A little more than 12 months ago, the first major cardio-oncology guidelines were published by the European Society of Cardiology (ESC).1 The extensive document embodied the immense progress of this subspecialty over its short existence.
In reaching this milestone, it is worth considering what advances have specifically been made in the management of left ventricular dysfunction caused by agents such as anthracyclines and trastuzumab, also known as cancer therapy–related cardiac dysfunction. This condition essentially gave birth to the concept of cardio-oncology. How we monitor for and manage cancer therapy–related cardiac dysfunction is still of significant consequence to oncology and hematology professionals today.
Monitoring Methods: From Reactive to Proactive
Historically, management of cancer therapy–related cardiac dysfunction has relied on a fundamental strategy of echocardiographic monitoring of left ventricular ejection fraction (LVEF) in patients receiving potentially cardiotoxic therapies. If a patient has a decline in LVEF, clinicians react accordingly with further diagnostic investigations and commencement of heart failure therapy and/or withhold cancer therapy. One limitation is the relatively wide margin of error in measuring LVEF, usually quoted in the order of 10% in absolute terms. Thus, other strategies have been studied, based on a typical premise that primary prevention therapies or more sensitive monitoring for “subclinical dysfunction” may prevent progressive cancer therapy–related cardiac dysfunction.
Lorcan Ruane, BSc, MBBS
Sandhir Prasad, MBBS, PhD
John Atherton, MBBS, PhD
Primary prevention medication has been tested including neurohormonal heart failure therapies and statins. Angiotensin-converting enzyme inhibitors or beta-blockers may be useful preventive agents, given how effective they are in treating heart failure. However, results have been mixed, with most trials showing, at best, small improvements in LVEF compared with placebo. Dexrazoxane, an iron-chelating agent, has been shown to reduce the incidence of heart failure in anthracycline cohorts and is approved for use in many countries in high-risk patients. However, larger studies are required before this can be recommended as a routine strategy.2
Early elevations in troponin or B-type natriuretic peptide may occur in the absence of echocardiographic changes and may predict future clinical left ventricular dysfunction.3 Global longitudinal strain (GLS) is an echocardiographic technique that assesses left ventricular function by automatically tracking the movement of ultrasound speckles in the left ventricular wall as a surrogate for contractility, rather than manually measuring left ventricular volumes to assess LVEF. Like biomarkers, this is a more sensitive tool and has been promoted as useful in cancer therapy monitoring, as it could enable clinicians to identify subclinical dysfunction and act earlier to prevent progressive cancer therapy–related cardiac dysfunction.4
Lack of Successful Translation Into Clinical Practice
There is one problem though: We don’t have enough evidence to show that using these strategies actually prevents clinical left ventricular dysfunction in a trial setting or in the real world, and this is reflected in the 2022 ESC cardio-oncology guidelines. Primary prevention medications as well as cardiac biomarker monitoring received only weak recommendations in certain populations. Although its general use is recommended, the role of GLS in dictating treatment decisions is also limited.
If the specificity of these monitoring strategies is not adequate, this may in part explain the lack of successful translation into clinical practice. A patient undergoing active cancer treatment is prone to intercurrent illness as well as volume and blood pressure changes, which can have subtle, transient effects on cardiac function. Furthermore, accurate GLS assessment relies on serial availability of adequate two-dimensional (2D)-echo image quality, which is not always possible.
Of note, these strategies all represent an intensification of management, whether through more medication or more sensitive monitoring, and they have potential risks. Heart failure medications can cause symptomatic hypotension and renal injury. Cardiac biomarker and GLS monitoring require frequent assessment to be useful and will tend to prioritize sensitivity over specificity. Consequently, there is a risk of clinicians acting on “false-positive” changes, resulting in needless heart failure therapy or worse, unnecessary cancer therapy interruption or cessation. We shouldn’t add to a cancer patient’s health-care burden with more medication or frequent, sensitive testing—unless there is good evidence the benefits outweigh the risks.
We must also consider the incidence and severity of cancer therapy–related cardiac dysfunction, which may be improving. Recent data from trials and cohort studies of patients receiving anthracyclines and trastuzumab demonstrated that although declines in LVEF can occur, the magnitude is not great; it is usually asymptomatic, and the rates of clinical heart failure are much lower than previously reported.5,6 More data are needed to confirm this, but if true, it only increases the potential risks of intensive prevention strategies.
