Preferences help
enabled [disable] Abstract
Number of results
2016 | 6 | 3 | A103-112
Article title

QT prolongation due to targeted anticancer therapy

Title variants
Languages of publication
A growing number of targeted anticancer agents has shown the unexpected ability to induce QT interval prolongation. In addition, standard chemotherapeutics and a variety of conditions such as electrolyte abnormalities, endocrine disorders, cardiac diseases, nutritional disturbances and other factors may be associated with long QT syndrome in cancer patients. Prolongation of the QT interval can lead to life-threatening ventricular arrhythmias, including ‘torsade de pointes’ (TdP). The association between long QT interval and ventricular arrhythmias remains the subject of many controversies. The QT interval represents the time interval of both ventricular depolarization and repolarization. Not only abnormalities of ion channels, but also changes in the myocardial microarchitecture and other factors and disorders frequently seen in cancer patients may participate in its prolongation and potential risk of ventricular arrhythmias. The aim of this review was to summarize current knowledge about QT prolongation in cancer patients with the special focus on targeted therapy.
Physical description
  • Institute of Pathological Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovak Republic; Clinic of Hematology and Transfusiology, Faculty of Medicine, Comenius University and Slovak Medical University, Bratislava, Slovak Republic
  • Institute of Pathological Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovak Republic; International Laser Centre, Department of Biophotonics, Bratislava, Slovak Republic
  • Institute of Pathological Physiology, Faculty of Medicine, Comenius University, Bratislava, Slovak Republic
  • 1. Tamargo J, Caballero R, Delpón E. Cancer chemotherapy and cardiac arrhythmias: a review. Drug Saf 2015; 38: 129-152.
  • 2. Chen MH, Kerkela R, Force T. Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation 2008; 118: 84-95.
  • 3. Talbert DR, Doherty KR, Trusk PB et al. A multi-parameter in vitro screen in human stem cell-derived cardiomyocytes identifies ponatinib-induced structural and functional cardiac toxicity. Toxicol Sci 2015; 143: 147-155.
  • 4. Full prescribing information for Tasigna (nilotinib) (package insert): [], accessed: November 8, 2015.
  • 5. Tam CS, Kantarjian H, Garcia-Manero G et al. Failure to achieve a major cytogenetic response by 12 months defines inadequate response in patients receiving nilotinib or dasatinib as second or subsequent line therapy for chronic myeloid leukemia. Blood 2008; 112: 516-518.
  • 6. Bello CL, Mulay M, Huang X et al. Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic- pharmacodynamic evaluation of sunitinib. Clin Cancer Res 2009; 15: 7045-7052.
  • 7. Natale RB, Thongprasert S, Greco FA et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non- -small-cell lung cancer. J Clin Oncol 2011; 29: 1059-1066.
  • 8. Full prescribing information for Caprelsa (vandetanib) (package insert) [], accessed: December 6, 2015.
  • 9. Ghatalia P, Je Y, Kaymakcalan MD et al. QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Br J Cancer 2015; 112(2): 296-305.
  • 10. Liu Y, Liu Y, Fan ZW et al. Meta-analysis of the risks of hypertension and QTc prolongation in patients with advanced non-small cell lung cancer who were receiving vandetanib. Eur J Clin Pharmacol 2015; 71: 541-547.
  • 11. Wells SA, Robinson BG, Gagel RF et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double- blind phase III trial. J Clin Oncol 2012; 30: 134-141.
  • 12. Zang J, Wu S, Tang L et al. Incidence and risk of QTc interval prolongation among cancer patients treated with vandetanib: a systematic review and meta-analysis. PLoS One 2012; 7(2): e30353.
  • 13. Dong Q, Fu XX, Du LL et al. Blocking of the human ether-a-go-go-related gene channel by imatinib mesylate. Biol Pharm Bull 2013; 36: 268-275.
  • 14. Lu Z, Wu CY, Jiang YP et al. Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome. Sci Transl Med 2012; 4: 131ra50.
  • 15. Doherty KR, Wappel RL, Talbert DR et al. Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. Toxicol Appl Pharmacol 2013; 272: 245-255.
  • 16. Kerkela R, Grazette L, Yacobi R et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12: 908-916.
