Cardiotoxicity Incidence and Impact

Cancer survival rates have improved significantly in recent decades due to advancement in detection and treatment. For example, breast-cancer-specific mortality decreased by 24% between 1990 and 2000,¹ and mortality rates for non-Hodgkin's lymphoma and leukemia fell by 2.5% and 1% each year, respectively, from 2003 to 2012.² Similarly, the mortality for childhood cancers has declined more than 50% between 1975 and 1977 to the current era.² Unfortunately, many of the drugs used to treat cancer can cause cardiac complications that could alter quality of life and decrease lifespan. Cardiovascular disease is the major competing cause of mortality now in elderly women diagnosed with breast cancer, with a 30% increased standardised incidence ratio of cardiovascular events, particularly heart failure (HF).³ Although the reason for this is multifactorial and includes decreased physical activity, radiotherapy, and increased ischemic heart disease due to vascular risk factors, it is thought to be at least partially driven by the direct cardiotoxic effects of chemotherapy agents.⁴

Although cardiotoxicity from cancer therapy can include coronary artery disease, cardiac arrhythmias, conduction abnormalities, and HF, the largest controversy is in the definition of cancer-therapy-related cardiomyopathy and HF. This article focuses on the latter. Drugs most commonly associated with HF include the anthracyclines and, to a lesser degree, biologic agents such as epidermal growth factor receptor inhibitors.⁵ The true incidence of cardiomyopathy and HF from cancer therapy is difficult to define and varies depending on the cancer treatment regimen, doses, and whether the data are from clinical trials or cohort studies. Although clinical trials are not representative of routine clinical practice, there has been concern that incidences from cohort studies are an overestimate. In the modern era, with restrictions on maximal anthracycline dose and careful cardiac monitoring, overt clinical HF and cardiac death occur in <2.5% of treated patients.⁶ However, a significant proportion of patients experience asymptomatic deterioration in left ventricular ejection fraction (LVEF) (5.1-18.6%),^7-10 which in the context of cardiotoxicity is associated with a higher incidence of cardiac events at follow-up.^11,12 We also know from the Framingham cohort¹³ and more recent data¹⁴ that mild left ventricular systolic dysfunction itself is associated with a 4.6- to 4.8-fold higher risk of subsequent symptomatic HF and a 1.6-fold higher risk of mortality.

Types of Cardiotoxicity

Suter and Ewer^15,16 proposed a pathophysiological system to identify drugs that have the potential for irreversible (type I) cardiac damage, such as anthracyclines, versus reversible (type II) cardiac damage, such as monoclonal antibodies. This proposed strategy was based on retrospective analysis of patients with cancer with HF after chemotherapy. Despite there being some molecular basis for these distinctions,^16-18 this concept is controversial. Recent work from Cardinale et al.¹¹ demonstrated that initiation of cardioprotective medications after a traditional diagnosis of type I anthracycline cardiotoxicity was associated with at least partial recovery of cardiac function in 82% of patients followed prospectively. Several sources have also called into question the reversibility of type II trastuzumab-induced cardiotoxicity, with prospective and retrospective data showing a significant portion of these patients having sustained decrements in LVEF.^19-21

Ejection-Fraction-Based Diagnosis of Cardiotoxicity

Definition of Cardiotoxicity

The definition of cardiotoxicity has significant practical implications for how patients are managed. Unfortunately, there is no universal definition of cardiotoxicity. The definitions used in the clinical trials differ, but all thematically define cardiotoxicity by a serial decline in LVEF. Various organizations have defined cardiotoxicity differently using different threshold changes in LVEF (Table 1).

