Cardiotoxicity: Cardiac Ischemia

  • Roberto Labianca
  • Chiara Lestuzzi
  • Cezar Iliescu
  • Laura Ghilardi


Several antineoplastic treatments have been associated with cardiac ischemia as a side effect. For most of them, however, large studies are lacking and the association is weak.


  1. 1.
    Polk A, Vistisen K, Vaage-Nilsen M, Nielsen DL. A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity. BMC Pharmacol Toxicol. 2014;15:47.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lemaire L, Malet-Martino MC, de Forni M, et al. Cardiotoxicity of commercial 5-fluorouracil vials stems from the alkaline hydrolysis of this drug. Br J Cancer. 1992;66:119–27.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Jensen SA, Sørensen JB. 5-fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity. Cancer Chemother Pharmacol. 2012;69:57–64.CrossRefPubMedGoogle Scholar
  4. 4.
    Kounis NG, Tsigkas GG, Almpanis G, Mazarakis A. Kounis syndrome is likely culprit of coronary vasospasm induced by capecitabine. J Oncol Pharm Pract. 2012;18:316–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Kido K, Adams VR, Morehead RS, Flannery AH. Capecitabine-induced ventricular fibrillation arrest: possible Kounis syndrome. J Oncol Pharm Pract. 2015.Google Scholar
  6. 6.
    Schöber C, Papageorgiou E, Harstrick A, et al. Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer. Cancer. 1993;72:2242–7.CrossRefPubMedGoogle Scholar
  7. 7.
    de Forni M, Malet-Martino MC, Jaillais P, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol. 1992;10:1795–801.CrossRefPubMedGoogle Scholar
  8. 8.
    Kosmas C, Kallistratos MS, Kopterides P, et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol. 2008;134:75–82.CrossRefPubMedGoogle Scholar
  9. 9.
    Lestuzzi C, Vaccher E, Talamini R, et al. Effort myocardial ischemia during chemotherapy with 5-fluorouracil: an underestimated risk. Ann Oncol. 2014;25:1059–64.CrossRefPubMedGoogle Scholar
  10. 10.
    Rezkalla S, Kloner RA, Ensley J, al-Sarraf M, Revels S, Olivenstein A, Bhasin S, Kerpel-Fronious S, Turi ZG. Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study. J Clin Oncol. 1989;7:509–14.CrossRefPubMedGoogle Scholar
  11. 11.
    Meyer CC, Calis KA, Burke LB, et al. Symptomatic cardiotoxicity associated with 5-fluorouracil. Pharmacotherapy. 1997;17:729–36.PubMedGoogle Scholar
  12. 12.
    Meydan N, Kundak I, Yavuzsen T, et al. Cardiotoxicity of de Gramont’s regimen: incidence, clinical characteristics and long-term follow-up. Jpn J Clin Oncol. 2005;35:265–70.CrossRefPubMedGoogle Scholar
  13. 13.
    Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC. Cardiotoxicity of cancer therapy. J Clin Oncol. 2005;23:7685–96. Review.CrossRefPubMedGoogle Scholar
  14. 14.
    Saif MW, Garcon MC, Rodriguez G, Rodriguez T. Bolus 5-fluorouracil as an alternative in patients with cardiotoxicity associated with infusion 5-fluorouracil and capecitabine: a case series. In Vivo. 2013;27:531–4.PubMedGoogle Scholar
  15. 15.
    Lestuzzi C, Viel E, Picano E, Meneguzzo N. Coronary vasospasm as a cause of effort-related myocardial ischemia during low-dose chronic continuous infusion of 5-fluorouracil. Am J Med. 2001;111:316–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Robben NC, Pippas AW, Moore JO. The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy. Cancer. 1993;71:493–509. Review.CrossRefPubMedGoogle Scholar
  17. 17.
    Saif MW, Shah MM, Shah AR. Fluoropyrimidine-associated cardiotoxicity: revisited. Expert Opin Drug Saf. 2009;8:191–202.CrossRefPubMedGoogle Scholar
  18. 18.
    Kobayashi N, Hata N, Yokoyama S, et al. A case of takotsubo cardiomyopathy during 5-fluorouracil treatment for rectal adenocarcinoma. J Nippon Med Sch. 2009;76:27–33.CrossRefPubMedGoogle Scholar
  19. 19.
    Jensen SA, Hasbak P, Mortensen J, Sørensen JB. Fluorouracil induces myocardial ischemia with increases of plasma brain natriuretic peptide and lactic acid but without dysfunction of left ventricle. J Clin Oncol. 2010;28:5280–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Ambrosy AP, Kunz PL, Fisher PA, Witteles MR. Capecitabine-induced chest pain relieved by diltiazem. Am J Cardiol. 2012;110:1623–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Miura K, Kinouchi M, Ishida K, et al. 5-fu metabolism in cancer and orally-administrable 5-fu drugs. Cancers (Basel). 2010;2:1717–30.CrossRefGoogle Scholar
  22. 22.
