin DM, Chan JA, Fogelman DR, Hess KR, Malinowski P, et al. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol. 2015;16(6):695–703. https://doi.org/10.1016/S1470-2045(15)70136-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mahmood ST, Agresta S, Vigil C, Zhao X, Han G, D’Amato G, et al. Phase II Study of Sunitinib Malate, a Multi-Targeted Tyrosine Kinase Inhibitor in Patients with Relapsed or Refractory Soft Tissue Sarcomas. Focus on 3 Prevalent Histologies: Leiomyosarcoma, Liposarcoma, and Malignant Fibrous Histiocytoma. Int J Cancer. 2011;129(8):1963–9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776586/.

  73. George S, Merriam P, Maki RG, Van den Abbeele AD, Yap JT, Akhurst T, et al. Multicenter Phase II Trial of Sunitinib in the Treatment of Nongastrointestinal Stromal Tumor Sarcomas. J Clin Oncol. 2009 Jul 1;27(19):3154–60. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716937/.

  74. Christine C, Axel LC, Isabelle R-C, Antoine I, Angela C, Nicolas I, et al. Sorafenib in patients with progressive epithelioid hemangioendothelioma. Cancer. 2013;119(14):2639–44. https://doi.org/10.1002/cncr.28109.

    Article  CAS  Google Scholar 

  75. Cortes JE, Kim D-W, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, et al. A phase 2 trial of ponatinib in philadelphia chromosome–positive leukemias. N Engl J Med. 2013;369:1783–96. https://doi.org/10.1056/NEJMoa1306494.

    Article  CAS  PubMed  Google Scholar 

  76. Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, et al. Randomized, placebo-controlled, phase iii study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2011;29(15):1997–2003. https://doi.org/10.1200/JCO.2010.29.4496.

    Article  CAS  PubMed  Google Scholar 

  77. Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, Lim R, Roman L, Shparyk Y, et al. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized. Phase III Trial. J Clin Oncol. 2013;31(10):1341–7. https://doi.org/10.1200/JCO.2012.45.1930.

    Article  CAS  PubMed  Google Scholar 

  78. Kupsch P, Henning BF, Passarge K, Richly H, Wiesemann K, Hilger RA, et al. Results of a phase I trial of sorafenib (BAY 43–9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin Colorectal Cancer. 2005;5(3):188–96. https://doi.org/10.3816/CCC.2005.n.030.

    Article  PubMed  Google Scholar 

  79. Mross K, Steinbild S, Baas F, Gmehling D, Radtke M, Voliotis D, et al. Results from an in vitro and a clinical/pharmacological phase I study with the combination irinotecan and sorafenib. Eur J Cancer. 2007;43(1):55–63. https://doi.org/10.1016/j.ejca.2006.08.032.

    Article  CAS  PubMed  Google Scholar 

  80. Kang Y, Lee KH, Shen L, Yeh K, Hong YS, Park YI, et al. 6150 - Randomized phase II study of capecitabine and cisplatin with or without sorafenib in patients with metastatic gastric cancer: STARGATE STUDY. Ann Oncol. 2014;25(suppl_4): iv210-iv253. http://dx.doi.org/10.1093/annonc/mdu334.

  81. Schmoll H-J, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Koski SL, et al. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol. 2012;30(29):3588–95. https://doi.org/10.1200/JCO.2012.42.5355.

    Article  CAS  PubMed  Google Scholar 

  82. Reck M. Nintedanib: examining the development and mechanism of action of a novel triple angiokinase inhibitor. Expert Rev Anticancer Ther. 2015;15(5):579–94. https://doi.org/10.1586/14737140.2015.1031218.

    Article  CAS  PubMed  Google Scholar 

  83. Strumberg D, Scheulen ME, Schultheis B, Richly H, Frost A, Büchert M, et al. Regorafenib (BAY 73–4506) in advanced colorectal cancer: a phase I study. Br J Cancer. 2012;106(11):1722–7. https://doi.org/10.1038/bjc.2012.153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12. https://doi.org/10.1016/S0140-6736(12)61900-X.

    Article  CAS  PubMed  Google Scholar 

  85. Li J, Qin S, Xu R, Yau TCC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(6):619–29. https://doi.org/10.1016/S1470-2045(15)70156-7.

