Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia

Abstract

Remarkable progress has been made in the development of new therapies for cancer, dramatically changing the landscape of treatment approaches for several malignancies and continuing to increase patient survival. Accordingly, adverse effects of cancer therapies that interfere with the continuation of best-possible care, induce life-threatening risks or lead to long-term morbidity are gaining increasing importance. Cardiovascular toxic effects of cancer therapeutics and radiation therapy are the epitome of such concerns, and proper knowledge, interpretation and management are needed and have to be placed within the context of the overall care of individual patients with cancer. Furthermore, the cardiotoxicity spectrum has broadened to include myocarditis with immune checkpoint inhibitors and cardiac dysfunction in the setting of cytokine release syndrome with chimeric antigen receptor T cell therapy. An increase in the incidence of arrhythmias related to inflammation such as atrial fibrillation can also be expected, in addition to the broadening set of cancer therapeutics that can induce prolongation of the corrected QT interval. Therefore, cardiologists of today have to be familiar not only with the cardiotoxicity associated with traditional cancer therapies, such as anthracycline, trastuzumab or radiation therapy, but even more so with an ever-increasing repertoire of therapeutics. This Review provides this information, summarizing the latest developments at the juncture of cardiology, oncology and haematology.

Fig. 1 |. Outline of cardiovascular toxic effects associated with cancer therapies.

Numerous cancer therapies have been associated with adverse effects and complications across the entirety of the cardiovascular system. As illustrated, some therapies have a very confined and others have a very broad cardiovascular toxicity profile. Classic chemical compounds are shown in blue, targeted therapies are shown in pink, immunotherapies are shown in purple and radiation therapy is shown in green. CAR, chimeric antigen receptor; HDAC, histone deacetylase; MEK, MAPK/ERK kinase; mTOR, mechanistic target of rapamycin; VEGF, vascular endothelial growth factor.

Fig. 2 |. Timeline of cancer therapy development.

The timeline presents landmarks in the development of cancer therapeutics. Three main eras can be distinguished on the basis of the type of agent: classic chemical compounds (shown in blue), targeted therapies (shown in pink) and immunotherapies (shown in purple). ACT, adoptive T cell therapy; ALL, acute lymphoblastic leukaemia; BCG, bacillus Calmette–Guérin; CAR, chimeric antigen receptor; CDK, cyclin-dependent kinase; CTLA4, cytotoxic T lymphocyte antigen 4; HDAC, histone deacetylase; HL, Hodgkin lymphoma; HPV, human papillomavirus; ICI, immune checkpoint inhibitor; MART1, melanoma antigen recognized by T cells 1; mTOR, mechanistic target of rapamycin; NHL, non-Hodgkin lymphoma; PD1, programmed cell death 1; TCR, T cell receptor.

Fig. 3 |. Main elements in the treatment of patients with cancer and atrial fibrillation.

In patients with cancer, predisposing conditions for atrial fibrillation should be identified and addressed if possible. These include common risk factors for atrial fibrillation such as old age (>60 years), valvular heart disease, hypertension, obstructive sleep apnoea, chronic kidney disease, diabetes mellitus and smoking. Cancer therapies that have been associated with the risk of atrial fibrillation are listed in TABLE 4 and include chemical compounds such as melphalan, targeted agents such as the tyrosine kinase inhibitor (TKI) ibrutinib and immunotherapies that increase inflammation and cytokine production such as immune checkpoint inhibitor and chimeric antigen receptor (CAR) T cell therapies. Various other factors are important in patients with cancer, including metabolic (such as hyperthyroidism) and electrolyte abnormalities, autonomic nervous system stimulation (pain or stress), cardiac infiltration or pericarditis and/or pericardial effusion. These predisposing factors can contribute to morbidity and death in patients with cancer. Atrial fibrillation symptoms include palpitations, chest discomfort and dyspnoea. Atrial fibrillation can lead to thromboembolism, myocardial ischaemia and heart failure. To reduce symptoms and the risk of complications, the decisions have to be made whether interventions should be pursued and what they should be. However, risk scores to guide decisions regarding anticoagulation have not been validated for patients with cancer. Similarly, results from landmark randomized clinical trials (RCTs) involving patients with atrial fibrillation cannot be easily translated to patients with cancer. ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; LAA, left atrial appendage; NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist.