Cardio-oncology: Ultrasound’s role in detecting cardiotoxicity

A 2019 report by the American Cancer Society shows that there are approximately 17 million cancer survivors in the United States.^{1, 2} Although new, potent, and targeted cancer therapies are to thank for this increasing survival rate, they are also behind one of the leading mortality causes amongst cancer patients: cancer therapy-induced cardiovascular disease.³

The long-term consequences of cancer treatment are at the genesis of the cardio-oncology field: an evolving multidisciplinary sub-specialty. It is focused on detecting, monitoring and treating cardiovascular dysfunction that occurs as a side effect of chemotherapy, radiotherapy, or other potentially cardiotoxic cancer-directed therapies while taking into account individual risk factors for developing certain cardiovascular (CV) complications.

Despite the lack of a clear evidence-based approach on how to detect cardiotoxicity, define or classify it, there are key factors that seem to gather consensus: time and accuracy in the identification of cardiotoxicity are crucial. This article focuses on the importance of early and accurate detection of cardiac dysfunction and how advanced imaging modalities can help clinicians with exactly that.

Cardiotoxicity: a definition

Cardiotoxicity can be defined as any functional or structural heart injury related to cancer treatment. Chemotherapy, radiotherapy and targeted therapy may all cause cardiotoxicity and cancer therapy-related cardiac dysfunction (CTRCD).

"Beyond oncologic therapies, cancer and CV diseases are connected by complex pathophysiological mechanisms and shared modifiable and non-modifiable risk factors that may increase the potential for cardiotoxicity.^4,5 For that reason, a comprehensive cardiovascular evaluation and monitoring, throughout the cancer process, is needed^32"

- Dr. Teresa López-Fernández

La Paz University Hospital, CIBER CV. IdiPAZ Research Institute

Cardiotoxicity: Signs, detection and surveillance strategies

In the cardiotoxicity detection arena, a lot has changed following the 1960’s recognition of the side effects of anthracyclines in cardiac dysfunction.⁶ Several strategies to detect cardiotoxicity have been used — X-ray, endometrial biopsy, blood tests, electrocardiogram, echocardiogram⁷ – each with its merits and limitations.

Signs and symptoms of cardiotoxicity may include chest pain, changes in heart rhythm, shortness of breath, and ankle swelling⁸. However, heart function can also decline without any noticeable signs of cardiotoxicity and some of these may not be present until months or years after the cancer treatment.

The challenges posed by a nonexistent universal definition of cardiotoxicity and CTRCD identification guidelines are evident⁹. The common indicator that brings organizations and experts together? A serial decline in left ventricular ejection fraction (LVEF), defined using a threshold change in LVEF. One of the most recent comes from the American Society of Echocardiography’s Expert Consensus report. It defined cardiotoxicity as an LVEF drop ≥10% from baseline to a value of <53% which is confirmed by both repeated cardiac imaging, performed 2-3 weeks after the initial decrease,⁶and GLS >15%

How to detect cardiotoxicity: the ultrasound’s role?

Non-invasive and accurate surveillance of LVEF by cardiac imaging ‘has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially cardiotoxic cancer treatment'.⁶

Recent publications 10 recognize advanced cardiac imaging for its growing accuracy and reproducibility as well as the personalization it offers through emerging imaging biomarkers and their potential to provide valuable insights in the interdisciplinary field of cardio-oncology. Among those emerging modalities are 2D and 3D echocardiography, global longitudinal strain (GLS) and cardiac magnetic resonance (CMR), cardiac biomarkers, and multi-gated acquisition scan (MUGA).

We spoke with Dr. Teresa López-Fernández about how cardiac ultrasound can help clinicians in detection, management, and follow-up cardio-oncology patients.

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Five questions on the role of cardiac imaging in early detection of cardiotoxicity due to anticancer therapies

What are the modalities that are used to detect, manage and follow-up cardio-oncology patients?
What are the modalities that are used to detect, manage and follow-up cardio-oncology patients?

Dr. Teresa López-Fernández: Cardiotoxicity includes nine main categories of CV complications*, being heart failure the most prevalent nowadays. In this scenario, cardiac imaging plays a critical role both from the diagnostic and the prognostic point of view.

Surveillance and diagnosis of cancer therapy related cardiac dysfunction (CTRCD) relies upon serial clinical, biomarker and cardiac imaging parameters, to identify patients at risk of heart failure^11,12. The imaging modalities chosen for cardiac surveillance will depend on the clinical scenario as well as on the local access and expertise. Echo and cardiac magnetic resonance imaging (MRI) are the preferred techniques for monitoring cancer treatment because, unlike MUGA, they provide comprehensive and radiation-free information of global cardiac function. Currently, echo is considered the method of choice to assess ventricular function in cancer patients because of its wide availability and lower cost ^11,12Echocardiography utilization was associated with higher use of cardioprotective medications possibly due to earlier detection of cardiotoxicity. CMR is recommended when echo results are thought to be unreliable and in selected high-risk patients1^3,14.

*Heart failure, hypertension, cardiac arrhythmias, coronary artery disease, peripheral vascular disease, pulmonary hypertension, valvular heart disease and pericardial diseases.
How common is the use of advanced echo imaging?
How common is the use of advanced echo imaging?

Dr. Teresa López-Fernández: Nowadays, in Europe, most of the patients were reviewed in general cardiology clinics and there is a low percentage of larger cardio-oncology structures¹⁵. As a result, the Simpson biplane method (2DEF) is the most common parameter used for CTRCD monitoring and new 3D echo and deformation parameters are restricted to academic centers, with cardio-oncology clinics^16,17.

