Electrophysiologic Toxicity of Chemoradiation

  • Merna A. Armanious
  • Shreya Mishra
  • Michael G. Fradley
Cardio-oncology (EH Yang, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Cardio-oncology


Purpose of Review

There is growing awareness of the link between oncology treatments and cardiovascular (CV) complications. This has led to the development of cardio-oncology, a specialty aimed at managing CV risk and disease in cancer patients and survivors. Cardiac arrhythmias are potential adverse CV complications of cancer treatments; however, these cardiotoxicities are often underappreciated due to the uncertain arrhythmogenic mechanisms of various chemotherapeutic agents.

Recent Findings

Chemotherapeutic agents can induce arrhythmias via direct electrophysiological effects on ion channels or intracellular signaling pathways, or indirectly from cardiac tissue damage.


As more drugs are being linked to the development of arrhythmias, a deeper understanding of the pathophysiology of their electrophysiological (EP) effects will be necessary. Expanding research in this field has allowed for the identification of novel agents with potential arrhythmogenic properties and the development of preventative measures, early recognition, and closer surveillance of patients more susceptible to these EP side effects.


Arrhythmias Chemotherapy Cardio-oncology QT prolongation 


Compliance with Ethical Standards

Conflict of Interest

Merna A. Armanious declares that she has no conflict of interest.

Shreya Mishra declares that she has no conflict of interest.

Michael G. Fradley has received compensation from Novartis for service as a consultant and from Ariad for participation on an advisory board.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.PubMedGoogle Scholar
  2. 2.
    Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009;53:2231–47.PubMedGoogle Scholar
  3. 3.
    Guglin M, Aljayeh M, Saiyad S, Ali R, Curtis AB. Introducing a new entity: chemotherapy-induced arrhythmia. Europace. 2009;11:1579–86.PubMedGoogle Scholar
  4. 4.
    •• Tamargo J, Caballero R, Delpon E. Cancer chemotherapy and cardiac arrhythmias: a review. Drug Saf. 2015;38:129–52. This article reviews documented arrhythmias and the electrophysiological pathophysiology associated with multiple chemotherapeutic agents, as well as reports on the relative frequency of various arrhythmias. PubMedGoogle Scholar
  5. 5.
    Viganego F, Singh R, Fradley M. Arrhythmias and other electrophysiology issues in cancer patients receiving chemotherapy or radiation. Curr Cardiol Rep. 2016;18:52.PubMedGoogle Scholar
  6. 6.
    •• Buza V, Rajagopalan B, Curtis AB. Cancer treatment-induced arrhythmias focus on chemotherapy and targeted therapies. Circ Arrhythm Electrophyisol. 2017;10:e005443.  https://doi.org/10.1161/CIRCEP.117.005443. This review describes the ECG changes and arrhythmias associated with various cancer treatments and provides the available evidence regarding the mechanisms by which cancer therapies cause arrhythmias. Google Scholar
  7. 7.
    Doxorubicin. FDA Package Insert. Available at https://www.accessdata. fda.gov/drugsatfda_docs/label/2012/062921s022lbl.pdf. Accessed 26 Nov 2017.
  8. 8.
    Wu T, Ong JJC, et al. Characteristics of wave fronts during ventricular fibrillation in human hearts with dilated cardiomyopathy: role of increased fibrosis in the generation of reentry. JACC. 1998;32(1):187–96.PubMedGoogle Scholar
  9. 9.
    Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869–79.PubMedGoogle Scholar
  10. 10.
    Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91(5):710–7.Google Scholar
  11. 11.
    Armenian AH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines. J Clin Oncol. 2017;35(8):893–911.  https://doi.org/10.1200/JCO.2016.70.5400. PubMedGoogle Scholar
  12. 12.
