Introduction

Cardiotoxicity, specifically heart failure (HF) or cardiomyopathy, is a recognized adverse effect associated with various cancer therapies. Reports of cardiotoxicity from anthracyclines and radiation therapy have been described for several decades. The recent proliferation of targeted anticancer therapies has led to a rise in the incidence of unanticipated cardiotoxicity caused by both on-target and off-target effects. The potential impact of cardiotoxicity on health care costs and health outcomes is significant not only because of its obvious effects on cardiac function and prognosis, but also because it can interfere with the delivery of curative cancer treatment and thus also reduce cancer-related quality of life and survival.

As the efficacy of cancer treatment continues to improve, more patients with cancer are surviving longer and are exposed to the potential late cardiovascular effects of cancer therapy. Significant resources have been devoted to identifying novel methods for risk stratification and early detection of subclinical cardiotoxicity. For example, baseline and/or serial cardiac testing with 12-lead electrocardiograms and/or transthoracic echocardiograms are currently standard of care for cardiotoxicity monitoring in patients treated with certain cardiotoxic therapies. However, the value of cardiotoxicity monitoring has been questioned given uncertainty over the efficacy of this practice. Here we briefly summarize the limited data on the subject and identify gaps in our understanding of the cost-effectiveness of cardiotoxicity monitoring.

Benefits and Risks of Monitoring for Cardiomyopathy and/or HF

Clinical practice recommendations and guidelines have been proposed by cardiology and oncology professional organizations for cardiotoxicity monitoring during and after cancer treatment; these are summarized in Table 1. Despite the widespread use of left ventricular ejection fraction (LVEF) assessment for cardiotoxicity monitoring, cost-effectiveness analysis is limited by the surprising lack of effectiveness data on routine cardiac imaging in patients with cancer.¹ Several recent studies have investigated whether a baseline LVEF is necessary in all patients prior to receiving anthracycline chemotherapy. Retrospective studies of both children and adults treated with anthracyclines have shown that a baseline LVEF assessment infrequently leads to changes in the cancer treatment regimen.^2-5 However, a study by Wang et al. of over 5,000 patients receiving anthracycline-based chemotherapy suggests that LVEF at baseline is predictive of major adverse cardiac events, including symptomatic HF and cardiac death.⁶

Table 1: Current Recommendations for Cardiotoxicity Monitoring

OrganizationRef	Population	Modality of Monitoring	Frequency of Imaging
American Society of Echocardiography and European Association of Cardiovascular Imaging7	Patients treated with cardiotoxic therapy, especially those considered to be at high risk, for example, multiple cardiovascular risk factors; preexisting left ventricular dysfunction; age >65 years; and treatment with high-dose anthracycline (>350mg/m2), trastuzumab, or certain tyrosine kinase inhibitors (e.g., vendothelial growth factor signaling pathway inhibitors such as sorafenib or sunitinib)	Echocardiogram (two-dimensional [2D], three-dimensional [3D], and stimulated), cardiac magnetic resonance imaging (CMRI) or multigated acquisition scan (MUGA) if poor quality images	Baseline assessment recommended prior to treatment. Recommended frequency of follow-up assessments is dependent on cancer treatment agent and dose.
American Society of Echocardiography and European Association of Cardiovascular Imaging8	Patients with prior radiotherapy exposure to cardiac structures	Echocardiogram, with follow-up CMRI or computed tomography (CT) as indicated; stress echocardiogram or CMRI for noninvasive assessment of coronary artery disease preferred over radionuclide imaging	Baseline echocardiogram before initiating radiotherapy. Screening echocardiogram 10 years after radiotherapy or 5 years after radiotherapy in high-risk patients. Noninvasive stress imaging 5-10 years after radiotherapy. Subsequent reassessment should be performed every 5 years.
Children's Oncology Group Long-Term Follow-up Guidelines9	Childhood, adolescent, or young adult cancer survivors treated with anthracyclines or radiation to cardiac structures	Echocardiogram	Baseline at entry into long-term follow-up. Frequency of subsequent follow-up is based on age at treatment, anthracycline dose, and radiation dose (every 1-5 years).
National Comprehensive Cancer Network – Breast Cancer Guidelines10	Patients with breast cancer treated with trastuzumab-based regimens	LVEF assessment (modality not specified)	At baseline and during treatment (optimal frequency of monitoring unknown)
National Comprehensive Cancer Network – Survivorship Guidelines11	Patents previously treated with anthracycline therapy with ≥1 cardiovascular risk factors*	Echocardiogram (2D, Doppler)	Consider echocardiogram within 1 year after completion of anthracycline therapy
Trastuzumab prescribing information12	Patients treated with trastuzumab-based therapy	Echocardiogram or MUGA	Immediately prior to initiation of trastuzumab, every 3 months during and upon completion of trastuzumab, and every 6 months at least 2 years following completion of trastuzumab.
American Society of Clinical Oncology Practice Guidelines13	Patients treated with cardiotoxic anticancer therapies (e.g., anthracyclines, radiotherapy to cardiac structures, or trastuzumab)	Echocardiogram (preferred), CMRI or MUGA if echocardiogram is not available or technically feasible	During active cancer treatment, routine surveillance can be considered in patients at increased risk. Consider an echocardiogram 6-12 months after completion of cancer treatment.