    Article  CAS  PubMed  Google Scholar 

  86. Grothey A, Van Cutsem E, Sobrero AF, Siena S, Falcone A, Ychou M, et al. Time course of regorafenib-associated adverse events in the phase III CORRECT study. J Clin Oncol. 2013;31(4_suppl):467. https://doi.org/10.1200/jco.2013.31.4_suppl.467.

  87. Van Cutsem E, Ciardiello F, Seitz JF, Hofheinz RD, Verma U, Garcia-Carbonero R, et al. 2139 CONSIGN: An open-label phase 3B study of regorafenib in patients with metastatic colorectal cancer (mCRC) who failed standard therapy. Eur J Cancer. 2015;51:378–9. https://doi.org/10.1016/S0959-8049(16)31060-7.

    Article  Google Scholar 

  88. Adenis A, de la Fouchardiere C, Paule B, Burtin P, Tougeron D, Wallet J, et al. Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBACCA) nested within a compassionate use program. BMC Cancer. 2016;16:412. https://doi.org/10.1186/s12885-016-2440-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Argilés G, Saunders MP, Rivera F, Sobrero A, Benson A III, Guillén Ponce C, et al. Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: a phase II trial. Eur J Cancer. 2015;51(8):942–9. https://doi.org/10.1016/j.ejca.2015.02.013.

    Article  CAS  PubMed  Google Scholar 

  90. O’Neil B, O’Reilly S, Kasbari S, Kim R, McDermott R, Moore D, et al. A multi-center, randomized, double-blind phase II trial of FOLFIRI + regorafenib or placebo for patients with metastatic colorectal cancer who failed one prior line of oxaliplatin-containing therapy. Ann Oncol. 2016;27(suppl_6):464PD–464PD. http://dx.doi.org/10.1093/annonc/mdw370.13.

  91. clinicaltrials.https://clinicaltrials.gov/NCT02835924.

  92. Clinicaltrials. Safety and effectiveness of regorafenib (Correlate). https://clinicaltrials.gov/NCT02042144.

  93. Lenz H-J, Van Cutsem E, Sobrero AF, Siena S, Falcone A, Ychou M, et al. Analysis of plasma protein biomarkers from the CORRECT phase III study of regorafenib for metastatic colorectal cancer. J Clin Oncol. 2013;31(15_suppl):3514. http://ascopubs.org/doi/abs/10.1200/jco.2013.31.15_suppl.3514.

  94. Ricotta R, Sartore-Bianchi A, Verrioli A, Vanzulli A, Siena S. Regorafenib for metastatic colorectal cancer. Lancet. 2013;381(9877):1537. https://doi.org/10.1016/S0140-6736(13)60976-9.

    Article  PubMed  Google Scholar 

  95. Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, et al. Randomized, double-blind, placebo-controlled phase iii trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016;34(13):1448–54. https://doi.org/10.1200/JCO.2015.63.5995.

    Article  CAS  PubMed  Google Scholar 

  96. Jiangsu Hengrui Pharmaceutical Co. Ltd. AiTan (apatinib mesylate tablets): product information sheet. 2014; http://www.xinyao.com.cn/yaopin/s128423.htm.

  97. Yu W, He J, Huang M, Luo H, Zhu W, ChenHuai’ X. Phase II study of apatinib in patients with advanced esophageal squamous cell carcinoma after failure of prior radiation and/or chemotherapy. An First People’s Hospital Affiliated to Nanjing Medical University, China.

  98. Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm. Phase II Trial. J Clin Oncol. 2013;31(26):3219–25. https://doi.org/10.1200/JCO.2013.48.8585.

    Article  CAS  PubMed  Google Scholar 

  99. Liu X, Qin S, Wang Z, Xu J, Xiong J, Bai Y, et al. Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study. J Hematol Oncol. 2017;10:153. https://doi.org/10.1186/s13045-017-0521-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Gridelli C, Rossi A, Maione P, Rossi E, Castaldo V, Sacco PC, et al. Vascular disrupting agents: a novel mechanism of action in the battle against non-small cell lung cancer. Oncologist. 2009;14(6):612–20. https://doi.org/10.1634/theoncologist.2008-0287.

