Consilium MedicumConsilium MedicumConsilium MedicumConsilium Medicum2075-17532542-2170Consilium Medicum10987910.26442/20751753.2022.6.201542ArticlesСтатьиReview ArticleCancer treatment and drug-induced QT interval prolongation: A reviewЛекарственно-индуцированное удлинение интервала QT на фоне применения противоопухолевых препаратовhttps://orcid.org/0000-0002-0795-8225OstroumovaOlga D.ОстроумоваОльга Дмитриевна
Russian Federation

D. Sci. (Med.), Prof.

д-р мед. наук, проф., зав. каф. терапии и полиморбидной патологии им. акад. М.С. Вовси; проф. каф. клинической фармакологии и пропедевтики внутренних болезней

ostroumova.olga@mail.ruhttps://orcid.org/0000-0001-5801-3742KochetkovAleksey I.КочетковАлексей Иванович
Russian Federation

Cand. Sci. (Med.)

канд. мед. наук, доц. каф. терапии и полиморбидной патологии им. акад. М.С. Вовси

ak_info@list.ruhttps://orcid.org/0000-0002-3900-758XDeValeria A.ДёВалерия Анатольевна
Russian Federation

Resident

ординатор каф. терапии и полиморбидной патологии им. акад. М.С. Вовси

devaleria97@mail.ruRussian Medical Academy of Continuous Professional EducationФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава РоссииSechenov First Moscow State Medical University (Sechenov University)ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет)150620222463913981508202215082022Copyright ©; 2022, Consilium MedicumCopyright ©; 2022, ООО "Консилиум Медикум"2022Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://consilium.orscience.ru/2075-1753/article/view/109879

Anticancer drugs can cause drug-induced prolongation of the QT interval. Prolongation of the QT interval is a known risk factor and an independent predictor of the development of life-threatening ventricular arrhythmias (polymorphic ventricular tachycardia, also called Torsades de Pointes), and sudden cardiac death in patients with and without structural heart disease. Healthcare practitioners should constantly evaluate the benefit/risk ratio prior to initiating treatment as well as continuing the chosen one. Some patients need particular attention, especially those who have risk factors such as comorbidities, taking drugs associated with QT interval prolongation, dehydration and electrolyte imbalance, etc. Despite apparent increase in the awareness among the patients and medical professionals, many scientists suggest that there is a lack of awareness about the true prevalence of these adverse events, which are at least 10 times greater than reported cases. This article discusses anticancer drugs that have an association with QT interval prolongation, and also possible strategies in the treatment of the patients with drug-induced QT interval prolongation.

Противоопухолевые препараты могут вызывать лекарственно-индуцированное удлинение интервала QT. В свою очередь, удлинение интервала QT является признанным фактором риска и независимым предиктором развития жизнеугрожающих желудочковых аритмий (прежде всего – полиморфной желудочковой тахикардии/Torsades de Pointes) и внезапной сердечной смерти у лиц как с наличием структурной патологии сердца, так и с ее отсутствием. Практикующие врачи должны постоянно оценивать отношение польза/риск при начале, а также продолжении выбранной терапии. Особое внимание необходимо обратить на пациентов с факторами риска, такими как наличие сопутствующих заболеваний, прием препаратов, ассоциированных с удлинением QT-интервала, дегидратация и электролитные нарушения и др. Несмотря на очевидный рост осведомленности пациентов и медицинского персонала, многие исследователи высказывают предположение о недостаточной степени информированности об истинной распространенности рассматриваемых нежелательных реакций, которая на самом деле превышает имеющиеся в настоящее время данные по меньшей мере в 10 раз. В данной статье рассматриваются противоопухолевые препараты, которые могут быть ассоциированы с удлинением интервала QT, а также особенности тактики ведения пациентов с лекарственно- индуцированным удлинением интервала QT.