  • 17. Freebern WJ, Fang HS, Slade MD et al. In Vitro Cardiotoxicity Potential Comparative Assessments of Chronic Myelogenous Leukemia Tyrosine Kinase Inhibitor Therapies: Dasatinib, Imatinib and Nilotinib. Blood (ASH Annual Meeting Abstracts) 2007; 110.
  • 18. Chu TF, Rupnick MA, Kerkela R et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007; 370: 2011-2019.
  • 19. Fedele C, Riccio G, Coppola C et al. Comparison of preclinical cardiotoxic effects of different ErbB2 inhibitors. Breast Cancer Res Treat 2012; 133: 511-521.
  • 20. Cortes JE, Kantarjian H, Shah NP et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012; 367: 2075-2088.
  • 21. 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.
  • 22. Larkin J, Del Vecchio M, Ascierto PA et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol 2014; 15: 436-444.
  • 23. Bronte E, Bronte G, Novo G et al. What links BRAF to the heart function? New insights from the cardiotoxicity of BRAF inhibitors in cancer treatment. Oncotarget 2015; 6(34): 35589-35601.
  • 24. Cortes JE, Kantarjian H, Foran JM et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3 – internal tandem duplication status. J Clin Oncol 2013; 31: 3681-3687.
  • 25. Tallman MS, Schiller G, Trone D et al. Results of a phase 2 randomized, open-label, study of lower doses of quizartinib (AC220; ASP2689) in subjects with FLT3-ITD positive relapsed or refractory acute myeloid leukemia (AML). Blood 2013; 122: 494.
  • 26. Levis M. Quizartinib for the treatment of FLT3/ITD acute myeloid leukemia. Future Oncol 2014; 10: 1571-1579.
  • 27. Cortes JE, Perl AE, Dombret H et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients ≥ 60 years of age with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia. Blood 2012; 120: 48.
  • 28. Badros A, Burger AM, Philip S et al. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 2009; 15: 5250-5257.
  • 29. Wang H, Cao Q, Dudek AZ. Phase II study of panobinostat and bortezomib in patients with pancreatic cancer progressing on gemcitabine-based therapy. Anticancer Res 2012; 32: 1027-1031.
  • 30. Walker AR, Klisovic R, Johnston JS et al. Pharmacokinetics and dose escalation of the heat shock protein inhibitor 17-allyamino-17-demethoxygeldanamycin in combination with bortezomib in relapsed or refractory acute myeloid leukemia. Leuk Lymphoma 2013; 54: 1996-2002.
  • 31. Woosley RL. QT drugs lists [], accessed: December 26, 2015.
  • 32. Orciuolo E, Buda G, Cecconi N et al. Unexpected cardiotoxicity in haematological bortezomib treated patients. Brit J Haematol 2007; 138: 396-397.
  • 33. Fu HY, Minamino T, Tsukamoto O et al. Overexpression of endoplasmic reticulum-resident chaperone attenuates cardiomyocyte death induced by proteasome inhibition. Cardiovasc Res 2008; 79: 600-610.
  • 34. Stadler WM, Margolin K, Ferber S et al. A phase II study of depsipeptide in refractory metastatic renal cell cancer. Clin Genitourin Cancer 2006; 5: 57-60.
  • 35. Bates SE, Rosing DR, Fojo T et al. Challenges of evaluating the cardiac effects of anticancer agents. Clin Cancer Res 2006; 12: 3871-3874.
  • 36. Full prescribing information for Farydak (panobinostat) (package insert) [], accessed: December 9, 2015.
  • 37. Munster PN, Rubin EH, Van Belle S et al. A single supratherapeutic dose of vorinostat does not prolong the QTc interval in patients with advanced cancer. Clin Cancer Res 2009; 15: 7077-7084.
  • 38. Lynch DR, Washam JB, Newby LK. QT interval prolongation and torsades de pointes in a patient undergoing treatment with vorinostat: a case report and review of the literature. Cardiol J 2012; 19: 434-438.
  • 39. Kerr JS, Galloway S, Lagrutta A et al. Nonclinical safety assessment of the histone deacetylase inhibitor vorinostat. Int J Toxicol 2010; 29: 3-19.
  • 40. Full prescribing information for Zolinza (vorinostat) (package insert) [], accessed: December 16, 2015.
  • 41. Wolf JL, Siegel D, Goldschmidt H et al. Phase II trial of the pan-deacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma. Leuk Lymphoma 2012; 53: 1820-1823.