    •• Mazur M, Wang F, Hodge DO, et al. Burden of cardiac arrhythmias in patients with anthracycline-related cardiomyopathy. JACC: Clin Electrophysiol. 2016;3(2):139–50.  https://doi.org/10.1016/j.jacep.2016.08.009. This was the first article to evaluate arrhythmia risk and incidence in patients with anthracycline-induced cardiomyopathy using data from implantable cardiac devices. Google Scholar
  13. 13.
    Fradley MG, Viganego F, Kip K, Martin A, Patel AA, Ismail-Khan R, et al. Rates and risk of arrhythmias in cancer survivors with chemotherapy-induced cardiomyopathy compared with patients with other cardiomyopathies. Open Heart. 2017;4:e000701.  https://doi.org/10.1136/openhrt-2017-000701.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Hahn VS, Lenihan DJ, Ky B. Cancer therapy-induced cardiotoxicity: basic mechanisms and potential cardioprotective therapies. J Am Heart Assoc. 2014;3(2):e000665.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Wang YX, Korth M. Effects of doxorubicin on excitation-contraction coupling in guinea pig ventricular myocardium. Circ Res. 1995;76(4):645–53.PubMedGoogle Scholar
  16. 16.
    Aversano RC, Boor PJ. Acute doxorubicin-induced cardiac arrhythmias during ether anesthesia. Res Commun Chem Pathol Pharmacol. 1983;41(2):345–8.PubMedGoogle Scholar
  17. 17.
    Olson RD, Mushlin PS, Brenner DE, Fleischer S, Cusack BJ, Chang BK, et al. Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci U S A. 1988;85(10):3585–9.PubMedPubMedCentralGoogle Scholar
  18. 18.
    O’Bryan RM, Luce JK, Talley RW, Gottlieb JA, Baker LH, Bonadonna G. Phase II evaluation of adriamycin in human neoplasia. Cancer. 1973;32(1):1–8.PubMedGoogle Scholar
  19. 19.
    Outomuro D, Grana DR, Azzato F, Milei J. Adriamycin-induced myocardial toxicity: new solutions for an old problem? Int J Cardiol. 2007;117(1):6–15.PubMedGoogle Scholar
  20. 20.
    Gottdiener JS, Appelbaum FR, Ferrans VJ, Deisseroth A, Ziegler J. Cardiotoxicity associated with high dose cyclophosphamide therapy. Arch Intern Med. 1981;141(6):758–63.PubMedGoogle Scholar
  21. 21.
    Kupari M, Volin L, Suokas A, Timonen T, Hekali P, Ruutu T, et al. Cardiac involvement in bone marrow transplantation: electrocardiographic changes, arrhythmias, heart failure and autopsy findings. Bone Marrow Transplant. 1990;5(2):91–8.PubMedGoogle Scholar
  22. 22.
    Ando M, Yokozawa T, Sawada J, Takaue Y, Togitani K, Kawahigashi N, et al. Cardiac conduction abnormalities in patients with breast cancer undergoing high-dose chemotherapy and stem cell transplantation. Bone Marrow Transplant. 2000;25(2):185–9.PubMedGoogle Scholar
  23. 23.
    Cazin B, Gorin NC, Laporte JP, Gallet B, Douay L, Lopez M, et al. Cardiac complications after bone marrow transplantation. A report on a series of 63 consecutive transplantations. Cancer. 1986;57(10):2061–9.PubMedGoogle Scholar
  24. 24.
    Ulrickson M, Aldridge J, Kim HT, Hochberg EP, Hammerman P, Dube C, et al. Busulfan and cyclophosphamide (Bu/Cy) as a preparative regimen for autologous stem cell transplantation in patients with non-Hodgkin lymphoma: a single institution experience. Biol Blood Marrow Transplant. 2009;15:1447–54.  https://doi.org/10.1016/j.bbmt.2009.07.014.PubMedGoogle Scholar
  25. 25.
    Feliz V, Saiyad S, Ramarao SM, Khan H, Leonelli F, Guglin M. Melphalan induced supraventricular tachycardia: incidence and risk factors. Clin Cardiol. 2011;34(6):356–9.PubMedGoogle Scholar
  26. 26.