Table 1: Definitions of Cardiotoxicity

	Definition	Modality of Measurement	Chemotherapy Agents	Comments
Alexander et al.22	Mild: Decline in LVEF > 10% Moderate: Decline in LVEF > 15% to final LVEF < 45% Severe: congestive HF	Multigated acquisition (MUGA) scan	Anthracycline
Schwartz et al.23	Decline in LVEF > 10% to final LVEF < 50%	MUGA scan	Anthracycline
Cardiac Review and Evaluation Committee24	1. Cardiomyopathy characterized by a decrease in LVEF globally or more severe in the septum 2. Sign and symptoms of HF 3. Decline of EF ≥5% to final ejection fraction < 55% with symptoms of congestive HF 4. Asymptomatic decline of LVEF ≥ 10% to final ejection fraction < 55%	MUGA scan and echocardiogram	Trastuzumab +/- Anthracycline
Common Terminology Criteria for Adverse Events, version 4.03 ( HF, left ventricular dysfunction)56		Not defined	N/A	Other definitions included such as troponin and clinical HF
American Society of Echocardiography and European Association of Cardiovascular Imaging24	≥10% decline in LVEF to final LVEF < 53% (suggests repeat imaging)	Echocardiography; two-dimensional (2D) and three-dimensional (3D) contrast, cardiac magnetic resonance imaging, MUGA scan	N/A	First guideline to include global longitudinal strain >15%

The earliest definition of cardiotoxicity during cancer treatment is from the work by Alexander et al.²² in which moderate cardiotoxicity due to doxorubicin was defined as a >15% fall in LVEF to <45% using serial MUGA scans. The largest MUGA-based study to date defined cardiotoxicity from anthracyclines as a >10% fall in LVEF to <50%.²³ Subsequently, during the review of trastuzumab treatment trials, the Cardiac Review and Evaluation Committee²⁴ defined cardiotoxicity as an asymptomatic reduction in LVEF by ≥10% or a symptomatic reduction of ≥5% to <55% (Table 1). More recently, the American Society of Echocardiography Consensus document defined cardiotoxicity as an LVEF drop ≥10% to a value of <53%.²⁵ Despite the common thread of sequential screening via cardiac imaging studies to identify cardiotoxicity, it is not clear which of these definitions should be adopted or whether one is more specific than the other for future development of clinical HF. Also, the frequency of cardiac screening during cancer treatment is not clear. The European Society for Medical Oncology working guidelines group,²⁶ the American Society of Echocardiography,²⁵ and the UK National Cancer Research Institute²⁷ do offer flow charts and recommendations to direct screening, but these are not evidenced based and not universally adopted.²⁸ The need for baseline cardiac assessment including assessment of LVEF prior to the initiation of potentially cardiotoxic chemotherapy is similarly controversial. Although the European Society for Medical Oncology²⁶ and the American Society of Echocardiography²⁵ would recommend basal evaluation of cardiac function prior to initiation, it is far from a universal practice. This is especially true prior to the initiation of anthracycline-based chemotherapy and less so with trastuzumab-based therapy where regional funding issues may drive increased rates of basal LVEF assessment.

Method of Detection of Cardiotoxicity

There is also controversy regarding the best method to follow LVEF during cancer treatment (Table 2). It is important that the diagnostic modality used has the accuracy and reproducibility to reliably identify a true change in LVEF. MUGA scan is one potential modality for screening. It has a low inter- and intra-observer variability (<5%), and the values obtained correlate well with cardiac magnetic resonance imaging (CMRI) and 3D echocardiography.^23,29-30 The disadvantage of MUGA is the potential for repeat exposure to 5-10 mSv of radiation at each time point.³¹ However, whether this level of radiation exposure is clinically significant is controversial for effective doses of <100 mSv, with many debating the concept of cumulative biologic effects of multiple low-dose exposures (linear no-threshold relationship).^32,33

Table 2: Utility of Methods for Assessment of Cardiotoxicity

	2D Echocardio-graphy	3D Echocardio-graphy	Global Longitudinal Strain	MUGA	CMRI	Troponin I
Cost	Low	Low	Low	Medium	Medium	Very low
Availability	++++	+++	+++	+++	++	+++
Reproducibility*	++	+++	+++	+++	++++	++++
Radiation	Nil	Nil	Nil	5-10 mSv	Nil	Nil
Detection of subclinical toxicity	Low	Low	High	Low	Medium	High
Additional diagnostic utility	Structural information, valvular heart disease, pericardial disease, diastolic function				Tissue characterization, pericardial disease	Has high negative predictive value when combined with global longitudinal strain.
* Inter/intra observer variability

