QT prolongation due to targeted anticancer therapy Review article
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Published:
Sep 2, 2016
Keywords:
QT prolongation, targeted therpy, torsade de pointes, cancer patiens
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Abstract
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.
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Setteyova L, Bacharova L, Mladosievicova B. QT prolongation due to targeted anticancer therapy. OncoReview [Internet]. 2016Sep.2 [cited 2024Apr.27];6(3(23):103-12. Available from: https://www.journalsmededu.pl/index.php/OncoReview/article/view/486
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Copyright: © Medical Education sp. z o.o. This is an Open Access article distributed under the terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). License (https://creativecommons.org/licenses/by-nc/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Address reprint requests to: Medical Education, Marcin Kuźma (marcin.kuzma@mededu.pl)
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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). Online: www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdf (Access: 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). Online: www.accessdata.fda.gov/drugsatfda_docs/label/2014/022405s007lbl.pdf (Access: 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. Online: www.crediblemeds.org/new-drug-list/ (Access: 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). Online: www.pharma.us.novartis.com/product/pi/pdf/farydak.pdf (Access: 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). Online: www.merck.com/product/usa/pi_circulars/z/zolinza/zolinza_pi.pdf (Access: 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. Online: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002878.pdf (Access: 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.
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