    Fradley MG, Barrett CD, Clark JR, Francis SA. Ventricular fibrillation cardiac arrest due to 5-fluorouracil cardiotoxicity. Tex Heart Inst J. 2013;40(4):472–6.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Yilmaz U, Oztop I, Ciloglu A, Okan T, Tekin U, Yaren A, et al. 5-fluorouracil increases the number and complexity of premature complexes in the heart: a prospective study using ambulatory ECG monitoring. Int J Clin Pract. 2007;61:795–801.  https://doi.org/10.1111/j.1742-1241.2007.01323.x.PubMedGoogle Scholar
  28. 28.
    de Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, et al. Cardiotoxicity of high dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol. 1992;10(11):1795–801.PubMedGoogle Scholar
  29. 29.
    Khan MA, Masood N, Husain N, Ahmad B, Aziz T, Naeem A. A retrospective study of cardiotoxicities induced by 5-fluouracil (5-FU) and 5-FU based chemotherapy regimens in Pakistani adult cancer patients at Shaukat Khanum Memorial Cancer Hospital & Research Center. J Pak Med Assoc. 2012;62:430–4.PubMedGoogle Scholar
  30. 30.
    Hrovatin E, Viel E, Lestuzzi C, Tartuferi L, Zardo F, Brieda M, et al. Severe ventricular dysrhythmias and silent ischemia during infusion of the antimetabolite 5-fluorouracil and cisplatin. J Cardiovasc Med (Hagerstown). 2006;7(8):637–40.Google Scholar
  31. 31.
    Keefe DL, Roistacher N, Pierri MK. Clinical cardiotoxicity of 5-fluorouracil. J Clin Pharmacol. 1993;33(11):1060–70.PubMedGoogle Scholar
  32. 32.
    Robben NC, Pippas AW, Moore JO. The syndrome of 5-fluorouracil cardiotoxicity. Cancer. 1993;71(2):493–509.PubMedGoogle Scholar
  33. 33.
    Santini D, Tonini G, Abbate A, Di Cosimo S, Gravante G, Vincenzi B, et al. Gemcitabine induced atrial fibrillation: a hitherto unreported manifestation of drug toxicity. Ann Oncol. 2000;11(4):479–81.PubMedGoogle Scholar
  34. 34.
    Gridelli C, Cigolari S, Gallo C, Manzione L, Ianniello GP, Frontini L, et al. Activity and toxicity of gemcitabine and gemcitabine + vinorelbine in advanced non-small cell lung cancer elderly patients: phase II data from the Multicenter Italian Lung cancer in the Elderly Study (MILES) randomized trial. Lung Cancer. 2001;31:277–84.PubMedGoogle Scholar
  35. 35.
    McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC, Ettinger DS, Armstrong DK, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med. 1989;111:273–9.PubMedGoogle Scholar
  36. 36.
    Arbuck SG, Strauss H, Rowinsky E, Christian M, Suffness M, Adams J, et al. A reassessment of cardiac toxicity associated with Taxol. J Natl Cancer Inst. 1992;15:117–30.Google Scholar
  37. 37.
    Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG, Donehower RC. Clinical toxicities encountered with paclitaxel (Taxol). Semin Oncol. 1993;20(4 Suppl 3):1–15.PubMedGoogle Scholar
  38. 38.
    Raja W, Mir MH, Dar I, Bandey MA, Ahmad I. Cisplatin induced paroxysmal supraventricular tachycardia. Indian J Med Paediatr Oncol. 2013;34(4):330–2.  https://doi.org/10.4103/0971-5851.125262.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Yavaş O, Aytemir K, Celik I. The prevalence of silent arrhythmia inpatients receiving cisplatin-based chemotherapy. Turkish J Cancer. 2008;38:12–5.Google Scholar
  40. 40.