Echocardiography has gained popularity as a technique to serially follow patients during chemotherapy. 3D echocardiography is more accurate and reproducible than 2D echocardiography for the measurement of LVEF and has the best temporal reproducibility during cancer therapy.^34-37 The latter is particularly important given the fact that LVEF changes as small as 10% are commonly used to define cardiotoxicity. If 2D techniques are used, careful attention to image acquisition and post-processing along with liberal use of contrast agents can help improve reproducibility.

CMRI is widely considered the reference method for measurement of left ventricular volumes and LVEF. There is currently very limited work on the routine use of CMRI for cardiotoxicity screening.^38,39 However, previous work has demonstrated that CMRI may be better able to identify small changes in LVEF during treatment.^40,41 At present, perhaps the best use of CMRI is when image quality is suboptimal or when there are discrepancies in the degree of fall in LVEF between different modalities. Unfortunately, measurements of LVEF via different imaging modalities are not interchangeable.^29,30,42 For this reason, it is suggested that serial comparisons over time be made with the same modality using the technique with the greatest experience and best reproducibility at each center.

Screening in Survivors

There is also controversy about the best approach to screening cancer survivors for cardiovascular complications. There is a lack of evidence-based recommendations on appropriate timing of screening (or the criteria to define cardiotoxicity). Although the European Society for Medical Oncology guidelines²⁶ provide recommendations for long-term cardiac screening and the Children's Oncology Group⁴³ makes some recommendations in childhood cancer survivors, the American Society of Clinical Oncology Cancer Survivorship Expert Panel deemed the lack of evidence from prospective sources insufficient to support practice guidelines to direct screening.⁴⁴ The best cardiac imaging method to identify cardiotoxicity in survivors is also not clear. In pediatric cancer survivors, Armstrong⁴⁵ found a high correlation between CMRI and 3D echocardiography but demonstrated that both 2D and 3D echocardiography have reduced sensitivity to identify LVEF < 50%. There is a developing interest in using myocardial strain measurements to identify subclinical left ventricular dysfunction; however, the type of strain measure, the threshold values, and the clinical relevance of these findings is unknown.^46-51

Myocardial-Strain-Based Diagnosis of Cardiotoxicity

The measurement of LVEF is a relatively insensitive tool for the diagnosis of cardiotoxicity during the early stage, when therapeutic interventions may have their largest impact. This is because the myocardium may be able to tolerate significant damage before exhaustion of the compensatory mechanism, resulting in overt systolic dysfunction. Myocardial strain, which measures myocardial deformation, has been considered as a potential measure to identify early subclinical myocardial injury (i.e., myocardial changes prior to a fall in LVEF or symptomatic HF).

A recent systematic review⁴⁶ reported the sensitivity and specificity of early reduction in deformation indices such as strain and strain rate for the prediction of subsequent reduction in LVEF or development of HF. The most studied parameter to identify subclinical injury during cancer treatment is global longitudinal strain. The degree of change in strain that predicts later cardiotoxicity differs between studies and varies between 10 and 15%.⁴⁶ Early studies demonstrated that relative reduction in global longitudinal strain of 10-11% at 3 or 6 months during treatment predicts subsequent cardiotoxicity in women treated with trastuzumab with or without anthracyclines for breast cancer.⁵² An absolute global longitudinal strain value of <20.5% at 6 months during trastuzumab therapy in women with breast cancer⁵² and <19% at 3 months in women treated with anthracyclines followed by trastuzumab has also been shown to predict cardiotoxicity.⁵³ However, due to variability in strain measurements, differences in strain values between vendors, and analysis software, serial measurements of global longitudinal strain appear to be more useful for predicting early cardiotoxicity. The American Society of Echocardiography is the first society to suggest a threshold change in global longitudinal strain by >15% during cancer treatment to define cardiotoxicity;²⁵ however, this threshold is different from those identified in several published studies.⁴⁶ Therefore, the most specific threshold to identify subclinical myocardial injury remains controversial. Furthermore, it is also not evident whether interventions based on isolated falls in myocardial strain prevent subsequent left ventricular dysfunction or HF. A multi-centre, randomized controlled trial (SUCCOUR [Strain Surveillance During Chemotherapy for Improving Cardiovascular Outcomes], trial ID: ACTRN12614000341628) is currently investigating this approach.

