Electrophysiologic Considerations in Cardio-Oncology
Although cardiovascular (CV) disease and cancer remain the two most common causes of mortality in the United States, significant advancements in both fields have improved outcomes dramatically. With the use of novel therapeutics, many malignancies can be treated as chronic diseases, and the number of cancer survivors continues to rise at a substantial pace. There is increased recognition, however, that many cancer treatments, including chemotherapy and radiation, can have adverse effects on the CV system. This has led to the development of cardio-oncology, a specialty aimed at managing risk and treating CV disease in patients with cancer and survivors. Although much of the initial focus has been on cardiomyopathy and congestive heart failure, many other CV complications can occur, including arrhythmias.1 Supraventricular tachycardias (SVT), particularly atrial fibrillation (AF), are quite common in this population and pose many unique management challenges. Similarly, QT prolongation is a frequent adverse event related to chemotherapy that can lead to premature cessation of possible life-saving treatments. Finally, some patients who require radiation therapy will present with an implantable cardiac device (pacemaker or defibrillator) in the radiation field, which necessitates special planning and precautions. It is important for cardio-oncologists to understand the nuances of treating these electrophysiologic issues in patients with cancer.
AF is associated with significant morbidity and mortality in both the general population and patients with cancer.2,3 Studies have demonstrated an association between AF and several malignancies including colon and breast cancer.4,5 Additionally, a recent study reported increased rates of AF in patients with non-life-threatening cancers who are not currently receiving therapy, even when controlling for traditional risk factors.6 Inflammation may be the explanation for increased rates of AF in this population.7 Treatment for these supraventricular arrhythmias can be challenging in patients with active malignancies. Many options to maintain sinus rhythm are contraindicated in the setting of specific chemotherapies. Anticoagulation, which is essential for stroke risk reduction, may not be possible in patients with cancer due to frequent bleeding and hematologic abnormalities (anemia and/or thrombocytopenia).
Many chemotherapeutics are associated with atrial arrhythmias. In some circumstances, the arrhythmia results from a different cardiotoxicity. For example, 5-fluorouracil is an antimetabolite used in the treatment of gastrointestinal and head and neck cancers. It is known to cause cardiac ischemia, likely via coronary vasospasm. In the setting of ischemia, AF has been observed.8-10 Anthracyclines are common class chemotherapeutics used to treat a variety of malignancies including breast cancer, leukemia, and lymphoma. Cardiomyopathy and congestive heart failure are the most commonly associated CV complications. Arrhythmias can occur in the setting of left ventricular dysfunction; however, AF has also been observed independent of other cardiotoxicities, with rates as high 10.3%.10-12 Additionally, anthracyclines prolong the action potential of Purkinje fibers, and studies on isolated myocytes confirm their arrhythmic potential.13,14 Although the exact mechanism is unclear, AF may result from anthracycline effects on ion channels or the accumulation of toxic metabolites.10
Tyrosine kinase inhibitors make up a class of novel chemotherapeutics that affect abnormal signaling pathways by blocking overactive or mutated protein kinases.15 Their use had led to dramatic improvements in the treatment of many cancers, but these agents have off-target effects that impact normal signaling in other tissues including cardiac myocytes. Multiple cardiotoxicities have been observed including arrhythmias. Ibrutinib, a tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia, is associated with significantly elevated rates of SVT and AF (3.5-10.8% across published studies). Patients treated with this agent also demonstrated elevated bleeding rates, so anticoagulation may not be an option if AF develops. Ibrutinib targets the Bruton's tyrosine kinase and the TEC protein kinase, which impact PI3K-AKT signaling.16,17 It is through these mechanisms that ibrutinib-induced AF is thought to develop. Studies with both human and murine myocytes have shown an association between decreased PI3K-AKT activity and AF.18 A recent study in rat myocytes exposed to ibrutinib confirmed reduced PI3K expression and AKT activity.19 Nonetheless, simple inhibition of this pathway is not sufficient to explain the increased rates of AF with ibrutinib. For example, idelalisib, another tyrosine kinase inhibitor used to treat chronic lymphocytic leukemia, also affects PI3K signaling without associated AF.20 This may be explained by the different PI3K heterodimer subunits targeted by these two agents.19,21,22 Finally, the second generation Bruton's tyrosine kinase inhibitor, acalabrutinib, has not demonstrated increased rates of AF, which may be due to its increased kinase selectivity.23