    Article  CAS  PubMed  Google Scholar 

  101. Chaplin DJ, Pettit GR, Parkins CS, Hill SA. Antivascular approaches to solid tumour therapy: evaluation of tubulin binding agents. Br J Cancer Suppl. 1996;27(Suppl. 27):S86–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Hill SA, Sampson LE, Chaplin DJ. Anti—vascular approaches to solid tumour therapy: evaluation of vinblastine and flavone acetic acid. Int J Cancer. 2018;63(1):119–23. https://doi.org/10.1002/ijc.2910630121.

    Article  Google Scholar 

  103. Hasani A, Leighl N. Classification and toxicities of vascular disrupting agents. Clin Lung Cancer. 2011;12(1):18–25. https://doi.org/10.3816/CLC.2011.n.002.

    Article  CAS  PubMed  Google Scholar 

  104. Buchanan CM, Shih J-H, Astin JW, Rewcastle GW, Flanagan JU, Crosier PS, et al. DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGFR2 in particular. Clin Sci. 2012;122(10):449–65. https://doi.org/10.1042/CS20110412.

    Article  CAS  PubMed  Google Scholar 

  105. Nihei Y, Suzuki M, Okano A, Tsuji T, Akiyama Y, Tsuruo T, et al. Evaluation of antivascular and antimitotic effects of tubulin binding agents in solid tumor therapy. Jpn J Cancer Res. 2005;90(12):1387–95. https://doi.org/10.1111/j.1349-7006.1999.tb00724.x.

    Article  Google Scholar 

  106. Boyland E, Boyland ME. Studies in tissue metabolism: the action of colchicine and B. typhosus extract. Biochem J. 1937;31(3):454–60. https://doi.org/10.1042/bj0310454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tozer GM, Prise VE, Wilson J, Cemazar M, Shan S, Dewhirst MW, et al. Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability. Cancer Res. 2001;61(17):6413–22.

    CAS  PubMed  Google Scholar 

  108. Tozer GM, Prise VE, Wilson J, Locke RJ, Vojnovic B, Stratford MRL, et al. Combretastatin A-4 phosphate as a tumor vascular-targeting agent. Cancer Res. 1999;59(7):1626–34.

    CAS  PubMed  Google Scholar 

  109. Siemann DW, Mercer E, Lepler S, Rojiani AM. Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy. Int J Cancer. 2002;99(1):1–6. https://doi.org/10.1002/ijc.10316.

    Article  CAS  PubMed  Google Scholar 

  110. Horsman MR, Siemann DW. Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies. Cancer Res. 2006;66(24):11520–39. https://doi.org/10.1158/0008-5472.CAN-06-2848.

    Article  CAS  PubMed  Google Scholar 

  111. Horsman MR. Therapeutic potential of using the vascular disrupting agent OXi4503 to enhance mild temperature thermoradiation. Int J Hyperth. 2015;31(5):453–9. https://doi.org/10.3109/02656736.2015.1024289.

    Article  CAS  Google Scholar 

  112. Landuyt W, Ahmed B, Nuyts S, Theys J, Op de Beeck M, Rijnders A, et al. In vivo antitumor effect of vascular targeting combined with either ionizing radiation or anti-angiogenesis treatment. Int J Radiat Oncol Biol Phys. 2001;49(2):443–50. https://doi.org/10.1016/S0360-3016(00)01470-X.

  113. Siemann DW, Chaplin DJ, Horsman MR. Realizing the potential of vascular targeted therapy: the rationale for combining vascular disrupting agents and anti-angiogenic agents to treat cancer. Cancer Invest. 2017;35(8):519–34. https://doi.org/10.1080/07357907.2017.1364745.

    Article  CAS  PubMed  Google Scholar 

  114. Ferrara N, Hillan KJ, Gerber H-P, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3:391. https://doi.org/10.1038/nrd1381.

    Article  CAS  PubMed  Google Scholar 

  115. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58–62. https://doi.org/10.1126/science.1104819.

    Article  CAS  PubMed  Google Scholar 

  116. Rivera LB, Bergers G. Tumor angiogenesis, from foe to friend. Science. 2015;349(6249):694–5. https://doi.org/10.1126/science.aad0862.