It could even be time to consider more streamlined approaches, such as targeting echocardiographic LVEF monitoring to high-risk patients alone. This has obvious benefits, but its feasibility and safety would, of course, depend on accurate identification of these patients. Many risk factors for cancer therapy–related cardiac dysfunction have been identified, including cancer therapy dose, combination regimens, and typical cardiovascular risk factors. However, the evidence supporting the use of risk-scoring models has not been convincing, with suboptimal discrimination for cancer therapy–related cardiac dysfunction in the real-world setting.7
A Need for Collaboration Between Oncologists and Cardiologists
If the incidence and severity of cancer therapy–related cardiac dysfunction have improved, it is interesting to consider why, especially given the lack of clinical impact from the management strategies discussed here. 2D-echo image quality is always improving, and with the addition of 3D technology, more accurate LVEF assessment may have helped. It is unclear just how often cardioprotective agents like dexrazoxane are used, but this could also be a contributing factor. Newer cancer therapies provide alternative approaches for those at very high cardiac risk.
Furthermore, improvements do appear to have coincided with the development of the cardio-oncology subspecialty. A formal cardio-oncology service enables closer collaboration between subspecialized cardiologists and oncologists. Mutual goals include accurate assessment of baseline risk, efficient monitoring, and effective treatment of cancer therapy–related cardiac dysfunction if required—all while ideally facilitating gold-standard cancer treatment. Such systems of care may well have reduced the incidence and severity of cancer therapy–related cardiac dysfunction.
Despite many attempts to optimize the management of cancer therapy–related cardiac dysfunction, traditional echocardiographic LVEF monitoring remains the most useful strategy. Others, supported by weak guideline recommendations, may still be used in certain centers, and further evidence of their clinical impact may come. However, if the incidence and severity of cancer therapy–related cardiac dysfunction have indeed improved, it will only be more difficult to prove a clinical benefit on top of the current standard of care.
No matter which measures clinicians employ going forward, one thing is certain: They need to appreciate the nuances of patients and their malignancies, as well as the benefits and limitations of the different cancer therapy–related cardiac dysfunction prevention strategies available. An effective cardio-oncology team will be integral to this.
Dr. Ruane is a cardiology trainee at The Prince Charles Hospital, Queensland, Australia, with an interest in echocardiography and cardio-oncology. Dr. Prasad is the Clinical Lead in Echocardiography, and Dr. Atherton is the Director of Cardiology, both at the Royal Brisbane and Women’s Hospital in Queensland, Australia.
DISCLOSURE: Dr. Ruane, Dr. Prasad, and Dr. Atherton reported no conflicts of interest.
REFERENCES
1. Lyon AR, López-Fernández T, Couch LS, et al: 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J 43:4229-4361, 2022.
2. Macedo AVS, Hajjar LA, Lyon AR, et al: Efficacy of dexrazoxane in preventing anthracycline cardiotoxicity in breast cancer. JACC CardioOncol 1:68-79, 2019.
3. Michel L, Mincu RI, Mahabadi AA, et al: Troponins and brain natriuretic peptides for the prediction of cardiotoxicity in cancer patients: A meta-analysis. Eur J Heart Fail 22:350-361, 2020.
4. Oikonomou EK, Kokkinidis DG, Kampaktsis PN, et al: Assessment of prognostic value of left ventricular global longitudinal strain for early prediction of chemotherapy-induced cardiotoxicity. A systematic review and meta-analysis. JAMA Cardiol 4:1007-1018, 2019.
5. Dent SF, Morse A, Burnette S, et al: Cardiovascular toxicity of novel HER2-targeted therapies in the treatment of breast cancer. Curr Oncol Rep 23:128, 2021.
6. Jeyaprakash P, Sangha S, Ellenberger K, et al: Cardiotoxic effect of modern anthracycline dosing on left ventricular ejection fraction: A systematic review and meta-analysis of placebo arms from randomised controlled trials. J Am Heart Assoc 10:e018802, 2021.
7. Suntheralingam S, Fan CPS, Calvillo-Argüelles O, et al: Evaluation of risk prediction models to identify cancer therapeutics related cardiac dysfunction in women with HER2+ breast cancer. J Clin Med 11:847, 2022.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