Atrial arrhythmias are also common complications of stem cell transplantation, with the median rates of SVT and AF ranging 8-10%.3,24,25 These arrhythmias are particularly common in patients exposed to melphalan as part of the preconditioning chemotherapy regimen. In one study, 11% of patients undergoing stem cell transplantation exposed to melphalan developed AF.26 On average, stem cell transplantation recipients who develop AF remain in the hospital 3 days longer than those without arrhythmic complications.25 In addition, these patients are more likely to require intensive care unit admissions and have higher in-hospital and 1-year mortality rates than those patients who do not develop AF.3
QT prolongation is a frequently observed adverse event in many patients with cancer who are receiving chemotherapy. Nevertheless, the risk of developing the life-threatening ventricular arrhythmia torsades de pointes (TdP) is generally quite low. In a study from MD Anderson evaluating patients enrolled in phase 1 clinical trials, 20% of patients had QT prolongation; however, arrhythmic events were clinically insignificant.27 Arrhythmic complications are generally observed only when the QT interval is greater than 500 ms or with changes of more than 60 ms.28 Multiple factors can contribute to QT prolongation in patients with cancer including chemotherapy, electrolyte disorders, the concomitant use of other QT-prolonging medications such as antibiotics or antiemetics, underlying CV disease, advanced age, and female gender.29 It is also well established that the QT interval is longer at slower heart rates and shorter at faster heart rates. As a result, multiple formulae have been developed to correct for these differences. Although Bazett's formula (QT/√RR) is most commonly used in general clinical practice, the Fridericia formula (QT/3√RR) is often considered more appropriate in the oncology population.30,31
Pharmaceuticals can lead to QT prolongation either from direct inhibition of potassium channels or via effects on intracellular signaling pathways such as PI3K.31,32 Arsenic trioxide is a chemotherapeutic agent used to treat relapsed or refractory acute promyelocytic leukemia and is commonly associated with QT prolongation. In one study, QT intervals of more than 500 ms were observed in 26% of participants; however, TdP was extremely rare.33 In patients treated with arsenic, it is recommended to hold therapy if the QT interval is greater than 500 ms. When the QT interval is below 460 ms, it can be restarted with careful attention to magnesium and potassium levels (>1.8 mEq/L and >4 mEq/L, respectively).34 Among the tyrosine kinase inhibitors, at least nine agents have either standard or black box warnings regarding QT interval prolongation.35 Vandetanib is used in the treatment of medullary thyroid cancer. In a meta-analysis of nine trials, all-grade QT prolongation occurred in 16-18% of subjects.36 Despite rare reports of ventricular arrhythmias, this agent has a black box warning for QT prolongation, and specific training is required to prescribe the drug.36,37 Nilotinib is used as first- or second-line therapy for chronic myelogenous leukemia. Median QT prolongation is 5-15 ms. In the initial nilotinib trials, rates of sudden cardiac death were reported at 0.3%, prompting a black box warning for nilotinib; however, preceding QT prolongation was never clearly documented in these cases.31,38,39
It is also increasingly common to encounter cardiovascular implantable electronic devices (CIEDs) such as pacemakers and defibrillators in patients with cancer. These devices pose unique challenges in patients receiving radiation therapy, particularly if the device is in the direct radiation field, as is the case with thoracic malignancies such as lung or breast cancer.40,41 Although modern devices are more tolerant of radiation therapy, malfunction can still occur. Defibrillators are generally more sensitive to these issues than pacemakers. The most commonly observed effects from radiation therapy to CIEDs include temporarily increased pacing/sensor rates and device resets and/or safety mode reversions. Less