    Article  CAS  PubMed  Google Scholar 

  117. Casazza A, Di Conza G, Wenes M, Finisguerra V, Deschoemaeker S, Mazzone M. Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene. 2013;33:1743. https://doi.org/10.1038/onc.2013.121.

    Article  CAS  PubMed  Google Scholar 

  118. Shan Y, Wang B, Zhang J. New strategies in achieving antiangiogenic effect: multiplex inhibitors suppressing compensatory activations of RTKs. Med Res Rev. 2018. https://doi.org/10.1002/med.21517.

  119. Rossi A, Latiano TP, Parente P, Chiarazzo C, Limosani F, Di Maggio G, et al. The potential role of nintedanib in treating colorectal cancer. Expert Opin Pharmacother. 2017;18(11):1153–62. https://doi.org/10.1080/14656566.2017.1346086.

    Article  CAS  PubMed  Google Scholar 

  120. Van Cutsem E, Prenen H, D’Haens G, Bennouna J, Carrato A, Ducreux M, et al. A phase I/II, open-label, randomised study of nintedanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in first-line metastatic colorectal cancer patients. Ann Oncol. 2015;26(10):2085–91. https://doi.org/10.1093/annonc/mdv286.

    Article  PubMed  Google Scholar 

  121. Van Cutsem E, Yoshino T, Hocke J, Oum’Hamed Z, Studeny M, Tabernero J. Rationale and design for the LUME-Colon 1 Study: a randomized, double-blind, placebo-controlled phase iii trial of nintedanib plus best supportive care versus placebo plus best supportive care in patients with advanced colorectal cancer refractory to stan. Clin Colorectal Cancer. 2016;15(1):91–94.e1. https://doi.org/10.1016/j.clcc.2015.09.005.

  122. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386–422. https://doi.org/10.1093/annonc/mdw235.

    Article  PubMed  Google Scholar 

  123. Peeters M, Strickland AH, Lichinitser M, Suresh AVS, Manikhas G, Shapiro J, et al. A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma. Br J Cancer. 2013;108(3):503–11. https://doi.org/10.1038/bjc.2012.594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Blay J-Y, Pápai Z, Tolcher AW, Italiano A, Cupissol D, López-Pousa A, et al. Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(5):531–40. https://doi.org/10.1016/S1470-2045(15)70102-6.

    Article  CAS  PubMed  Google Scholar 

  125. LoRusso PM, Gadgeel SM, Wozniak A, Barge AJ, Jones HK, DelProposto ZS, et al. Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors. Invest New Drugs. 2008;26(2):159–67. https://doi.org/10.1007/s10637-008-9112-9.

    Article  CAS  PubMed  Google Scholar 

  126. Cutroneo PM, Giardina C, Ientile V, Potenza S, Sottosanti L, Ferrajolo C, et al. Overview of the safety of anti-VEGF drugs: analysis of the italian spontaneous reporting system. Drug Saf. 2017;40(11):1131–40. https://doi.org/10.1007/s40264-017-0553-y.

    Article  CAS  PubMed  Google Scholar 

  127. Lankhorst S, Saleh L, Danser AJ, van den Meiracker AH. Etiology of angiogenesis inhibition-related hypertension. Curr Opin Pharmacol. 2014;21:7–13. https://doi.org/10.1016/j.coph.2014.11.010.

    Article  CAS  PubMed  Google Scholar 

  128. Roviello G, Pacifico C, Corona P, Generali D. Risk of hypertension with ramucirumab-based therapy in solid tumors: data from a literature based meta-analysis. Invest New Drugs. 2017;35(4):518–23.

    Article  CAS  Google Scholar 

  129. Hamnvik O-PR, 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(2):311–9. https://doi.org/10.1002/cncr.28972.

    Article  CAS  PubMed  Google Scholar 

  130. 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(6):409–25. https://doi.org/10.1016/j.jash.2018.03.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ranpura V, Pulipati B, Chu D, Zhu X, Wu S. Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis. Am J Hypertens. 2010;23(5):460–8. https://doi.org/10.1038/ajh.2010.25.