    Thix CA, Königsrainer I, Kind R, Wied P, Schroeder TH. Ventricular tachycardia during hyperthermic intraperitoneal chemotherapy. Anaesthesia. 2009;64:1134–6.  https://doi.org/10.1111/j.1365-2044.2009.05993.x.PubMedGoogle Scholar
  41. 41.
    Tomkowski WZ, Wiśniewska J, Szturmowicz M, Kuca P, Burakowski J, Kober J, et al. Evaluation of intrapericardial cisplatin administration in cases with recurrent malignant pericardial effusion and cardiac tamponade. Support Care Cancer. 2004;12(1):53–7.PubMedGoogle Scholar
  42. 42.
    Bischiniotis TS, Lafaras CT, Platogiannis DN, Moldovan L, Barbetakis NG, Katseas GP. Intrapericardial cisplatin administration after pericardiocentesis in patients with lung adenocarcinoma and malignant cardiac tamponade. Hell J Cardiol. 2005;46(5):324–9.Google Scholar
  43. 43.
    Richards WG, Zellos L, Bueno R, Jaklitsch MT, Jänne PA, Chirieac LR, et al. Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma. J Clin Oncol. 2006;24(10):1561–7.PubMedGoogle Scholar
  44. 44.
    Roboz GJ, Ritchie EK, Carlin RF, Samuel M, Gale L, Provenzano-Gober JL, et al. Prevalence, management, and clinical consequences of QT interval prolongation during treatment with arsenic trioxide. J Clin Oncol. 2014;32:3723–3723-3728.  https://doi.org/10.1200/JCO.2013.51.2913.PubMedGoogle Scholar
  45. 45.
    Hu J, Shen ZX, Sun GL, Chen SJ, Wang ZY, Chen Z. Long-term survival and prognostic study in acute promyelocytic leukemia treated with all-trans-retinoic acid, chemotherapy, and As2O3: an experience of 120 patients at a single institution. Int J Hematol. 1999;70:248–60.PubMedGoogle Scholar
  46. 46.
    Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–60.PubMedGoogle Scholar
  47. 47.
    Barbey JT, Pezzullo JC, Soignet SL. Effect of arsenic trioxide on QT interval in patients with advanced malignancies. J Clin Oncol. 2003;21:3609–15.PubMedGoogle Scholar
  48. 48.
    Beer TM, Tangen CM, Nichols CR, Margolin KA, Dreicer R, Stephenson WT, et al. Southwest oncology group phase II study of arsenic trioxide in patients with refractory germ cell malignancies. Cancer. 2006;106(12):2624–9.PubMedGoogle Scholar
  49. 49.
    Westervelt P, Brown RA, Adkins DR, Khoury H, Curtin P, Hurd D, et al. Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood. 2001;98(2):266–71.PubMedGoogle Scholar
  50. 50.
    Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172–87.PubMedGoogle Scholar
  51. 51.
    Xu Z, Cang S, Yang T, Liu D. Cardiotoxicity of tyrosine kinase inhibitors in chronic myelogenous leukemia therapy. Hematol Rev. 2009;1:17–21.Google Scholar
  52. 52.
    McMullen JR, Boey EJ, Ooi JY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124:3829–30.PubMedGoogle Scholar
  53. 53.
    Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011–9.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243–50.  https://doi.org/10.1182/blood-2017-07-793786.PubMedGoogle Scholar
  55. 55.
    Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–23.PubMedPubMedCentralGoogle Scholar
  56. 56.
    • Brown JR, Moslehi J, O’Brien S, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017;102(10):1796–805.  https://doi.org/10.3324/haematol.2017.171041. This study pooled data from randomized controlled studies to report on atrial fibrillation incidence with ibrutinib treatment, identify risk factor, and discuss management. PubMedPubMedCentralGoogle Scholar
  57. 57.
    Leong DP, Caron F, illis C, Duan A, Healey JS, Fraser G, et al. The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis. Blood. 2016;128:138–40.  https://doi.org/10.1182/blood-2016-05-712828.PubMedGoogle Scholar
  58. 58.