frequent complications include early battery depletion, oversensing, pacing inhibition, and complete device failure. Although cumulative radiation dose can lead to CIED malfunction, the majority of complications occur as a result of neutron production from high-energy beams, greater than 10 MV. At these energy levels, even scatter radiation from beams directed a significant distance from the CIED can affect functionality, with device resets, loss of random access memory, and electromagnetic interference reported.41-45 A study from MD Anderson reported a 7% device-malfunction rate in patients with CIEDs who were receiving radiation therapy at neutron producing doses >10 MV. Despite these findings, the majority of these patients tolerate radiation therapy without complication.44
Although guidelines and recommendations have been published regarding the safe and appropriate management of CIEDs in patients with cancer who are receiving radiation, there is little standardization in protocols among radiation therapy centers. This is likely the result of frequently changing CIED technology, different recommendations among the major device manufacturers, and lack of communication among all members of the treatment team. In general, prior to radiation therapy, cumulative dose to the device should be estimated. Although there is no "safe" amount of radiation to a CIED, cumulative radiation dose should not exceed 5 Gy. The use of lower energy radiation therapy (<10 MV) is also recommended.46-49 The use of shielding to prevent the effects of scatter radiation is not generally considered useful, however. Electrocardiographic monitoring should be considered for high-risk patients, such as those who are pacemaker dependent, and tachyarrhythmia therapy should be temporarily disabled in defibrillators. Regular in-person or remote interrogation should also be performed during radiation therapy. Finally, if the CIED generator is directly in the field of radiation therapy, device repositioning should be considered while taking into account potential risks associated with the procedure.46,48,49
Treating CV disease in patients with cancer can be quite challenging. This is especially true when managing the electrophysiologic complications of cancer therapy. SVT and AF are commonly observed in the setting of certain chemotherapeutics and stem cell transplantation; however, typical management strategies are often not possible in these patients. Similarly, QT prolongation is a frequently observed complication of chemotherapy; however, the risk of TdP is generally quite low, and cessation of therapy due to QT prolongation should be minimized. Finally, patients with CIEDs require special attention and planning to avoid complications associated with radiation therapy. It is essential for cardio-oncologists to be comfortable with these electrophysiologic issues in order to provide optimal care to patients with cancer.
- Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 2009;53:2231-47.
- Writing Group Members, Lloyd-Jones D, Adams RJ, et al. Heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation 2010;121:e46-215.
- Tonorezos ES, Stillwell EE, Calloway JJ, et al. Arrhythmias in the setting of hematopoietic cell transplants. Bone Marrow Transplant 2015;50:1212-6.
- Erichsen R, Christiansen CF, Mehnert F, Weiss NS, Baron JA, Sorensen HT. Colorectal cancer and risk of atrial fibrillation and flutter: a population-based case-control study. Intern Emerg Med 2012;7:431-8.
- Guzzetti S, Costantino G, Vernocchi A, Sada S, Fundaro C. First diagnosis of colorectal or breast cancer and prevalence of atrial fibrillation. Intern Emerg Med 2008;3:227-31.
- O'Neal WT, Lakoski SG, Qureshi W, et al. Relation between cancer and atrial fibrillation (from the REasons for Geographic And Racial Differences in Stroke Study). Am J Cardiol 2015;115:1090-4.
- Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003;108:3006-10.
- 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;10:1795-1801.
- Polk A, Vaage-Nilsen M, Vistisen K, Nielsen DL. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev 2013;39:974-84.
- Tamargo J, Caballero R, Delpon E. Cancer chemotherapy and cardiac arrhythmias: a review. Drug Saf 2015;38:129-52.
- Guglin M, Aljayeh M, Saiyad S, Ali R, Curtis AB. Introducing a new entity: chemotherapy-induced arrhythmia. Europace 2009;11:1579-86.
- Kilickap S, Barista I, Akgul E, Aytemir K, Aksoy S, Tekuzman G. Early and late arrhythmogenic effects of doxorubicin. South Med J 2007;100:262-5.
- Binah O, Cohen IS, Rosen MR. The effects of adriamycin on normal and ouabain-toxic canine Purkinje and ventricular muscle fibers. Circ Res 1983;53:655-62.