Serum Biomarker-Based Diagnosis of Cardiotoxicity

Multiple studies have shown that measurement of troponin I after initiation of chemotherapy has utility in predicting occurrence and severity of cardiotoxicity in both patients treated with anthracyclines¹² and patients on combined chemotherapy regimens that include trastuzumab.^19,54

Sawaya et al. has shown that a significant increase in troponin I (>30 ng/mL) among patients with HER-2-positive breast cancer treated with sequential anthracycline with trastuzumab was predictive of subsequent cardiotoxicity. Interestingly, the study also found that when combined with global longitudinal strain, troponin I measurements had a negative predictive value of 91% for the future development of cardiotoxicity.⁵³ More pronounced cardiotoxicity appears to be associated with both the earlier rise in troponin (within 72 hours) and persisting troponin positivity (persisting up to 1 month post-treatment has an 85% sensitivity for development of major cardiac events). In addition, a persistent absence of troponin release has a 99% negative predictive value for cardiotoxicity.^12,55

Despite the above, the literature has not clearly defined the optimal troponin assay to use, the threshold for risk prediction, the timing of measurements in relationship to chemotherapy, or troponin's prognostic utility with biologic agents whose presumptive mechanism of cardiotoxicity may not result from cell death. The 2012 European Society for Medical Oncology guidelines²⁶ recommended troponin testing at baseline and after each chemotherapy session (level of evidence III). The 2014 American Society of Echocardiography²⁵ guidelines recommend baseline troponin at the initiation of both type I and type II chemotherapy agents and the measurement of troponin before and 24 hours after each chemotherapy cycle to aid in detection of subclinical cardiotoxicity. Ultimately, given their reproducibility and relative lack of expense, cardiac biomarkers may become an important part of the diagnostic armamentarium for cardiotoxicity when their utility is better defined.

Conclusion

Multiple controversies exist in the definition of cardiotoxicity related to cancer therapy. A universal definition of cardiotoxicity with established prognostic value is needed. The optimal timing of screening during cancer therapy and in survivors and the best modality to identify reduction in ventricular function will need to be established. With growing interest in the use of myocardial strain to identify subclinical myocardial injury, a threshold change that has prognostic value will need to be defined. Whether interventions based on a change in strain alters prognosis will need to be defined. Although serum biomarkers may be ideal to detect early cardiac injury, the timing of measurements, the assays to use, and the prognostic implication of biomarker-based intervention will need to be established. In an era when cancer therapy is extremely effective and survivorship issues are considered even at the start of cancer therapy, it is prudent for oncologists and cardiologists to work together to resolve the controversies in the diagnosis of cardiotoxicity. This is required prior to consideration of interventions that can minimize or eliminate the risk of cardiac disease in cancer survivors.

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Keywords: Cardiotoxicity, Anthracyclines, Antibodies, Monoclonal, Arrhythmias, Cardiac, Biological Factors, Biological Products, Breast Neoplasms, Cardiomyopathies, Cell Death, Cohort Studies, Coronary Artery Disease, Doxorubicin, Echocardiography, Echocardiography, Three-Dimensional, Heart Diseases, Heart Failure, Heart Valve Diseases, Leukemia, Lymphoma, Non-Hodgkin, Magnetic Resonance Imaging, Medical Oncology, Myocardium, Receptor, Epidermal Growth Factor, Receptor, ErbB-2, Risk Factors, Stroke Volume, Survival Rate, Troponin I, Ventricular Dysfunction, Left, Ventricular Function

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