    Wang ML, Blum KA, Martin P, Goy A, Auer R, Kahl BS, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015;126:739–45.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Shatzel JJ, Olson SR, Tao DL, McCarty OJT, Danilov AV, DeLoughery TG. Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies. J Thromb Haemost. 2017;15(5):835–47.  https://doi.org/10.1111/jth.13651.PubMedGoogle Scholar
  60. 60.
    Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507–16.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124:2450–8.PubMedGoogle Scholar
  62. 62.
    Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation (ARISTOTLE). N Engl J Med. 2011;365(11):981–2.  https://doi.org/10.1056/NEJMoa1107039. PubMedGoogle Scholar
  63. 63.
    Pretorius L, Du XJ, Woodcock EA, et al. Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation. Am J Pathol. 2009;175:998–1009.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Lannutti BJ, Meados SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117:591–4.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323–32.  https://doi.org/10.1056/NEJMoa1509981.PubMedGoogle Scholar
  66. 66.
    Lampson BL, Yu L, Glynn RJ, et al. Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood J. 2017;  https://doi.org/10.1182/blood-2016-10-742437.
  67. 67.
    Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200–11.PubMedGoogle Scholar
  68. 68.
    Steinberg M. Dasatinib: a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Clin Ther. 2007;29:2289–308.  https://doi.org/10.1016/j.clinthera.2007.11.005.PubMedGoogle Scholar
  69. 69.
    Locatelli M, Criscitiello C, Esposito A, Minchella I, Goldhirsch A, Cipolla C, et al. QTc prolongation induced by targeted biotherapies used in clinical practice and under investigation: a comprehensive review. Target Oncol. 2015;10:27–43.PubMedGoogle Scholar
  70. 70.
    Larsan RA, Hochhaus A, Saglio G, et al. Cardiac safety profile of imatinib and nilotinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): results from ENESTnd. Blood. 2010;116:2291.Google Scholar
  71. 71.
    Fradley MG, Moslehi J. QT prolongation and oncology drug development. Card Electrophysiol Clin. 2015;7:341–55.PubMedGoogle Scholar
  72. 72.
    Tartarone A, Gallucci G, Lazzari C, Lerose R, Lombardi L, Aieta M. Crizotinib-induced cardiotoxicity: the importance of a proactive monitoring and management. Future Oncol. 2015;11:2043–8.  https://doi.org/10.2217/fon.15.47.PubMedGoogle Scholar
  73. 73.
    Khozin S, Blumenthal GM, Zhang L, Tang S, Brower M, Fox E, et al. FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. Clin Cancer Res. 2015;21:2436–9.  https://doi.org/10.1158/1078-0432.CCR-14-3157.PubMedGoogle Scholar
  74. 74.
    Ou SH, Tang Y, Polli A, Wilner KD, Schnell P. Factors associated with sinus bradycardia during crizotinib treatment: a retrospective analysis of two large-scale multinational trials (PROFILE 1005 and 1007). Cancer Med. 2016;5:617–22.  https://doi.org/10.1002/cam4.622.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarization (QT interval). Drug Saf. 2013;36:295–316.PubMedGoogle Scholar
  76. 76.
    Fradley MG, Pinilla-Ibarz J. Arrhythmic complications of tyrosine kinase inhibitors. Futur Cardiol. 2015;11(4):395–9.Google Scholar
  77. 77.
    Bello CL, Mulay M, Huang X, Patyna S, Dinolfo M, Levine S, et al. Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic-pharmacodynamic evaluation of sunitinib. Clin Cancer Res. 2009;15:7045–52.  https://doi.org/10.1158/1078-0432.CCR-09-1521.PubMedGoogle Scholar
  78. 78.
    Flaherty L, Hamid O, Linette G, et al. A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States. Cancer J. 2014;20:18–24.  https://doi.org/10.1097/PPO.0000000000000024. PubMedPubMedCentralGoogle Scholar
  79. 79.
    Hall PS, Harshman LC, Srinivas S, Witteles RM. The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Heart Fail. 2013;1(1):72–8.  https://doi.org/10.1016/j.jchf.2012.09.001.PubMedGoogle Scholar
  80. 80.