    Kelly C, Bhuva N, Harrison M, Buckley A, Saunders M. Use of raltitrexed as an alternative to 5-fluorouracil and capecitabine in cancer patients with cardiac history. Eur J Cancer. 2013;49:2303–10.CrossRefPubMedGoogle Scholar
  23. 23.
    Ransom D, Wilson K, Fournier M, et al. Final results of Australasian Gastrointestinal Trials Group ARCTIC study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines. Ann Oncol. 2014;25(1):117–21.CrossRefPubMedGoogle Scholar
  24. 24.
    Deboever G, Hiltrop N, Cool M, Lambrecht G. Alternative treatment options in colorectal cancer patients with 5-fluorouracil- or capecitabine-induced cardiotoxicity. Clin Colorectal Cancer. 2013;12:8–14.CrossRefPubMedGoogle Scholar
  25. 25.
    Kroep JR, van Werkhoven E, Polee M, et al. Randomised study of tegafur-uracil plus leucovorin versus capecitabine as first-line therapy in elderly patients with advanced colorectal cancer—TLC study. J Geriatr Oncol. 2015;6:307–15.CrossRefPubMedGoogle Scholar
  26. 26.
    Ishizuka M, Kubota K, Nemoto T, et al. Administration of adjuvant oral tegafur/uracil chemotherapy post hepatocellular carcinoma resection: a randomized controlled trial. Asian J Surg. 2015.Google Scholar
  27. 27.
    Sadahiro S, Morita S, Sasaki K, et al. Treatment rationale and study design for clinical trial on the efficacy of UFT/LV for stage II colorectal cancer with risk factors for recurrence (JFMC46-1201). Clin Colorectal Cancer. 2015;14:277–80.CrossRefPubMedGoogle Scholar
  28. 28.
    Sorrentino MF, Kim J, Foderaro AE, Truesdell AG. 5-fluorouracil induced cardiotoxicity: review of the literature. Cardiol J. 2012;19:453–8. Review.CrossRefPubMedGoogle Scholar
  29. 29.
    Lestuzzi C, Crivellari D, Rigo F, et al. Capecitabine cardiac toxicity presenting as effort angina: a case report. J Cardiovasc Med (Hagerstown). 2010;11:700–3.CrossRefGoogle Scholar
  30. 30.
    Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol. 2010;49:287–97.CrossRefPubMedGoogle Scholar
  31. 31.
    Chen XL, Lei YH, Liu CF, et al. Angiogenesis inhibitor bevacizumab increases the risk of ischemic heart disease associated with chemotherapy: a meta-analysis. PLoS One. 2013;8:e66721.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2008;26:5204–12.CrossRefPubMedGoogle Scholar
  33. 33.
    Vaklavas C, Lenihan D, Kurzrock R, Tsimberidou AM. Anti-vascular endothelial growth factor therapies and cardiovascular toxicity: what are the important clinical markers to target? Oncologist. 2010;15:130–41. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Haas NB, Manola J, Ky B, et al. Effects of adjuvant sorafenib and sunitinib on cardiac function in renal cell carcinoma patients without overt metastases: results from ASSURE, ECOG 2805. Clin Cancer Res. 2015;21:4048–54.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Nachman RL, Rafii S. Platelets, petechiae, and preservation of the vascular wall. N Engl J Med. 2008;359:1261–70.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96:1788–95.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Kajdaniuk D, Marek B, Borgiel-Marek H, Kos-Kudła B. Vascular endothelial growth factor (VEGF)—part 1: in physiology and pathophysiology. Endokrynol Pol. 2011;62:444–55. Review.PubMedGoogle Scholar
  38. 38.
    Vuorio T, Jauhiainen S, Ylä-Herttuala S. Pro- and anti-angiogenic therapy and atherosclerosis with special emphasis on vascular endothelial growth factors. Expert Opin Biol Ther. 2012;12:79–92.CrossRefPubMedGoogle Scholar
  39. 39.
    Toyota E, Warltier DC, Brock T, et al. Vascular endothelial growth factor is required for coronary collateral growth in the rat. Circulation. 2005;112:2108–13.CrossRefPubMedGoogle Scholar
  40. 40.
    Bry M, Kivelä R, Leppänen VM, Alitalo K. Vascular endothelial growth factor-B in physiology and disease. Physiol Rev. 2014;94:779–94.CrossRefPubMedGoogle Scholar
  41. 41.