Serial cardiac imaging performed in patients treated with cardiotoxic therapies such as trastuzumab has led to the detection of asymptomatic LVEF declines. Whether an asymptomatic LVEF decline under these circumstances is a clinically significant or actionable event, or more importantly whether it is predictive of later progression to clinical HF, remains unknown, and data on this area have been conflicting.^14-16 In a large prospective clinical trial of patients receiving anthracycline-based chemotherapy followed by trastuzumab, baseline and post-anthracycline LVEF were identified as potential risk factors for HF; after regression analysis, only baseline LVEF remained statistically significant. One proposed benefit of detecting an asymptomatic LVEF decline is that it would allow for early implementation of cardioprotective interventions (e.g., interruption of cardiotoxic therapies or initiation of cardioprotective drugs). This approach is consistent with the current HF management guidelines published by the American College of Cardiology and American Heart Association based largely on the experience in patients with hypertensive or coronary heart disease.¹⁷ On the other hand, monitoring patients solely because they are receiving cancer therapy may result in patient harm. For example, the known variability of LVEF measurements attributable to the technical limitations of each imaging modality¹⁸ could result in a patient being incorrectly classified as having cardiotoxicity. This would lead to additional time and effort needed to confirm a false-positive finding, delay treatment, or compromise the delivery of cancer therapy by favoring a safer but less efficacious regimen. Furthermore, unnecessary cardiotoxicity monitoring wastes limited healthcare resources and contributes to the rising cost of healthcare. Another example is the generally benign cardiac course of patients found to have mild abnormalities of LVEF during trastuzumab therapy. It may not be appropriate to monitor and treat their left ventricular dysfunction with the same rigor used for patients with hypertensive or coronary heart disease.

Cost-Effectiveness Analysis of Cardiotoxicity Monitoring

To address the issues outlined above, cost-effectiveness analysis is a useful method for evaluating health outcomes and resource costs for a specific health intervention and can inform clinical decisions on resource allocation to maximize the net health benefit. To date, few studies have been performed to examine the cost-effectiveness of cardiotoxicity monitoring in patients with cancer (Table 2). Early studies evaluated the cost-effectiveness of serial MUGA scans during anthracycline therapy.^19,20 More recently, the cost-effectiveness of cardiac imaging at different time intervals was the focus of two independently conducted studies in childhood cancer survivors previously treated with anthracycline chemotherapy. A study by Yeh et al. showed that screening every 2 years by echocardiography or every 5 years by CMRI in childhood cancer survivors treated with high-dose anthracyclines (>250mg/m²) or every 10 years by CMRI in childhood cancer survivors treated with low-dose anthracyclines (<250mg/m²) was cost-effective using an incremental cost-effectiveness threshold of $100,000 per quality-adjusted life-year (QALY) gained.²¹ These findings suggest that cardiac monitoring that is less frequent than currently recommended by the Children's Oncology Group guidelines may be warranted. Similarly, a study by Wong et al. concluded that decreasing the screening intervals from 1-, 2-, and 5-year intervals to 2-, 4 -5-, and 10-year intervals could maintain 80% of the health benefits at half the cost.²² The studies by Yeh and Wong and colleagues support the importance of cardiotoxicity monitoring in childhood cancer survivors to reduce the incidence of cardiovascular late-effects of cancer therapy; however, in clinical practice, the optimal frequency of monitoring is likely influenced by patient-specific variables (e.g., pre-existing cardiovascular risk profile and treatment exposures).²³