    Telli ML, Witteles RM, Fisher GA, Srinivas S. Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol. 2008;19:1613–8.PubMedGoogle Scholar
  81. 81.
    Tolcer AW, Appleman LJ, Shapiro GI, et al. A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer. Cancer Chemother Pharmacol. 2011;67:751–64.  https://doi.org/10.1007/s00280-010-1372-3.Google Scholar
  82. 82.
    Petrini I, Lencioni M, Ricasoli M, Iannopollo M, Orlandini C, Oliveri F, et al. Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2012;69:773–80.  https://doi.org/10.1007/s00280-011-1753-2.PubMedGoogle Scholar
  83. 83.
    Piotrowski G, Gawor R, Slomka R, et al. Cardioverter-defibrillator in the treatment of arrhythmia induced by trastuzumab used in the adjuvant setting in a patient with positive human epidermal growth factor receptor type-2 breast cancer. Kardiol Pol. 2012;70:756–7.PubMedGoogle Scholar
  84. 84.
    Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–42.PubMedGoogle Scholar
  85. 85.
    Arai Y, Tadokoro J, Mitani K. Ventricular tachycardia associated with infusion of rituximab in mantle cell lymphoma. Am J Hematol. 2005;78(4):317–8.PubMedGoogle Scholar
  86. 86.
  87. 87.
    Kordelas L, Bauer S, Schuler M, et al. Successful resuscitation of a patient with ventricular fibrillation due to hypomagnesemia under cetuximab therapy. Tumor Diagn Ther. 2014;35:25–7.Google Scholar
  88. 88.
    Orcioulo E, Buda G, Cecconi N, Galimberi S, Versari D, Cervetti G, et al. Unexpected cardiotoxicity in haematological bortezomib treated patients. Br J Haematol. 2007;138(3):396–403.Google Scholar
  89. 89.
    Berenson JR, Jagannath S, Barlogie B, Siegel DT, Alexanian R, Richardson PG, et al. Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. Cancer. 2005;104(10):2141–8.PubMedGoogle Scholar
  90. 90.
    Xiao Y, Yin J, Wei J, Shang Z. Incidence and risk of cardiotoxicity associated with bortezomib in the treatment of cancer: a systematic review and meta-analysis. PLoS One. 2014;9(1):e87671.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Siegel D, Martin T, Nooka A, Harvey RD, Vij R, Niesvizky R, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98:1753–61.  https://doi.org/10.3324/haematol.2013.089334.PubMedPubMedCentralGoogle Scholar
  92. 92.
    • Atrash S, Tullos A, Panozzo S, et al. Cardiac complications in relapsed and refractory multiple myeloma patients treated with carfilzomib. Blood Cancer J. 2015;5:e272.  https://doi.org/10.1038/bcj.2014.93. This study reports data on patients who developed significant cardiovascular adverse events necessitating hospitalization during the first two cycles of therapy with carfilzomib either alone or with dexamethasone. It also reviews echocardiogram findings before and after treatment as well as BNP measurements. PubMedPubMedCentralGoogle Scholar
  93. 93.
    Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, et al. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol. 2004;22:2108–21.PubMedGoogle Scholar
  94. 94.
    Honton B, Despas F, Dumonteil N, Rouvellat C, Roussel M, Carrie D, et al. Bortezomib and heart failure: case-report and review of the French Pharmacovigilance database. Fundam Clin Pharmacol. 2014;28:349–52.PubMedGoogle Scholar
  95. 95.
    Enrico O, Gabriele B, Nadia C, Sara G, Daniele V, Giulia C, et al. Unexpected cardiotoxicity in haematological bortezomib treated patients. Br J Haematol. 2007;138:396–7.PubMedGoogle Scholar
  96. 96.
    Phase 3 study with carfilzomib and dexamethasone versus bortezomib and dexamethasone for relapsed multiple myeloma patients (ENDEAVOR). (http://clinicaltrials.gov/show/NCT01568866).