Unfortunately, CTRCD monitoring exclusively based on 2DEF is not sensitive enough to detect early stages of myocardial dysfunction, essentially because intra-technical variability (8-11%) is sometimes higher than the threshold used to define cardiotoxicity 1^3,14,18.In addition, imaging prescription practices were driven by chemotherapy regimen rather than by the individual risk of major adverse cardiac events

Because the overall goal of echo monitoring is the correct adjudication of stage B heart failure¹⁹, the use of more sensitive and reproducible parameters like 3D echo and myocardial deformation imaging is recommended to identify patients at risk of heart failure so that modern therapies can be initiated^20,21,22
What role does echocardiography play in managing and following up on cardio-oncology patients?
What role does echocardiography play in managing and following up on cardio-oncology patients?

Dr. Teresa López-Fernández: We use echo to stratify patients’ risk before cancer therapy, to identify cardiovascular injury, to predict recovery from injury, and to detect cardiac damage in long-term cancer survivors¹⁷.

To improve the integration of echocardiography in cardio-oncology, we face three main challenges. First, we need advanced echo tools that will work in large numbers of patients (implications for time consumption, costs and availability) with different cardiotoxicity profiles or expected risks. Second, we must be aware that oncologists are not cardiac imaging experts and therefore we need to translate data into clear conclusions, to help in the clinical decision making. Third, CTRCD diagnosis is not enough and multidisciplinary teamwork is essential for complex decision-making that improve clinical outcomes.
Is there a benefit to using 3DEF vs. 2DEF along with GLS?
Is there a benefit to using 3DEF vs. 2DEF along with GLS?

Dr. Teresa López-Fernández: CTRCD is a continuous phenomenon starting with myocardial cell injury and followed by progressive left ventricular dysfunction that, if disregarded and not treated, progressively leads to overt HF2³. 2DEF identifies cardiotoxicity too late, only when a significant functional impairment has already occurred, precluding any chance of effective prevention, because the more time passes the less recovery possibilities we have.²⁴ 3DEcho increases the ability to detect smaller changes in LVEF over 2DE and provides lower temporal variability than 2DEcho for the longitudinal follow up of patients undergoing chemo. The technique compares well with CMR and nadir EF values are identified by 3DE earlier than by 2DE in cancer patients who develop cardiotoxicity^13,14,25.

Despite these benefits, time and expertise needed to analyze 3D echo has proven to be a barrier to widescale clinical acceptance. To improve the integration of 3DE into clinical practice we need fully automated quantification software, like dynamic heart model, to both reduce the learning curve and minimize time consumption.

Another important question is if cardiac monitoring just based on EF is enough. As you know, the heart has a helical structure composed of three coordinated layers of myocardial fibers and LVEF only evaluates radial function. The longitudinal component of LV deformation is more sensitive than 2DEF to detect the presence of preclinical myocardial diseases in different clinical scenarios, particularly in general population at risk of HF2⁶ . Global longitudinal strain has been shown to be a feasible technique without additional time consumption for image acquisition and with minimal time-consuming analysis using new automatic methods. GLS has better reproducibility than standard 2DEF when performed by trained operators or after a short training period. Until we have the results of the Succour trial,2⁷ a surveillance strategy based on 3DE and GLS to identify early changes in ventricular function and guide cardioprotective therapy seems the best strategy in high-risk patients undergoing cardiotoxic chemotherapy.
How often should a patient be monitored?
How often should a patient be monitored?

Dr. Teresa López-Fernández: Patients receiving cancer therapies should be considered to be at risk of heart failure (stage A heart failure) and left ventricular function surveillance is recommended for early identification of asymptomatic myocardial damage (stage B heart failure)²⁸.

Before administering potentially cardiotoxic treatments, a comprehensive screening including echo assessment is recommended to exclude relevant cardiac problems and to optimize CV therapy when needed. Baseline echo is particularly important to stratify cardiotoxicity risk in patients with preexisting CV conditions or previous cancer treatments. We know that a baseline reduced or low normal LVEF (50-55%) nearly triples the risk of cardiac events²⁹. In these patients, with low normal EF, or in those at higher cardiovascular risk, baseline GLS further improves HF prediction³⁰.

During the active phase of the treatment, echo plays a critical role both from the diagnostic and the prognostic point of view. Echo monitoring strategy depends on the planned therapeutic scheme and patients´ risks. Left ventricular function is generally re-evaluated every 3-6 months, in case of heart failure suspicion and at the end of treatment ^11,12,31.

Serial screening allows for early identification and management of CTRCD. The ideal strategy is to compare 3DE and GLS measurements obtained during chemotherapy with one obtained at baseline, allowing the patient to serve as his or her own control. The strongest predictor of CTRCD, defined as a subclinical left ventricular dysfunction, is a relative drop in GLS> 15% from baseline.^11,13,14

While the merits of echocardiography in detecting CTRCD in patients with cancer are recognized, there remain real challenges for it in the cardio-oncologic setting – such as image quality, accuracy, costs, availability and the need to train specialists to help in clinical decision-making.

Philips cardiovascular ultrasound applications aim to bridge that gap. Powered by anatomical intelligence and automation technologies, Philips combines 3D imaging with fast and reproducible GLS measurements, for better accuracy, in less time. Accurate baseline echocardiography exams, follow-ups, and change assessments are easy to visualize and edit by experts and new operators – all in the same machine, no extra equipment required.

Our commitment: delivering high-quality critical cardiac measurements in seconds. Better therapy management and planning for more patients in less time to help clinicians quickly and confidently assess cardiotoxicity symptoms and guide their selection of appropriate therapies.

Reviewed by: Dr. Teresa Lopéz-Fernández. La Paz University Hospital, CIBER CV. IdiPAZ Research Institute

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