drug-induced diseaseQT interval prolongationtorsade de pointescanceranticancer drugлекарственно-индуцированное заболеваниеудлинение интервала QTполиморфная желудочковая тахикардияраконкологические заболеванияпротивоопухолевая терапияЦибулькин Н.А. Синдром удлиненного интервала QT – основные клинико-патофизиологические аспекты. Практическая медицина. 2012;5(60):98-103 [Cibulkin NA. Long QT syndrome – main clinical and pathophysiological aspects. Prakticheskaja medicina. 2012;5(60):98-103 (in Russian)].Haddad PM, Anderson IM. Antipsychotic-Related QTc Prolongation, Torsade de Pointes and Sudden Death. Drugs. 2002;62(11):1649-71. DOI:10.2165/00003495-200262110-00006Желудочковые нарушения ритма. Желудочковые тахикардии и внезапная сердечная смерть. Клинические рекомендации МЗ РФ. 2020. Режим доступа: https://mz19.ru/upload/iblock/dea/ZHeludochkovye-narusheniya-ritma.-ZHeludochkovye-takhikardii-2020.pdf/ Ссылка активна на: 29.12.2021 [Ventricular arrhythmias. Ventricular tachycardia and sudden cardiac death. Clinical recommendations of the Ministry of Health of the Russian Federation. 2020. Available at: https://mz19.ru/upload/iblock/dea/ZHeludochkovye-narusheniya-ritma.-ZHeludochkovye-takhikardii-2020.pdf. Accessed 29.12.2021 (in Russian)].Головина Г.А., Зафираки В.К., Космачева Е.В. Медикаментозно-индуцированный синдром удлиненного интервала QT. Вестник аритмологии. 2020;27(3):42-52 [Golovina GA, Zafiraki VK, Kosmacheva EV. Drug-induced long QT syndrome. Vestnik aritmologii. 2020;27(3):42-52 (in Russian)].Aktürk G, Kalkan Ş. Drug-Induced QT Interval Prolongation: Mechanisms, Risk Factors, Genetics and Clinical Management. J Basic Clin Health Sci. 2019;3(5):193-8. DOI:10.30621/jbachs.2019.712Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012;3(5):241-53. DOI:10.1177/2042098612454283Vejpongsa P, Yeh ET. Prevention of anthracycline-induced cardiotoxicity: challenges and opportunities. J Am Coll Cardiol. 2014;64(9):938-45. DOI:10.1016/j.jacc.2014.06.1167Sarapa N, Huang M, Varterasian M, et al. Risk management and eligibility critieria for QT assessment in patients with advanced cancer. J Clin Oncol. 2005;23(16; Suppl.):3047.Yusuf SW, Razeghi P, Yeh ETH. The Diagnosis and Management of Cardiovascular Disease in Cancer Patients. Curr Probl Cardiol. 2008;33(4):163-96. DOI:10.1016/j.cpcardiol.2008.01.002Остроумова О.Д., Голобородова И.В. Влияние отдельных групп лекарственных препаратов на риск удлинения интервала QTс. Consilium Medicum. 2019;21(10):95-106 [Ostroumova OD, Goloborodova IV. The influence of certain groups of drugs on the QTc interval prolongation. Consilium Medicum. 2019;21(10):95-106 (in Russian)]. DOI:10.26442/20751753.2019.10.190447Остроумова О.Д., Голобородова И.В. Лекарственно-индуцированное удлинение интервала QT: распространенность, факторы риска, лечение и профилактика. Consilium Medicum. 2019;21(5):62-7 [Ostroumova OD, Goloborodova IV. Drug-induced prolongation of the QT interval: prevalence, risk factors, treatment and prevention. Consilium Medicum. 2019;21(5):62-7 (in Russian)]. DOI:10.26442/20751753.2019.5.190415Woosley RL, Heise CW, Gallo T. CredibleMeds. Available at: https://crediblemeds.org/ Accessed: 29.12.2021.Porta-Sánchez A, Gilbert C, Spears D, et al. Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review. J Am Heart Assoc. 2017;6(12):007724. DOI:10.1161/JAHA.117.007724Roden DM. A current understanding of drug-induced QT prolongation and its implications for anticancer therapy. Cardiovasc Res. 2019;115(5):895-903. DOI:10.1093/cvr/cvz013Cohen-Rabbie S, Berges AC, Rekić D, et al. QT Prolongation Risk Assessment in Oncology: Lessons Learned From Small-Molecule New Drug Applications Approved During 2011–2019. J Clin Pharmacol. 