- Gorelik J, Vodyanoy I, Shevchuk AI, Diakonov IA, Lab MJ, Korchev YE. Esmolol is antiarrhythmic in doxorubicin-induced arrhythmia in cultured cardiomyocytes - determination by novel rapid cardiomyocyte assay. FEBS Lett 2003;548:74-8.
- Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005;353:172-87.
- 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.
- Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369:507-16.
- 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.
- McMullen JR, Boey EJ, Ooi JY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood 2014;124:3829-30.
- Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370:997-1007.
- Gopal AK, Kahl BS, de Vos S, et al. PI3K δ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014;370:1008-18.
- Lannutti BJ, Meadows 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.
- Byrd JC, Harrington B, O'Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374:323-32.
- Peres E, Levine JE, Khaled YA, et al. Cardiac complications in patients undergoing a reduced-intensity conditioning hematopoietic stem cell transplantation. Bone Marrow Transplant 2010;45:149-52.
- Singla A, Hogan WJ, Ansell SM, et al. Incidence of supraventricular arrhythmias during autologous peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2013;19:1233-7.
- Feliz V, Saiyad S, Ramarao SM, Khan H, Leonelli F, Guglin M. Melphalan-induced supraventricular tachycardia: incidence and risk factors. Clin Cardiol 2011;34:356-9.
- Naing A, Veasey-Rodrigues H, Hong DS, et al. Electrocardiograms (ECGs) in phase I anticancer drug development: the MD Anderson Cancer Center experience with 8518 ECGs. Ann Oncol 2012;23:2960-3.
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- Curigliano G, Spitaleri G, Fingert HJ, et al. Drug-induced QTc interval prolongation: a proposal towards an efficient and safe anticancer drug development. Eur J Cancer 2008;44:494-500.
- Curigliano G, Spitaleri G, de Braud F, et al. QTc prolongation assessment in anticancer drug development: clinical and methodological issues. Ecancermedicalscience 2009;3:130.
- Fradley MG, Moslehi J. QT prolongation and oncology drug development. Card Electrophysiol Clin 2015;7:341-55.
- 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;4:131ra150.
- 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.
- Barbey JT. Cardiac toxicity of arsenic trioxide. Blood. 2001;98:1632.
- Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval). Drug Saf 2013;36:295-316.
- 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:e30353.
- Locatelli M, Criscitiello C, Esposito A, et al. QTc prolongation induced by targeted biotherapies used in clinical practice and under investigation: a comprehensive review. Target Oncol 2015;10:27-43.
- Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:2542-51.
- 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;112:516-8.
- Crossley GH, Poole JE, Rozner MA, et al. The Heart Rhythm Society (HRS)/American Society of Anesthesiologists (ASA) Expert Consensus Statement on the perioperative management of patients with implantable defibrillators, pacemakers and arrhythmia monitors: facilities and patient management this document was developed as a joint project with the American Society of Anesthesiologists (ASA), and in collaboration with the American Heart Association (AHA), and the Society of Thoracic Surgeons (STS). Heart Rhythm 2011;8:1114-54.
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Keywords: Action Potentials, Anemia, Anthracyclines, Anti-Bacterial Agents, Antiemetics, Antimetabolites, Arsenicals, Atrial Fibrillation, Breast Neoplasms, Cardiomyopathies, Cardiotoxicity, Chronic Disease, Colon, Coronary Vasospasm, Death, Sudden, Cardiac, Defibrillators, Drug Repositioning, Electromagnetic Phenomena, Fluorouracil, Head and Neck Neoplasms, Heart Failure, Heart Rate, Inflammation, Intensive Care Units, Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Promyelocytic, Acute, Lymphoma, Mantle-Cell, Magnesium, Melphalan, Myocytes, Cardiac, Phosphatidylinositol 3-Kinases, Piperidines, Potassium, Potassium Channels, Protein Kinases, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Purkinje Fibers, Pyrazoles, Pyrimidines, Quinazolines, Risk Factors, Risk Reduction Behavior, Stem Cell Transplantation, Stroke, Tachycardia, Supraventricular, Thrombocytopenia, Thyroid Neoplasms, Torsades de Pointes, Ventricular Dysfunction, Left, Waldenstrom Macroglobulinemia
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