    Kivelä R, Bry M, Robciuc MR, et al. VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart. EMBO Mol Med. 2014;6:307–21.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Jiménez-Navarro MF, González FJ, Caballero-Borrego J, Investigadores RECAVA (Red Temática de Investigación Cooperativa de Enfermedades Cardiovasculares), et al. Coronary disease extension determines mobilization of endothelial progenitor cells and cytokines after a first myocardial infarction with ST elevation. Rev Esp Cardiol. 2011;64:1123–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Elice F, Rodeghiero F, Falanga A, Rickles FR. Thrombosis associated with angiogenesis inhibitors. Best Pract Res Clin Haematol. 2009;22:115–28.CrossRefPubMedGoogle Scholar
  44. 44.
    Conti E, Romiti A, Musumeci MB, et al. Arterial thrombotic events and acute coronary syndromes with cancer drugs: are growth factors the missed link?: what both cardiologist and oncologist should know about novel angiogenesis inhibitors. Int J Cardiol. 2013;167:2421–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Kuenen BC, Levi M, Meijers JC, et al. Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients. Arterioscler Thromb Vasc Biol. 2002;22:1500–5.CrossRefPubMedGoogle Scholar
  46. 46.
    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.CrossRefPubMedGoogle Scholar
  47. 47.
    Hang XF, Xu WS, Wang JX. Risk of high-grade bleeding in patients with cancer treated with bevacizumab: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol. 2011;67:613–23.CrossRefPubMedGoogle Scholar
  48. 48.
    Economopoulou P, Kotsakis A, Kapiris I, Kentepozidis N. Cancer therapy and cardiovascular risk: focus on bevacizumab. Cancer Manag Res. 2015;7:133–43. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Steingart RM, Bakris GL, Chen HX, et al. Management of cardiac toxicity in patients receiving vascular endothelial growth factor signaling pathway inhibitors. Am Heart J. 2012;163:156–63.CrossRefPubMedGoogle Scholar
  50. 50.
    Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232–9. Erratum in: J Natl Cancer Inst. 2008;100:156. J Natl Cancer Inst. 2008;100:685.CrossRefPubMedGoogle Scholar
  51. 51.
    Silvestre JS, Smadja DM, Lévy BI. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications. Physiol Rev. 2013;93:1743–802.CrossRefPubMedGoogle Scholar
  52. 52.
    Ramos C, Napoleão P, Selas M, et al. Prognostic value of VEGF in patients submitted to percutaneous coronary intervention. Dis Markers. 2014;2014:135357.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Katsaros KM, Kastl SP, Krychtiuk KA, et al. An increase of VEGF plasma levels is associated with restenosis of drug-eluting stents. EuroIntervention. 2014;10:224–30.CrossRefPubMedGoogle Scholar
  54. 54.
    Quintas-Cardama A, Kantarjian H, Cortes J. Nilotinib-associated vascular events. Clin Lymphoma Myeloma Leuk. 2012;12:337–40.CrossRefPubMedGoogle Scholar
  55. 55.
    Brauchli YB, Wais T, Gratwohl A, et al. Fatal myocardial infarction during nilotinib treatment in a 60-year-old male patient. Acta Oncol (Stockholm, Sweden). 2010;49:523–5.CrossRefGoogle Scholar
  56. 56.
    Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783–96.CrossRefPubMedGoogle Scholar
  57. 57.
    Escudier SM, Kantarjian HM, Estey EH. Thrombosis in patients with acute promyelocytic leukemia treated with and without all-trans retinoic acid. Leuk Lymphoma. 1996;20:435–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Oh JH, Baum DD, Pham S, et al. Long-term complications of platinum-based chemotherapy in testicular cancer survivors. Med Oncol. 2007;24:175–81.CrossRefPubMedGoogle Scholar
  59. 59.
    Evans C, Williams M, Mazhar D. Long-term cardiovascular risk following platinum-based chemotherapy for germ cell tumors. Future Oncol. 2010;6:1365–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Fung C, Fossa SD, Williams A, Travis LB. Long-term morbidity of testicular cancer treatment. Urol Clin North Am. 2015;42:393–408.CrossRefPubMedGoogle Scholar
  61. 61.
    Dieckmann KP, Struss WJ, Budde U. Evidence for acute vascular toxicity of cisplatin-based chemotherapy in patients with germ cell tumour. Anticancer Res. 2011;31:4501–5.PubMedGoogle Scholar
  62. 62.
    Willemse PP, van der Meer RW, Burggraaf J, et al. Abdominal visceral and subcutaneous fat increase, insulin resistance and hyperlipidemia in testicular cancer patients treated with cisplatin-based chemotherapy. Acta Oncol. 2014;53:351–60.CrossRefPubMedGoogle Scholar
  63. 63.