    Article  CAS  PubMed  Google Scholar 

  132. Liu B, Ding F, Zhang D, Wei GH. Risk of venous and arterial thromboembolic events associated with VEGFR-TKIs: a meta-analysis. Cancer Chemother Pharmacol. 2017;80(3):487–95. https://doi.org/10.1007/s00280-017-3386-6.

    Article  CAS  PubMed  Google Scholar 

  133. Alahmari AK, Almalki ZS, Alahmari AK, Guo JJ. Thromboembolic events associated with bevacizumab plus chemotherapy for patients with colorectal cancer: a meta-analysis of randomized controlled trials. Am Heal Drug Benefits. 2016;9(4):221–32.

    Google Scholar 

  134. Abdel-Qadir H, Ethier J-L, Lee DS, Thavendiranathan P, Amir E. Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: a systematic review and meta-analysis. Cancer Treat Rev. 2017;53:120–7. https://doi.org/10.1016/j.ctrv.2016.12.002.

    Article  CAS  PubMed  Google Scholar 

  135. Arnold D, Fuchs CS, Tabernero J, Ohtsu A, Zhu AX, Garon EB, et al. Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. Ann Oncol. 2017;28(12):2932–42. https://doi.org/10.1093/annonc/mdx514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Santoni M, Guerra F, Conti A, Lucarelli A, Rinaldi S, Belvederesi L, et al. Incidence and risk of cardiotoxicity in cancer patients treated with targeted therapies. Cancer Treat Rev. 2017;59:123–31. https://doi.org/10.1016/j.ctrv.2017.07.006.

    Article  CAS  PubMed  Google Scholar 

  137. Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, et al. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: Updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017;28(9):2128–34. https://doi.org/10.1093/annonc/mdx322.

    Article  CAS  PubMed  Google Scholar 

  138. Izzedine H, Charles Soria J, Escudier B. Proteinuria and VEGF-targeted therapies: an underestimated toxicity? J Nephrol. 2013;26.

  139. Qi W-X, Shen Z, Tang L-N, Yao Y. Bevacizumab increases the risk of gastrointestinal perforation in cancer patients: a meta-analysis with a focus on different subgroups. Eur J Clin Pharmacol. 2014;70(8):893–906. https://doi.org/10.1007/s00228-014-1687-9.

    Article  CAS  PubMed  Google Scholar 

  140. LA, Lunghi A, Petreni P, Brugia M, Laffi A, Giommoni E, et al. Osteonecrosis of the jaw and angiogenesis inhibitors: a revival of a rare but serous side effect. Curr Med Chem 2017; 24:3068–76. http://www.eurekaselect.com/node/152365/article.

  141. Guarneri V, Miles D, Robert N, Diéras V, Glaspy J, Smith I, et al. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat. 2010;122(1):181–8. https://doi.org/10.1007/s10549-010-0866-3.

    Article  CAS  PubMed  Google Scholar 

  142. Makita N, Iiri T. Tyrosine kinase inhibitor-induced thyroid disorders: a review and hypothesis. Thyroid. 2013;23(2):151–9. https://doi.org/10.1089/thy.2012.0456.

    Article  CAS  PubMed  Google Scholar 

  143. Dowlati A, Robertson K, Cooney M, Petros WP, Stratford M, Jesberger J, et al. A Phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin A-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer. Cancer Res. 2002;62(12):3408–16.

    CAS  PubMed  Google Scholar 

  144. Takahashi S, Nakano K, Yokota T, Shitara K, Muro K, Sunaga Y, et al. Phase 1 study of ombrabulin in combination with cisplatin (CDDP) in Japanese patients with advanced solid tumors. Jpn J Clin Oncol. 2016;46(11):1000–7. https://doi.org/10.1093/jjco/hyw122.

    Article  Google Scholar 

  145. Subbiah IM, Lenihan DJ, Tsimberidou AM. Cardiovascular toxicity profiles of vascular-disrupting agents. Oncologist. 2011;16(8):1120–30. https://doi.org/10.1634/theoncologist.2010-0432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Lara PN, Douillard J-Y, Nakagawa K, von Pawel J, McKeage MJ, Albert I, et al. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non–small-cell lung cancer. J Clin Oncol. 2011;29(22):2965–71. https://doi.org/10.1200/JCO.2011.35.0660.