Table 2: Summary of Cost-Effectiveness Studies for Cardiotoxicity Monitoring

Study (Year)Ref	Patient Population	Monitoring Alternatives	Perspective	Conclusion
Bertoldi (2012)24	Patients with chronic myelogenous leukemia receiving imatinib	Annual echocardiogram Annual B-type natriuretic peptide, with echocardiogram only in patients with abnormal B-type natriuretic peptide No screening	Healthcare payer	Systematic screening for cardiotoxicity in patients treated with imatinib is associated with a high cost per diagnosis.
Nolan (2016)25	Patients with cancer receiving cardiotoxic chemotherapy	Cardioprotective medications after a diagnosis of LVEF-defined cardiotoxicity (i.e., asymptomatic LVEF decline by >10% to <55% or symptomatic HF) Universal cardioprotective medications for all patients at the time of chemotherapy Cardioprotective medications after a diagnosis of strain-defined cardiotoxicity (i.e., decline in global longitudinal strain of ≥11% from baseline)	Healthcare payer	Strain-guided cardioprotection provides more QALYs at lower cost than universal or LVEF-guided cardioprotection.
Shureiqi (2002)19	Patients with cancer receiving doxorubicin chemotherapy	Baseline MUGA before chemotherapy No baseline MUGA	Healthcare payer	MUGA scans are most cost-effective in patients 40 years or older who will receive a cumulative doxorubicin dose of at least 350mg/m2.
Wong (2014)22	Childhood cancer survivors	Screening per Children's Oncology Group guidelines No screening	Societal	Following Children's Oncology Group guidelines could extend life expectancy of a childhood cancer survivor by 6.1 months, increase QALYs by 1.6 months, and reduce HF risk at 30 years by 18%. However, less frequent screening than currently recommended by Children's Oncology Group guidelines maintained 80% of the health benefits at nearly half the cost.
Yeh (2014)21	Childhood cancer survivors	Echocardiogram every 1 year Echocardiogram every 2 years Echocardiogram every 5 years Echocardiogram every 10 years All patients with a positive test result receive treatment with subsequent angiotensin-converting enzyme inhibitor or beta-blocker.	Societal	Preferred cardiotoxicity monitoring strategy at a $100,000/QALY cost-effectiveness threshold: For patients receiving <250mg/m2 of anthracyclines (doxorubicin equivalent dose): CMRI every 10 years For patients receiving ≥250mg/m2 of anthracyclines (doxorubicin equivalent dose): 2D echocardiogram every 2 years or CMRI every 5 years

Other studies have focused on the cost-effectiveness of different screening modalities that incorporate conventional cardiac imaging with novel imaging or blood-based biomarkers. A study by Nolan et al. evaluated the cost-effectiveness of different strategies of cardioprotection for the prevention of chemotherapy-induced cardiotoxicity.²⁵ A Markov model was developed to compare the following three strategies:

1. Standard of care LVEF monitoring and initiation of cardioprotective medications for an overt LVEF decline
2. Universal prophylactic cardioprotective medications in all patients
3. 2D echo strain-guided management with initiation of cardioprotective medications in patients with a decline in global longitudinal strain

Findings from this study suggest that cardiotoxicity monitoring that incorporates global longitudinal strain assessment provides more QALYs at lower cost than standard of care or universal prophylactic cardioprotection.

Sensitivity analyses, which evaluate the effect of changes in the different elements of a cost-effectiveness model, were carried out for the studies detailed above and revealed that cost-effectiveness of cardiotoxicity monitoring was influenced by variability of several model inputs such as the cost and accuracy of cardiotoxicity monitoring, estimates for the incidence of cardiotoxicity, and the efficacy of treatment for cardiotoxicity. Cardiotoxicity monitoring is most useful in clinical scenarios in which the incidence of cardiotoxicity is high, the cost of monitoring is low, and the treatment for cardiotoxicity is efficacious.

Conclusion

Carefully designed cost-effectiveness studies are needed to inform the development of evidence-based practice guidelines on the optimal modality and frequency of cardiac monitoring during and after cancer treatment. However, in order to conduct informative and meaningful cost-effectiveness analyses, important gaps of knowledge need to be addressed. Lack of a universally accepted definition of cardiotoxicity has resulted in variability in the reported incidence of cardiotoxicity associated with different cancer therapies. Standardization of cardiotoxicity definitions will allow accurate ascertainment of cardiotoxicity incidence across clinical trials and cohort studies of real-world patients. More studies are also needed to investigate the effectiveness of cardiotoxicity monitoring, particularly the utility of imaging-guided interventions for improving health outcomes in cancer patients. Only then can an economic analysis be performed to accurately determine the cost-effectiveness of cardiotoxicity monitoring. In clinical scenarios in which the expected rate of cardiotoxicity is low, routine or frequent monitoring for cardiotoxicity may not be justified and is likely to result in limited clinical benefit but significant healthcare costs. Until more data are available, we suggest that clinicians broadly apply current practice guidelines or recommendations as only a general framework that must be tailored on a case-by-case basis. Clinical decisions on the optimal modality or timing of cardiac monitoring can be further individualized after considering a patient's preexisting cardiovascular risk factors, the risk of cardiotoxicity associated with the planned anticancer treatment regimen, the benefits and alternatives of the cancer care, and the risk that a false-positive result will adversely affect the treatment outcome.

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Keywords: Anthracyclines, Cardiotoxicity, Cardiotoxins, Risk Factors, Patient Harm, Stroke Volume, Pharmaceutical Preparations, Cardiovascular Diseases, Echocardiography, Ventricular Dysfunction, Left, Cardiomyopathies, Heart Failure, Coronary Disease, Electrocardiography, Regression Analysis, Risk Assessment, Neoplasms, Biomarkers

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