    Haugnes HS, Wethal T, Aass N, et al. Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J Clin Oncol. 2010;28:4649–57.CrossRefPubMedGoogle Scholar
  64. 64.
    van den Belt-Dusebout AW, Nuver J, de Wit R, et al. Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol. 2006;24:467–75.CrossRefPubMedGoogle Scholar
  65. 65.
    Fung C, Fossa SD, Milano MT, et al. Cardiovascular disease mortality after chemotherapy or surgery for testicular nonseminoma: a population-based study. J Clin Oncol. 2015;33:3105–15.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Christensen JF, Bandak M, Campbell A, et al. Treatment-related cardiovascular late effects and exercise training countermeasures in testicular germ cell cancer survivorship. Acta Oncol. 2015;54:592–9.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Margolin KA, Rayner AA, Hawkins MJ, et al. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J Clin Oncol. 1989;7(4):486–98.CrossRefPubMedGoogle Scholar
  68. 68.
    Sonnenblick M, Rosin A. Cardiotoxicity of interferon. A review of 44 cases. Chest. 1991;99:557–61.CrossRefPubMedGoogle Scholar
  69. 69.
    Kruit WH. Cardiotoxicity as a dose-limiting factor in a schedule of high dose bolus therapy with interleukin-2 and alpha-interferon. An unexpected frequent complication. Cancer. 1994;74:2850–6.CrossRefPubMedGoogle Scholar
  70. 70.
    Rowinsky EK, McGuire WP, Guarnieri T, et al. Cardiac disturbances during the administration of taxol. J Clin Oncol. 1991;9:1704–12.CrossRefPubMedGoogle Scholar
  71. 71.
    Coates AS, Keshaviah A, Thurlimann B, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007;25:486–92.CrossRefPubMedGoogle Scholar
  72. 72.
    Yang TL, Wu TC, Huang CC, et al. Association of tamoxifen use and reduced cardiovascular events among Asian females with breast cancer. Circ J. 2014;78:135–40.CrossRefPubMedGoogle Scholar
  73. 73.
    Amir E, Seruga B, Niraula S, et al. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst. 2011;103:1299–309.CrossRefPubMedGoogle Scholar
  74. 74.
    Hackshaw A, Roughton M, Forsyth S, et al. Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer. J Clin Oncol. 2011;29:1657–63.CrossRefPubMedGoogle Scholar
  75. 75.
    Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010;28:509–18.CrossRefPubMedGoogle Scholar
  76. 76.
    Ribeiro J, Sousa B, Cardoso F. Optimal approach in early breast cancer: adjuvant and neoadjuvant treatment. EJC Suppl. 2013;11:3–22.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Basaria S, Muller DC, Carducci MA, et al. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer. 2006;106:581–8.CrossRefPubMedGoogle Scholar
  78. 78.
    Shahani S, Braga-Basaria M, Basaria S. Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. J Clin Endocrinol Metab. 2008;93:2042–9.CrossRefPubMedGoogle Scholar
  79. 79.
    Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448–56.CrossRefPubMedGoogle Scholar
  80. 80.
    Keating NL, O’Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2010;102:39–46.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Saigal CS, Gore JL, Krupski TL, Urologic Diseases in America Project, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer. 2007;110:1493–500.CrossRefPubMedGoogle Scholar
  82. 82.
    Hu JC, Williams SB, O’Malley AJ, et al. Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism. Eur Urol. 2012;61:1119–28.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Keating NL, O’Malley AJ, Freedland SJ, Smith MR. Does comorbidity influence the risk of myocardial infarction or diabetes during androgen-deprivation therapy for prostate cancer? Eur Urol. 2013;64:159–66.CrossRefPubMedGoogle Scholar
  84. 84.
    Jespersen CG, Nørgaard M, Borre M. Androgen-deprivation therapy in treatment of prostate cancer and risk of myocardial infarction and stroke: a nationwide Danish population-based cohort study. Eur Urol. 2014;65:704–9.CrossRefPubMedGoogle Scholar
  85. 85.
    O’Farrell S, Garmo H, Holmberg L, et al. Risk and timing of cardiovascular disease after androgen-deprivation therapy in men with prostate cancer. J Clin Oncol. 2015;33:1243–51.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Roberto Labianca
    • 1
  • Chiara Lestuzzi
    • 2
  • Cezar Iliescu
    • 3
  • Laura Ghilardi
    • 1
  1. 1.Dipartimento Interaziendale Provinciale OncologicoCancer Center Ospedale Papa Giovanni XXIIIBergamoItaly
  2. 2.Cardiology UnitIRCCS CRO-National Cancer InstituteAviano (PN)Italy
  3. 3.Cardiac Catheterization Laboratory, Cardiology DepartmentMD Anderson Cancer CenterHoustonUSA

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