  97. 97.
    Fahdi IE, Gaddam V, Saucedo JF, Kishan CV, Vyas K, Deneke MG, et al. Bradycardia during therapy for multiple myeloma with thalidomide. Am J Cardiol. 2004;93(8):1052–5.PubMedGoogle Scholar
  98. 98.
    Kaur A, Yu SS, Lee AJ, Chiao TB. Thalidomide-induced sinus bradycardia. Ann Pharmacother. 2003;37:1040–3.PubMedGoogle Scholar
  99. 99.
    Rajkumar SV, Rosinol L, Hussein M, et al. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol. 2008;26:2171–7.  https://doi.org/10.1200/JCO.2007.14.1853.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Lenalidomide. FDA package insert. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021880s049lbl.pdf. Accessed 2 May 2017.
  101. 101.
    Shah MH, Binkley P, Chan K, Xiao J, Arbogast D, Collamore M, et al. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res. 2006;12:3997–4003.PubMedGoogle Scholar
  102. 102.
    Noonan AM, Eisch RA, Liewehr DJ, Sissung TM, Venzon DJ, Flagg TP, et al. Electrocardiographic studies of romidepsin demonstrate its safety and identify a potential role for K(ATP) channel. Clin Cancer Res. 2013;19:3095–104.  https://doi.org/10.1158/1078-0432.CCR-13-0109.PubMedGoogle Scholar
  103. 103.
    Piekarz RL, Frye AR, Wright JJ, Steinberg SM, Liewehr DJ, Rosing DR, et al. Cardiac studies in patients treated with depsipeptide FK229, in a phase II trial for T-cell lymphoma. Clin Cancer Res. 2006;12(12):3762–73.PubMedGoogle Scholar
  104. 104.
    Sandor V, Bakke S, Robey RW, Kang MH, Blagosklonny MV, Bender J, et al. Phase I trial of the histone deactylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res. 2002;8(3):718–28.PubMedGoogle Scholar
  105. 105.
    Rathkopf DE, Picus J, Hussain A, Ellard S, Chi KN, Nydam T, et al. A phase 2 study of intravenous panobinostat in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol. 2013;72:537–44.  https://doi.org/10.1007/s00280-013-2224-8.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Varricchi G, Galdiero MR, Tocchetti CG. Cardiac toxicity of immune checkpoint inhibitors: cardio-oncology meets immunology. Circulation. 2017;136(21):1989–92.  https://doi.org/10.1161/CIRCULATIONAHA.117.029626.PubMedGoogle Scholar
  107. 107.
    Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319–22.  https://doi.org/10.1126/science.291.5502.319.PubMedGoogle Scholar
  108. 108.
    Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375:1749–55.  https://doi.org/10.1056/NEJMoa1609214.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Heinzerling L, Ott PA, Hodi FS, Husain AN, Tajmir-Riahi A, Tawbi H, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer. 2016;4:50.  https://doi.org/10.1186/s40425-016-0152-y. PubMedPubMedCentralGoogle Scholar
  110. 110.
    Behling J, Kaes J, Munzel T, et al. New-onset third-degree atrioventricular block because of autoimmune-induced myositis under treatment with anti-programmed cell death-1 (nivolumab) for metastatic melanoma. Melanoma Res. 2017;27:155–8.PubMedGoogle Scholar
  111. 111.
    Zheng PP, Li J, Kros JM. Breakthroughs in modern cancer therapy and elusive cardiotoxicity: critical research-practic gaps, challenges, and insights. Med Res Rev. 2018;38(1):325–76.  https://doi.org/10.1002/med.21463.PubMedGoogle Scholar
  112. 112.
    Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, Emery L, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122(6):863–71.  https://doi.org/10.1182/blood-2013-03-490565.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics. 2016;3:16011.  https://doi.org/10.1038/mto.2016.11. PubMedPubMedCentralGoogle Scholar
  114. 114.