  • 42. Shah MH, Binkley P, Chan K et al. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 2006; 12: 3997-4003.
  • 43. Curigliano G, Cardinale D, Suter T et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012; 23: vii155-vii66.
  • 44. Kim PY. QT monitoring. In: Yeh ETH (ed). MD Anderson Practice in Onco-Cardiology. 2016: 15-25.
  • 45. Cipolla C. QT monitoring during oncology trials: Can we realistically expect to learn anything? In: Lenihan D, Cipolla C (ed). Proceedings of the Fifth Annual International Symposium of the International CardiOncology Society; Oct 5-6. Silver Spring, Maryland 2011: 34-36.
  • 46. Brell JM. Prolonged QTc interval in cancer therapeutic drug development: defining arrhythmic risk in malignancy. Prog Cardiovasc Dis 2010; 53: 164-172.
  • 47. Zeltser D, Justo D, Halkin A et al. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine 2003; 82: 282-290.
  • 48. International Conference on Harmonisation; guidance on E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs; availability. Notice. Fed Regist 2005; 70: 61134-61135.
  • 49. International Conference on Harmonisation; guidance on E14 the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs (R3) – questions and answers. 2015 [ 2009/09/WC500002878.pdf], accessed: November 24, 2015.
  • 50. Becker TK, Yeung SCJ. Drug-induced QT interval prolongation in cancer patients. Oncol Rev 2010; 4: 223-232.
  • 51. Kim PY, Ewer MS. Chemotherapy and QT prolongation: overview with clinical perspective. Curr Treat Options Cardiovasc Med 2014; 16: 303.
  • 52. Johannesen L, Vicente J, Mason JW et al. Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil. Clin Pharmacol Ther 2014; 96: 549-558.
  • 53. Miragoli M, Gaudesius G, Rohr S. Electrotonic modulation of cardiac impulse conduction by myofibroblasts. Circ Res 2006; 98: 801-810.
  • 54. Miragoli M, Salvarani N, Rohr S. Myofibroblasts induce ectopic activity in cardiac tissue. Circ Res 2007; 101: 755-758.
  • 55. Wu KC, Weiss RG, Thiemann DR et al. Late gadolinium enhancement by cardiovascular magnetic resonance heralds an adverse prognosis in nonischemic cardiomyopathy. J Am Coll Cardiol 2008; 51: 2414-2421.
  • 56. Longo DL, Rockey DC, Bell PD et al. Fibrosis–a common pathway to organ injury and failure. N Engl J Med 2015; 372: 1138-1149.
  • 57. Carver JR, Desai CJ. Cardiovascular Toxicity of Antitumor Drugs: Dimension of the Problem in Adult Settings. In: Minotti G (ed). Cardiotoxicity of Non-cardiovascular Drugs. Wiley Online Library, 2010: 127-200.
  • 58. Earm YE, Ho WK, So I. Effects of adriamycin on ionic currents in single cardiac myocytes of the rabbit. J Mol Cell Cardiol 1994; 26: 163-172.
  • 59. Ducroq J, Moha ou Maati H, Guilbot S et al. Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for I(Ks). Br J Pharmacol 2010; 159: 93-101.
  • 60. Chang RY, Lee MY, Kan CB et al. Oxaliplatin-induced acquired long QT syndrome with torsades de pointes and myocardial injury in a patient with dilated cardiomyopathy and rectal cancer. J Chin Med Assoc 2013; 76: 466-469.
  • 61. Thomas D, Hammerling BC, Wu K et al. Inhibition of cardiac HERG currents by the DNA topoisomerase II inhibitor amsacrine: mode of action. Br J Pharmacol 2004; 142: 485-494.
  • 62. He J, Kargacin ME, Kargacin GJ et al. Tamoxifen inhibits Na+ and K+ currents in rat ventricular myocytes. Am J Physiol Heart Circ Physiol 2003; 285: H661-668.
  • 63. Liu XK, Katchman A, Ebert SN et al. The antiestrogen tamoxifen blocks the delayed rectifier potassium current, IKr, in rabbit ventricular myocytes. J Pharmacol Exp Ther 1998; 287: 877-883.
  • 64. Full prescribing information for Fareston (toremifene) (package insert) [ Information/human/000091/WC500020689.pdf], accessed: November 14, 2015.