    Article  CAS  PubMed  Google Scholar 

  147. Munoz J, Hong D, Kurzrock R. Anticoagulation-induced severe bleeding in a patient receiving bevacizumab therapy. Int J Hematol. 2012;95(1):1–2. https://doi.org/10.1007/s12185-011-0984-7.

    Article  PubMed  Google Scholar 

  148. Rey J-B, Launay-Vacher V, Tournigand C. Regorafenib as a single-agent in the treatment of patients with gastrointestinal tumors: an overview for pharmacists. Target Oncol. 2015;10(2):199–213. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457933/.

  149. Fraile Gil S, Hidalgo Correas FJ, Lara Alvarez MA GMF. [Bevacizumab-induced serious heart failure in a patient treated with anthracyclines]. Farm Hosp. 2007;31(4):256–7.

  150. Ferri N, Bellosta S, Baldessin L, Boccia D, Racagni G, Corsini A. Pharmacokinetics interactions of monoclonal antibodies. Pharmacol Res. 2016;111:592–9. https://doi.org/10.1016/j.phrs.2016.07.015.

    Article  CAS  PubMed  Google Scholar 

  151. Suenaga M, Fuse N, Yamaguchi T, Yamanaka Y, Motomura S, Matsumoto H, et al. Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms. J Clin Pharmacol. 2014;54(5):495–502. https://doi.org/10.1002/jcph.246.

  152. https://www.ema.europa.eu/en/medicines/human/EPAR/avastin.

  153. Chow LQM, Smith DC, Tan AR, Denlinger CS, Wang D, Shepard DR, et al. Lack of pharmacokinetic drug–drug interaction between ramucirumab and paclitaxel in a phase II study of patients with advanced malignant solid tumors. Cancer Chemother Pharmacol. 2016;78:433–41. https://doi.org/10.1007/s00280-016-3098-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. https://www.ema.europa.eu/documents/product-information/cyramza-epar-product-information_it.pdf.

  155. https://www.ema.europa.eu/documents/overview/zaltrap-epar-summary-public_en.pdf.

  156. Wang K, Stark FS, Schlothauer T, Lahr A, Cosson V, Zhi J, et al. An apparent clinical pharmacokinetic drug–drug interaction between bevacizumab and the anti-placental growth factor monoclonal antibody RO5323441 via a target-trapping mechanism. Cancer Chemother Pharmacol. 2017;79(4):661–71. https://doi.org/10.1007/s00280-017-3242-8.

    Article  CAS  PubMed  Google Scholar 

  157. https://www.ema.europa.eu/documents/product-information/stivarga-epar-product-information_it.pdf.

  158. Schultheis B, Folprecht G, Kuhlmann J, Ehrenberg R, Hacker UT, Köhne CH, et al. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol. 2013;24(6):1560–7. https://doi.org/10.1093/annonc/mdt056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Huijbers EJM, van Beijnum JR, Thijssen VL, Sabrkhany S, Nowak-Sliwinska P, Griffioen AW. Role of the tumor stroma in resistance to anti-angiogenic therapy. Drug Resist Updat. 2016;25:26–37. https://doi.org/10.1016/j.drup.2016.02.002.

    Article  PubMed  Google Scholar 

  160. Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70(15):6171–80. https://doi.org/10.1158/0008-5472.CAN-10-0153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother. 2008;57(1):97–106. https://doi.org/10.1007/s00262-007-0353-9.

    Article  PubMed  Google Scholar 

  162. Elamin YY, Rafee S, Toomey S, Hennessy BT. Immune effects of bevacizumab: killing two birds with one stone. Cancer Microenviron. 2015;8(1):15–21. https://doi.org/10.1007/s12307-014-0160-8.

    Article  CAS  PubMed  Google Scholar 

  163. Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci USA. 2012;109(43):17561–6. https://doi.org/10.1073/pnas.1215397109.