    Siegel JP, Puri RK. Interleukin-2 toxicity. J Clin Oncol. 1991;9:694–704.PubMedGoogle Scholar
  115. 115.
    Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med. 1987;316:889–97.PubMedGoogle Scholar
  116. 116.
    Margolin KA, Rayner AA, Hawkins MJ, Atkins MB, Dutcher JP, Fisher RI, et al. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J Clin Oncol. 1989;7:486–98.PubMedGoogle Scholar
  117. 117.
    Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105–16.  https://doi.org/10.1200/JCO.1999.17.7.2105.PubMedGoogle Scholar
  118. 118.
    Weiss RB, Grillo-Lopez AJ, Marsoni S, et al. Amsacrine-associated cardiotoxicity: an analysis of 82 cases. J Clin Oncol. 1986;4:918–28.  https://doi.org/10.1200/JCO.1986.4.6.918.PubMedGoogle Scholar
  119. 119.
    Arlin ZA, Feldman EJ, Mittelman A, Ahmed T, Puccio C, Chun HG, et al. Amsacrine is safe and effective therapy for patients with myocardial dysfunction and acute leukemia. Cancer. 1991;68:1198–200.PubMedGoogle Scholar
  120. 120.
    Shinar E, Hasin Y. Acute electrocardiographic changes induced by amsacrine. Cancer Treat Rep. 1984;68(9):1169–72.PubMedGoogle Scholar
  121. 121.
    Gomez DR, Yusuf SW, Munsell M, et al. A prospective exploratory analysis of cardiac biomarkers and electrocardiogram abnormalities in patients receiving thoracic radiation therapy with high-dose heart exposure. J Thorac Oncol. 2014;9(10):1554–60.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Adams MJ, Lipshultz SE, Schwartz C, et al. Radiation-associated cardiovascular disease: manifestations and management. Semin Radiat Oncol. 2003;13:346–56.PubMedGoogle Scholar
  123. 123.
    Vasic N, Stevic R, Pesut D, Jovanovic D. Acute left bundle branch block as a complication of brachytherapy for lung cancer. Respir Med. 2011;105(Suppl 1):S78–80.  https://doi.org/10.1016/S0954-6111(11)70016-6. PubMedGoogle Scholar
  124. 124.
    Tsagalou EP, Kanakakis J, Anastasiou-Nana MI. Complete heart block after mediastinal irradiation in a patient with the Wolff-Parkinson-White syndrome. Int J Cardiol. 2005;104(1):108–10.PubMedGoogle Scholar
  125. 125.
    Groarke JD, Tanquturi VK, Hainer J, et al. Abnormal exercise response in long-term survivors of Hodgkin’s lymphoma treated with thoracic irradiation: evidence of cardiac autonomic dysfunction and impact on outcomes. J Am Coll Cardiol. 2015;65(6):573–83.  https://doi.org/10.1016/j.jacc.2014.11.035.PubMedGoogle Scholar
  126. 126.
    Adams MJ, Lipsitz SR, Colan SD, Tarbell NJ, Treves ST, Diller L, et al. Cardiovascular status in long-term survivors of Hodgkin’s disease treated with chest radiotherapy. J Clin Oncol. 2004;22(15):3139–48.PubMedGoogle Scholar
  127. 127.
    Huang CC, Huang TL, Hsu HC, Chen HC, Lin HC, Chien CY, et al. Long-term effects of neck irradiation on cardiovascular autonomic function: a study in nasopharyngeal carcinoma patients after radiotherapy. Muscle Nerve. 2013;47(3):344–50.  https://doi.org/10.1002/mus.23530.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Merna A. Armanious
    • 1
    • 2
  • Shreya Mishra
    • 1
  • Michael G. Fradley
    • 1
    • 2
  1. 1.Division of Cardiovascular MedicineUniversity of South FloridaTampaUSA
  2. 2.Cardio-Oncology ProgramH. Lee Moffitt Cancer Center & Research InstituteTampaUSA

Personalised recommendations