Cardio-Oncology: From an Electrophysiology Perspective

Cardio-oncology is a rapidly growing field that focuses on the surveillance, prevention, early diagnosis, and management of the cardiotoxicities associated with anti-cancer therapies. Cancer-related therapies can have a wide range of cardiovascular effects that often demand close collaboration between the cardiologist and oncologist, with the goal of preventing or minimizing the cessation of anti-cancer therapy. The cardiovascular consequences of cancer-related therapies include many important electrophysiologic concerns, including conduction system disease, QT prolongation, and ventricular and atrial arrhythmias. This article will provide an overview of some of the key electrophysiologic considerations in the world of cardio-oncology.

Conduction system disease in the form of bradycardia and heart block can be due to a variety of mechanisms in the cancer population. Myocardial fibrosis from old age, radiation therapy, or cardiac amyloidosis can all cause conduction system abnormalities. Several chemotherapy agents have been implicated in the development of conduction system disease. Paclitaxel, an anti-microtubule agent used in the treatment of a wide variety of solid tumors, has been found to cause asymptomatic bradycardia in the range of 0.1-31% of patients, and can cause first-degree AV block in about 25% of patients.¹ It has been proposed that paclitaxel has this effect via interaction with the Purkinje system and extracardiac autonomic control.² The bradycardia associated with paclitaxel is oftentimes not associated with clinical symptoms. 

Thalidomide is another antineoplastic agent associated with bradycardia. In a post-marketing surveillance study of 10,450 patients, bradycardia developed in 0.12%.³ Of 669 patients pretreated with intensive melphalan-based chemotherapy and autologous hematopoietic stem cell transplantation, 12% of the patients randomized to thalidomide experienced bradycardia and syncope, with one-third of those patients eventually receiving permanent pacemakers.⁴ The mechanism behind this interaction is not completely understood. It has been proposed that thalidomide causes bradycardia through central nervous system effects and/or activation of the vasovagal nervous pathway. The bradycardia associated with thalidomide typically resolves with dose adjustment or holding additional therapy. 

Fluorouracil (5FU) and capecitabine, the oral prodrug of 5FU, are most commonly known to cause chest pain, ischemia, and vasospasm; however, there can also be significant symptomatic bradycardia requiring pacemaker placement in order to continue therapy.⁵ 

The small molecule tyrosine kinase inhibitors (TKI) comprise a class of agents that block mutated or overactive protein kinases. These agents have dramatically improved the treatment of many different cancers, but they can also cause various cardiotoxicities by off-target effects on other tissues, including myocardial cells that share similar signaling pathways with the intended target. Alectinib is a new TKI given in metastatic non-small cell lung cancer and is frequently associated with bradycardia in 5%.⁶ Bradycardia is generally asymptomatic, exposure-dependent, and responds to withholding treatment and dose reduction.⁶

Immune checkpoint inhibitors (ICI) are a new class of anti-cancer therapy that cause an antitumor immune response. Their widespread use in multiple cancer types will lead to a greater recognition of cardiotoxicities. Early reports in patients with melanoma, who had received combination immunotherapy and developed fatal myocarditis, were found to have significant electrical instability manifesting as complete heart block and ventricular tachycardia.⁷ In less severe cases of ICI cardiotoxicity, arrhythmias and new mild conduction abnormalities were noted on the ECG.⁸

A prolonged QTc interval, defined as greater than 460 ms in women and 450 ms in men, increases the risk for malignant tachyarrhythmias, such as Torsades de pointes and sudden cardiac death. An estimated 10-36% of oncology patients⁹ have prolonged QTc intervals. For this reason, the Fridericia formula (QT/³√RR) is often used to calculate the corrected QT interval in the cancer population, rather than the more commonly used Bazett’s formula (QT/√RR).¹⁰ QT prolongation in the field of oncology is likely due to several reasons. First, cancer is generally an age-related disease, and increased age is associated with prolonged QT. Second, cancer patients are often highly comorbid, and may have other cardiovascular diseases including structural heart disease or coronary artery disease, which can lead to subendocardial ischemia and cause QT prolongation. Furthermore, cancer patients are particularly prone to QT prolongation as they are oftentimes on QT prolonging agents such as antiemetics, antifungals, and antibiotics. Additionally, cancer patients often experience nausea, vomiting, poor oral intake, and diarrhea, which can lead to significant electrolyte disturbances and further QT prolongation. 

Many chemotherapy agents have been found to prolong the QT interval as well. Arsenic trioxide is an agent used to treat relapsed or refractory acute promyelocytic leukemia and has been found to cause QT prolongation, with a reported incidence of 26-93% in study populations.¹¹ The QT prolongation associated with arsenic trioxide can lead to the development of life-threatening ventricular tachyarrhythmias in up to 30% of individuals.¹¹ Thus, close surveillance of the QT interval is needed for individuals treated with arsenic trioxide. Those patients whose QT interval prolongs should promptly be hospitalized for continuous telemetry monitoring and electrolyte replenishment, if needed. The drug should be discontinued until the QT interval returns to normal. Most QT interval prolongation associated with arsenic trioxide occurs one to five weeks after infusion, with normalization of the QT interval before week eight, which is when the next round of therapy is typically given.  

Several TKIs have also been found to prolong the QT interval, likely through the inhibition of the phosphoinositide 3-kinase (PI3K) signaling pathway, which affects multiple cardiac ion currents.⁹ The QT prolongation associated with most TKIs are relatively mild, with a very low incidence of Torsades de pointes and sudden cardiac death. 

Atrial arrhythmias such as atrial fibrillation (AFib) and supraventricular tachycardia (SVT) are another frequently described complication of chemotherapy. Anthracyclines are well-established anti-cancer agents used in the treatment of a wide variety of both solid and liquid cancers. Although left ventricular dysfunction and cardiomyopathy are the most widely known and researched cardiotoxicities associated with these agents, AFib has also been observed independent of these cardiotoxicities, with rates as high as 10.3%.⁹ Ibrutinib is a TKI that is used in the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia.¹² It is associated with elevated rates of both AFib and SVT, with an estimated incidence in the range of 6-16% across published studies. Ibrutinib targets Bruton’s tyrosine kinase, which can interfere with P13K-AKT signaling.¹³ In addition, there are several risk factors associated with ibrutinib-associated AFib, including older age, hypertension, coronary artery disease, systolic or diastolic heart failure, moderate or greater mitral regurgitation, and left atrial abnormality on ECG.¹³ Therefore, there is likely a two-hit mechanism for the development of AFib on ibrutinib, including both the inhibition of PI3K-AKT signaling and underlying structural heart disease.¹³

Atrial arrhythmias can also be seen at the time of stem cell transplantation, with rates of SVT and AFib in the 8-10% range.¹⁴ Those individuals who receive melphalan as preconditioning treatment are particularly susceptible to these arrhythmias, with one study noting that 11% of these individuals developed AFib.¹⁵ The decision to anticoagulate individuals for AFib often requires a careful risk-benefit calculus. Although cancer patients with AFib are at increased stroke risk due to advanced age and other comorbidities, they are also at higher risk of bleeding due to thrombocytopenia or platelet dysfunction, kidney disease, or critical illness. Thus, a shared decision between patient and provider regarding the appropriateness and safety of anticoagulation therapy is essential. There is now greater recognition of differences in AFib management in patients with and without cancer. Patients with cancer and AFib are less likely to see a cardiologist and fill an anticoagulation prescription. Those who do see a cardiologist have a reduced risk of stroke.¹⁶

Radiation therapy can be problematic in individuals with implantable pacemakers and defibrillators, particularly if the electronic device is in the radiation field, as is the case for thoracic malignancies such as lung or breast cancer.¹⁷ The most commonly observed effects of radiation therapy on implantable devices include temporarily increasing pacing and sensor rates, device resets, and/or safety mode reversions.¹² The majority of complications occur from high-energy beams greater than 10 MV, with a reported device malfunction rate of >7% at these levels.¹⁷ 

The field of oncology continues to expand as we identify new targets in the treatment of cancer. With the development of new therapeutic agents, it is reasonable to expect the field of cardio-oncology to grow as well. With a knowledge and understanding of the potential electrophysiologic consequences of cancer-related therapies, we can ensure that patients receive optimal therapy for their cancer.

Disclosures: The authors have no conflicts of interest to report regarding the content herein.   

References

1. Arbuck SG, Strauss H, Rowinsky E, et al. A reassessment of cardiac toxicity associated with Taxol. J Natl Cancer Inst Monogr. 1993;15:117-130.
2. McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med. 1989;111(4):273-279.
3. Clark TE, Edom N, Larson J, Lindsey LJ. Thalomid (Thalidomide) capsules: a review of the first 18 months of spontaneous postmarketing adverse event surveillance, including off-label prescribing. Drug Saf. 2001;24(2):87-117.
4. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354(10):1021-1030.
5. Ang C, Kornbluth M, Thirlwell MP, Rajan RD. Capecitabine-induced cardiotoxicity: case report and review of literature. Curr Oncol. 2010;17(1):59-63.
6. Morcos PN, Bogman K, Hubeaux S, et al. Effect of alectinib on cardiac electrophysiology: results from intensive electrocardiogram monitoring from the pivotal phase II NP28761 and NP28673 studies. Cancer Chemother Pharmacol. 2017;79(3):559-568.
7. Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med. 2016;375:1749-1755.
8. Lyon AR, Yousaf N, Battisti NM, Moslehi J, Larkin J. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol. 2018;19:e447-e458.
9. Tamargo J, Caballero R, Delpón E. Cancer chemotherapy and cardiac arrhythmias: a review. Drug Saf. 2015;38(2):129-152.
10. Fradley MG, Moslehi J. QT Prolongation and Oncology Drug Development. Card Electrophysiol Clin. 2015;7(2):341-355.
11. Barbey JT, Pezzullo JC, Soignet SL. Effect of arsenic trioxide on QT interval in patients with advanced malignancies. J Clin Oncol. 2003;21(19):3609-3615.
12. Fradley MG. Electrophysiologic Considerations of Cardio-Oncology. American College of Cardiology. Published June 7, 2016 Available at https://bit.ly/2PnkdCp. Accessed November 12, 2018.
13. Lentz R, Feinglass J, Ma S, Akhter N. Risk Factors for the Development of Atrial Fibrillation on Ibrutinib. Leuk Lymphoma. 2018. (manuscript accepted)
14. 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(1):149-152.
15. 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):356-359.
16. O’Neal WT, Claxton JS, Sandesara PB, et al. Provider Specialty, Anticoagulation, and Stroke Risk in Patients with Atrial Fibrillation and Cancer. J Am Coll Cardiol. 2018;72(16):1913-1922.
17. Gomez DR, Poenisch F, Pinnix CC, et al. Malfunctions of implantable cardiac devices in patients receiving proton beam therapy: incidence and predictors. Int J Radiat Oncol Biol Phys. 2013;87(3):570-575.