    Article  PubMed  Google Scholar 

  164. Leong S, Eckhardt SG, Chan E, Messersmith WA, Spratlin J, Camidge DR, et al. A phase I study of sunitinib combined with modified FOLFOX6 in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2012;70(1):65–74. https://doi.org/10.1007/s00280-012-1880-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Starling N, Vázquez-Mazón F, Cunningham D, Chau I, Tabernero J, Ramos FJ, et al. A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer. Ann Oncol. 2012;23(1):119–27. https://doi.org/10.1093/annonc/mdr046.

    Article  CAS  PubMed  Google Scholar 

  166. Van Cutsem E, Bajetta E, Valle J, Köhne C-H, Randolph Hecht J, Moore M, et al. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol. 2011;29(15):2004–10. https://doi.org/10.1200/JCO.2010.29.5436.

    Article  CAS  PubMed  Google Scholar 

  167. Xu R, Shen L, Wang K, Wu G, Shi C, Ding K, et al. A randomized, double-blind, parallel-group, placebo-controlled, multicenter, phase II clinical study of famitinib in the treatment of advanced metastatic colorectal cancer. J Clin Oncol. 2015;33(3_suppl):513. https://doi.org/10.1200/jco.2015.33.3_suppl.513.

  168. Xu R-H, Li J, Bai Y, Xu J, Liu T, Shen L, et al. Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study. J Hematol Oncol. 2017;10:22. https://doi.org/10.1186/s13045-016-0384-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Li J, Qin S, Xu R, al et. Effect of fruquintinib vs. placebo on overall survival in patients with previously treated metastatic colorectal cancer: the fresco randomized clinical trial. JAMA. 2018;319(24):2486–96. http://dx.doi.org/10.1001/jama.2018.7855.

  170. Pavlakis N, Sjoquist KM, Martin AJ, Tsobanis E, Yip S, Kang Y-K, et al. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo-controlled phase II Trial. J Clin Oncol. 2016;34(23):2728–35. https://doi.org/10.1200/JCO.2015.65.1901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Hans Prenen, Angelo Claudio Palozzo, and Fotios Loupakis are co-senior authors.

Authors and Affiliations

  1. Unit of Medical Oncology 1, Veneto Institute of Oncology IOV—IRCCS, Padua, Italy

    Letizia Procaccio, Vincenzo Dadduzio, Francesca Bergamo, Alessandra Anna Prete, Sara Lonardi & Fotios Loupakis

  2. Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy

    Letizia Procaccio

  3. Department of Pharmaceutical and Pharmacological Sciences, School of Hospital Pharmacy, University of Padua, Padua, Italy

    Vera Damuzzo & Alberto Russi

  4. Pharmacy, Veneto Institute of Oncology IOV—IRCCS, Padua, Italy

    Francesca Di Sarra, Federica Todino & Angelo Claudio Palozzo

  5. Oncology Department, University Hospital Antwerp, Edegem, Belgium

    Hans Prenen

  6. Center for Oncological Research, Antwerp University, Edegem, Belgium

    Hans Prenen

Authors
  1. Letizia Procaccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vera Damuzzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesca Di Sarra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alberto Russi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Federica Todino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vincenzo Dadduzio
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Francesca Bergamo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alessandra Anna Prete
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sara Lonardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hans Prenen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Angelo Claudio Palozzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Fotios Loupakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fotios Loupakis.

Ethics declarations

Conflict of interest

Letizia Procaccio, Vera Damuzzo, Francesca Di Sarra, Alberto Russi, Federica Todino, Vincenzo Dadduzio, Francesca Bergamo, Alessandra Anna Prete, Sara Lonardi, Hans Prenen, Angelo Claudio Palozzo and Fotios Loupakis have no conflicts of interest that are directly relevant to the content of this study.

Funding

No sources of funding were used to conduct this study or prepare this manuscript.

Additional information

Part of a theme issue on “Safety of Novel Anticancer Therapies: Future Perspectives”. Guest Editors: Rashmi R. Shah, Giuseppe Curigliano.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Procaccio, L., Damuzzo, V., Di Sarra, F. et al. Safety and Tolerability of Anti-Angiogenic Protein Kinase Inhibitors and Vascular-Disrupting Agents in Cancer: Focus on Gastrointestinal Malignancies. Drug Saf 42, 159–179 (2019). https://doi.org/10.1007/s40264-018-0776-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-018-0776-6

Search

Navigation