2021;61(8):1106-17. DOI:10.1002/jcph.1844Lazzerini PE, Bertolozzi I, Acampa M, et al. Androgen Deprivation Therapy for Prostatic Cancer in Patients With Torsades de Pointes. Front Pharmacol. 2020;11:684. DOI:10.3389/fphar.2020.00684Abu Rmilah AA, Lin G, Begna KH, et al. Risk of QTc prolongation among cancer patients treated with tyrosine kinase inhibitors. Int J Cancer. 2020;147(11):3160-7. DOI:10.1002/ijc.33119Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol. 2018;36(3):231-7. DOI:10.1200/JCO.2017.74.7162Larkin 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(4):436-44. DOI:10.1016/S1470-2045(14)70051-8Duan J, Tao J, Zhai M, et al. Anticancer drugs-related QTc prolongation, torsade de pointes and sudden death: current evidence and future research perspectives. Oncotarget. 2018;9(39):25738-49. DOI:10.18632/oncotarget.25008Dréno B, Ribas A, Larkin J, et al. Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study. Ann Oncol. 2017;28(5):1137-44. DOI:10.1093/annonc/mdx040Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689-99. DOI:10.1056/NEJMoa1411817Schiefer M, Hendriks LEL, Dinh T, et al. Current perspective: Osimertinib-induced QT prolongation: new drugs with new side-effects need careful patient monitoring. Eur J Cancer. 2018;91:92-8. DOI:10.1016/j.ejca.2017.12.011Hortobagyi GN. Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial. Breast Cancer Res. 2018;20(1):123. DOI:10.1186/s13058-018-1050-7Khozin S, Blumenthal GM, Zhang L, et al. FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. Clin Cancer Res. 2015;21(11):2436-9. DOI:10.1158/1078-0432.CCR-14-3157Wang 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(3):1027-31.Lenihan DJ, Kowey PR. Overview and management of cardiac adverse events associated with tyrosine kinase inhibitors. Oncologist. 2013;18:900-8. DOI:10.1634/theoncologist.2012-0466Barbey JT, Pezzullo JC, Soignet SL. Effect of arsenic trioxide on QT interval in patients with advanced malignancies. J Clin Oncol. 2003;21:3609-15. DOI:10.1200/JCO.2003.10.009Wacker A, Lersch C, Scherpinski U, et al. High incidence of angina pectoris in patients treated with 5-fluorouracil. A planned surveillance study with 102 patients. Oncology. 2003;65(2):108-12. DOI:10.1159/000072334Koca D, Salman T, Unek IT, et al. Clinical and electrocardiography changes in patients treated with capecitabine. Chemotherapy. 2011;57(5):381-7. DOI:10.1159/000331645Kuittinen T, Jantunen E, Vanninen E, et al. Late potentials and QT dispersion after high-dose chemotherapy in patients with non-Hodgkin lymphoma. Clin Physiol Funct Imaging. 2010;30(3):175-80. DOI:10.1111/j.1475-097X.2009.00920.xHancox JC, Caves RE, Choisy SC, et al. QT interval prolongation and torsades de pointes with oxaliplatin. Ther Adv Drug Saf. 2016;7(6):261-3. DOI:10.1177/2042098616666081Yin W, Karyagina EV, Lundberg AS, et al. Pharmacokinetics, bioavailability and effects on electrocardiographic parameters of oral fludarabine phosphate. Biopharm Drug Dispos. 2010;31(1):72-81. DOI:10.1002/bdd.690Conte PF, Gennari A. Anthracyclines-paclitaxel combinations in the treatment of breast cancer. Ann Oncol. 1997;8(10):939-43. DOI:10.1023/a:1008208002779Kamineni P, Prakasa K, Hasan SP, et al. Cardiotoxicities of paclitaxel in African Americans. J Natl Med Assoc. 2004;96(7):995.Rowinsky EK, McGuire WP, Guarnieri T, et al. Cardiac disturbances during the administration of taxol. J Clin Oncol. 1991;9(9):1704-12. DOI:10.1200/JCO.1991.9.9.1704Ghatalia 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. DOI:10.1038/bjc.2014.564National Cancer Institute DCTD Division of Cancer Treatment & Diagnosis. Common terminology criteria for adverse events (CTCAE). 2017. Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed 21.12.2021.Strevel EL, Ing DJ, Siu LL. Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol. 2007;25(22):3362. DOI:10.1200/JCO.2006.09.6925Martin P, Oliver S, Kennedy SJ, et al. Pharmacokinetics of vandetanib: three phase I studies in healthy subjects. Clin Ther. 2012;34(1):221-37. DOI:10.1016/j.clinthera.2011.11.011Blackhall FH, O'brien M, Schmid P, et al. A phase I study of Vandetanib in combination with vinorelbine/cisplatin or gemcitabine/cisplatin as first-line treatment for advanced non-small cell lung cancer. J Thorac Oncol. 2010;5(8):1285-8. DOI:10.1097/JTO.0b013e3181e3a2d1Liu 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(5):541-7. DOI:10.1007/s00228-015-1831-1Anon. DailyMed – CAPRELSA – vandetanib tablet. National Library of Medicine. 2017. Available at: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e5721cb8-4185-47b9-bbb3-1c587e558a03&type=display. Accessed 21.12.2021.Tolcher 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(4):751-64. DOI:10.1007/s00280-010-1372-3Schmidinger 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(32):5204-12. DOI:10.1200/JCO.2007.15.6331Bergh J, Mariani G, Cardoso F, et al. Clinical and pharmacokinetic study of sunitinib and docetaxel in women with advanced breast cancer. Breast. 2012;21(4):507-13. DOI:10.1016/j.breast.2012.01.012Kaley TJ, Wen P, Schiff D, et al. Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma. Neuro Oncol. 2015;17(1):116-21. DOI:10.1093/neuonc/nou148Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12(9):841-51. DOI:10.1016/S1470-2045(11)70201-7Larson RA, Yin OQ, Hochhaus A, et al. Population pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase. Eur J Clin Pharmacol. 2012;68(5):723-33. DOI:10.1007/s00228-011-1200-7Abbas R, Chalon S, Leister C, et al. Evaluation of the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects. Cancer Chemother Pharmacol. 2013;71(1):123-32. DOI:10.1007/s00280-012-1987-7Abbas R, Hug BA, Leister C, et al. A randomized, crossover, placebo- and moxifloxacin-controlled study to evaluate the effects of bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor, on cardiac repolarization in healthy adult subjects. Int J Cancer. 2012;131(3):304-11. DOI:10.1002/ijc.27348Piekarz RL, Frye AR, Wright JJ, et al. Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res. 2006;12(12):3762-73. DOI:10.1158/1078-0432.CCR-05-2095Bates SE, Rosing DR, Fojo T, et al. Challenges of evaluating the cardiac effects of anticancer agents. Clin Cancer Res. 2006;12(13):3871-4. DOI:10.1158/1078-0432.CCR-06-1017Lü S, Wang J, Xu X, et al. Bortezomib in combination with epirubicin, dexamethasone and thalidomide is a highly effective regimen in the treatment of multiple myeloma: a single-center experience. Int J Hematol. 2009;89(1):34-8. DOI:10.1007/s12185-008-0218-9Messinger Y, Gaynon P, Raetz E, et al. Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia (TACL) consortium. Pediatr Blood Cancer. 2010;55(2):254-9. DOI:10.1002/pbc.22456Maison-Blanche P, Vermorken JB, Goksel T, et al. A randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel. J Cardiovasc Pharmacol. 2013;61(6):495-504. DOI:10.1097/FJC.0b013e31828b73ffIbrahim MA, Do DV, Sepah YJ, et al. Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin A-4 phosphate. BMC Pharmacol Toxicol. 2013;14:7. DOI:10.1186/2050-6511-14-7Kloth JS, Pagani A, Verboom MC, et al. Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors. Br J Cancer. 2015;112(6):1011-6. DOI:10.1038/bjc.2015.82Coppola C, Rienzo A, Piscopo G, et al. Management of QT prolongation induced by anti-cancer drugs: Target therapy and old agents. Different algorithms for different drugs. Cancer Treat Rev. 2018;63:135-43. DOI:10.1016/j.ctrv.2017.11.009