  • 65. Lee HA, Kim EJ, Hyun SA et al. Electrophysiological effects of the anti-cancer drug lapatinib on cardiac repolarization. Basic Clin Pharmacol Toxicol 2010; 107: 614-618.
  • 66. Chen X, Shan H, Zhao J et al. L-type calcium current (ICa, L) and inward rectifier potassium current (IK1) are involved in QT prolongation induced by arsenic trioxide in rat. Cell Physiol Biochem 2010; 26: 967-974.
  • 67. Drolet B, Simard C, Roden DM. Unusual effects of a QT-prolonging drug, arsenic trioxide, on cardiac potassium currents. Circulation 2004; 109: 26-29.
  • 68. van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol 2010; 70: 16-23.
  • 69. National Cancer Institute. Cancer therapy evaluation program, common terminology for adverse events, version 4.0, DCTD, NCI, NIH, DHHS. 2010 [], accessed: December 13, 2015.
  • 70. Kumar S, Marfatia R, Tannenbaum S et al. Doxorubicin-induced cardiomyopathy 17 years after chemotherapy. Tex Heart Inst J 2012; 39: 424-427.
  • 71. Toro-Salazar OH, Gillan E, O‘Loughlin MT et al. Occult cardiotoxicity in childhood cancer survivors exposed to anthracycline therapy. Circ Cardiovasc Imaging 2013; 6: 873-880.
  • 72. Migrino RQ, Aggarwal D, Konorev E et al. Early detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography. Ultrasound Med Biol 2008; 34: 208-214.
  • 73. Bauters F, Plouvier B, Breviere G et al. Cardiac insufficiency caused by the use of daunorubicin. Clinical and developmental study of 4 recent cases. Sem Hop Paris 1975; 51: 1949-1957.
  • 74. Wilcox R, James P, Toghill P. Endomyocardial fibrosis associated with daunorubicin therapy. Br Heart J 1976; 38: 860.
  • 75. Torti FM, Bristow MM, Lum BL et al. Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy. Cancer Res 1986; 46: 3722-7372.
  • 76. Kupari M, Volin L, Suokas A et al. Cardiac involvement in bone marrow transplantation: electrocardiographic changes, arrhythmias, heart failure and autopsy findings. Bone Marrow Transplant 1990; 5: 91-98.
  • 77. Mills BA, Roberts RW. Cyclophosphamide-induced cardiomyopathy. A report of two cases and review of the english literature. Cancer 1979; 43: 2223-2226.
  • 78. Kumar S, Gupta RK, Samal N. 5-fluorouracil induced cardiotoxicity in albino rats. Mater Med Pol 1995; 27: 63-66.
  • 79. Tsibiribi P, Bui-Xuan C, Bui-Xuan B et al. Cardiac lesions induced by 5-fluorouracil in the rabbit. Hum Exp Toxicol 2006; 25: 305-309.
  • 80. Delle H, Rocha JR, Cavaglieri RC et al. Antifibrotic effect of tamoxifen in a model of progressive renal disease. J Am Soc Nephrol 2012; 23: 37-48.
  • 81. Chu W, Li C, Qu X et al. Arsenic-induced interstitial myocardial fibrosis reveals a new insight into drug-induced long QT syndrome. Cardiovasc Res 2012; 96: 90-98.
  • 82. Ewer SM, Yusuf SW. Cardiac arrhythmias in the cancer patient. In: Yeh E (ed). Cancer and the heart. People‘s Medical Publishing House 2013: 190-209.
  • 83. Giudicessi JR, Ackerman MJ. Genotype-and phenotype-guided management of congenital long QT syndrome. Curr Probl Cardiol 2013; 38: 417-455.
  • 84. Viskin S. Long QT syndromes and torsade de pointes. Lancet 1999; 354: 1625-1633.
  • 85. Khan IA. Long QT syndrome: diagnosis and management. Am Heart J 2002; 143: 7-14.
  • 86. Salama G, Bett GC. Sex differences in the mechanisms underlying long QT syndrome. Am J Physiol Heart Circ Physiol 2014; 307: H640-H648.
  • 87. Yue Y, Castrichini M, Srivastava U et al. Pathogenesis of the novel autoimmune-associated long QT syndrome. Circulation 2015; 132(4): 230-240.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.